Cyclic peptide containing carboxylic acid substitution against acinetobacter baumannii and use thereof

Abstract

Provided are a class of cyclic peptides containing carboxylic acid substitution against Acinetobacter baumannii and use thereof. Particularly, the present invention relates to a compound of formula (I) containing a carboxylic acid substituent or a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof, and a preparation method therefor, as well as use thereof in the preparation of a medicament for treating or preventing an infection and a disease caused by Acinetobacter baumannii.

Description

Carboxylic acid-substituted cyclic peptides for use against Acinetobacter baumannii and their applications

[0001] This application claims priority to Chinese Patent Application No. 2024101565934 filed on February 2, 2024, Chinese Patent Application No. 2024103279265 filed on March 19, 2024, and Chinese Patent Application No. 202411206968.X filed on August 29, 2024. The entire contents of the aforementioned Chinese patent applications are incorporated herein by reference. Technical Field

[0002] The present invention relates to a class of carboxylic acid-substituted cyclic peptides for use against Acinetobacter baumannii and their applications. Specifically, it relates to compounds containing carboxylic acid substituents represented by formula (I), their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, their preparation methods, and their use in preparing drugs for treating or preventing infections and diseases caused by Acinetobacter baumannii. Background Art

[0003] Acinetobacter baumannii (scientific name: Acinetobacter baumannii, commonly known as "AB bacteria"), a Gram-negative bacterium, is a strictly aerobic, non-lactose-fermenting, opportunistic pathogen. It lacks flagella and is not very mobile, but is extremely resilient and widely found in nature. Furthermore, the bacterium has strong adhesion, readily attaching to various medical materials. It is also found on healthy human skin (25%) and pharynx (7%), as well as in conjunctivae, saliva, gastrointestinal tract, and vaginal secretions. It has been identified as an ESKAPE pathogen (Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp., Enterococcus faecalis, Staphylococcus aureus), a group of highly antibiotic-resistant pathogens that cause the majority of nosocomial infections.

[0004] The treatment of Acinetobacter baumannii infections has always been a significant clinical challenge, as the bacterium can easily develop resistance to various disinfectants and antimicrobial agents, posing a significant threat to critically ill patients and those in ICUs. The widespread spread of strains such as CRAB (carbapenem-resistant Acinetobacter baumannii), MDR-AB (multidrug-resistant Acinetobacter baumannii), and XDR-AB (pandrug-resistant Acinetobacter baumannii) has become a nightmare for both physicians and patients. Therefore, the development of drugs to treat infections and diseases caused by Acinetobacter baumannii is urgent. Summary of the Invention

[0005] In the first aspect of the present invention, the present invention provides a compound, a compound represented by formula (I), a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof,

[0006] in,

[0007] X1 is N or CR x1 ;

[0008] X2 is N or CR x2 ;

[0009] X3 is N or CR x3 ;

[0010] X4 is N or CR x4 ;

[0011] X5 is N or CR x5 ;

[0012] X6 is N or CR x6 ;

[0013] X7 is N or CR x7 ;

[0014] X8 is N or CR x8 ;

[0015] X9 is N or CR x9 ;

[0016] X 10 N or CR x10 ;

[0017] X 11 N or CR x11 ;

[0018] R1 is -(CH2) m -C 6-12 Aryl, -(CH2) m -5-12 membered heteroaryl or -(CH2) m -3-12 membered heterocycloalkyl; said C 6-12 Aryl, 5-12 membered heteroaryl and 3-12 membered heterocycloalkyl are each independently optionally substituted by g R a replace;

[0019] Each R a are independently H, halogen, OH, NH2, CN, COOH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 3-8 Cycloalkyl;

[0020] R2, R4, R6 and R9 are independently H, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 3-8 Cycloalkyl;

[0021] R3 is -C 1-10 Alkyl, -C 0-10 Alkyl-NR 31 R 32 、-C 0-10 Alkyl-C(=O)NR 31 R 32 、-C 0-10 Alkyl-NR 31 -C(=O)NR 31 R 32 、-C 0-10 Alkyl-OC 1-10 Alkyl-NR 31 R 32 、-C 0-10 Alkyl-SC 1-10 Alkyl-NR 31 R 32 、-C 0-10 Alkyl-NR 31 -C 1-10 Alkyl-NR 31 R 32 、-C 0-10 Alkyl-C(=O)-C 1-10 Alkyl-NR 31 R 32 、-C 0-10 Alkyl-C 3-8 Cycloalkyl-C 0-10 Alkyl-NR 31 R 32 or -C 0-10 Alkyl-3-12 membered heterocycloalkyl-C 1-10 Alkyl-NR 31 R 32 , said R3 is further replaced by 1, 2, 3 or 4 R b replace;

[0022] R5 is -C 1-10 Alkyl, -C 0-10 Alkyl-NR 51 R 52 、-C 0-10 Alkyl-C(=O)NR 51 R 52 、-C 0-10 Alkyl-NR 51 -C(=O)NR 51 R 52 、-C 0-10 Alkyl-OC 1-10 Alkyl-NR 51 R 52 、-C 0-10 Alkyl-SC 1-10Alkyl-NR 51 R 52 、-C 0-10 Alkyl-NR 51 -C 1-10 Alkyl-NR 51 R 52 、-C 0-10 Alkyl-C(=O)-C 1-10 Alkyl-NR 51 R 52 、-C 0-10 Alkyl-C 3-8 Cycloalkyl-C 0-10 Alkyl-NR 51 R 52 or -C 0-10 Alkyl-3-12 membered heterocycloalkyl-C 1-10 Alkyl-NR 51 R 52 , said R5 is further replaced by 1, 2, 3 or 4 R c replace;

[0023] R 31 、R 32 、R 51 and R 52 are independently H or C 1-6 alkyl;

[0024] R 5’ H or C 1-6 alkyl;

[0025] R7 and R8 are independently H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 3-8 Cycloalkyl;

[0026] R 10 H, F, Cl, Br, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl or -O-3-8 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl and -O-3-8 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R 101 replace;

[0027] R 11 H, F, Cl, Br, OH, NH2, CN, C1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl or -O-3-8 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl and -O-3-8 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R 111 replace;

[0028] Each R 101 are independently H, F, Cl, Br, OH, NH2, CN or COOH;

[0029] Each R 111 are independently H, F, Cl, Br, OH, NH2, CN or COOH;

[0030] Or, R 10 With R 11 and the carbon atom to which it is attached together form ring A, wherein ring A is C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl, the C 3-8 3-membered cycloalkyl and 3-8-membered heterocycloalkyl are 1a replace;

[0031] Each R 1a are independently H, F, Cl, Br, OH, NH2, CN, COOH or C 1-6 Alkyl, the C 1-6 Alkyl is optionally substituted with 1, 2, 3 or 4 R groups, each independently;

[0032] R is independently H, F, Cl, Br, OH, NH2, CN, ═O, ═S, COOH or C 1-6 alkyl;

[0033] R x1 、R x2 、R x3 and R x4 are independently H, F, Cl, Br, OH, NH2, CN, COOH, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 The alkyl group is optionally substituted by 1, 2, 3 or 4 R d replace;

[0034] R x5 、R x6 and R x7are independently H, F, Cl, Br, OH, NH2, CN, COOH, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 The alkyl group is optionally substituted with 0, 1, 2, 3 or 4 R e replace;

[0035] R x8 、R x9 、R x10 and R x11 are independently H, F, Cl, Br, OH, NH2, CN, COOH, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 The alkyl group is optionally substituted by 1, 2, 3 or 4 R f replace;

[0036] Each R b 、R c 、R d 、R e and R f are independently H, F, Cl, Br, OH, NH2, CN, ═O, COOH or C 1-6 alkyl;

[0037] Each m is independently 1, 2, 3 or 4;

[0038] g is 1, 2, 3, or 4;

[0039] n is 1, 2, 3 or 4.

[0040] In an optional embodiment of the present invention, the compound represented by the above formula (I), its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs,

[0041] in,

[0042] X1 is N or CR x1 ;

[0043] X2 is N or CR x2 ;

[0044] X3 is N or CR x3 ;

[0045] X4 is N or CR x4 ;

[0046] X5 is N or CR x5 ;

[0047] X6 is N or CR x6 ;

[0048] X7 is N or CR x7 ;

[0049] X8 is N or CR x8 ;

[0050] X9 is N or CR x9 ;

[0051] X 10 N or CR x10 ;

[0052] X 11 N or CR x11 ;

[0053] R1 is -(CH2) m -C 6-12 Aryl, -(CH2) m -5-12 membered heteroaryl or -(CH2) m -3-12 membered heterocycloalkyl; said C 6-12 Aryl, 5-12 membered heteroaryl and 3-12 membered heterocycloalkyl are each independently optionally substituted by g R a replace;

[0054] Each R a are independently H, halogen, OH, NH2, CN, COOH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 3-8 Cycloalkyl;

[0055] R2, R4, R6 and R9 are independently H, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 3-8 Cycloalkyl;

[0056] R3 is -C 1-10 Alkyl, -C 0-10 Alkyl-NR 31 R 32 、-C 0-10 Alkyl-C(=O)NR 31 R 32 、-C 0-10 Alkyl-NR 31 -C(=O)NR 31 R 32 、-C 0-10 Alkyl-OC 1-10 Alkyl-NR 31 R 32 、-C 0-10Alkyl-SC 1-10 Alkyl-NR 31 R 32 、-C 0-10 Alkyl-NR 31 -C 1-10 Alkyl-NR 31 R 32 、-C 0-10 Alkyl-C(=O)-C 1-10 Alkyl-NR 31 R 32 、-C 0-10 Alkyl-C 3-8 Cycloalkyl-C 0-10 Alkyl-NR 31 R 32 or -C 0-10 Alkyl-3-12 membered heterocycloalkyl-C 1-10 Alkyl-NR 31 R 32 , said R3 is further replaced by 1, 2, 3 or 4 R b replace;

[0057] R5 is -C 1-10 Alkyl, -C 0-10 Alkyl-NR 51 R 52 、-C 0-10 Alkyl-C(=O)NR 51 R 52 、-C 0-10 Alkyl-NR 51 -C(=O)NR 51 R 52 、-C 0-10 Alkyl-OC 1-10 Alkyl-NR 51 R 52 、-C 0-10 Alkyl-SC 1-10 Alkyl-NR 51 R 52 、-C 0-10 Alkyl-NR 51 -C 1-10 Alkyl-NR 51 R 52 、-C 0-10 Alkyl-C(=O)-C 1-10 Alkyl-NR 51 R 52 、-C 0-10 Alkyl-C 3-8 Cycloalkyl-C 0-10 Alkyl-NR 51 R 52 or -C 0-10Alkyl-3-12 membered heterocycloalkyl-C 1-10 Alkyl-NR 51 R 52 , said R5 is further replaced by 1, 2, 3 or 4 R c replace;

[0058] R 31 、R 32 、R 51 and R 52 are independently H or C 1-6 alkyl;

[0059] R 5’ H or C 1-6 alkyl;

[0060] R7 and R8 are independently H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 3-8 Cycloalkyl;

[0061] R 10 H, F, Cl, Br, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl or -O-3-8 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl and -O-3-8 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R 101 replace;

[0062] R 11 H, F, Cl, Br, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl or -O-3-8 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl and -O-3-8 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R 111 replace;

[0063] Each R 101are independently H, F, Cl, Br, OH, NH2, CN or COOH;

[0064] Each R 111 are independently H, F, Cl, Br, OH, NH2, CN or COOH;

[0065] Or, R 10 With R 11 and the carbon atom to which it is attached together form ring A, wherein ring A is C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl, the C 3-8 3-membered cycloalkyl and 3-8-membered heterocycloalkyl are 1a replace;

[0066] Each R 1a are independently H, F, Cl, Br, OH, NH2, CN, COOH or C 1-6 Alkyl, the C 1-6 Alkyl is optionally substituted with 1, 2, 3 or 4 R groups, each independently;

[0067] R is independently H, F, Cl, Br, OH, NH2, CN, ═O, ═S, COOH or C 1-6 alkyl;

[0068] R x1 、R x2 、R x3 and R x4 are independently H, F, Cl, Br, OH, NH2, CN, COOH or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted by 1, 2, 3 or 4 R d replace;

[0069] R x5 、R x6 and R x7 are independently H, F, Cl, Br, OH, NH2, CN, COOH or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with 0, 1, 2, 3 or 4 R e replace;

[0070] R x8 、R x9 、R x10 and R x11 are independently H, F, Cl, Br, OH, NH2, CN, COOH or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted by 1, 2, 3 or 4 Rf replace;

[0071] Each R b 、R c 、R d 、R e and R f are independently H, F, Cl, Br, OH, NH2, CN, ═O, COOH or C 1-6 alkyl;

[0072] Each m is independently 1, 2, 3 or 4;

[0073] g is 1, 2, 3, or 4;

[0074] n is 1, 2, 3 or 4.

[0075] In an optional embodiment of the present invention, the compound represented by the above formula (I), its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs,

[0076] in,

[0077] X1 is N or CR x1 ;

[0078] X2 is N or CR x2 ;

[0079] X3 is N or CR x3 ;

[0080] X4 is N or CR x4 ;

[0081] X5 is N or CR x5 ;

[0082] X6 is N or CR x6 ;

[0083] X7 is N or CR x7 ;

[0084] X8 is N or CR x8 ;

[0085] X9 is N or CR x9 ;

[0086] X 10 N or CR x10 ;

[0087] X 11 N or CR x11 ;

[0088] R1 is -(CH2) m -C6-12 Aryl, -(CH2) m -5-12 membered heteroaryl or -(CH2) m -3-12 membered heterocycloalkyl; said C 6-12 Aryl, 5-12 membered heteroaryl and 3-12 membered heterocycloalkyl are each independently optionally substituted by g R a replace;

[0089] Each R a are independently H, halogen, OH, NH2, CN, COOH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 3-8 Cycloalkyl;

[0090] R2, R4, R6 and R9 are independently H, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 3-8 Cycloalkyl;

[0091] R3 is -C 1-10 Alkyl, -C 0-10 Alkyl-NR 31 R 32 、-C 0-10 Alkyl-C(=O)NR 31 R 32 、-C 0-10 Alkyl-NR 31 -C(=O)NR 31 R 32 、-C 0-10 Alkyl-OC 1-10 Alkyl-NR 31 R 32 、-C 0-10 Alkyl-SC 1-10 Alkyl-NR 31 R 32 、-C 0-10 Alkyl-NR 31 -C 1-10 Alkyl-NR 31 R 32 、-C 0-10 Alkyl-C 3-8 Cycloalkyl-C 0-10 Alkyl-NR 31 R 32 or -C 0-10 Alkyl-3-12 membered heterocycloalkyl-C 1-10 Alkyl-NR 31 R 32, said R3 is further replaced by 1, 2, 3 or 4 R b replace;

[0092] R5 is -C 1-10 Alkyl, -C 0-10 Alkyl-NR 51 R 52 、-C 0-10 Alkyl-C(=O)NR 51 R 52 、-C 0-10 Alkyl-NR 51 -C(=O)NR 51 R 52 、-C 0-10 Alkyl-OC 1-10 Alkyl-NR 51 R 52 、-C 0-10 Alkyl-SC 1-10 Alkyl-NR 51 R 52 、-C 0-10 Alkyl-NR 51 -C 1-10 Alkyl-NR 51 R 52 、-C 0-10 Alkyl-C 3-8 Cycloalkyl-C 0-10 Alkyl-NR 51 R 52 or -C 0-10 Alkyl-3-12 membered heterocycloalkyl-C 1-10 Alkyl-NR 51 R 52 , said R5 is further replaced by 1, 2, 3 or 4 R c replace;

[0093] R 31 、R 32 、R 51 and R 52 are independently H or C 1-6 alkyl;

[0094] R 5’ H or C 1-6 alkyl;

[0095] R7 and R8 are independently H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 3-8 Cycloalkyl;

[0096] R 10 F, Cl, Br, OH, NH2, CN, C1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl or -OC 3-8 Heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl and -OC 3-8 Heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 R 101 replace;

[0097] R 11 H, F, Cl, Br, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl or -OC 3- 8 heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl and -OC 3-8 Heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 R 111 replace;

[0098] Each R 101 are independently H, F, Cl, Br, OH, NH2, CN or COOH;

[0099] Each R 111 are independently H, F, Cl, Br, OH, NH2, CN or COOH;

[0100] Or, R 10 With R 11 and the carbon atom to which it is attached together form ring A, wherein ring A is C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl, the C 3-8 3-membered cycloalkyl and 3-8-membered heterocycloalkyl are 1a replace;

[0101] Each R 1a are independently H, F, Cl, Br, OH, NH2, CN, COOH or C 1-6 Alkyl, the C 1-6 Alkyl is optionally substituted with 1, 2, 3 or 4 R groups, each independently;

[0102] R is independently H, F, Cl, Br, OH, NH2, CN, ═O, ═S, COOH or C 1-6 alkyl;

[0103] R x1 、R x2 、R x3 and R x4 are independently H, F, Cl, Br, OH, NH2, CN, COOH or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted by 1, 2, 3 or 4 R d replace;

[0104] R x5 、R x6 and R x7 are independently H, F, Cl, Br, OH, NH2, CN, COOH or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with 0, 1, 2, 3 or 4 R e replace;

[0105] R x8 、R x9 、R x10 and R x11 are independently H, F, Cl, Br, OH, NH2, CN, COOH or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted by 1, 2, 3 or 4 R f replace;

[0106] Each R b 、R c 、R d 、R e and R f are independently H, F, Cl, Br, OH, NH2, CN, COOH or C 1-6 alkyl;

[0107] Each m is independently 1, 2, 3 or 4;

[0108] g is 1, 2, 3, or 4;

[0109] n is 1, 2, 3 or 4.

[0110] In an optional embodiment of the present invention, 1, 2, 3 or 4 ring atoms of the 5-12 membered heteroaryl group are heteroatoms independently selected from O, S and N, and the rest are carbon atoms.

[0111] In an optional embodiment of the present invention, the type of heteroatom in the 5-12 membered heteroaryl group is N, and the number of heteroatoms is 1.

[0112] In an optional embodiment of the present invention, 1, 2, 3 or 4 ring atoms of the 3-12 membered heterocycloalkyl group are heteroatoms independently selected from O, S and N, and the rest are carbon atoms.

[0113] In an optional embodiment of the present invention, 1, 2, 3 or 4 ring atoms of the 3-8 membered heterocycloalkyl group are heteroatoms independently selected from O, S and N, and the rest are carbon atoms.

[0114] In an optional embodiment of the present invention, the type of heteroatom in the 3-12 membered heterocycloalkyl group and the 3-8 membered heterocycloalkyl group is O, and the number of heteroatoms is 1.

[0115] In an optional embodiment of the present invention, the above-mentioned ring A is C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, the C 3-6 3-membered cycloalkyl and 3-6 membered heterocycloalkyl are 1a replace.

[0116] In an optional embodiment of the present invention, the above-mentioned ring A is C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, the C 3-6 3-membered cycloalkyl and 3-6 membered heterocycloalkyl are 1a Substitution; the heteroatom type in the 3-6 membered heterocycloalkyl is O, and the number of heteroatoms is 1.

[0117] In an optional embodiment of the present invention, the above-mentioned ring A is C 3-6 membered cycloalkyl, the C 3-6 The cycloalkyl group is composed of n R 1a replace.

[0118] In an optional embodiment of the present invention, each of the above R 1a are independently H, F, Cl, Br, OH, NH2, CN, -COOH or C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2, 3 or 4 R groups, each independently.

[0119] In an optional embodiment of the present invention, the above R are independently H, F, Cl, Br, OH, NH2, CN, =O, =S, COOH or -CH3.

[0120] In an optional embodiment of the present invention, each of the above R 1a are each independently H.

[0121] In an optional embodiment of the present invention, the above-mentioned ring A is D1 is a single bond, -O-, -S-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-O-, -CH2-CH2-O-, -CH2-S- or -CH2-CH2-S-.

[0122] In an optional embodiment of the present invention, the above-mentioned ring A is

[0123] In an optional embodiment of the present invention, the above R 10 H, F, Cl, Br, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -OC 3-6 Cycloalkyl or -O-3-6 membered heterocycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -OC 3-6 Cycloalkyl and -O-3-6 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R 101 replace.

[0124] In an optional embodiment of the present invention, the above R 10 H, F, Cl, Br, OH, NH2, CN, C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2, 3 or 4 R 101 replace.

[0125] In an optional embodiment of the present invention, the above R 10 H or C 1-3 alkyl.

[0126] In an optional embodiment of the present invention, the above R 10 C 1-3 alkyl.

[0127] In an optional embodiment of the present invention, the above R 10 is H or CH3.

[0128] In an optional embodiment of the present invention, the above R 11 H, F, Cl, Br, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -OC 3-6 Cycloalkyl or -O-3-6 membered heterocycloalkyl, the C 1-3 Alkyl, C1-3 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -OC 3-6 Cycloalkyl and -O-3-6 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R 111 replace.

[0129] In an optional embodiment of the present invention, the above R 11 H, F, Cl, Br, OH, NH2, CN, C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2, 3 or 4 R 111 replace.

[0130] In an optional embodiment of the present invention, the above R 11 H or C 1-3 alkyl.

[0131] In an optional embodiment of the present invention, the above R 11 is H or CH3.

[0132] In an optional embodiment of the present invention, the above-mentioned group fragment for

[0133] In an optional embodiment of the present invention, the above R1 is -(CH2) m -5-10 membered heteroaryl, said 5-10 membered heteroaryl being optionally substituted by g R a replace.

[0134] In an optional embodiment of the present invention, the above R1 is -(CH2) m -benzo 5-membered heteroaryl, the benzo 5-membered heteroaryl is optionally substituted by g R a replace.

[0135] In an optional embodiment of the present invention, the above R1 is -(CH2) m -5,6-dicyclic heteroaryl, wherein the 5,6-dicyclic heteroaryl is optionally substituted by g R a replace.

[0136] In an optional embodiment of the present invention, the above R1 is -(CH2) m -pyrrolophenyl, said pyrrolophenyl being optionally substituted by g R a replace.

[0137] In an optional embodiment of the present invention, the above g is 1, 2, 3 or 4.

[0138] In an optional embodiment of the present invention, the above g is 1.

[0139] In an optional embodiment of the present invention, the above m is 1, 2, 3 or 4.

[0140] In an optional embodiment of the present invention, the above m is 1.

[0141] In an optional embodiment of the present invention, the above R1 is

[0142] In an optional embodiment of the present invention, each of the above R a are independently H, halogen or C 1-3 alkyl.

[0143] In an optional embodiment of the present invention, each of the above R a are independently H or C 1-3 alkyl.

[0144] In an optional embodiment of the present invention, each of the above R a are each independently H.

[0145] In an optional embodiment of the present invention, each of the above R a are independently H or CH3.

[0146] In an optional embodiment of the present invention, the above R1 is

[0147] In an optional embodiment of the present invention, the above R3 is -C 1-6 Alkyl-NR 31 R3, -C 1-6 Alkyl-C(=O)NR 31 R 32 、-C 1-6 Alkyl-NR 31 -C(=O)NR 31 R 32 、-C 1-6 Alkyl-OC 1-6 Alkyl-NR 31 R 32 、-C 1-6 Alkyl-SC 1-6 Alkyl-NR 31 R 32 、-C 1-6 Alkyl-NR 31 -C 1-6 Alkyl-NR 31 R 32 、-C 0-6 Alkyl-C 3-6 Cycloalkyl-C 0-6 Alkyl-NR 31 R 32 or -C0-6 Alkyl-3-8 membered heterocycloalkyl-C 0-6 Alkyl-NR 31 R 32 , said R3 is further replaced by 1, 2, 3 or 4 R b replace.

[0148] In an optional embodiment of the present invention, the above R3 is -C 1-6 Alkyl-NR 31 R3, -C 1-6 Alkyl-OC 1-6 Alkyl-NR 31 R 32 、-C 0-6 Alkyl-C 3-6 Cycloalkyl-C 0-6 Alkyl-NR 31 R 32 or -C 0-6 Alkyl-3-8 membered heterocycloalkyl-C 0-6 Alkyl-NR 31 R 32 , said R3 is further replaced by 1, 2, 3 or 4 R b The type of heteroatom in the 3-8 membered heterocycloalkyl group is O, and the number of heteroatoms is 1.

[0149] In an optional embodiment of the present invention, the above R3 is -C 1-6 Alkyl-NR 31 R3 or -C 1-6 Alkyl-OC 1-6 Alkyl-NR 31 R 32 , said R3 is further replaced by 1, 2, 3 or 4 R b replace.

[0150] In an optional embodiment of the present invention, the above R3 is -C 1-6 Alkyl-NR 31 R3, said R3 is further replaced by 1, 2, 3 or 4 R b replace.

[0151] In an optional embodiment of the present invention, the above R 31 and R 32 are each independently H.

[0152] In an optional embodiment of the present invention, the above R3 is -C 2-5 Alkyl-NH2, -C 1-3 Alkyl-OC 1-3 Alkyl-NH2, -C 1-3 Alkyl-SC 1-3 Alkyl-NH2, -C0-3 Alkyl-cyclopropyl-C 0-3 Alkyl-NH2, -C 0-3 Alkyl-cyclobutyl-C 0-3 Alkyl-NH2, -C 0-3 Alkyl-oxacyclopropyl-C 0-3 Alkyl-NH2 or -C 0-3 Alkyl-oxetanyl-C 0-3 Alkyl-NH2, said R3 is further substituted by 1, 2, 3 or 4 R b replace.

[0153] In an optional embodiment of the present invention, the above R3 is -(CH2) 2-5 -NH2, -(CH2) 1-3 -O-(CH2) 1-3 -NH2, -(CH2) 1-3 -S-(CH2) 1-3 -NH2, -(CH2) 0- 3-cyclopropyl-(CH2) 0-3 -NH2, -(CH2) 0-3 -cyclobutyl-(CH2) 0-3 -NH2, -(CH2) 0-3 -Oxypropyl-(CH2) 0-3 -NH2 or -(CH2) 0-3 -Oxetanyl-(CH2) 0- 3-NH2, said R3 is further replaced by 1, 2, 3 or 4 R b replace.

[0154] In an optional embodiment of the present invention, the above R3 is -(CH2) 2-5 -NH2, -(CH2) 1-3 -O-(CH2) 1-3 -NH2, -(CH2) 0-3 -cyclopropyl-(CH2) 0-3 -NH2, -(CH2) 0-3 -cyclobutyl-(CH2) 0-3 -NH2, -(CH2) 0-3 -Oxypropyl-(CH2) 0-3 -NH2 or -(CH2) 0-3 -Oxetanyl-(CH2) 0-3 -NH2, said R3 is further replaced by 1, 2, 3 or 4 R b replace.

[0155] In an optional embodiment of the present invention, the above R3 is -(CH2) 2-5-NH2 or -(CH2) 1-3 -O-(CH2) 1-3 -NH2, said R3 is further replaced by 1, 2, 3 or 4 R b replace.

[0156] In an optional embodiment of the present invention, the above R3 is -(CH2) 2-5 -NH2, said R3 is further replaced by 1, 2, 3 or 4 R b replace.

[0157] In an optional embodiment of the present invention, the above R3 is -(CH2)3-NH2, -(CH2)4-NH2, -(CH2)-O-(CH2)2-NH2, -(CH2)-cyclopropyl-(CH2)2-NH2, -(CH2)2-cyclopropyl-(CH2)-NH2, -(CH2)-oxetanyl-(CH2)2-NH2 or -(CH2)2-oxetanyl-(CH2)-NH2, and the R3 is further replaced by 1, 2, 3 or 4 R b replace.

[0158] In an optional embodiment of the present invention, the above R3 is The R3 is further replaced by 1, 2, 3 or 4 R b replace.

[0159] In an optional embodiment of the present invention, each of the above R b are independently H, F, Cl, and Br.

[0160] In an optional embodiment of the present invention, each of the above R b are independently H or F.

[0161] In an optional embodiment of the present invention, each of the above R b are each independently H.

[0162] In an optional embodiment of the present invention, the above R3 is

[0163] In an optional embodiment of the present invention, the above R5 is -C 1-6 Alkyl-NR 51 R 52 、-C 1-6 Alkyl-C(=O)NR 51 R 52 、-C 1-6 Alkyl-NR 51 -C(=O)NR 51 R 52 、-C 1-6 Alkyl-OC 1-6Alkyl-NR 51 R 52 、-C 1-6 Alkyl-SC 1-6 Alkyl-NR 51 R 52 、-C 1-6 Alkyl-NR 51 -C 1-6 Alkyl-NR 51 R 52 、-C 0-6 Alkyl-C 3-6 Cycloalkyl-C 0-6 Alkyl-NR 51 R 52 or -C 0-6 Alkyl-3-8 membered heterocycloalkyl-C 0-6 Alkyl-NR 51 R 52 , said R5 is further replaced by 1, 2, 3 or 4 R c replace.

[0164] In an optional embodiment of the present invention, the above R5 is -C 1-6 Alkyl-NR 51 R 52 or -C 1-6 Alkyl-C(=O)NR 51 R 52 , said R5 is further replaced by 1, 2, 3 or 4 R c replace.

[0165] In an optional embodiment of the present invention, the above R5 is -C 1-6 Alkyl-NR 51 R 52 , said R5 is further replaced by 1, 2, 3 or 4 R c replace.

[0166] In an optional embodiment of the present invention, the above R 51 and R 52 are each independently H.

[0167] In an optional embodiment of the present invention, the above R5 is -C 2-5 Alkyl-NH2, -C 1-6 Alkyl-C(=O)NH2, -C 1-3 Alkyl-OC 1-3 Alkyl-NH2, -C 1-3 Alkyl-SC 1-3 Alkyl-NH2, -C 0-3 Alkyl-C 3-6 Cycloalkyl-C 0-3 Alkyl-NH2 or -C 0-3Alkyl-3-6 membered heterocycloalkyl-C 0-3 Alkyl-NH2, said R5 is further replaced by 1, 2, 3 or 4 R c replace.

[0168] In an optional embodiment of the present invention, the above R5 is -C 2-5 Alkyl-NH2, -C 1-6 Alkyl-C(=O)NH2, -C 1-3 Alkyl-OC 1-3 Alkyl-NH2, -C 1-3 Alkyl-SC 1-3 Alkyl-NH2, -C 0-3 Alkyl-cyclopropyl-C 0-3 Alkyl-NH2, -C 0-3 Alkyl-cyclobutyl-C 0-3 Alkyl-NH2, -C 0-3 Alkyl-oxacyclopropyl-C 0-3 Alkyl-NH2 or -C 0-3 Alkyl-oxetanyl-C 0-3 Alkyl-NH2, said R5 is further replaced by 1, 2, 3 or 4 R c replace.

[0169] In an optional embodiment of the present invention, the above R5 is -(CH2) 2-5 -NH2, -(CH2) 2-5 -C(=O)NH2, -(CH2) 1-3 -O-(CH2) 1-3 -NH2, -(CH2) 1-3 -S-(CH2) 1-3 -NH2, -(CH2) 0-3 -cyclopropyl-(CH2) 0-3 -NH2, -(CH2) 0-3 -cyclobutyl-(CH2) 0-3 -NH2, -(CH2) 0-3 -Oxypropyl-(CH2) 0-3 -NH2 or -(CH2) 0-3 -Oxetanyl-(CH2) 0-3 -NH2, said R5 is further replaced by 1, 2, 3 or 4 R c replace.

[0170] In an optional embodiment of the present invention, the above R5 is -(CH2) 2-5 -NH2 or -(CH2) 2-5 -C(=O)NH2, wherein R5 is further replaced by 1, 2, 3 or 4 R c replace.

[0171] In an optional embodiment of the present invention, the above R5 is described further 1, 2, 3 or 4 R c replace.

[0172] In an optional embodiment of the present invention, the above R5 is described further 1, 2, 3 or 4 R c replace.

[0173] In an optional embodiment of the present invention, the above R5 is

[0174] In an optional embodiment of the present invention, each of the above R c are independently H, F, Cl or Br.

[0175] In an optional embodiment of the present invention, each of the above R c are each independently H.

[0176] In an optional embodiment of the present invention, the above R5 is

[0177] In an optional embodiment of the present invention, the above R2, R4, R6 and R9 are independently H, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Halogenated alkyl.

[0178] In an optional embodiment of the present invention, the above R2 is C 1-3 Alkyl or C 1-3 Deuterated alkyl.

[0179] In an optional embodiment of the present invention, the above R2 is C 1-3 alkyl.

[0180] In an optional embodiment of the present invention, the above R2 is CH3 or CD3.

[0181] In an optional embodiment of the present invention, R4, R6 and R9 are each independently H.

[0182] In an optional embodiment of the present invention, the above R5 ’ For H.

[0183] In an optional embodiment of the present invention, the above R7 and R8 are independently H, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3Alkoxy or C 3-6 Cycloalkyl.

[0184] In an optional embodiment of the present invention, R7 and R8 are each independently H.

[0185] In an optional embodiment of the present invention, each of the above R d 、R e and R f are independently H, F, Cl, Br, OH, NH2, CN or COOH.

[0186] In an optional embodiment of the present invention, the above R x1 、R x2 、R x3 and R x4 are independently H, F or Cl.

[0187] In an optional embodiment of the present invention, the above R x1 、R x2 、R x3 and R x4 are each independently H.

[0188] In an optional embodiment of the present invention, the above X2 is CR x2 .

[0189] In an optional embodiment of the present invention, the above X3 is CR x3 .

[0190] In an optional embodiment of the present invention, the above X4 is N.

[0191] In an optional embodiment of the present invention, the above R x5 、R x6 and R x7 are independently H, F, Cl or C 1-3 Alkoxy.

[0192] In an optional embodiment of the present invention, the above R x5 、R x6 and R x7 are independently H or C 1-3 Alkoxy.

[0193] In an optional embodiment of the present invention, the above R x5 、R x6 and R x7 are independently H, F, Cl or -OCH3.

[0194] In an optional embodiment of the present invention, the above R x5 、R x6 and R x7are independently H, F or Cl.

[0195] In an optional embodiment of the present invention, the above R x6 and R x7 are each independently H.

[0196] In an optional embodiment of the present invention, the above X5 is CR x5 .

[0197] In an optional embodiment of the present invention, the above X6 is CR x6 .

[0198] In an optional embodiment of the present invention, the above X7 is CR x7 .

[0199] In an optional embodiment of the present invention, the above R x8 、R x9 、R x10 and R x11 are independently H, F or Cl.

[0200] In an optional embodiment of the present invention, the above R x8 、R x10 and R x11 are each independently H.

[0201] In an optional embodiment of the present invention, the above R x9 H or F.

[0202] In an optional embodiment of the present invention, X8 is CR x8 .

[0203] In an optional embodiment of the present invention, X9 is CR x9 .

[0204] In an optional embodiment of the present invention, X 10 CR x10 .

[0205] In an optional embodiment of the present invention, X 11 CR x11 .

[0206] In an optional embodiment of the present invention, the above-mentioned group fragment for

[0207] In an optional embodiment of the present invention, the above-mentioned group fragment for The a end is connected to S.

[0208] In an optional embodiment of the present invention, the above-mentioned group fragment for

[0209] In an optional embodiment of the present invention, the above-mentioned group fragment for The a end and connect.

[0210] In an optional embodiment of the present invention, the above-mentioned group fragment for

[0211] In an optional embodiment of the present invention, the above-mentioned group fragment for The a end and connect.

[0212] In an optional embodiment of the present invention, the above-mentioned group fragment for

[0213] In an optional embodiment of the present invention, the above-mentioned group fragment for The a end and connect.

[0214] In an optional embodiment of the present invention, the compound represented by the above formula (I) has the structural formula (I-1):

[0215] in,

[0216] m, n, g, ring A, X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 、X 11 、R a 、R 1a , R2, R3, R4, R5, R5 ’ , R6, R7, R8, and R9 are as defined in the present invention (in any embodiment).

[0217] In an optional embodiment of the present invention, the compound represented by the above formula (I) has the structural formula (I-2):

[0218] in,

[0219] D1 is a single bond, -CH2-, -O-, -S-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-O-, -CH2-CH2-O-, -CH2-S- or -CH2-CH2-S-;

[0220] m, g, X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 、X 11 、R a , R2, R3, R4, R5, R5 ’ , R6, R7, R8, and R9 are as defined in the present invention (in any embodiment).

[0221] In an optional embodiment of the present invention, the compound represented by the above formula (I) has the structural formula (I-3):

[0222] in,

[0223] Q1 and Q2 are each independently a single bond, -O-, -C(=O)-, -CR b R b -、-C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-;

[0224] h, h', r and r' are each independently 0, 1, 2 or 3;

[0225] D1 is a single bond, -O-, -S-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-O-, -CH2-CH2-O-, -CH2-S- or -CH2-CH2-S-;

[0226] g、X1、X2、X3、X4、X5、X6、X7、X8、X9、X 10 、X 11 、R a 、R b and R2 are as defined herein (in any embodiment).

[0227] In an optional embodiment of the present invention, the compound represented by the above formula (I) has the structural formula (I-3):

[0228] in,

[0229] Q1 and Q2 are each independently -O-, -C(=O)-, or -CR b R b -、-C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-;

[0230] h, h', r and r' are each independently 0, 1, 2 or 3;

[0231] D1 is a single bond, -O-, -S-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-O-, -CH2-CH2-O-, -CH2-S- or -CH2-CH2-S-;

[0232] g、X1、X2、X3、X4、X5、X6、X7、X8、X9、X 10 、X 11 、R a 、R b and R2 are as defined herein (in any embodiment).

[0233] In an optional embodiment of the present invention, the compound represented by the above formula (I) has the structural formula (I-3):

[0234] in,

[0235] Q1 and Q2 are each independently -C(=O)-, -CR b R b -、-C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-;

[0236] h, h', r and r' are each independently 0, 1, 2 or 3;

[0237] D1 is a single bond, -O-, -S-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-O-, -CH2-CH2-O-, -CH2-S- or -CH2-CH2-S-;

[0238] g、X1、X2、X3、X4、X5、X6、X7、X8、X9、X 10 、X 11 、R a 、R b and R2 are as defined herein (in any embodiment).

[0239] In an optional embodiment of the present invention, the compound represented by the above formula (I) has the structural formula (I-3):

[0240] in,

[0241] Q1 and Q2 are each independently a single bond, -O-, -C(=O)-, -CR b R b -、-C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-;

[0242] r and r' are each independently 1, 2 or 3;

[0243] h and h' are each independently 0, 1, 2 or 3;

[0244] g is 1, 2, 3, or 4;

[0245] D1 is a single bond, -O-, -S-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-O-, -CH2-CH2-O-, -CH2-S- or -CH2-CH2-S-;

[0246] R2 is C 1-3 Alkyl or C 1-3 deuterated alkyl;

[0247] Each R a are independently H, halogen or C 1-3 alkyl;

[0248] Each R b are independently H, F, Cl, Br, OH, NH2, CN or COOH;

[0249] X1 is N or CR x1 ;

[0250] X2 is N or CR x2 ;

[0251] X3 is N or CR x3 ;

[0252] X4 is N or CR x4 ;

[0253] X5 is N or CR x5 ;

[0254] X6 is N or CR x6 ;

[0255] X7 is N or CR x7 ;

[0256] X8 is N or CR x8 ;

[0257] X9 is N or CR x9 ;

[0258] X 10 N or CR x10 ;

[0259] X 11 N or CR x11 ;

[0260] R x1 、R x2 、R x3 and R x4 are independently H, F or Cl;

[0261] R x5 、R x6 and R x7 are independently H, F, Cl or -OCH3;

[0262] R x8 、R x9 、R x10 and R x11 are independently H, F or Cl.

[0263] In an optional embodiment of the present invention, the compound represented by the above formula (I) has the structural formula (I-3):

[0264] in,

[0265] Q1 and Q2 are each independently -O-, -C(=O)-, or -CR b R b -、-C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-;

[0266] r and r' are each independently 1, 2 or 3;

[0267] h and h' are each independently 0, 1, 2 or 3;

[0268] g is 1, 2, 3, or 4;

[0269] D1 is a single bond, -O-, -S-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-O-, -CH2-CH2-O-, -CH2-S- or -CH2-CH2-S-;

[0270] R2 is C 1-3 Alkyl or C 1-3 deuterated alkyl;

[0271] Each R a are independently H, halogen or C 1-3 alkyl;

[0272] Each R b are independently H, F, Cl, Br, OH, NH2, CN or COOH;

[0273] X1 is N or CR x1 ;

[0274] X2 is N or CRx2 ;

[0275] X3 is N or CR x3 ;

[0276] X4 is N or CR x4 ;

[0277] X5 is N or CR x5 ;

[0278] X6 is N or CR x6 ;

[0279] X7 is N or CR x7 ;

[0280] X8 is N or CR x8 ;

[0281] X9 is N or CR x9 ;

[0282] X 10 N or CR x10 ;

[0283] X 11 N or CR x11 ;

[0284] R x1 、R x2 、R x3 and R x4 are independently H, F or Cl;

[0285] R x5 、R x6 and R x7 are independently H, F or Cl;

[0286] R x8 、R x9 、R x10 and R x11 are independently H, F or Cl.

[0287] In an optional embodiment of the present invention, the compound represented by the above formula (I) has the structural formula (I-3):

[0288] in,

[0289] Q1 and Q2 are each independently -C(=O)-, -CR b R b -、-C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-;

[0290] r and r' are each independently 1, 2 or 3;

[0291] h and h' are each independently 0, 1, 2 or 3;

[0292] g is 1, 2, 3, or 4;

[0293] D1 is a single bond, -O-, -S-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-O-, -CH2-CH2-O-, -CH2-S- or -CH2-CH2-S-;

[0294] R2 is C 1-3 Alkyl or C 1-3 deuterated alkyl;

[0295] Each R a are independently H, halogen or C 1-3 alkyl;

[0296] Each R b are independently H, F, Cl, Br, OH, NH2, CN or COOH;

[0297] X1 is N or CR x1 ;

[0298] X2 is N or CR x2 ;

[0299] X3 is N or CR x3 ;

[0300] X4 is N or CR x4 ;

[0301] X5 is N or CR x5 ;

[0302] X6 is N or CR x6 ;

[0303] X7 is N or CR x7 ;

[0304] X8 is N or CR x8 ;

[0305] X9 is N or CR x9 ;

[0306] X 10 N or CR x10 ;

[0307] X 11 N or CR x11 ;

[0308] R x1 、R x2 、Rx3 and R x4 are independently H, F or Cl;

[0309] R x5 、R x6 and R x7 are independently H, F or Cl;

[0310] R x8 、R x9 、R x10 and R x11 are independently H, F or Cl.

[0311] In an optional embodiment of the present invention, the above Q1 and Q2 are independently a single bond, -O-, -C(=O)-, -CR b R b -、-C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-.

[0312] In an optional embodiment of the present invention, the above Q1 is a single bond, -O-, -CR b R b -、-C 3-6 Cycloalkyl- or 3- to 8-membered heterocycloalkyl.

[0313] In an optional embodiment of the present invention, the above Q1 and Q2 are independently a single bond, -C(=O)-, -O-, -CR b R b -, -cyclopropyl-, -cyclobutyl-, -oxetanyl- or -azetidinyl-.

[0314] In an optional embodiment of the present invention, the above Q1 is a single bond, -O-, -CR b R b -, -cyclopropyl-, -cyclobutyl-, -oxetanyl- or -azetidinyl-.

[0315] In an optional embodiment of the present invention, the above Q2 is a single bond or -C(=O)-.

[0316] In an optional embodiment of the present invention, the above Q1 and Q2 are independently -C(=O)-, -O-, -CR b R b -, -cyclopropyl-, -cyclobutyl-, -oxetanyl- or -azetidinyl-.

[0317] In an optional embodiment of the present invention, the above Q1 and Q2 are independently a single bond, -C(=O)-, -O-, -CH2-, -CF2-,

[0318] In an optional embodiment of the present invention, the above Q1 and Q2 are independently -C(=O)-, -O-, -CH2-, -CF2-,

[0319] In an optional embodiment of the present invention, the above compound has the structural formula (I-3A):

[0320] in,

[0321] Q1 and Q2 are each independently a single bond, -O-, -C(=O)-, -CR b R b -、-C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-;

[0322] r and r' are each independently 1, 2 or 3;

[0323] h and h' are each independently 0, 1, 2 or 3;

[0324] g is 1, 2, 3, or 4;

[0325] D1 is a single bond, -O-, -S-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-O-, -CH2-CH2-O-, -CH2-S- or -CH2-CH2-S-;

[0326] R2 is C 1-3 Alkyl or C 1-3 deuterated alkyl;

[0327] Each R a are independently H, halogen or C 1-3 alkyl;

[0328] Each R b are independently H, F, Cl, Br, OH, NH2, CN or COOH;

[0329] X1 is N or CR x1 ;

[0330] X2 is N or CR x2 ;

[0331] X3 is N or CR x3 ;

[0332] X4 is N or CR x4 ;

[0333] X5 is N or CR x5 ;

[0334] X6 is N or CR x6 ;

[0335] X7 is N or CR x7 ;

[0336] X8 is N or CR x8 ;

[0337] X9 is N or CR x9 ;

[0338] X 10 N or CR x10 ;

[0339] X 11 N or CR x11 ;

[0340] R x1 、R x2 、R x3 and R x4 are independently H, F or Cl;

[0341] R x5 、R x6 and R x7 are independently H, F, Cl or -OCH3;

[0342] R x8 、R x9 、R x10 and R x11 are independently H, F or Cl.

[0343] In an optional embodiment of the present invention, the above compound has the structural formula (I-3A):

[0344] in,

[0345] Q1 and Q2 are each independently -O-, -C(=O)-, or -CR b R b -、-C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-;

[0346] Preferably, Q1 and Q2 are independently -C(=O)-, -O-, or -CR b R b -, -cyclopropyl-, -cyclobutyl-, -oxetanyl-, or -azetidinyl;

[0347] Further preferably, Q1 and Q2 are independently -C(=O)-, -O-, -CH2-, -CF2-,

[0348] r and r' are each independently 1, 2 or 3;

[0349] h and h' are each independently 0, 1, 2 or 3;

[0350] g is 1, 2, 3, or 4;

[0351] D1 is a single bond, -O-, -S-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-O-, -CH2-CH2-O-, -CH2-S- or -CH2-CH2-S-;

[0352] R2 is C 1-3 Alkyl or C 1-3 deuterated alkyl;

[0353] Each R a are independently H, halogen or C 1-3 alkyl;

[0354] Each R b are independently H, F, Cl, Br, OH, NH2, CN or COOH;

[0355] X1 is N or CR x1 ;

[0356] X2 is N or CR x2 ;

[0357] X3 is N or CR x3 ;

[0358] X4 is N or CR x4 ;

[0359] X5 is N or CR x5 ;

[0360] X6 is N or CR x6 ;

[0361] X7 is N or CR x7 ;

[0362] X8 is N or CR x8 ;

[0363] X9 is N or CR x9 ;

[0364] X 10 N or CR x10 ;

[0365] X 11 N or CR x11 ;

[0366] R x1 、Rx2 、R x3 and R x4 are independently H, F or Cl;

[0367] R x5 、R x6 and R x7 are independently H, F or Cl;

[0368] R x8 、R x9 、R x10 and R x11 are independently H, F or Cl.

[0369] In an optional embodiment of the present invention, the above compound has the structural formula (I-3A):

[0370] in,

[0371] Q1 and Q2 are each independently -C(=O)-, -CR b R b -、-C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-;

[0372] Preferably, Q1 and Q2 are independently -C(=O)-, -O-, or -CR b R b -, -cyclopropyl-, -cyclobutyl-, -oxetanyl-, or -azetidinyl;

[0373] Further preferably, Q1 and Q2 are independently -C(=O)-, -O-, -CH2-, -CF2-,

[0374] r and r' are each independently 1, 2 or 3;

[0375] h and h' are each independently 0, 1, 2 or 3;

[0376] g is 1, 2, 3, or 4;

[0377] D1 is a single bond, -O-, -S-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-O-, -CH2-CH2-O-, -CH2-S- or -CH2-CH2-S-;

[0378] R2 is C 1-3 Alkyl or C 1-3 deuterated alkyl;

[0379] Each R a are independently H, halogen or C 1-3alkyl;

[0380] Each R b are independently H, F, Cl, Br, OH, NH2, CN or COOH;

[0381] X1 is N or CR x1 ;

[0382] X2 is N or CR x2 ;

[0383] X3 is N or CR x3 ;

[0384] X4 is N or CR x4 ;

[0385] X5 is N or CR x5 ;

[0386] X6 is N or CR x6 ;

[0387] X7 is N or CR x7 ;

[0388] X8 is N or CR x8 ;

[0389] X9 is N or CR x9 ;

[0390] X 10 N or CR x10 ;

[0391] X 11 N or CR x11 ;

[0392] R x1 、R x2 、R x3 and R x4 are independently H, F or Cl;

[0393] R x5 、R x6 and R x7 are independently H, F or Cl;

[0394] R x8 、R x9 、R x10 and R x11 are independently H, F or Cl.

[0395] In an optional embodiment of the present invention, the above compound has the structural formula (I-3A2):

[0396] Q1, g, Ra ,R2,X1,X2,X3,X5,X6,X7,X8,X9,X 10 and D1 are as defined in the present invention.

[0397] In an optional embodiment of the present invention, the above compound has the structural formula (I-3A1):

[0398] g、R a ,R2,X1,X2,X3,X5,X6,X7,X8,X9,X 10 and D1 are as defined in the present invention.

[0399] In an optional embodiment of the present invention, the compound represented by the above formula (I) has the structural formula (I-4):

[0400] Among them, R a are independently H, halogen or C 1-3 alkyl;

[0401] g is 1, 2, 3, or 4;

[0402] R2 is H, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 alkyl halide;

[0403] R3 is -C 1-6 Alkyl-NR 31 R3 or -C 1-6 Alkyl-OC 1-6 Alkyl-NR 31 R 32 , said R3 is further replaced by 1, 2, 3 or 4 R b replace;

[0404] R b are independently H, F, Cl, and Br;

[0405] R 31 and R 32 are independently H;

[0406] R5 is -C 1-6 Alkyl-NR 51 R 52 , said R5 is further replaced by 1, 2, 3 or 4 R c replace;

[0407] R 51 and R 52 are independently H;

[0408] R care independently H, F, Cl or Br;

[0409] X1 is N or CR x1 ;

[0410] X2 is N or CR x2 ;

[0411] X3 is N or CR x3 ;

[0412] X4 is N or CR x4 ;

[0413] X5 is N or CR x5 ;

[0414] X6 is N or CR x6 ;

[0415] X7 is N or CR x7 ;

[0416] X8 is N or CR x8 ;

[0417] X9 is N or CR x9 ;

[0418] X 10 N or CR x10 ;

[0419] X 11 N or CR x11 ;

[0420] R x1 、R x2 、R x3 and R x4 are independently H, F or Cl;

[0421] R x5 、R x6 and R x7 are independently H, F, Cl or C 1-3 alkoxy;

[0422] R x8 、R x9 、R x10 and R x11 are independently H, F or Cl;

[0423] R 10 H or C 1-3 alkyl;

[0424] R 11 H or C 1-3 alkyl;

[0425] Or, R 10 With R 11 and the carbon atom to which it is attached together form ring A, wherein ring A is C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, the C 3-6 3-membered cycloalkyl and 3-6 membered heterocycloalkyl are 1a Substitution; the heteroatom species in the 3-6 membered heterocycloalkyl group is O, and the number of heteroatoms is 1;

[0426] n is 1, 2, 3, or 4;

[0427] R 1a are each independently H.

[0428] In an optional embodiment of the present invention, the compound represented by the above formula (I) has the structural formula (I-5):

[0429] Where R2 is C 1-3 alkyl;

[0430] R3 is -C 1-6 Alkyl-NR 31 R3 or -C 1-6 Alkyl-OC 1-6 Alkyl-NR 31 R 32 , said R3 is further replaced by 1, 2, 3 or 4 R b replace;

[0431] R b are independently H;

[0432] R 31 and R 32 are independently H;

[0433] R5 is -C 1-6 Alkyl-NR 51 R 52 , said R5 is further replaced by 1, 2, 3 or 4 R c replace;

[0434] R 51 and R 52 are independently H;

[0435] R c are independently H;

[0436] X1 is N or CR x1 ;

[0437] X2 is CR x2 ;

[0438] X3 for CR x3;

[0439] X4 is N;

[0440] X5 for CR x5 ;

[0441] X6 is N or CR x6 ;

[0442] X7 for CR x7 ;

[0443] X8 for CR x8 ;

[0444] X9 for CR x9 ;

[0445] X 10 CR x10 ;

[0446] X 11 CR x11 ;

[0447] R x1 、R x2 、R x3 and R x4 are independently H;

[0448] R x5 H, F, Cl or C 1-3 alkoxy;

[0449] R x6 and R x7 are independently H;

[0450] R x8 、R x10 and R x11 are independently H;

[0451] R x9 is H, F or Cl;

[0452] R 10 C 1-3 alkyl;

[0453] R 11 H or C 1-3 alkyl;

[0454] Or, R 10 With R 11 and the carbon atom to which it is attached together form ring A, wherein ring A is C 3-6 membered cycloalkyl, the C 3-6 The membered cycloalkyl group is substituted by n H atoms;

[0455] n is 1, 2, 3, or 4;

[0456] R 1a are independently H;

[0457] When X6 is N, R x9 is F or Cl.

[0458] In an optional embodiment of the present invention, the compound is selected from any one of the following compounds or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

[0459] In an optional embodiment of the present invention, the compound is selected from any one of the following compounds or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

[0460] In an optional embodiment of the present invention, the pharmaceutically acceptable salt comprises hydrochloride or formate.

[0461] In a second aspect of the present invention, a pharmaceutical composition is provided, characterized in that it comprises the above-mentioned compound or its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs.

[0462] In an optional embodiment of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

[0463] In an optional embodiment of the present invention, the amount of the above-mentioned compound or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is a therapeutically effective amount.

[0464] In the third aspect of the present invention, the present invention proposes the use of the compound described in the first aspect or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition described in the second aspect of the present invention in the preparation of a medicament for treating or preventing infections and diseases caused by Acinetobacter baumannii.

[0465] In a fourth aspect, the present invention provides a method for treating or preventing infections and diseases caused by Acinetobacter baumannii using the compound described in the first aspect or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition described in the second aspect of the present invention.

[0466] In a fifth aspect of the present invention, the present invention proposes the use of the compound described in the first aspect above or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition described in the second aspect of the present invention for preparing a drug against Acinetobacter baumannii.

[0467] Terms and Definitions

[0468] Unless otherwise specified, the terms and definitions used in this application, including the specification and claims, are as follows.

[0469] Those skilled in the art will understand that, according to the conventions used in the art, in the structural formula of this application, Used to depict chemical bonds, which are the points where a moiety or substituent is attached to a core or backbone structure.

[0470] Unless otherwise specified, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0471] Unless otherwise specified, the term "pharmaceutically acceptable salts" refers to salts of pharmaceutically acceptable non-toxic acids or bases including salts of inorganic acids and bases, and organic acids and bases.

[0472] In addition to pharmaceutically acceptable salts, the present invention also contemplates other salts that may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or that may be useful in the identification, characterization, or purification of the compounds of the present invention.

[0473] Unless otherwise specified, the term "pharmaceutical composition" means a mixture of one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism.

[0474] Unless otherwise specified, the term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients enhance the handling properties of pharmaceutical formulations, i.e., by increasing flowability and / or cohesiveness, making the formulation more suitable for direct compression.

[0475] Unless otherwise specified, the term "prodrug" refers to a compound of the present invention that can be converted to a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the present invention are prepared by modifying functional groups within the compound. These modifications can be removed by conventional procedures or in vivo to yield the parent compound. Prodrugs include compounds in which a hydroxyl or amino group within a compound of the present invention is attached to any group. When a prodrug of a compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group or free amino group, respectively.

[0476] Unless otherwise specified, the term "stereoisomer" refers to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0477] Depending on the choice of raw materials and methods, the compounds of the present invention may exist in the form of one of the possible isomers or a mixture thereof, for example as pure optical isomers, or as a mixture of isomers, such as a racemic and diastereomeric mixture, depending on the number of asymmetric carbon atoms. When describing an optically active compound, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (–) are the symbols used to specify the rotation of plane polarized light caused by the compound, where (–) or L indicates that the compound is left-handed. Compounds prefixed with (+) or D are right-handed. With respect to a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of the isomers are often referred to as mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. Many geometric isomers of alkenes, C=N double bonds, etc. can also exist in the compounds described herein, and all such stable isomers are contemplated by the present invention. When the compounds described herein contain olefinic double bonds, unless otherwise specified, such double bonds include both E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in either the cis- or trans- configuration.

[0478] When bonds to chiral carbon atoms in formulae of the present invention are depicted as straight lines, it is understood that both the (R) and (S) configurations of the chiral carbon atoms and the enantiomerically pure compounds and mixtures thereof are encompassed within the scope of the formulae. The diagrammatic representations of racemates and enantiomerically pure compounds herein are adapted from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, wedge-shaped bonds and dashed bonds are used to represent the absolute configuration of a stereocenter.

[0479] Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. Compounds of the invention containing asymmetrically substituted carbon atoms can be separated in optically active form or racemic form. Resolution of a racemic mixture of a compound can be carried out by any of a number of methods known in the art. An exemplary method includes fractional recrystallization using a chiral resolving acid that is an optically active, salified organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids such as the D and L forms of β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include α-methyl-benzylamine (e.g., S and R forms or diastereoisomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. The resolution of the racemic mixture can also be carried out by eluting on a chromatographic column filled with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). High performance liquid chromatography (HPLC) can also be used to carry out supercritical fluid chromatography (SFC). The selection of specific methods and elution conditions, chromatographic column selection can be selected by those skilled in the art according to the structure of the compound and test results. Further, optically pure starting materials or reagents of known configuration can also be used to obtain any enantiomer or diastereomer of the compound described in the present invention through stereoorganic synthesis.

[0480] Unless otherwise specified, the term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom in a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist as two or more interconvertible species. Prototropic tautomers arise from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually produce a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0481] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed key Indicates the relative configuration of a stereocenter.

[0482] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture with physical and chemical properties consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0483] In embodiments of the present invention, protons can occupy two or more positions of the cyclic form of the heterocyclic ring system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, tetrazole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically fixed to one form by appropriate substitution. For example:

[0484] Due to resonance, the hydrogen atoms of the nitrogen atoms of tetrazole can be on any of the four nitrogen atoms.

[0485] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0486] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For the oral dosage forms of the present invention, an "effective amount" of an active substance in the composition means the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0487] Unless otherwise specified, the terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

[0488] Unless otherwise specified, the term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is a keto group (i.e., =0), it means that two hydrogen atoms are replaced. Keto substitution does not occur on aromatic groups.

[0489] Unless otherwise specified, the terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0490] The term "optionally substituted" means that the group may be substituted or not substituted, and unless otherwise specified, the type and number of the substituents may be any based on chemical feasibility.

[0491] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. For example, R 1 Be g R a When g is 2, 3 or 4, each R a Are independent options and can be the same or different.

[0492] In addition, combinations of substituents and / or their variants are permitted only if such combinations result in stable compounds. In addition, when multiple rings (parallel rings, spiro rings, or bridged rings) are substituted with substituents, it means that each hydrogen atom on the ring may be replaced, for example Represents R a It can replace the hydrogen on the pyrrole ring as well as the hydrogen on the benzene ring.

[0493] Unless otherwise specified, the term “C 1-6 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. 1-6 Alkyl groups include C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6 and C5 alkyl, etc.; which can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-6Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, and the like.

[0494] Unless otherwise specified, the term “C 1-3 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0495] The term "halo" by itself or as part of another substituent is used interchangeably with the term "halogen-substituted."

[0496] Unless otherwise specified, "haloalkyl" or "halo-substituted alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogens.

[0497] Unless otherwise specified, the term “C 1-6 "Alkoxy" refers to an alkyl group containing 1 to 6 carbon atoms which is attached to the rest of the molecule via an oxygen atom. 1-6 Alkoxy groups include C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6, C5, C4 and C3 alkoxy, etc. 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexyloxy, and the like.

[0498] Unless otherwise specified, the term “C 1-3 "Alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule via an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 、C 2-3 , C3 and C2 alkoxy, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0499] Unless otherwise specified, the term “C 3-12 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 12 carbon atoms, including monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, fused and bridged rings. 3-12 Cycloalkyl groups include C 3-10 、C 3-8 、C 3-6 、C 3-5 、C 4-8 、C 4-6 、C 4-5 、C 5-8 or C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, and the like.

[0500] Unless otherwise specified, the term “C 3-8 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 8 carbon atoms, including monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, fused and bridged rings. 3-8 Cycloalkyl groups include C 3-6 、C 3-5 、C 4-8 、C 4-6 、C 4-5 、C 5-8 or C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, and the like.

[0501] Unless otherwise specified, the term “C 3-6 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic or bicyclic ring system. 3-6 Cycloalkyl groups include C 3-5 、C 4-5 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0502] Unless otherwise specified, Cn-n+m or Cn-Cn+m includes any one of n to n+m carbons, e.g., C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 , and C12 , also includes any range from n to n+m, such as C 1-12 Including C 1-3 、C 1-6 、C 1-9 、C 3-6 、C 3-9 、C 3-12 、C 6-9 、C 6-12 , and C 9-12 Similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any range from n to n+m, for example, a 3-12-membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 6-7-membered ring, a 6-8-membered ring, and a 6-10-membered ring, etc.

[0503] Unless otherwise specified, the term "3-12 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 12 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, annular and bridged rings. In addition, with respect to the "3-12 membered heterocycloalkyl", heteroatoms can occupy the position at which the heterocycloalkyl is connected to the rest of the molecule. For example, 3-12 membered heterocycloalkyl includes but is not limited to 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered, 3-10-membered, 3-8-membered, 4-6-membered, etc. Examples of “3-12 membered heterocycloalkyl” include, but are not limited to, oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, and hexahydropyridazinyl.

[0504] Unless otherwise specified, the term "4-8 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 4 to 8 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, cyclic and bridged rings. In addition, with respect to the "6-8 membered heterocycloalkyl", heteroatoms can occupy the position at which the heterocycloalkyl is connected to the rest of the molecule. For example, 4-8 membered heterocycloalkyl includes but is not limited to 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 4-6-membered, etc. Examples of 4-8 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, and hexahydropyridazinyl.

[0505] Unless otherwise specified, the terms "5-12 membered heteroaromatic ring" and "5-12 membered heteroaryl" are used interchangeably herein, and the term "5-12 membered heteroaryl" refers to a cyclic group consisting of 5 to 12 ring atoms with a conjugated π electron system, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms independently selected from O, S and N, and the remainder are carbon atoms. It can be a monocyclic, fused bicyclic or fused tricyclic ring system, wherein each ring is aromatic. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)p, where p is 1 or 2). The 5-12 membered heteroaryl can be attached to the rest of the molecule via a heteroatom or carbon atom. The 5-12 membered heteroaryl includes 5-10 membered, 5-8 membered, 5-7 membered, 5-6 membered, 5 membered and 6 membered heteroaryl groups, etc. Examples of the 5-12 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl), thiazolyl (including 2-thiazolyl, 4-thiazolyl) 1-oxazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-1-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), benzoxazolyl, indolyl (including 5-indolyl, etc.), isoquinolyl (including 1-isoquinolyl and 5-isoquinolyl, etc.), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.) or quinolyl (including 3-quinolyl and 6-quinolyl, etc.).

[0506] Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" are used interchangeably herein, and the term "5-6 membered heteroaryl" refers to a monocyclic group consisting of 5 to 6 ring atoms with a conjugated π electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the remainder are carbon atoms. Wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)p, where p is 1 or 2). The 5-6 membered heteroaryl can be attached to the rest of the molecule via a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl), and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0507] Unless otherwise specified, the term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo.

[0508] Additionally, it should be noted that, unless otherwise expressly stated, the term "independently" used in the present invention should be broadly construed to mean that the individual entities described are independent of one another and may independently represent the same or different specific groups. More specifically, the term "independently" can mean that specific options expressed by identical symbols in different groups do not affect each other, or that specific options expressed by identical symbols in the same group do not affect each other.

[0509] Unless otherwise specified, the term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0510] Unless otherwise specified, the term "therapeutically effective amount" means the amount of an active compound or drug that will elicit the biological or medical response that a researcher, veterinarian, physician, or other clinician is seeking in a tissue, system, animal, individual, or human, and includes one or more of the following: (1) prevent disease, e.g., prevent a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but who is not yet experiencing or developing the pathology or symptoms of the disease. (2) inhibit disease, e.g., inhibit the disease, disorder, or condition (i.e., prevent further development of the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition. (3) alleviate disease, e.g., alleviate the disease, disorder, or condition (i.e., reverse the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition.

[0511] As used herein, the term "treat" and other similar synonyms include the following meanings:

[0512] (i) preventing a disease or condition from occurring in a mammal, particularly where such mammal is susceptible to the disease or condition but has not yet been diagnosed as having the disease or condition;

[0513] (ii) inhibiting the disease or condition, i.e., curbing its development;

[0514] (iii) alleviate the disease or condition, that is, cause regression of the disease or condition; or

[0515] (iv) Alleviate the symptoms of the disease or condition.

[0516] The abbreviations used in the present invention are defined as follows: DCM represents dichloromethane; DMF represents N,N-dimethylformamide; Fmoc represents 9-fluorenylmethyloxycarbonyl; Boc represents tert-butyloxycarbonyl; Trp represents tryptophan; Pip represents piperidine; DIEA represents N,N-diisopropylethylamine; Lys represents lysine; Orn represents ornithine; HATU represents benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate; NMP represents N-methylpyrrolidone; MTBE represents methyl tert-butyl ether; HFIP represents hexafluoroisopropanol; 2-CTC represents 2-chlorotrityl chloride resin; DMAP represents 4-dimethylaminopyridine; and Pd(dppf)Cl2 represents 1,1'-bis(diphenylphosphinoferrocenepalladium dichloride). Beneficial effects

[0517] According to the embodiments of the present invention, the present invention has at least one of the following technical effects:

[0518] The present invention provides novel structural compounds, and their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, which have excellent pharmacokinetic properties, good efficacy and drugability, and can be used to effectively treat or prevent infections and diseases caused by Acinetobacter baumannii. The compounds of the present invention have a strong inhibitory effect on Acinetobacter baumannii. DETAILED DESCRIPTION

[0519] The present invention will be further described below in conjunction with specific examples. It should be understood that the following description is only the most preferred embodiment of the present invention and should not be considered as limiting the scope of protection of the present invention. Based on a full understanding of the present invention, the experimental methods in the following examples that do not specify specific conditions are generally carried out under conventional conditions or under conditions recommended by the manufacturer. Those skilled in the art may make non-essential changes to the technical solutions of the present invention, and such changes should be considered as included in the scope of protection of the present invention.

[0520] Preparation of intermediate A1:

[0521] The synthesis steps are as follows: Synthesis Table 1:

[0522] 1.1 Operation steps:

[0523] 1.1.1 Weigh 60 g of 2-CTC resin (1.197 mmol / g) into a reactor and swell the resin with 10 V DCM. Add amino acid (10 g) and 4.0 eq. DIEA, stir for 3 h, then add MeOH and stir for 0.5 h.

[0524] 1.1.2 Drain and rinse with 10V DMF 6 times, blowing nitrogen for 30 seconds each time.

[0525] 1.1.3 Add 10V 20% Pip / DMF (1st: 10 min; 2nd: 10 min)*2 into the reactor.

[0526] 1.1.4 After the reaction is completed, the resin is washed with 10V DMF six times. The ninhydrin / chloranil test is positive.

[0527] 1.1.5 Weigh 3.0 eq of amino acid, 4.0 eq of DIEA, and 10 V of DMF into the reactor, then add 3 eq of HATU and stir with N2 for 1 hour.

[0528] 1.1.6 After the reaction is completed, the ninhydrin / chloranil test is negative. The reaction solution is removed and the resin is washed with 10V DMF six times.

[0529] 1.1.7 Repeat steps 1.1.2-1.1.5 according to Table 1 to sequentially condense the above amino acids 1-3.

[0530] 1.1.8 Wash the resin twice with MeOH and twice with MTBE, and drain the resin to obtain compound A1-4.

[0531] 1.2 Reductive amination:

[0532] 1.2.1 Weigh the peptide resin (A1-4) into a flask, add 10V 49.7% trimethyl orthoformate / 49.7% NMP / 0.6% acetic acid, 1.5eq compound A1-5, stir at room temperature for 3 hours, add 10eq Na(CN)BH3, and stir at room temperature for 10 hours (if the reaction is not complete, continue stirring for an extended period of time).

[0533] 1.2.2 Drain and rinse with 10V DMF 6 times, blowing nitrogen for 30 seconds each time.

[0534] 1.2.3 Add 10V 20% Pip / DMF (1st: 10 min; 2nd: 10 min)*2 to the reactor.

[0535] 1.2.4 After the reaction is completed, the resin is washed with 10V DMF six times. The ninhydrin / chloranil test is positive.

[0536] 1.2.5 Wash the resin twice with MeOH and twice with MTBE, and then drain the resin to obtain compound A1-6.

[0537] 1.3 Cutting, cracking and condensation ring closure:

[0538] 1.3.1 Weigh the peptide resin (Compound A1-6) into a centrifuge tube, add 10V 30% HFIP / 70% DCM reagent, decompose at room temperature for 2.5 hours, filter, and spin-dry the filtrate to obtain a crude product.

[0539] 1.3.2 The crude product was dissolved in 10V DMF, and 1.5eq HATU and 2eq DIEA were added. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was quenched by pouring into ice water. The mixture was extracted three times with ethyl acetate and three times with saturated brine. After drying over anhydrous sodium sulfate, the mixture was concentrated and dried by spin-drying. The product, Intermediate A1, was isolated and purified by column chromatography (EA:PE = 80%-100%).

[0540] Example 1: Preparation of Compound 1

[0541] 1-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 1)

[0542] The synthetic route of compound 1 is as follows:

[0543] Step 1: Synthesis of 1-(4-((7S,10S,13S)-13-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 1-2)

[0544] tert-butyl 3-(((7S,10S,13S)-17-bromo-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxy-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thio[5,8,11,14]tetraazacycloheptadecan-13-yl)methyl)-1H- Indole-1-carboxylate (Intermediate A1) (200 mg, 0.2 mmol) and 1-(4-borylphenyl)cyclopropane-1-carboxylic acid (61.8 mg, 0.3 mmol) were dissolved in dioxane (4 mL) and water (0.8 mL). Potassium carbonate (82.9 mg, 0.6 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (14 mg, 0.02 mmol) were added. The atmosphere was purged with nitrogen three times and the temperature was raised to 85°C for 16 hours. The reaction solution was diluted with water (30 mL) and the pH was adjusted to 5 with dilute hydrochloric acid (2 M). The mixture was extracted with ethyl acetate (10 mL × 3), the organic layers were combined, washed with saturated brine (20 mL), dried over sodium sulfate, and concentrated to obtain a crude product. The product was purified by preparative separation (chromatographic column: YMC-Triart Prep C18 7μm The reaction mixture was stirred at 30 mm*40 cm; mobile phase A: 0.1% ammonia water; mobile phase B: acetonitrile; flow rate: 42 ml / min) to give 1-(4-((7S,10S,13S)-13-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 1-2) (60 mg, yield: 27.8%).

[0545] LC-MS, M / Z(ESI):1131.9[M+H] +

[0546] Step 2: Synthesis of 1-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 1)

[0547] 1-(4-((7S,10S,13S)-13-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,1 5,16-Dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 1-2) (30 mg, 26.5 μmol) was dissolved in dioxane (0.3 mL), and hydrogen chloride / dioxane (0.3 mL, 4 M) solution was added at 20°C, and stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure to dryness to obtain a crude product, which was then purified by preparative chromatography (chromatographic column: YMC-Actus Triart C18ExRS-5μm 100*30mm; mobile phase A: 0.1% HCl; mobile phase B: acetonitrile; flow rate: 42ml / min) to obtain the hydrochloride of 1-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacyclohepten-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 1).

[0548] LC-MS, M / Z(ESI):831.4[M+H] +

[0549] Example 2: Preparation of Compound 2

[0550] 3-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)oxetane-3-carboxylic acid (Compound 2)

[0551] The synthetic route of compound 2 is as follows:

[0552] Step 1: Synthesis of tert-butyl 3-(4-bromophenyl)oxetane-3-carboxylate (Compound 2-2)

[0553] At 25°C, the raw materials 3-(4-bromophenyl)oxetane-3-carboxylic acid (1 g, 3.89 mmol) and (Boc)2O (1.01 g, 4.67 mmol) were dissolved in tetrahydrofuran (10 mL), and then DMAP (570.26 mg, 4.67 mmol) was added. The reaction mixture was stirred at 25°C for 16 hours. LCMS monitoring showed that the raw material reaction was complete and the desired product was generated. After the reaction was completed. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 20:1-10:1, gradient elution) to obtain tert-butyl 3-(4-bromophenyl)oxetane-3-carboxylate (Compound 2-2) (750.0 mg, yield 61.56%).

[0554] Step 2: Synthesis of tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetane-3-carboxylate (Compound 2-3)

[0555] At 25°C, the raw materials tert-butyl 3-(4-bromophenyl)oxetane-3-carboxylate (Compound 2-2) (700.0 mg, 2.24 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,-5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxoborolane (681.09 mg, 2.68 mmol) were dissolved in 1.4-dioxane (10 mL), followed by the addition of Pd(dppf)Cl2 (163.99 mg, 223.51 μmol) and potassium acetate (438.71 mg, 4.47 mmol). After nitrogen was replaced, the reaction mixture was stirred at 80°C for 5 hours. LCMS monitoring indicated that the reaction of the raw materials was complete and the desired product was produced. After the reaction was completed. The reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate (10 × 3). The organic phase was washed with brine (10 × 2) and dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1-3:1, gradient elution) to obtain tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetane-3-carboxylate ((Compound 2-3) 350.0 mg, 30.51% yield).

[0556] LC-MS (ESI) [M+H] + -56=305.2

[0557] Step 3: Synthesis of tert-butyl 3-(((7S,10S,13S)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-17-(4-(3-(tert-butoxycarbonyl)oxetane-3-yl)phenyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadeca-13-yl)methyl)-1H-indole-1-carboxylate (Compound 2-4)

[0558] tert-Butyl 3-(((7S,10S,13S)-17-bromo-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-13-yl)methyl)-1H-indole-1-carboxylate (Intermediate A1)(1 94.33 mg, 185.06 μmol), tert-butyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]oxetane-3-carboxylate (Compound 2-3) (100 mg, 277.58 μmol) and sodium carbonate (48.58 mg, 462.64 μmol) were dissolved in a 1,4-dioxane (3 mL) : water (0.5 mL) = 6:1 system, and then tetrakistriphenylphosphine palladium (42.71 mg, 37.01 μmol) was added to the solution. The mixture was heated to 120°C in a microwave under a nitrogen atmosphere and stirred for 40 minutes. LCMS detected the desired product. The solution was concentrated under vacuum and the residue was purified by reverse phase (0.1% aqueous formic acid) to give tert-butyl 3-(((7S,10S,13S)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-17-(4-(3-(tert-butoxycarbonyl)oxetan-3-yl)phenyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-13-yl)methyl)-1H-indole-1-carboxylate (Compound 2-4).

[0559] LC-MS(ESI)[M-300-56 / 2+1] + =424.6

[0560] Step 4: Synthesis of 3-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)oxetane-3-carboxylic acid (Compound 2)

[0561] Tert-butyl 3-(((7S,10S,13S)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-17-(4-(3-(tert-butoxycarbonyl)oxetan-3-yl)phenyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-13-yl)methyl)-1H-indole-1-carboxylate (Compound 2-4) (50 mg, 41.55 μmol) was dissolved in a solution of trifluoroacetic acid (1 mL):dichloromethane (2 mL). The reaction mixture was stirred at 25° C. for 2 hours. The desired product was detected by LCMS. The solution was concentrated under vacuum and the residue was purified by reverse phase HPLC (0.1% aqueous formic acid) to give the formate salt of 3-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)oxetane-3-carboxylic acid (Compound 2).

[0562] LC-MS (ESI) [M+1] + =847.3

[0563] Example 3: Preparation of Compound 3

[0564] 2-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)-2-methylpropanoic acid (Compound 3)

[0565] The synthetic route of compound 3 is as follows:

[0566] Step 1: Synthesis of 2-(4-((7S,10S,13S)-13-((1-(tert-butyloxycarbonyl)-1H-indol-3-yl)methyl)-10-(4-((tert-butyloxycarbonyl)amino)butyl)-7-(3-((tert-butyloxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)-2-methylpropanoic acid (Compound 3-1)

[0567] Add 3-(((7S,10S,13S)-17-bromo-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14] To tert-butyl (1,13-tetraazacycloheptadecan-1H-indole-1-carboxylate (Intermediate A1) (119 mg, 0.571 mmol), potassium carbonate (118 mg, 0.858 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (42 mg, 0.057 mmol) were added to dioxane (5 mL) and water (1 mL). The atmosphere was purged with nitrogen three times and the temperature was raised to 90°C for 16 hours. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 2). The organic layers were combined, washed with saturated brine (10 mL), dried over sodium sulfate, and concentrated to obtain a crude product. Reverse column preparation, separation and purification were used to obtain 2-(4-((7S,10S,13S)-13-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)-2-methylpropanoic acid (Compound 3-1) (110 mg, yield 33.9%).

[0568] LC-MS, M / Z(ESI):1133.5[M+H] +

[0569] Step 2: Synthesis of 2-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)-2-methylpropanoic acid (Compound 3)

[0570] 2-(4-((7S,10S,13S)-13-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15, 16-Dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)-2-methylpropanoic acid (Compound 3-1) (110 mg, 0.097 mmol) was dissolved in dioxane (0.3 mL), and hydrogen chloride / dioxane (1 mL, 4 M) solution was added at 20°C, and stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure to dryness to obtain a crude product, which was dissolved in acetonitrile / water (1 / 1, 6 mL) solution and purified by reverse column preparative purification to obtain the hydrochloride salt of 2-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)-2-methylpropanoic acid (Compound 3).

[0571] LC-MS, M / Z(ESI):833.4[M+H] +

[0572] Example 4: Preparation of target compound 4

[0573] 1-(5-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)pyridin-2-yl)cyclopropane-1-carboxylic acid (Compound 4)

[0574] The synthetic route of compound 4 is as follows:

[0575] Step 1: Synthesis of methyl 1-(5-bromopyridin-2-yl)cyclopropane-1-carboxylate (Compound 4-2)

[0576] 1-(5-Bromopyridin-2-yl)cyclopropane-1-carboxylic acid (Compound 4-1) (1 g, 4.1 mmol) was dissolved in methanol (15 mL). Thionyl chloride (0.62 mL, 8.2 mmol) was added dropwise at 0°C. The mixture was reacted at 25°C for 2 hours. The reaction mixture was then heated to 50°C and allowed to react for 2 hours. The reaction mixture was diluted with water (50 mL) and adjusted to pH 7 with saturated sodium bicarbonate solution (3 mL). The mixture was extracted with ethyl acetate (20 mL x 2). The organic layers were combined, washed with saturated brine (10 mL), dried over sodium sulfate, and concentrated to obtain the crude product. Purification by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 100:1-5:1, gradient elution) afforded methyl 1-(5-bromopyridin-2-yl)cyclopropane-1-carboxylate (Compound 4-2) (1 g, 94.3% yield).

[0577] LC-MS, M / Z(ESI):257.8[M+H] +

[0578] Step 2: Synthesis of {6-[1-(methoxycarbonyl)cyclopropyl]pyridin-3-yl}boronic acid (Compound 4-3)

[0579] Methyl 1-(5-bromopyridin-2-yl)cyclopropane-1-carboxylate (Compound 4-2) (1 g, 3.9 mmol) and triisopropyl borate (2.9 g, 15.6 mmol) were dissolved in anhydrous tetrahydrofuran (20 mL). The atmosphere was replaced with argon three times. n-Butyllithium (3.1 mL, 2.5 M) was added dropwise at -78°C and stirred at -78°C for 1 hour. The reaction solution was warmed to 0°C and diluted with water (50 mL). Diluted hydrochloric acid (1 M) was added to adjust the pH to 5. The mixture was extracted with ethyl acetate (20 mL x 2). The organic layers were combined and washed with saturated brine (20 mL), dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was separated and purified by reverse column chromatography (water:acetonitrile (V / V) = 100:1-0:1, 0.1% formic acid, gradient elution) to give {6-[1-(methoxycarbonyl)cyclopropyl]pyridin-3-yl}boronic acid (Compound 4-3) (280 mg, yield 66.3%).

[0580] LC-MS, M / Z(ESI):221.9[M+H] +

[0581] Step 3: Synthesis of tert-butyl 3-(((7S,10S,13S)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-17-(6-(1-(methoxycarbonyl)cyclopropyl)pyridin-3-yl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-13-yl)methyl)-1H-indole-1-carboxylate (Compound 4-4)

[0582] tert-Butyl 3-(((7S,10S,13S)-17-bromo-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-13-yl)methyl)-1H-indole-1-carboxylate (Intermediate A1) (250 mg, 0.24 mmol) and {6-[1-(methoxycarbonyl)cyclopropyl]pyridin-3-yl}boronic acid (Compound 4-3) (106 mg, 0.48 mmol) were dissolved in dioxane (5 mL) and water (1 mL), and potassium carbonate (99.5 mg, 0.72 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (35 mg, 0.048 mmol) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 95°C for 16 hours. The reaction solution was diluted with water (30 mL) and the pH was adjusted to 7 with dilute hydrochloric acid (1 M). The mixture was extracted with ethyl acetate (10 mL×3), the organic layers were combined, washed with saturated brine (20 mL), dried over sodium sulfate, and concentrated to obtain a crude product. Preparative separation and purification (Chromatographic column: YMC-Triart Prep C18 7μm 30mm*40cm; mobile phase A: 0.1% ammonia water; mobile phase B: acetonitrile; flow rate: 42ml / min) to obtain 3-(((7S,10S,13S)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-17-(6-(1-(methoxycarbonyl)cyclopropyl)pyridin-3-yl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-13-yl)methyl)-1H-indole-1-carboxylic acid tert-butyl ester (compound 4-4) (75mg, yield 27.5%).

[0583] LC-MS, M / Z(ESI):1146.7[M+H] +

[0584] Step 4: Synthesis of 1-(5-((7S,10S,13S)-13-((1-(tert-butyloxycarbonyl)-1H-indol-3-yl)methyl)-10-(4-((tert-butyloxycarbonyl)amino)butyl)-7-(3-((tert-butyloxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)pyridin-2-yl)cyclopropane-1-carboxylic acid (Compound 4-5)

[0585] 3-(((7S,10S,13S)-10-(4-((tert-butyloxycarbonyl)amino)butyl)-7-(3-((tert-butyloxycarbonyl)amino)propyl)-17-(6-(1-(methoxycarbonyl)cyclopropyl)pyridin-3-yl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b Tert-butyl pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-13-yl)methyl)-1H-indole-1-carboxylate (Compound 4-4) (75 mg, 0.065 mmol) was dissolved in methanol (1.5 mL). A solution of sodium hydroxide (17 mg, 0.425 mmol) in water (0.5 mL) was added at 0°C and reacted at 25°C for 6 hours. The reaction solution was adjusted to pH 7 with dilute hydrochloric acid (1 M) and concentrated to obtain a crude product. Acetonitrile (3 mL) was added for dilution and concentrated to obtain a crude product. Dioxane (3 mL) was added to dilute the mixture, filtered, and the filtrate was concentrated to give 1-(5-((7S,10S,13S)-13-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)pyridin-2-yl)cyclopropane-1-carboxylic acid (Compound 4-5).

[0586] LC-MS,M / Z(ESI):1032.5,1132.6[M+H] +

[0587] Step 5: Synthesis of 1-(5-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)pyridin-2-yl)cyclopropane-1-carboxylic acid (Compound 4)

[0588] 1-(5-((7S,10S,13S)-13-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14, 1,5,16-Dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)pyridin-2-yl)cyclopropane-1-carboxylic acid (130 mg, 0.115 mmol) was dissolved in dioxane (2 mL). Hydrogen chloride / dioxane (2 mL, 4 M) solution was added at 20°C, and the mixture was stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure to dryness to obtain a crude product, which was then separated and purified (chromatographic column: YMC-Triart Prep C18 7μm 30mm*40cm; mobile phase A: 0.05% hydrochloric acid; mobile phase B: acetonitrile; flow rate: 42ml / min) to obtain the hydrochloride of 1-(5-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)pyridin-2-yl)cyclopropane-1-carboxylic acid (Compound 4).

[0589] LC-MS, M / Z(ESI):832.6[M+H] +

[0590] Example 5: Preparation of target compound 5

[0591] 1-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-7,10-bis(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 5)

[0592] The synthetic route of compound 5 is as follows:

[0593] Step 1: Synthesis of tert-butyl 3-(((7S,10S,13S)-17-bromo-7,10-bis(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-13-yl)methyl)-1H-indole-1-carboxylate (Compound 5-1) by reference to the preparation method of intermediate A1.

[0594] Step 2: Synthesis of 1-(4-((7S,10S,13S)-13-((1-(tert-butyloxycarbonyl)-1H-indol-3-yl)methyl)-7,10-bis(3-((tert-butyloxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid compound 5-2)

[0595] Add tert-butyl 3-(((7S,10S,13S)-17-bromo-7,10-bis(3-((tert-butyloxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-13-yl)methyl)-1H-indole-1-carboxylate (Chemical) to a single-necked bottle. Compound 5-1) (200 mg, 0.193 mmol), 1-(4-borylphenyl)cyclopropane-1-carboxylic acid (Compound 1A) (99 mg, 0.483 mmol), dioxane (4 mL) and water (1 mL) were added with potassium carbonate (106.5 mg, 0.772 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (30 mg, 0.039 mmol). The atmosphere was replaced with nitrogen three times, and the temperature was raised to 90°C for 16 hours. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (10 mL × 2). The organic layers were combined, washed with saturated brine (10 mL), dried over sodium sulfate, and concentrated to obtain a crude product. The reaction was separated and purified using a reverse column (conditions: formic acid, MeCN / H2O) to obtain 1-(4-((7S,10S,13S)-13-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)-7,10-bis(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (compound 5-2).

[0596] LC-MS, M / Z(ESI):1117.5[M+H] +

[0597] Step 3: Synthesis of 1-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-7,10-bis(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 5)

[0598] 1-(4-((7S,10S,13S)-13-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)-7,10-bis(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 5-2) (100 mg, 0.090 mmol) was dissolved in dioxane (0.3 mL), and hydrogen chloride / dioxane (1 mL, 4 M) solution was added at 20°C, and stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure to dryness to obtain a crude product, which was dissolved in acetonitrile / water (1 / 1, 6 mL) and purified by reverse column preparation (conditions: formic acid, MeCN / H2O) to obtain 1-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-7,10-bis(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid formate (Compound 5).

[0599] LC-MS, M / Z(ESI):817.3[M+H] +

[0600] Example 6: Preparation of target compound 6

[0601] 1-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrazino[2,3-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 6)

[0602] The synthetic route of compound 6 is as follows:

[0603] Step 1: Synthesis of tert-butyl 3-(((7S,10S,13S)-17-bromo-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrazino[2,3-p][1]thia[5,8,11,14]tetraazacycloheptadecan-13-yl)methyl)-1H-indole-1-carboxylate (Compound 6-1) by reference to the preparation method of intermediate A1.

[0604] Step 2: Synthesis of 1-(4-((7S,10S,13S)-13-((1-(tert-butyloxycarbonyl)-1H-indol-3-yl)methyl)-10-(4-((tert-butyloxycarbonyl)amino)butyl)-7-(3-((tert-butyloxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrazino[2,3-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 6-2)

[0605] 3-(((7S,10S,13S)-17-bromo-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrazino[2,3-p][1]thia[5,8,11,14]tetraazacycloheptadecan-13-yl)methyl)-1H-indole-1-carboxylic acid Butyl ester (Compound 6-1) (100 mg, 0.095 mmol) and 1-(4-borylphenyl)cyclopropane-1-carboxylic acid (Compound 1A) (39.2 mg, 0.19 mmol) were dissolved in dioxane (2 mL) and water (0.4 mL), potassium carbonate (45.9 mg, 0.33 mmol) and [1,1'-bis(di-tert-butylphosphino)ferrocene] palladium dichloride (12.3 mg, 0.02 mmol) were added, the atmosphere was replaced with argon three times, and the temperature was raised to 80 ° C for 16 hours. The reaction solution was diluted with water (30 mL) and the pH was adjusted to 7 with dilute hydrochloric acid (1 M). It was extracted with ethyl acetate (10 mL × 3), the organic layers were combined, the organic phases were washed with saturated brine (20 mL), dried over sodium sulfate, and concentrated to obtain a crude product. Preparative separation and purification (chromatographic column: YMC-Triart Prep C18 7μm 30mm*40cm; mobile phase A: 0.1% ammonia water; mobile phase B: acetonitrile; flow rate: 42mL / min) to obtain 1-(4-((7S,10S,13S)-13-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrazino[2,3-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (compound 6-2).

[0606] LC-MS, M / Z(ESI):1132.6[M+H] +

[0607] Step 3: Synthesis of 1-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrazino[2,3-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 6)

[0608] 1-(4-((7S,10S,13S)-13-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrazino[2,3-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 6-2) (45 mg, 0.04 mmol) was dissolved in dioxane (1 mL), and a hydrogen chloride / dioxane (2 mL, 4 M) solution was added at 20°C, and the mixture was stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure to dryness to obtain a crude product, which was then separated and purified (chromatographic column: YMC-Triart Prep C18 7μm 30mm*40cm; mobile phase A: 0.05% hydrochloric acid; mobile phase B: acetonitrile; flow rate: 42ml / min) to obtain the hydrochloride of 1-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrazino[2,3-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 6).

[0609] LC-MS, M / Z(ESI):832.0[M+H] +

[0610] Example 7: Preparation of target compound 7

[0611] 1-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-((2-aminoethoxy)methyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 7)

[0612] The synthetic route of compound 7 is as follows:

[0613] Step 1: Synthesis of tert-butyl 3-(((7S,10S,13S)-17-bromo-10-((2-((tert-butoxycarbonyl)amino)ethoxy)methyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-13-yl)methyl)-1H-indole-1-carboxylate (Compound 7-1) by reference to the preparation method of intermediate A1.

[0614] Step 2: Synthesis of 1-(4-((7S,10S,13S)-13-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)-10-((2-((tert-butoxycarbonyl)amino)ethoxy)methyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 7-2)

[0615] 3-(((7S,10S,13S)-17-bromo-10-((2-((tert-butoxycarbonyl)amino)ethoxy)methyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacyclode ... Tert-butyl heptadecan-13-yl)methyl)-1H-indole-1-carboxylate (Compound 7-1) (47.0 mg, 0.23 mmol) was dissolved in dioxane (2 mL) and water (0.4 mL), and potassium carbonate (45.9 mg, 0.33 mmol) and [1,1'-bis(di-tert-butylphosphino)ferrocene] palladium dichloride (14.2 mg, 0.02 mmol) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 80°C for 16 hours. Water (30 mL) was added to the reaction solution for dilution, and the pH was adjusted to 5 with dilute hydrochloric acid (1 M). The mixture was extracted with ethyl acetate (10 mL × 3), the organic layers were combined, and the organic phases were washed with saturated brine (20 mL), dried over sodium sulfate, and concentrated to obtain a crude product. Preparative separation and purification (Chromatographic column: YMC-Triart Prep C18 7μm 30mm*40cm; mobile phase A: 0.1% ammonia water; mobile phase B: acetonitrile; flow rate: 42ml / min) to obtain 1-(4-((7S,10S,13S)-13-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)-10-((2-((tert-butoxycarbonyl)amino)ethoxy)methyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (compound 7-2).

[0616] LC-MS, M / Z(ESI):1133.6[M+H] +

[0617] Step 3: Synthesis of 1-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-((2-aminoethoxy)methyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 7)

[0618] 1-(4-((7S,10S,13S)-13-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)-10-((2-((tert-butoxycarbonyl)amino)ethoxy)methyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14 ,15,16-Dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 7-2) (45 mg, 0.04 mmol) was dissolved in dioxane (1 mL), and hydrogen chloride / dioxane (2 mL, 4 M) solution was added at 20°C and stirred at 20°C for 3 hours. The reaction solution was concentrated under reduced pressure to dryness to obtain a crude product, which was then separated and purified (chromatographic column: YMC-Triart Prep C18 7μm 30mm*40cm; mobile phase A: 0.05% hydrochloric acid; mobile phase B: acetonitrile; flow rate: 42ml / min) to obtain the hydrochloride of 1-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-((2-aminoethoxy)methyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 7).

[0619] LC-MS, M / Z(ESI):833.2[M+H] +

[0620] Example 8: Preparation of target compound 8

[0621] 2-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)propanoic acid (Compound 8)

[0622] The synthetic route of compound 8 is as follows:

[0623] Step 1: Synthesis of tert-butyl 3-(((7S,10S,13S)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-17-(4-(1-methoxy-1-oxopropan-2-yl)phenyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-13-yl)methyl)-1H-indole-1-carboxylate (Compound 8-2)

[0624] Add tert-butyl 3-(((7S,10S,13S)-17-bromo-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadeca-13-yl)methyl)-1H-indole-1-carboxylate (intermediate) into the single-necked bottle. To the mixture of compound A1) (200 mg, 0.190 mmol), methyl 2-(4-(4,4,5,5-tetramethyl-1,3-dioxaborolan-2-yl)phenyl)propanoate (Compound 8-1) (110 mg, 0.380 mmol), potassium carbonate (78 mg, 0.57 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (14 mg, 0.019 mmol) were added dioxane (2 mL) and water (0.5 mL). The atmosphere was replaced with nitrogen three times, and the temperature was raised to 90°C for 16 hours. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (10 mL × 2). The organic layers were combined, washed with saturated brine (10 mL), dried over sodium sulfate, and concentrated to obtain a crude product. The reaction was separated and purified using a reverse column (conditions: formic acid, MeCN / H2O) to obtain tert-butyl 3-(((7S,10S,13S)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-17-(4-(1-methoxy-1-oxopropane-2-yl)phenyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-13-yl)methyl)-1H-indole-1-carboxylate (compound 8-2).

[0625] LC-MS, M / Z(ESI):1133.5[M+H] +

[0626] Step 2: Synthesis of 2-(4-((7S,10S,13S)-13-((1-(tert-butyloxycarbonyl)-1H-indol-3-yl)methyl)-10-(4-((tert-butyloxycarbonyl)amino)butyl)-7-(3-((tert-butyloxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)propionic acid (Compound 8-3)

[0627] 3-(((7S,10S,13S)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-17-(4-(1-methoxy-1-oxopropan-2-yl)phenyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydro- Tert-butyl benzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-13-yl)methyl)-1H-indole-1-carboxylate (Compound 8-2) (150 mg, 0.132 mmol) was dissolved in methanol (5 mL) and water (1 mL), and lithium hydroxide (9 mg, 0.340 mmol) was added thereto, and stirred at 40°C for 2 hours. The reaction solution was concentrated under reduced pressure to dryness to obtain a crude product, which was dissolved in acetonitrile / water (1 / 1, 6 mL) and purified by reverse column preparative purification (condition: formic acid, MeCN / H2O) to obtain 2-(4-((7S,10S,13S)-13-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)propanoic acid (Compound 8-3).

[0628] LC-MS, M / Z(ESI):1119.5[M+H] +

[0629] Step 3: Synthesis of 2-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)propionic acid (Compound 8)

[0630] 2-(4-((7S,10S,13S)-13-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)propanoic acid (Compound 8-3) (80 mg, 0.071 mmol) was dissolved in dioxane (0.5 mL), and hydrogen chloride / dioxane (1 mL, 4 M) solution was added at 20°C, and stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure to dryness to obtain a crude product, which was dissolved in acetonitrile / water (1 / 1, 6 mL) and purified by reverse column preparative purification (conditions: formic acid, MeCN / H2O) to obtain the formate salt of 2-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)propanoic acid (Compound 8).

[0631] LC-MS, M / Z(ESI):819.3[M+H] +

[0632] Example 9: Preparation of target compound 9

[0633] 1-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrodipyrido[2,3-b:4',3'-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 9)

[0634] The synthetic route of compound 9 is as follows:

[0635] Step 1: Synthesis of tert-butyl 3-(((7S,10S,13S)-17-bromo-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrodipyrido[2,3-b:4',3'-p][1]thia[5,8,11,14]tetraazacycloheptadecan-13-yl)methyl)-1H-indole-1-carboxylate (Compound 9-1) by reference to the preparation method of intermediate A1.

[0636] Step 2: Synthesis of 1-(4-((7S,10S,13S)-13-((1-(tert-butyloxycarbonyl)-1H-indol-3-yl)methyl)-10-(4-((tert-butyloxycarbonyl)amino)butyl)-7-(3-((tert-butyloxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrodipyrido[2,3-b:4',3'-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 9-2)

[0637] Add 3-(((7S,10S,13S)-17-bromo-10-(4-((tert-butyloxycarbonyl)amino)butyl)-7-(3-((tert-butyloxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrodipyrido[2,3-b:4',3'-p][1]thia[5,8,11,14]tetraazacycloheptadecan-13-yl)methyl)-1H-indole into a single-necked bottle. To tert-butyl dole-1-carboxylate (Compound 9-1) (100 mg, 0.095 mmol), 1-(4-borylphenyl)cyclopropane-1-carboxylic acid (Compound 1A) (49 mg, 0.237 mmol), dioxane (2 mL) and water (0.5 mL) were added potassium carbonate (52.4 mg, 0.38 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (14 mg, 0.019 mmol). The atmosphere was purged with nitrogen three times and the temperature was raised to 90°C for 16 hours. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (10 mL × 2). The organic layers were combined, washed with saturated brine (10 mL), dried over sodium sulfate, and concentrated to obtain a crude product. The reaction was separated and purified using a reverse column (conditions: formic acid, MeCN / H2O) to obtain 1-(4-((7S,10S,13S)-13-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrodipyrido[2,3-b:4',3'-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (compound 9-2).

[0638] LC-MS, M / Z(ESI):1132.5[M+H] +

[0639] Step 3: Synthesis of 1-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrodipyrido[2,3-b:4',3'-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 9)

[0640] 1-(4-((7S,10S,13S)-13-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16 -dodecahydrodipyrido[2,3-b:4',3'-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 9-2) (20 mg, 0.018 mmol) was dissolved in dioxane (0.3 mL), and hydrogen chloride / dioxane (1 mL, 4 M) solution was added at 20 ° C, and stirred at 20 ° C for 2 hours. The reaction solution was concentrated under reduced pressure to dryness to obtain a crude product, which was dissolved in acetonitrile / water (1 / 1, 6 mL) and purified by reverse column preparation (conditions: formic acid, MeCN / H2O) to obtain the formate salt of 1-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrodipyrido[2,3-b:4',3'-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 9).

[0641] LC-MS, M / Z(ESI):832.3[M+H] +

[0642] Example 10: Preparation of target compound 10

[0643] 1-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-20-methoxy-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 10)

[0644] The synthetic route of compound 10 is as follows:

[0645] Step 1: Synthesis of tert-butyl 3-(((7S,10S,13S)-17-bromo-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-20-methoxy-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-13-yl)methyl)-1H-indole-1-carboxylate (Compound 10-1) by reference to the preparation method of intermediate A1.

[0646] Step 2: Synthesis of 1-(4-((7S,10S,13S)-13-((1-(tert-butyloxycarbonyl)-1H-indol-3-yl)methyl)-10-(4-((tert-butyloxycarbonyl)amino)butyl)-7-(3-((tert-butyloxycarbonyl)amino)propyl)-20-methoxy-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 10-2)

[0647] Add 3-(((7S,10S,13S)-17-bromo-10-(4-((tert-butyloxycarbonyl)amino)butyl)-7-(3-((tert-butyloxycarbonyl)amino)propyl)-20-methoxy-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-13-yl)methyl)-1H To tert-butyl indole-1-carboxylate (Compound 10-1) (100 mg, 0.093 mmol), 1-(4-borylphenyl)cyclopropane-1-carboxylic acid (Compound 1A) (48 mg, 0.231 mmol), dioxane (2 mL) and water (0.5 mL) were added potassium carbonate (51 mg, 0.37 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (14 mg, 0.019 mmol). The atmosphere was purged with nitrogen three times and the temperature was raised to 90°C for 16 hours. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (10 mL × 2). The organic layers were combined, washed with saturated brine (10 mL), dried over sodium sulfate, and concentrated to obtain a crude product. The reaction was separated and purified using a reverse column (conditions: formic acid, MeCN / H2O) to obtain 1-(4-((7S,10S,13S)-13-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-20-methoxy-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (compound 10-2).

[0648] LC-MS, M / Z(ESI):1161.5[M+H] +

[0649] Step 3 Synthesis of 1-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-20-methoxy-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 10)

[0650] 1-(4-((7S,10S,13S)-13-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-20-methoxy-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14, 1,5,16-Dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 10-2) (40 mg, 0.034 mmol) was dissolved in dioxane (0.3 mL), and hydrogen chloride / dioxane (1 mL, 4 M) solution was added at 20°C, and stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure to dryness to obtain a crude product, which was dissolved in acetonitrile / water (1 / 1, 6 mL) and purified by reverse column preparative purification (conditions: formic acid, MeCN / H2O) to obtain the formate salt of 1-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-20-methoxy-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 10).

[0651] LC-MS, M / Z(ESI):861.3[M+H] +

[0652] Example 11: Preparation of target compound 11

[0653] 1-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-7-(2-aminoethyl)-10-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 11)

[0654] The synthetic route of compound 11 is as follows:

[0655] Step 1: Synthesis of tert-butyl 3-(((7S,10S,13S)-17-bromo-7-(2-((tert-butoxycarbonyl)amino)ethyl)-10-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-13-yl)methyl)-1H-indole-1-carboxylate (Compound 11-1) was performed by referring to the preparation process of A1.

[0656] Step 2: Synthesis of 1-(4-((7S,10S,13S)-13-((1-(tert-butyloxycarbonyl)-1H-indol-3-yl)methyl)-7-(2-((tert-butyloxycarbonyl)amino)ethyl)-10-(3-((tert-butyloxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 11)

[0657] 3-(((7S,10S,13S)-17-bromo-7-(2-((tert-butoxycarbonyl)amino)ethyl)-10-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-13-yl)methyl)-1H-indole-1-carboxylic acid Butyl ester (Compound 11-1) (100 mg, 0.01 mmol) and 1-(4-borylphenyl)cyclopropane-1-carboxylic acid (Compound 1A) (41.2 mg, 0.2 mmol) were dissolved in dioxane (2 mL) and water (0.4 mL), potassium carbonate (48.4 mg, 0.35 mmol) and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (12.9 mg, 0.02 mmol) were added, the atmosphere was replaced with argon three times, and the temperature was raised to 80 ° C for 16 hours. The reaction solution was diluted with water (30 mL) and the pH was adjusted to 7 with dilute hydrochloric acid (1 M). It was extracted with ethyl acetate (10 mL × 3), the organic layers were combined, washed with saturated brine (20 mL), dried over sodium sulfate, and concentrated to obtain a crude product. Preparative separation and purification (chromatographic column: YMC-Triart Prep C18 7μm 30mm*40cm; mobile phase A: 0.1% ammonia water; mobile phase B: acetonitrile; flow rate: 42ml / min) to obtain 1-(4-((7S,10S,13S)-13-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)-7-(2-((tert-butoxycarbonyl)amino)ethyl)-10-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (compound 11-2).

[0658] LC-MS, M / Z(ESI):1104.0[M+H] +

[0659] Step 3: Synthesis of 1-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-7-(2-aminoethyl)-10-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 11)

[0660] 1-(4-((7S,10S,13S)-13-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)-7-(2-((tert-butoxycarbonyl)amino)ethyl)-10-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 11-2) (60 mg, 0.05 mmol) was dissolved in dioxane (1 mL), and hydrogen chloride / dioxane (2 mL, 4 M) solution was added at 20°C, and stirred at 20°C for 3 hours. The reaction solution was concentrated under reduced pressure to dryness to obtain a crude product, which was then separated and purified (chromatographic column: YMC-Triart Prep C18 7μm 30mm*40cm; mobile phase A: 0.05% hydrochloric acid; mobile phase B: acetonitrile; flow rate: 42ml / min) to obtain the hydrochloride salt of 1-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-7-(2-aminoethyl)-10-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 11).

[0661] LC-MS, M / Z(ESI):803.1[M+H] +

[0662] Example 12: Preparation of target compound 12

[0663] 2-(5-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)pyridin-2-yl)-2-methylpropanoic acid (Compound 12)

[0664] The synthetic route of target compound 12 is as follows:

[0665] Step 1: Synthesis of (6-(1-methoxy-2-methyl-1-oxopropan-2-yl)pyridin-3-yl)boronic acid (12-2)

[0666] To a solution of methyl 2-(5-bromopyridin-2-yl)-2-methylpropanoate (12-1) (3 g, 11.6 mmol) and pinacol diboron (5.9 g, 23.2 mmol) in dioxane (30 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (980 mg, 1.2 mmol) and potassium acetate (3.4 g, 34.8 mmol). The argon atmosphere was replaced three times and the mixture was stirred at 110°C for 18 h. The reaction solution was poured into water (100 mL) and extracted with ethyl acetate (30 mL*3). The organic phases were combined, washed with saturated brine (30 mL*2), filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 1) to give (6-(1-methoxy-2-methyl-1-oxopropan-2-yl)pyridin-3-yl)boronic acid (Compound 12-2) (1.8 g, yield 50.7%).

[0667] LC-MS, M / Z(ESI):305.3[M+H] +

[0668] Step 2: Synthesis of tert-butyl 3-(((7S,10S,13S)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-17-(6-(1-methoxy-2-methyl-1-oxopropane-2-yl)pyridin-3-yl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-13-yl)methyl)-1H-indole-1-carboxylate (Compound 12-3)

[0669] To tert-butyl 3-(((7S,10S,13S)-17-bromo-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-13-yl)methyl)-1H-indole-1-carboxylate (Medium To a solution of intermediate A1) (200 mg, 0.19 mmol) and (6-(1-methoxy-2-methyl-1-oxopropan-2-yl)pyridin-3-yl)boronic acid (Compound 12-2) (85 mg, 0.38 mmol) in dioxane (2 mL) and water (0.5 mL) were added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (16 mg, 0.02 mmol) and potassium carbonate (79 mg, 0.57 mmol). The argon atmosphere was replaced three times and the mixture was stirred at 95 ° C for 18 h. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate (5 mL * 3). The organic phases were combined, washed with saturated brine (5 mL * 2), filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (dichloromethane / methanol (V / V) = 1 / 0-10 / 1) to give tert-butyl 3-(((7S,10S,13S)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-17-(6-(1-methoxy-2-methyl-1-oxopropan-2-yl)pyridin-3-yl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-13-yl)methyl)-1H-indole-1-carboxylate (Compound 12-3).

[0670] LC-MS, M / Z(ESI):1149.3[M+H] +

[0671] Step 3: Synthesis of 2-(5-((7S,10S,13S)-13-((1-(tert-butyloxycarbonyl)-1H-indol-3-yl)methyl)-10-(4-((tert-butyloxycarbonyl)amino)butyl)-7-(3-((tert-butyloxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)pyridin-2-yl)-2-methylpropanoic acid (Compound 12-4)

[0672] To 3-(((7S,10S,13S)-10-(4-((tert-butyloxycarbonyl)amino)butyl)-7-(3-((tert-butyloxycarbonyl)amino)propyl)-17-(6-(1-methoxy-2-methyl-1-oxopropan-2-yl)pyridin-3-yl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[ To a solution of tert-butyl 1H-indole-1-carboxylate (compound 12-3) (70 mg, 0.06 mmol) in tetrahydrofuran (1 mL), methanol (0.5 mL) and water (0.3 mL) was added lithium hydroxide monohydrate (25 mg, 0.6 mmol), and stirred at 50°C for 2 h. Water (10 mL) was added to the reaction solution, and the pH was adjusted to 5-6 with 1N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate (3 mL*5). The organic phases were combined, washed with saturated brine (5 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to give 2-(5-((7S,10S,13S)-13-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)pyridin-2-yl)-2-methylpropanoic acid (Compound 12-4).

[0673] LC-MS, M / Z(ESI):1135.3[M+H] +

[0674] Step 4: Synthesis of 2-(5-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)pyridin-2-yl)-2-methylpropanoic acid (Compound 12)

[0675] To a solution of 2-(5-((7S,10S,13S)-13-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)pyridin-2-yl)-2-methylpropanoic acid (compound 12-4) (60 mg, 0.5 mmol) in dioxane (1 mL) was slowly added hydrochloric acid (1 mL, 4 M solution in dioxane), and then stirred at room temperature for 5 h. The reaction solution was concentrated to obtain a crude product. The crude product was subjected to reverse phase preparation (column: Phenomenex Synergi C18 100*25mm*4μm; solvent: A=water+0.1vol% hydrochloric acid (99%), B=acetonitrile; gradient: 5%-95%, 7 minutes) to obtain the hydrochloride salt of 2-(5-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)pyridin-2-yl)-2-methylpropanoic acid (Compound 12).

[0676] LC-MS, M / Z(ESI):835.0[M+H] +

[0677] Example 13: Preparation of target compound 13

[0678] 1-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrodipyrido[2,3-b:4',3'-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)-2-fluorophenyl)cyclopropane-1-carboxylic acid (Compound 13)

[0679] The synthetic route of target compound 13 is as follows:

[0680] Step 1: Synthesis of tert-butyl 3-(((7S,10S,13S)-17-bromo-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrodipyrido[2,3-b:4',3'-p][1]thia[5,8,11,14]tetraazacycloheptadecan-13-yl)methyl)-1H-indole-1-carboxylate (Compound 13-3) by reference to the preparation method of intermediate A1.

[0681] Step 2: Synthesis of 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 13-2)

[0682] To a solution of 1-(4-bromo-2-fluorophenyl)cyclopropane-1-carboxylic acid (Compound 13-1) (0.5 g, 1.93 mmol) and pinacol borate (980 mg, 3.86 mmol) in dioxane (5 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (158 mg, 0.193 mmol) and potassium acetate (568 mg, 5.79 mmol). The argon atmosphere was replaced three times, and the mixture was stirred at 110°C for 18 h. The reaction mixture was poured into water (10 mL), adjusted to pH 6-7 with 1N aqueous hydrochloric acid, and extracted with ethyl acetate (3 mL*3). The combined organic phases were washed with saturated brine (3 mL*2), filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-0 / 1) to give 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 13-2).

[0683] LC-MS, M / Z(ESI):305.3[M-1] -

[0684] Step 3: Synthesis of 1-(4-((7S,10S,13S)-13-((1-(tert-butyloxycarbonyl)-1H-indol-3-yl)methyl)-10-(4-((tert-butyloxycarbonyl)amino)butyl)-7-(3-((tert-butyloxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrodipyrido[2,3-b:4',3'-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)-2-fluorophenyl)cyclopropane-1-carboxylic acid (Compound 13-4)

[0685] To tert-butyl 3-(((7S,10S,13S)-17-bromo-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrodipyrido[2,3-b:4',3'-p][1]thia[5,8,11,14]tetraazacycloheptadecan-13-yl)methyl)-1H-indole-1-carboxylate (Compound 13-3) To a solution of 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 13-2) (58 mg, 0.19 mmol) in dioxane (1 mL) and water (0.3 mL) were added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (7.7 mg, 0.01 mmol) and potassium carbonate (41 mg, 0.3 mmol). The argon atmosphere was replaced three times and the mixture was stirred at 95°C for 18 h. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate (5 mL*3). The organic phases were combined, washed with saturated brine (5 mL*2), filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (dichloromethane / methanol (V / V) = 1 / 0-10 / 1) to give 1-(4-((7S,10S,13S)-13-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrodipyrido[2,3-b:4',3'-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)-2-fluorophenyl)cyclopropane-1-carboxylic acid (compound 13-4).

[0686] LC-MS, M / Z(ESI):1151.1[M+H] +

[0687] Step 4: Synthesis of 1-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrodipyrido[2,3-b:4',3'-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)-2-fluorophenyl)cyclopropane-1-carboxylic acid (Compound 13)

[0688] To 1-(4-((7S,10S,13S)-13-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15, 16-dodecahydrodipyrido[2,3-b:4',3'-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)-2-fluorophenyl)cyclopropane-1-carboxylic acid (Compound 13-4) (70 mg, 0.06 mmol) in dioxane (1 mL) was slowly added with hydrochloric acid (1 mL, 4 M dioxane solution), and then stirred at room temperature for 5 h. The reaction solution was concentrated to obtain a crude product. The crude product was subjected to reverse phase preparation (column: Phenomenex Synergi C18 100*25mm*4μm; solvent: A=water+0.1 volume% hydrochloric acid (99%), B=acetonitrile; gradient: 5%-95%, 7 minutes) to obtain the hydrochloride salt of 1-(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrodipyrido[2,3-b:4',3'-p][1]thia[5,8,11,14]tetraazacycloheptadecan-17-yl)-2-fluorophenyl)cyclopropane-1-carboxylic acid (Compound 13).

[0689] LC-MS, M / Z(ESI):850.0[M+H] +

[0690] Example 14: Preparation of target compound 14

[0691] 1-(5-{(7S,10S,13S)-10-(4-aminobutyl)-7-(3-aminopropyl)-20-fluoro-13-[(1H-indol-3-yl)methyl]-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydropyrido[2,3-b][1,5,8,11,14]benzothioxotetraazacycloheptadecen-17-yl}pyridin-2-yl)cyclopropane-1-carboxylic acid (target compound 14)

[0692] The synthetic route of compound 14 is as follows:

[0693] Step 1: Preparation of tert-butyl 3-{[(7S,10S,13S)-17-bromo-10-{4-[(tert-butoxycarbonyl)amino]butyl}-7-{3-[(tert-butoxycarbonyl)amino]propyl}-20-fluoro-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydropyrido[2,3-b][1,5,8,11,14]benzothioxotetraazacycloheptadecacyclo-13-yl]methyl}-1H-indole-1-carboxylate (Compound A2): Refer to the preparation method of intermediate A1.

[0694] Step 2: Synthesis of 1-(5-boropyridin-2-yl)cyclopropane-1-carboxylic acid (Compound 14-2)

[0695] 1-(5-Bromopyridin-2-yl)cyclopropane-1-carboxylic acid (Compound 14-1) (2 g, 8.2 mmol) and triisopropyl borate (3.9 g, 20.7 mmol) were dissolved in anhydrous tetrahydrofuran (20 mL). The atmosphere was replaced with argon three times, and n-butyllithium (7.3 mL, 2.5 M) was added dropwise at -78°C. The mixture was stirred at -78°C for 0.5 hours. The reaction mixture was warmed to 0°C and quenched with water (10 mL). The pH was then adjusted to 5 by adding dilute hydrochloric acid (1 M). The mixture was extracted with ethyl acetate (10 mL), and the aqueous phase was concentrated to 3 mL. The product was then purified by reverse-phase column chromatography (water:acetonitrile (v / v) = 100:1 to 0:1, 0.1% formic acid, gradient elution) to afford 1-(5-boropyridin-2-yl)cyclopropane-1-carboxylic acid (Compound 14-2) (900 mg, 52.6% yield).

[0696] LC-MS, M / Z(ESI):207.9[M+H] +

[0697] Step 3: Synthesis of 1-{5-[(7S,10S,13S)-10-{4-[(tert-butoxycarbonyl)amino]butyl}-7-{3-[(tert-butoxycarbonyl)amino]propyl}-13-{[1-(tert-butoxycarbonyl)-1H-indol-3-yl]methyl}-20-fluoro-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydropyrido[2,3-b][1,5,8,11,14]benzothiotetraazacycloheptadecan-17-yl]pyridin-2-yl}cyclopropane-1-carboxylic acid (Compound 14-3)

[0698] 3-{[(7S,10S,13S)-17-bromo-10-{4-[(tert-butoxycarbonyl)amino]butyl}-7-{3-[(tert-butoxycarbonyl)amino]propyl}-20-fluoro-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydropyrido[2,3-b][1,5,8,11,14]benzothioxotetraazacycloheptadecacyclo-13-yl]methyl}-1H-indole-1-carboxylic acid Tert-butyl ester (Compound A2) (520 mg, 0.49 mmol) and 1-(5-boropyridin-2-yl)cyclopropane-1-carboxylic acid (Compound 14-2) (207 mg, 0.1 mmol) were dissolved in dioxane (6 mL) and water (1.2 mL). Potassium carbonate (236 mg, 1.71 mmol) and [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (63 mg, 0.1 mmol) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 100°C for 16 hours. The reaction solution was diluted with water (30 mL) and the pH was adjusted to 6 with dilute hydrochloric acid (1 M). Extraction was performed with ethyl acetate (10 mL x 3). The organic layers were combined, washed with saturated brine (20 mL), dried over sodium sulfate, and concentrated to obtain a crude product. The mixture was separated and purified by reverse column chromatography (water:acetonitrile (V / V) = 100:1-0:1, 0.1% formic acid, gradient elution) to give 1-{5-[(7S,10S,13S)-10-{4-[(tert-butoxycarbonyl)amino]butyl}-7-{3-[(tert-butoxycarbonyl)amino]propyl}-13-{[1-(tert-butoxycarbonyl)-1H-indol-3-yl]methyl}-20- Fluoro-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydropyrido[2,3-b][1,5,8,11,14]benzothioxotetraazacycloheptadecan-17-yl]pyridin-2-yl}cyclopropane-1-carboxylic acid (Compound 14-3) (300 mg, yield: 53.6%).

[0699] LC-MS, M / Z(ESI):1150.69[M+H] +

[0700] Step 3: Synthesis of 1-(5-{(7S,10S,13S)-10-(4-aminobutyl)-7-(3-aminopropyl)-20-fluoro-13-[(1H-indol-3-yl)methyl]-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydropyrido[2,3-b][1,5,8,11,14]benzothiotetraazacycloheptadecen-17-yl}pyridin-2-yl)cyclopropane-1-carboxylic acid (Compound 14)

[0701] 1-{5-[(7S,10S,13S)-10-{4-[(tert-butoxycarbonyl)amino]butyl}-7-{3-[(tert-butoxycarbonyl)amino]propyl}-13-{[1-(tert-butoxycarbonyl)-1H-indol-3-yl]methyl}-20-fluoro-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14, 15,16-Dodecahydropyrido[2,3-b][1,5,8,11,14]benzothioxotetraazacycloheptadecan-17-yl]pyridin-2-yl}cyclopropane-1-carboxylic acid (Compound 14-3) (200 mg, 0.17 mmol) was dissolved in dioxane (3 mL), and hydrogen chloride / dioxane (5 mL, 4 M) solution was added at 20 ° C, and stirred at 20 ° C for 3 hours. The reaction solution was concentrated under reduced pressure to dryness to obtain a crude product, which was then separated and purified (chromatographic column: YMC-Triart Prep C18 7 μm 30 mm*40 cm; mobile phase A: 0.05% hydrochloric acid; mobile phase B: acetonitrile; flow rate: 42 ml / min) to obtain the hydrochloride salt of 1-(5-{(7S,10S,13S)-10-(4-aminobutyl)-7-(3-aminopropyl)-20-fluoro-13-[(1H-indol-3-yl)methyl]-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydropyrido[2,3-b][1,5,8,11,14]benzothiotetraazacycloheptadecen-17-yl}pyridin-2-yl)cyclopropane-1-carboxylic acid (Compound 14).

[0702] LC-MS, M / Z(ESI):849.6[M+H] +

[0703] Biological testing:

[0704] Antibiotic minimum inhibitory concentration (MIC) testing

[0705] The in vitro antibacterial activity of antibiotics was tested by the minimum inhibitory concentration experiment. The test bacteria was Acinetobacter baumannii (ATCC19606) purchased from Beijing Beina Chuanglian Biotechnology Research Institute with the catalog number BNCC337173; the culture medium was sterile cation-adjusted M-HII broth (BD, catalog number 212322). The test compound was dissolved in the cation-adjusted M-HII broth medium and prepared into a working solution with a maximum concentration of 64 μg / mL. The solution was serially diluted twice with the culture medium and the diluted culture medium was transferred to a sterile 96-well culture plate with 100 μL per well. A control well without the compound was also set up. Subsequently, Acinetobacter baumannii was prepared with the culture medium to a final concentration of ~1×10 6 CFU / mL working solution was added to each well of a 96-well plate, 100 μL per well, and a blank well containing no compound and no bacteria was set up at the same time. After mixing, the 96-well plate was placed in a 37°C incubator and cultured for 16 hours. After the incubation was completed, the 96-well plate was transferred to a microplate reader (Molecular Devices, SpectraMax iD5), the absorbance at OD600 of each well was detected, and the inhibition rate of bacterial growth at different compound concentrations was calculated. The lowest concentration at which the compound inhibited bacteria by ≥80% was the minimum inhibitory concentration of the compound.

[0706] Table 2: Minimum inhibitory concentrations of the compounds of the present invention against Acinetobacter baumannii

[0707] Detection shows that the compound of the present invention has a strong inhibitory effect on Acinetobacter baumannii.

Claims

1. A compound represented by formula (I), its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, in, X1 is N or CR x1 ; X2 is N or CR x2 ; X3 is N or CR x3 ; X4 is N or CR x4 ; X5 is N or CR x5 ; X6 is N or CR x6 ; X7 is N or CR x7 ; X8 is N or CR x8 ; X9 is N or CR x9 ; X 10 N or CR x10 ; X 11 N or CR x11 ; R1 is -(CH2) m -C 6-12 Aryl, -(CH2) m -5-12 membered heteroaryl or -(CH2) m -3-12 membered heterocycloalkyl; said C 6-12 Aryl, 5-12 membered heteroaryl and 3-12 membered heterocycloalkyl are each independently optionally substituted by g R a replace; Each R a are independently H, halogen, OH, NH2, CN, COOH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 3-8 Cycloalkyl; R2, R4, R6 and R9 are independently H, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 3-8 Cycloalkyl; R3 is -C 1-10 Alkyl, -C 0-10 Alkyl-NR 31 R 32 、-C 0-10 Alkyl-C(=O)NR 31 R 32 、-C 0-10 Alkyl-NR 31 -C(=O)NR 31 R 32 、-C 0-10 Alkyl-OC 1-10 Alkyl-NR 31 R 32 、-C 0-10 Alkyl-SC 1-10 Alkyl-NR 31 R 32 、-C 0-10 Alkyl-NR 31 -C 1-10 Alkyl-NR 31 R 32 、-C 0-10 Alkyl-C(=O)-C 1-10 Alkyl-NR 31 R 32 、-C 0- 10 Alkyl-C 3-8 Cycloalkyl-C 0-10 Alkyl-NR 31 R 32 or -C 0-10 Alkyl-3-12 membered heterocycloalkyl-C 1-10 Alkyl-NR 31 R 32 , said R3 is further replaced by 1, 2, 3 or 4 R b replace; R5 is -C 1-10 Alkyl, -C 0-10 Alkyl-NR 51 R 52 、-C 0-10 Alkyl-C(=O)NR 51 R 52 、-C 0-10 Alkyl-NR 51 -C(=O)NR 51 R 52 、-C 0-10 Alkyl-OC 1-10 Alkyl-NR 51 R 52 、-C 0-10 Alkyl-SC 1-10 Alkyl-NR 51 R 52 、-C 0-10 Alkyl-NR 51 -C 1-10 Alkyl-NR 51 R 52 、-C 0-10 Alkyl-C(=O)-C 1-10 Alkyl-NR 51 R 52 、-C 0- 10 Alkyl-C 3-8 Cycloalkyl-C 0-10 Alkyl-NR 51 R 52 or -C 0-10 Alkyl-3-12 membered heterocycloalkyl-C 1-10 Alkyl-NR 51 R 52 , said R5 is further replaced by 1, 2, 3 or 4 R c replace; R 31 、R 32 、R 51 and R 52 are independently H or C 1-6 alkyl; R 5’ H or C 1-6 alkyl; R7 and R8 are independently H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 3-8 Cycloalkyl; R 10 H, F, Cl, Br, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl or -O-3-8 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl and -O-3-8 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R 101 replace; R 11 H, F, Cl, Br, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl or -O-3-8 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl and -O-3-8 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R 111 replace; Each R 101 are independently H, F, Cl, Br, OH, NH2, CN or COOH; Each R 111 are independently H, F, Cl, Br, OH, NH2, CN or COOH; Or, R 10 With R 11 and the carbon atom to which it is attached together form ring A, wherein ring A is C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl, the C 3-8 3-membered cycloalkyl and 3-8-membered heterocycloalkyl are 1a replace; Each R 1a are independently H, F, Cl, Br, OH, NH2, CN, COOH or C 1-6 Alkyl, the C 1-6 Alkyl is optionally substituted with 1, 2, 3 or 4 R groups, each independently; R is independently H, F, Cl, Br, OH, NH2, CN, ═O, ═S, COOH or C 1-6 alkyl; R x1 、R x2 、R x3 and R x4 are independently H, F, Cl, Br, OH, NH2, CN, COOH, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 The alkyl group is optionally substituted by 1, 2, 3 or 4 R d replace; R x5 、R x6 and R x7 are independently H, F, Cl, Br, OH, NH2, CN, COOH, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 The alkyl group is optionally substituted with 0, 1, 2, 3 or 4 R e replace; R x8 、R x9 、R x10 and R x11 are independently H, F, Cl, Br, OH, NH2, CN, COOH, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 The alkyl group is optionally substituted by 1, 2, 3 or 4 R f replace; Each R b 、R c 、R d 、R e and R f are independently H, F, Cl, Br, OH, NH2, CN, ═O, COOH or C 1-6 alkyl; Each m is independently 1, 2, 3 or 4; g is 1, 2, 3, or 4; n is 1, 2, 3 or 4.

2. The compound according to claim 1, characterized in that The compound represented by formula (I) satisfies one or more of the following conditions: (1a) Ring A is C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, the C 3-6 3-membered cycloalkyl and 3-6 membered heterocycloalkyl are 1a replace; (2a) Each R 1a are independently H, F, Cl, Br, OH, NH2, CN, COOH or C 1-3 Alkyl, the C 1-3 Alkyl is optionally substituted with 1, 2, 3 or 4 R groups, each independently; (3a) R is each independently H, F, Cl, Br, OH, NH2, CN, ═O, ═S, COOH, or -CH3; (4a)R 10 H, F, Cl, Br, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -OC 3-6 Cycloalkyl or -O-3-6 membered heterocycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -OC 3-6 Cycloalkyl and -O-3-6 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R 101 replace; (5a)R 11 H, F, Cl, Br, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -OC 3-6 Cycloalkyl or -O-3-6 membered heterocycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -OC 3-6 Cycloalkyl and -O-3-6 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R 111 replace; (6a) R1 is -(CH2) m -5-10 membered heteroaryl, said 5-10 membered heteroaryl being optionally substituted by g R a replace; (7a) g is 1, 2, 3 or 4; (8a) m is 1, 2, 3 or 4; (9a) Each R a are independently H, halogen or C 1-3 alkyl; (10a) R3 is -C 1-6 Alkyl-NR 31 R3, -C 1-6 Alkyl-C(=O)NR 31 R 32 、-C 1-6 Alkyl-NR 31 -C(=O)NR 31 R 32 、-C 1-6 Alkyl-OC 1-6 Alkyl-NR 31 R 32 、-C 1-6 Alkyl-SC 1-6 Alkyl-NR 31 R 32 、-C 1-6 Alkyl-NR 31 -C 1-6 Alkyl-NR 31 R 32 、-C 0-6 Alkyl-C 3-6 Cycloalkyl-C 0-6 Alkyl-NR 31 R 32 or -C 0-6 Alkyl-3-8 membered heterocycloalkyl-C 0-6 Alkyl-NR 31 R 32 , said R3 is further replaced by 1, 2, 3 or 4 R b replace; (11a)R 31 and R 32 are independently H; (12a) Each R b are independently H, F, Cl, and Br; (13a) R5 is -C 1-6 Alkyl-NR 51 R 52 、-C 1-6 Alkyl-C(=O)NR 51 R 52 、-C 1-6 Alkyl-NR 51 -C(=O)NR 51 R 52 、-C 1-6 Alkyl-OC 1-6 Alkyl-NR 51 R 52 、-C 1-6 Alkyl-SC 1-6 Alkyl-NR 51 R 52 、-C 1-6 Alkyl-NR 51 -C 1-6 Alkyl-NR 51 R 52 、-C 0-6 Alkyl-C 3-6 Cycloalkyl-C 0-6 Alkyl-NR 51 R 52 or -C 0-6 Alkyl-3-8 membered heterocycloalkyl-C 0-6 Alkyl-NR 51 R 52 , said R5 is further replaced by 1, 2, 3 or 4 R c replace; (14a)R 51 and R 52 are independently H; (15a) Each R c are independently H, F, Cl or Br; (16a) R2 is H, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 alkyl halide; (17a) R4, R6 and R9 are independently H, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 alkyl halide; (18a)R5 ’ is H; (19a) R7 and R8 are independently H, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy or C 3-6 Cycloalkyl; (20a) Each R d 、R e and R f are independently H, F, Cl, Br, OH, NH2, CN, COOH; (21a)R x1 、R x2 、R x3 and R x4 are independently H, F or Cl; (22a)X2 is CR x2 ; (23a)X3 is CR x3 ; (24a) X4 is N; (25a)R x5 、R x6 and R x7 are independently H, F, Cl or C 1-3 alkoxy; (26a)X5 is CR x5 ; (27a)X6 is CR x6 ; (28a)X7 is CR x7 ; (29a)R x8 、R x10 and R x11 are independently H, F or Cl; (30a)R x9 is H, F or Cl; (31a)X8 is CR x8 ; (32a)X9 is CR x9 ; (33a)X 10 CR x10 ; (34a)X 11 CR x11 ; (35a) The pharmaceutically acceptable salt comprises hydrochloride or formate; (36a) The 5-12 membered heteroaryl group has 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, and the rest are carbon atoms; the 3-12 membered heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, and the rest are carbon atoms; the 3-8 membered heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, and the rest are carbon atoms.

3. The compound according to claim 2, characterized in that The compound represented by formula (I) satisfies one or more of the following conditions: (1b) Ring A is C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, the C 3-6 3-membered cycloalkyl and 3-6 membered heterocycloalkyl are 1a Substitution; the heteroatom species in the 3-6 membered heterocycloalkyl group is O, and the number of heteroatoms is 1; (2b) Each R 1a are independently H; (3b)R 10 H, F, Cl, Br, OH, NH2, CN, C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2, 3 or 4 R 101 replace; (4b)R 11 H, F, Cl, Br, OH, NH2, CN, C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2, 3 or 4 R 111 replace; (5b) R1 is -(CH2) m -benzo 5-membered heteroaryl, the benzo 5-membered heteroaryl is optionally substituted by g R a replace; (6b) g is 1; (7b) m is 1; (8b) Each R a are independently H or C 1-3 alkyl; (9b) R3 is -C 1-6 Alkyl-NR 31 R3, -C 1-6 Alkyl-OC 1-6 Alkyl-NR 31 R 32 、-C 0-6 Alkyl-C 3-6 Cycloalkyl-C 0-6 Alkyl-NR 31 R 32 or -C 0-6 Alkyl-3-8 membered heterocycloalkyl-C 0-6 Alkyl-NR 31 R 32 , said R3 is further replaced by 1, 2, 3 or 4 R b Substitution, the heteroatom species in the 3-8 membered heterocycloalkyl is O, and the number of heteroatoms is 1; (10b) Each R b are independently H or F; (11b) R5 is -C 1-6 Alkyl-NR 51 R 52 or -C 1-6 Alkyl-C(=O)NR 51 R 52 , said R5 is further replaced by 1, 2, 3 or 4 R c replace; (12b) Each R c are independently H; (13b) R2 is C 1-3 Alkyl or C 1-3 deuterated alkyl; (14b) R4, R6 and R9 are each independently H; (15b) R7 and R8 are each independently H; (16b)R x1 、R x2 、R x3 and R x4 are independently H; (17b)R x5 、R x6 and R x7 are independently H or C 1-3 alkoxy; (18b)R x8 、R x10 and R x11 are independently H; (19b)R x9 H or F.

4. The compound according to claim 3, characterized in that The compound represented by formula (I) satisfies one or more of the following conditions: (1c) Ring A is C 3-6 membered cycloalkyl, the C 3-6 The cycloalkyl group is composed of n R 1a replace; (2c)R 10 H or C 1-3 alkyl; (3c)R 11 H or C 1-3 alkyl; (4c) R1 is -(CH2) m -5,6-dicyclic heteroaryl, wherein the 5,6-dicyclic heteroaryl is optionally substituted by g R a replace; (5c) Each R a are independently H or CH3; (6c) R3 is -C 1-6 Alkyl-NR 31 R3 or -C 1-6 Alkyl-OC 1-6 Alkyl-NR 31 R 32 , said R3 is further replaced by 1, 2, 3 or 4 R b replace; (7c) Each R b are independently H; (8c) R5 is -C 1-6 Alkyl-NR 51 R 52 , said R5 is further replaced by 1, 2, 3 or 4 R c replace; (9c) R2 is C 1-3 alkyl.

5. The compound according to claim 4, characterized in that The compound represented by formula (I) satisfies one or more of the following conditions: (1d)R 10 C 1-3 alkyl; (2d) R1 is -(CH2) m -pyrrolophenyl, said pyrrolophenyl being optionally substituted by g R a replace; (3d) Each R a are independently H; (4d) R3 is -C 1-6 Alkyl-NR 31 R3, said R3 is further replaced by 1, 2, 3 or 4 R b replace.

6. The compound according to claim 1, characterized in that The compound represented by formula (I) satisfies one or both of the following conditions: (1e) R3 is -C 2-5 Alkyl-NH2, -C 1-3 Alkyl-OC 1-3 Alkyl-NH2, -C 1-3 Alkyl-SC 1-3 Alkyl-NH2, -C 0-3 Alkyl-cyclopropyl-C 0-3 Alkyl-NH2, -C 0-3 Alkyl-cyclobutyl-C 0-3 Alkyl-NH2, -C 0-3 Alkyl-oxacyclopropyl-C 0-3 Alkyl-NH2 or -C 0-3 Alkyl-oxetanyl-C 0-3 Alkyl-NH2, said R3 is further substituted by 1, 2, 3 or 4 R b replace; (2e) R5 is -C 2-5 Alkyl-NH2, -C 1-6 Alkyl-C(=O)NH2, -C 1-3 Alkyl-OC 1-3 Alkyl-NH2, -C 1-3 Alkyl-SC 1-3 Alkyl-NH2, -C 0-3 Alkyl-C 3-6 Cycloalkyl-C 0-3 Alkyl-NH2 or -C 0-3 Alkyl-3-6 membered heterocycloalkyl-C 0-3 Alkyl-NH2, said R5 is further replaced by 1, 2, 3 or 4 R c replace.

7. The compound according to claim 6, characterized in that The compound represented by formula (I) satisfies one or both of the following conditions: (1f) R3 is -(CH2) 2-5 -NH2, -(CH2) 1-3 -O-(CH2) 1-3 -NH2, -(CH2) 1-3 -S-(CH2) 1-3 -NH2, -(CH2) 0-3 -cyclopropyl-(CH2) 0-3 -NH2, -(CH2) 0- 3-cyclobutyl-(CH2) 0-3 -NH2, -(CH2) 0-3 -Oxypropyl-(CH2) 0-3 -NH2 or -(CH2) 0-3 -Oxetanyl-(CH2) 0-3 -NH2, said R3 is further replaced by 1, 2, 3 or 4 R b replace; (2f) R5 is -C 2-5 Alkyl-NH2, -C 1-6 Alkyl-C(=O)NH2, -C 1-3 Alkyl-OC 1-3 Alkyl-NH2, -C 1-3 Alkyl-SC 1-3 Alkyl-NH2, -C 0-3 Alkyl-cyclopropyl-C 0-3 Alkyl-NH2, -C 0-3 Alkyl-cyclobutyl-C 0-3 Alkyl-NH2, -C 0-3 Alkyl-oxacyclopropyl-C 0-3 Alkyl-NH2 or -C 0-3 Alkyl-oxetanyl-C 0-3 Alkyl-NH2, said R5 is further replaced by 1, 2, 3 or 4 R c replace.

8. The compound according to claim 7, characterized in that The compound represented by formula (I) satisfies one or both of the following conditions: (1g) R3 is -(CH2) 2-5 -NH2, -(CH2) 1-3 -O-(CH2) 1-3 -NH2, -(CH2) 0-3 -cyclopropyl-(CH2) 0-3 -NH2, -(CH2) 0-3 -cyclobutyl-(CH2) 0-3 -NH2, -(CH2) 0-3 -Oxypropyl-(CH2) 0-3 -NH2 or -(CH2) 0-3 -Oxetanyl-(CH2) 0-3 -NH2, said R3 is further replaced by 1, 2, 3 or 4 R b replace; (2g) R5 is -(CH2) 2-5 -NH2, -(CH2) 2-5 -C(=O)NH2, -(CH2) 1-3 -O-(CH2) 1-3 -NH2, -(CH2) 1-3 -S-(CH2) 1-3 -NH2, -(CH2) 0-3 -cyclopropyl-(CH2) 0-3 -NH2, -(CH2) 0-3 -cyclobutyl-(CH2) 0-3 -NH2, -(CH2) 0-3 -Oxypropyl-(CH2) 0-3 -NH2 or -(CH2) 0-3 -Oxetanyl-(CH2) 0-3 -NH2, said R5 is further replaced by 1, 2, 3 or 4 R c replace.

9. The compound according to claim 8, characterized in that The compound represented by formula (I) satisfies one or both of the following conditions: (1h) R3 is -(CH2) 2-5 -NH2 or -(CH2) 1-3 -O-(CH2) 1-3 -NH2, said R3 is further replaced by 1, 2, 3 or 4 R b preferably, R3 is -(CH2) 2- 5-NH2, said R3 is further replaced by 1, 2, 3 or 4 R b replace; (2h) R5 is -(CH2) 2-5 -NH2 or -(CH2) 2-5 -C(=O)NH2, wherein R5 is further replaced by 1, 2, 3 or 4 R c replace.

10. The compound according to claim 1, characterized in that The compound represented by formula (I) satisfies one or more of the following conditions: (1i) Ring A is D1 is a single bond, -CH2-, -O-, -S-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-O-, -CH2-CH2-O-, -CH2-S- or -CH2-CH2-S-; (2i)R1 is (3i) R3 is -(CH2)3-NH2, -(CH2)4-NH2, -(CH2)-O-(CH2)2-NH2, -(CH2)-cyclopropyl-(CH2)2-NH2, -(CH2)2-cyclopropyl-(CH2)-NH2, -(CH2)-oxetanyl-(CH2)2-NH2 or -(CH2)2-oxetanyl-(CH2)-NH2, wherein R3 is further replaced by 1, 2, 3 or 4 R b preferably, R3 The R3 is further replaced by 1, 2, 3 or 4 R b replace; (4i)R5 is described further 1, 2, 3 or 4 R c replace; (5i)R x5 、R x6 and R x7 are independently H, F, Cl or -OCH3.

11. The compound according to claim 10, characterized in that The compound represented by formula (I) satisfies one or more of the following conditions: (1j) Ring A is (2j)R 10 is H or CH3; (3j)R 11 is H or CH3; (4j)R1 is (5j)R3 is (6j)R5 is (7j) R2 is CH3 or CD3; (8j)R x5 、R x6 and R x7 are independently H, F or Cl.

12. The compound according to claim 1, characterized in that The compound represented by formula (I) satisfies one or more of the following conditions: (1k) for (2k) group fragment for Preferably, the group fragment for Wherein end a is connected to S; (3k) group fragment for Preferably, the group fragment for The a end and connection; more preferably, a group fragment for The a end and connect; (4k) Group fragment for Preferably, the group fragment for The a end and connect.

13. The compound according to claim 1, characterized in that The compound represented by formula (I) is selected from any of the following schemes: Option 1: The compound represented by formula (I) has the structural formula (I-1): in, m, n, g, ring A, X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 、X 11 、R a 、R 1a , R2, R3, R4, R5, R5 ’ , R6, R7, R8, R9 are as defined in any one of claims 1 to 12; Option 2: The compound represented by formula (I) has the structural formula (I-2): in, D1 is a single bond, -O-, -S-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-O-, -CH2-CH2-O-, -CH2-S- or -CH2-CH2-S-; m, g, X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 、X 11 、R a , R2, R3, R4, R5, R5 ’ , R6, R7, R8, R9 are as defined in any one of claims 1 to 12; Option 3: The compound represented by formula (I) has the structural formula (I-3): in, Q1 and Q2 are each independently a single bond, -O-, -C(=O)-, -CR b R b -、-C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-; h, h', r and r' are each independently 0, 1, 2 or 3; D1 is a single bond, -O-, -S-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-O-, -CH2-CH2-O-, -CH2-S- or -CH2-CH2-S-; g、X1、X2、X3、X4、X5、X6、X7、X8、X9、X 10 、X 11 、R a 、R b and R2 is as defined in any one of claims 1 to 12; Option 4: The compound represented by formula (I) has the structural formula (I-4): Among them, R a are independently H, halogen or C 1-3 alkyl; g is 1, 2, 3, or 4; R2 is H, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 alkyl halide; R3 is -C 1-6 Alkyl-NR 31 R3 or -C 1-6 Alkyl-OC 1-6 Alkyl-NR 31 R 32 , said R3 is further replaced by 1, 2, 3 or 4 R b replace; R b are independently H, F, Cl, and Br; R 31 and R 32 are independently H; R5 is -C 1-6 Alkyl-NR 51 R 52 , said R5 is further replaced by 1, 2, 3 or 4 R c replace; R 51 and R 52 are independently H; R c are independently H, F, Cl or Br; X1 is N or CR x1 ; X2 is N or CR x2 ; X3 is N or CR x3 ; X4 is N or CR x4 ; X5 is N or CR x5 ; X6 is N or CR x6 ; X7 is N or CR x7 ; X8 is N or CR x8 ; X9 is N or CR x9 ; X 10 N or CR x10 ; X 11 N or CR x11 ; R x1 、R x2 、R x3 and R x4 are independently H, F or Cl; R x5 、R x6 and R x7 are independently H, F, Cl or C 1-3 alkoxy; R x8 、R x9 、R x10 and R x11 are independently H, F or Cl; R 10 H or C 1-3 alkyl; R 11 H or C 1-3 alkyl; Or, R 10 With R 11 and the carbon atom to which it is attached together form ring A, wherein ring A is C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, the C 3-6 3-membered cycloalkyl and 3-6 membered heterocycloalkyl are 1a Substitution; the heteroatom species in the 3-6 membered heterocycloalkyl group is O, and the number of heteroatoms is 1; n is 1, 2, 3, or 4; R 1a are independently H; Option 5: The compound represented by formula (I) has the structural formula (I-5): Where R2 is C 1-3 alkyl; R3 is -C 1-6 Alkyl-NR 31 R3 or -C 1-6 Alkyl-OC 1-6 Alkyl-NR 31 R 32 , said R3 is further replaced by 1, 2, 3 or 4 R b replace; R b are independently H; R 31 and R 32 are independently H; R5 is -C 1-6 Alkyl-NR 51 R 52 , said R5 is further replaced by 1, 2, 3 or 4 R c replace; R 51 and R 52 are independently H; R c are independently H; X1 is N or CR x1 ; X2 is CR x2 ; X3 for CR x3 ; X4 is N; X5 for CR x5 ; X6 is N or CR x6 ; X7 for CR x7 ; X8 for CR x8 ; X9 for CR x9 ; X 10 CR x10 ; X 11 CR x11 ; R x1 、R x2 、R x3 and R x4 are independently H; R x5 H, F, Cl or C 1-3 alkoxy; R x6 and R x7 are independently H; R x8 、R x10 and R x11 are independently H; R x9 is H, F or Cl; R 10 C 1-3 alkyl; R 11 H or C 1-3 alkyl; Or, R 10 With R 11 and the carbon atom to which it is attached together form ring A, wherein ring A is C 3-6 membered cycloalkyl, the C 3-6 The membered cycloalkyl group is substituted by n H atoms; n is 1, 2, 3, or 4; R 1a are independently H; When X6 is N, R x9 is F or Cl.

14. The compound according to claim 13, characterized in that In the compound represented by formula (I-3): Q1 and Q2 are each independently a single bond, -O-, -C(=O)-, -CR b R b -、-C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-; Preferably, Q1 and Q2 are independently a single bond, -C(=O)-, -O-, or -CR b R b -, -cyclopropyl-, -cyclobutyl-, -oxetanyl-, or -azetidinyl; Further preferably, Q1 and Q2 are independently a single bond, -C(=O)-, -O-, -CH2-, -CF2-, r and r' are each independently 1, 2 or 3; h and h' are each independently 0, 1, 2 or 3; g is 1, 2, 3, or 4; D1 is a single bond, -O-, -S-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-O-, -CH2-CH2-O-, -CH2-S- or -CH2-CH2-S-; R2 is C 1-3 Alkyl or C 1-3 deuterated alkyl; Each R a are independently H, halogen or C 1-3 alkyl; Each R b are independently H, F, Cl, Br, OH, NH2, CN or COOH; X1 is N or CR x1 ; X2 is N or CR x2 ; X3 is N or CR x3 ; X4 is N or CR x4 ; X5 is N or CR x5 ; X6 is N or CR x6 ; X7 is N or CR x7 ; X8 is N or CR x8 ; X9 is N or CR x9 ; X 10 N or CR x10 ; X 11 N or CR x11 ; R x1 、R x2 、R x3 and R x4 are independently H, F or Cl; R x5 、R x6 and R x7 are independently H, F, Cl or -OCH3; R x8 、R x9 、R x10 and R x11 are independently H, F or Cl.

15. The compound according to claim 14, characterized in that The compound represented by formula (I-3) is selected from any of the following schemes: Option 1: The compound represented by formula (I-3) has the structural formula (I-3A): Option 2: The compound represented by formula (I-3) has the structural formula (I-3A2): Option 3: The compound represented by formula (I-3) has the structural formula (I-3A1):

16. The compound according to claim 1, characterized in that It is selected from any one of the following compounds or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

17. The compound according to claim 16, characterized in that It is selected from any one of the following compounds or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs: Preferably, the pharmaceutically acceptable salt comprises hydrochloride or formate.

18. A pharmaceutical composition, characterized in that It comprises the compound according to any one of claims 1 to 17 or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug; preferably, the pharmaceutical composition includes a pharmaceutically acceptable carrier or excipient.

19. Use of the compound according to any one of claims 1 to 17 or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition according to claim 18 in the preparation of a medicament for treating or preventing an infection and a disease caused by Acinetobacter baumannii or in the preparation of an anti-Acinetobacter baumannii medicament.

20. A method for treating or preventing infections and diseases caused by Acinetobacter baumannii using the compound according to any one of claims 1 to 17 or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition according to claim 18.

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