Cyclic peptide for resisting acinetobacter baumannii and application thereof

Abstract

The invention relates to an acinetobacter baumannii resistant cyclic peptide and application thereof, in particular to a compound shown in a formula (I), a tautomer, a stereoisomer, a hydrate, a solvate, pharmaceutically acceptable salt or prodrug of the compound and a preparation method of the tautomer, the stereoisomer, the hydrate, the solvate and the pharmaceutically acceptable salt or prodrug of the compound. The invention further discloses application of the acinetobacter baumannii in preparation of drugs for treating or preventing infection and diseases caused by the acinetobacter baumannii. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a class of cyclic peptides for resisting Acinetobacter baumannii and applications thereof, and specifically to a compound represented by formula (I), its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs and preparation methods thereof, as well as applications thereof in preparing drugs for treating or preventing infections and diseases caused by Acinetobacter baumannii. Background Art

[0002] Acinetobacter baumannii (scientific name: Acinetobacter baumannii, commonly known as: AB bacteria), belongs to Gram-negative bacteria, is a strictly aerobic, non-lactose fermenting conditional pathogen, does not have flagella, has low mobility, but has strong vitality, and can be widely found in nature. In addition, the bacteria has strong adhesion and is easy to adhere to various medical materials. It also exists in the skin (25%) and pharynx (7%) of healthy people, and also exists in conjunctiva, saliva, gastrointestinal tract and vaginal secretions; it has been identified as ESKAPE pathogens (Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter, Enterococcus faecalis, Staphylococcus aureus), which is a group of pathogens with high antibiotic resistance that cause most nosocomial infections.

[0003] The treatment of Acinetobacter baumannii infection has always been a big problem in clinical practice, because Acinetobacter baumannii is very easy to develop resistance to various disinfectants and antibacterial drugs, which poses a great threat to critically ill patients and patients in ICU wards. The widespread spread of CRAB (carbapenem-resistant Acinetobacter baumannii), MDR-AB (multidrug-resistant Acinetobacter baumannii), XDR-AB (pan-drug-resistant Acinetobacter baumannii), etc. has become a nightmare for doctors and patients. Therefore, it is very urgent to invent drugs to treat infections and diseases caused by Acinetobacter baumannii. Summary of the invention

[0004] In the first aspect of the present invention, the present invention provides a compound, which is a compound represented by formula (I), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug,

[0005]

[0006] in,

[0007] X 1 N or C (-L x1 -R x1 );

[0008] X 2 N or C (-L x2 -R x2 );

[0009] X3 N or C (-L x3 -R x3 );

[0010] X 4 N or C (-L x4 -R x4 );

[0011] X 5 N or C (-L x5 -R x5 );

[0012] X 6 N or C (-L x6 -R x6 );

[0013] X 7 N or C (-L x7 -R x7 );

[0014] X 8 N or C (-L x8 -R x8 );

[0015] R 1 -(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;

[0016] R 3 For -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 , -C0-10 Alkyl-NH-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 , the R 3 Further 0, 1, 2, 3 or 4 R b replace;

[0017] R 2 H, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 3-8 Cycloalkyl;

[0018] R 4 , R 6 and R 9 H, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-8 Cycloalkyl;

[0019] R 5 For -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-NH-C 1-10 Alkyl-NR51 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 , the R 5 Further 0, 1, 2, 3 or 4 R c replace;

[0020] R 5’ H or C 1-6 alkyl;

[0021] R 7 and R 8 H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-8 Cycloalkyl;

[0022] R 31 , R 32 , R 51 and R 52 are independently H or C 1-6 alkyl;

[0023] -L x1 -、-L x2 -、-L x3 -、-L x4 -、-L x5 -、-L x6 -、-L x7 -and-L x8 - are independently a single bond, -O-, -S-, -NH-, -C(=O)-, -S(=O)- or -S(=O)2-;

[0024] 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 with 0, 1, 2, 3 or 4 R dreplace;

[0025] R x5 , R x6 and R x7 are independently H, F, Cl, Br, OH, NH2, CN, C 1-6 Alkyl, or carboxylic acid and its bioisostere, the C 1-6 The alkyl group is optionally substituted with 0, 1, 2, 3 or 4 R d replace;

[0026] R x8 C 3-8 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 Aryl or 5-12 membered heteroaryl, the C 3-8 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 The aryl group and the 5-12 membered heteroaryl group are each independently optionally substituted by n R e replace;

[0027] Each R a are independently H, halogen, OH, NH2, CN, COOH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-8 Cycloalkyl;

[0028] Each R e are independently H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -SC 1-6 Alkyl or carboxylic acid and its bioisostere, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino and -SC 1-6 The alkyl group is optionally substituted with 1, 2, 3 or 4 R groups, each independently;

[0029] R is independently H, halogen, OH, NH2, CN, =O, =S, COOH or C 1-6 alkyl;

[0030] Each R b , R c and R d are independently F, Cl, Br, OH, NH2, CN, ═O, COOH or C 1-6 alkyl;

[0031] m is 1, 2, 3 or 4;

[0032] g is 1, 2, 3 or 4;

[0033] n is 1, 2, 3 or 4;

[0034] In addition, the R 3 and R 5 One of the following conditions is met:

[0035] a) When R 3 For unsubstituted -C 0-10 Alkyl-NR 31 R 32 , and R 5 For -C 0-10 Alkyl-NR 51 R 52 or -C 0-10 Alkyl-C(=O)NR 51 R 52 When the R5 is further replaced by 1, 2, 3 or 4 R c replace; or,

[0036] b) When R 3 For unsubstituted -C 0-10 Alkyl-NR 31 R 32 , and R 5 For -C 0-10 Alkyl-NR 51 R 52 -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-NH-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 When the R 5 Further 0, 1, 2, 3 or 4 R c Replacement; or, c) when R 3is -C substituted with 1, 2, 3 or 4 F 0-10 Alkyl-NR 31 R 32 , R 5 For unsubstituted -C 0-10 Alkyl-NR 51 R 52 When R x5 is not Cl; or, d) when R 5 For unsubstituted -C 0-10 Alkyl-NR 51 R 52 , and R 3 For -C 0-10 Alkyl-NR 31 R 32 When the R3 is further replaced by 1, 2, 3 or 4 R b replace; or,

[0037] e) When R 5 For unsubstituted -C 0-10 Alkyl-NR 51 R 52 , and R 3 For -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-NH-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 , the R 3 Further 0, 1, 2, 3 or 4 R b replace.

[0038] In an optional embodiment of the present invention, the compound represented by formula (I), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug,

[0039]

[0040] in,

[0041] X 1 N or C (-L x1 -R x1 );

[0042] X 2 N or C (-L x2 -R x2 );

[0043] X 3 N or C (-L x3 -R x3 );

[0044] X 4 N or C (-L x4 -R x4 );

[0045] X 5 N or C (-L x5 -R x5 );

[0046] X 6 N or C (-L x6 -R x6 );

[0047] X 7 N or C (-L x7 -R x7 );

[0048] X 8 N or C (-L x8 -R x8 );

[0049] R 1 -(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;

[0050] R 3 For -C 1-10Alkyl, -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-NH-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 , the R 3 Further 0, 1, 2, 3 or 4 R b replace;

[0051] R 2 , R 4 , R 6 and R 9 H, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-8 Cycloalkyl;

[0052] R 5 For -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-NR51 R 52 , -C 0-10 Alkyl-SC 1-10 Alkyl-NR 51 R 52 , -C 0-10 Alkyl-NH-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 , the R 5 Further 0, 1, 2, 3 or 4 R c replace;

[0053] R 5’ H or C 1-6 alkyl;

[0054] R 7 and R 8 H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-8 Cycloalkyl;

[0055] R 31 , R 32 , R 51 and R 52 are independently H or C 1-6 alkyl;

[0056] -L x1 -、-L x2 -、-L x3 -、-L x4 -、-L x5 -、-L x6 -、-L x7 -and-L x8 - are independently a single bond, -O-, -S-, -NH-, -C(=O)-, -S(=O)- or -S(=O)2-;

[0057] R x1 , R x2 , R x3 and R x4 are independently H, F, Cl, Br, OH, NH2, CN, COOH or C1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted with 0, 1, 2, 3 or 4 R d replace;

[0058] R x5 , R x6 and R x7 are independently H, F, Cl, Br, OH, NH2, CN, C 1-6 Alkyl, or carboxylic acid and its bioisostere, the C 1-6 The alkyl group is optionally substituted with 0, 1, 2, 3 or 4 R d replace;

[0059] R x8 C 3-8 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 Aryl or 5-12 membered heteroaryl, the C 3-8 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 The aryl group and the 5-12 membered heteroaryl group are each independently optionally substituted by n R e replace;

[0060] Each R a are independently H, halogen, OH, NH2, CN, COOH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-8 Cycloalkyl;

[0061] Each R e are independently H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -SC 1-6 Alkyl or carboxylic acid and its bioisostere, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino and -SC 1-6 The alkyl group is optionally substituted with 1, 2, 3 or 4 R groups, each independently;

[0062] R is independently H, halogen, OH, NH2, CN, =O, =S, COOH or C 1-6 alkyl;

[0063] Each R b , R c and R d are independently F, Cl, Br, OH, NH2, CN, COOH or C 1-6 alkyl;

[0064] m is 1, 2, 3 or 4;

[0065] g is 1, 2, 3 or 4;

[0066] n is 1, 2, 3 or 4;

[0067] In addition, the R 3 and R 5 One of the following conditions is met:

[0068] a) When R 3 For unsubstituted -C 0-10 Alkyl-NR 31 R 32 , and R 5 For -C 0-10 Alkyl-NR 51 R 52 or -C 0-10 Alkyl-C(=O)NR 51 R 52 When the R5 is further replaced by 1, 2, 3 or 4 R c replace; or,

[0069] b) When R 3 For unsubstituted -C 0-10 Alkyl-NR 31 R 32 , and R 5 For -C 0-10 Alkyl-NR 51 R 52 -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-NH-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 When the R 5Further 0, 1, 2, 3 or 4 R c replace; or,

[0070] c) When R 3 is -C substituted with 1, 2, 3 or 4 F 0-10 Alkyl-NR 31 R 32 , R 5 For unsubstituted -C 0-10 Alkyl-NR 51 R 52 When R x5 Not Cl; or

[0071] d) When R 5 For unsubstituted -C 0-10 Alkyl-NR 51 R 52 , and R 3 For -C 0-10 Alkyl-NR 31 R 32 When the R3 is further replaced by 1, 2, 3 or 4 R b replace; or,

[0072] e) When R 5 For unsubstituted -C 0-10 Alkyl-NR 51 R 52 , and R 3 For -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-NH-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-NR31 R 32 , the R 3 Further 0, 1, 2, 3 or 4 R b replace.

[0073] According to an embodiment of the present invention, the above compound may further include at least one of the following technical features:

[0074] In an optional embodiment of the present invention, the C 6-12 Aryl is independently phenyl or naphthyl, for example phenyl.

[0075] In an optional embodiment of the present invention, the heteroatom types of the 5-12 membered heteroaryl group are each independently selected from one or two of N, O and S, and the number of heteroatoms is each independently 1, 2, 3 or 4; preferably, the heteroatom types are each independently selected from one or two of N and O, and the number of heteroatoms is each independently 1 or 2.

[0076] In an optional embodiment of the present invention, the 5-12 membered heteroaryl group is independently a monocyclic or polycyclic ring, the polycyclic ring may be a cyclic ring; the polycyclic ring may be a bicyclic ring or a tricyclic ring; preferably, the 5-12 membered heteroaryl group is independently a 5-7 membered monocyclic heteroaryl group or a 9-10 membered bicyclic heteroaryl group, preferably an indolyl group (e.g. ).

[0077] In an optional embodiment of the present invention, the heteroatom types of the 3-12 membered heterocycloalkyl are each independently selected from one or two of N, O and S, and the number of heteroatoms is each independently 1, 2 or 3; preferably, the heteroatom types are each independently selected from one or two of N and O, and the number of heteroatoms is each independently 1 or 2.

[0078] In an optional embodiment of the present invention, the 3-12 membered heterocycloalkyl group may be independently monocyclic or polycyclic, the polycyclic group may be bridged, fused or spirocyclic, and the polycyclic group may be bicyclic or tricyclic; preferably, the 3-12 membered heterocycloalkyl group may be independently 4-7 membered monocyclic heterocycloalkyl group, 8-10 membered bicyclic heterocycloalkyl group or 10-12 membered tricyclic heterocycloalkyl group; preferably, oxetane (e.g. ).

[0079] In an optional embodiment of the present invention, the C 1-10 The alkyl groups are independently C 1-6 Alkyl, preferably C 1-3 Alkyl, for example methyl, ethyl, n-propyl or isopropyl, for example methyl.

[0080] In an optional embodiment of the present invention, the C 0-10 The alkyl groups are independently C 0-6Alkyl, preferably C 0-3 Alkyl, such as a single bond, methyl, ethyl, n-propyl or isopropyl, such as methyl; when C 0-10 When the number of carbon atoms in the alkyl group is 0, it represents a single bond.

[0081] In an optional embodiment of the present invention, the C 3-8 The cycloalkyl groups are independently C 3-6 Cycloalkyl, such as cyclopropyl (e.g. ), cyclobutyl (e.g. ), cyclopentyl or cyclohexyl.

[0082] In an optional embodiment of the present invention, the C 1-6 The deuterated alkyl groups are independently C 1-3 Deuterated alkyl, such as -CD3.

[0083] In an optional embodiment of the present invention, the C 1-6 The haloalkyl is independently C 1-3 Haloalkyl, for example -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl or -CH2CH2CF3.

[0084] In an optional embodiment of the present invention, the C 1-6 The alkyl groups are independently C 1-3 Alkyl, for example methyl, ethyl, n-propyl or isopropyl, for example methyl or ethyl.

[0085] In an optional embodiment of the present invention, the carboxylic acid and its bioisostere are independently -C(=O)-R e1 、-S(=O)2-R e1 or a 5-6 membered heteroaryl group, each R e1 are independently H, OH, -CH3 or -NH-C(=O)-CH3; the carboxylic acid and its bioisostere are independently preferably -COOH, -S(=O)2-OH, -S(=O)2-NH-C(=O)-CH3 or

[0086] In an optional embodiment of the present invention, the halogen is independently selected from fluorine, chlorine, bromine or iodine.

[0087] In an optional embodiment of the present invention, the C 1-6 The alkoxy groups are independently C 1-3 Alkoxy, for example methoxy, ethoxy, n-propoxy or isopropoxy, for example methoxy or ethoxy.

[0088] In an optional embodiment of the present invention, the C 1-6 The alkylamino groups are independently C 1-3Alkylamino, for example -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3 or -NHCH(CH3)2.

[0089] In an optional embodiment of the present invention, each R a are independently H or CH3.

[0090] In an optional embodiment of the present invention, R 1 -(CH2) m -5-10 membered heteroaryl, the 5-10 membered heteroaryl is optionally substituted by g R a replace.

[0091] In an optional embodiment of the present invention, R1 is -(CH2) m -benzo 5-membered heteroaryl, the benzo 5-membered heteroaryl is optionally substituted by g R a replace.

[0092] In an optional embodiment of the present invention, R 1 -(CH2) m -5,6-diphenylamine heteroaryl, wherein the 5,6-diphenylamine heteroaryl is optionally substituted by g R a replace.

[0093] In an optional embodiment of the present invention, R 1 -(CH2) m -pyrrolophenyl, the pyrrolophenyl optionally substituted by g R a replace.

[0094] In an optional embodiment of the present invention, g is 1, 2, 3 or 4.

[0095] In an optional embodiment of the present invention, m is 1, 2, 3 or 4.

[0096] In an optional embodiment of the present invention, R 1 for

[0097] In an optional embodiment of the present invention, R 1 for

[0098] In an optional embodiment of the present invention, each R b , R c and R d are independently F or Cl.

[0099] In an optional embodiment of the present invention, R 31 and R 32 are each independently H.

[0100] In an optional embodiment of the present invention, R 3 For -C 1-6 Alkyl-NR 31 R 32 , -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-NH-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 , the R 3 Further 0, 1, 2, 3 or 4 R b replace.

[0101] In an optional embodiment of the present invention, R 3 For -C 2-5 Alkyl-NH2, -C 0-3 Alkyl-C 3-6 Cycloalkyl-C 0-3 Alkyl -NH2 or -C 0-3 Alkyl-3-8 membered heterocycloalkyl-C 0-3 Alkyl-NH2, the R 3 Further 0, 1, 2, 3 or 4 R b replace.

[0102] In an optional embodiment of the present invention, R 3 For -C 2-5 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, the R 3 Further 0, 1, 2, 3 or 4 R b replace.

[0103] In an optional embodiment of the present invention, R 3 For -C 2-5 Alkyl -NH2 or -C 0-3 Alkyl-C 3-6 Cycloalkyl-C 0-3 Alkyl-NH2, the R 3 Further 0, 1, 2, 3 or 4 R b replace.

[0104] In an optional embodiment of the present invention, R 3 for The R 3 Further 0, 1, 2, 3 or 4 R b replace.

[0105] In an optional embodiment of the present invention, R 3 for The R 3 Further 0, 1, 2, 3 or 4 R b replace.

[0106] In an optional embodiment of the present invention, R 3 for

[0107] In an optional embodiment of the present invention, R 3 for

[0108] In an optional embodiment of the present invention, R 51 and R 52 are each independently H.

[0109] In an optional embodiment of the present invention, R 5 For -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 51R 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-NH-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 , the R 5 Further 0, 1, 2, 3 or 4 R c replace.

[0110] In an optional embodiment of the present invention, R 5 For -C 2-5 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, the R 5 Further 0, 1, 2, 3 or 4 R c replace.

[0111] In an optional embodiment of the present invention, R 5 for The R 5 Further 0, 1, 2, 3 or 4 R c replace.

[0112] In an optional embodiment of the present invention, R 5 for

[0113] In an optional embodiment of the present invention, when R 3 for R 5 for When R x5 Not Cl.

[0114] In an optional embodiment of the present invention, when R 3 for When R 5 for

[0115] In an optional embodiment of the present invention, each R e are independently H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -SC 1-6 Alkyl, -C(=O)-R e1 、-C(=O)NH-R e1 、-N(R e1 )C(=O)-R e1 、-ON(R e1 )C(=O)-R e1 、-S(=O)-R e1 、-S(=O)2-R e1 、-NH-S(=O)2-R e1 、-C(=O)-NH-S(=O)2-R e1 、-NH-C(=O)-NH-S(=O)2-R e1 、-NH-C(=O)-NH-C(=O)-R e1 、-P(=O)(-R e1 2. C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl, C 6-12 Aryl or 5-12 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -SC 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 membered heteroaryl are each independently optionally substituted by 1, 2, 3 or 4 R;

[0116] Each R e1 are independently H, OH, NH2, ONa, OK (potassium ion), C 1-6 Alkyl, C 1-6 Alkoxy, -NH-C 1-6 Alkyl, -N(-C 1-6 Alkyl)2, -NH-C(=O)C 1-6 alkyl, C6-12 aryl or 5-12 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, -NH-C1-6 Alkyl, -N(-C 1-6 Alkyl)2, -NH-C(=O)C 1-6 Alkyl, C6-12 aryl and 5-12 membered heteroaryl are each independently optionally substituted by 1, 2, 3 or 4 R;

[0117] R is independently H, halogen, OH, NH2, CN, =O, =S, COOH or C 1-6 alkyl.

[0118] In an optional embodiment of the present invention, each R is independently H, F, Cl, OH, NH2, CN, =O, =S or -CH3.

[0119] In an optional embodiment of the present invention, each R e1 are independently H, OH, -C 1-3 Alkyl, -NH-C 1-3 Alkyl or -NH-C(=O)C 1-3 alkyl.

[0120] In an optional embodiment of the present invention, each R e1 Each is independently H, OH, -CH3 or -NH-C(=O)-CH3.

[0121] In an optional embodiment of the present invention, each R e are independently H, halogen, OH, NH2, CN, -C(=O)-R e1 、-S(=O)-R e1 、-S(=O)2-R e1 , C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, -SC 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl or 5-6 membered heteroaryl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, -SC 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl and 5-6 membered heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 R groups.

[0122] In an optional embodiment of the present invention, each R e are independently H, F, Cl, Br, OH, COOH, -S(=O)2-OH, -S(=O)2-NH-C(=O)-CH3 or

[0123] In an optional embodiment of the present invention, R x8 C 6-10 Aryl or 5-6 membered heteroaryl, the C 6-10 The aryl group and the 5-6 membered heteroaryl group are each independently optionally substituted by n R e replace.

[0124] In an optional embodiment of the present invention, R x8 is a phenyl group, the phenyl group is optionally substituted by n R e replace.

[0125] In an optional embodiment of the present invention, n is 1, 2, 3 or 4.

[0126] In an optional embodiment of the present invention, R x8 for

[0127] In an optional embodiment of the present invention, R 2 , R 4 , R 6 and R 9 H, C 1-3 Alkyl and C 1-3 Halogenated alkyl.

[0128] In an optional embodiment of the present invention, R 2 H, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 Deuterated alkyl.

[0129] In an optional embodiment of the present invention, R 2 It is CH3 or CD3.

[0130] In an optional embodiment of the present invention, R 2 For CH3.

[0131] In an optional embodiment of the present invention, R 4 , R 6 and R 9 H, C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0132] In an optional embodiment of the present invention, R 4 , R 6 and R 9 are each independently H.

[0133] In an optional embodiment of the present invention, R 5’For H.

[0134] In an optional embodiment of the present invention, R 7 and R 8 H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 3-6 Cycloalkyl.

[0135] In an optional embodiment of the present invention, R 7 and R 8 are each independently H.

[0136] In an optional embodiment of the present invention, R x1 , R x2 , R x3 , R x4 , R x5 , R x6 and R x7 are each independently H, F or Cl.

[0137] In an optional embodiment of the present invention, R 3 and R 5 At least one of them is -C 0-10 Alkyl-C 0-3 Halogenated alkyl-C 0-10 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 .

[0138] In an optional embodiment of the present invention, the compound represented by formula (I) has the structural formula (I-1) or (I-2):

[0139]

[0140] in,

[0141] Q and Q1 are independently -C(=O)-, -O-, -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-, wherein -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl- are each independently optionally substituted by 1 or 2 halogens;

[0142] h, h', r and r' are independently 0, 1, 2, 3, 4, 5, or 6;

[0143] X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , R 1 , R 2 , R 4 , R 5’ , R 6 , R 7 , R 8 and R 9 As defined in the present invention.

[0144] In an optional embodiment of the present invention, the compound represented by formula (I) has the structural formula (I-1) or (I-2):

[0145]

[0146] in,

[0147] Q and Q1 are independently -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-;

[0148] h, h', r and r' are independently 0, 1, 2, 3, 4, 5, or 6;

[0149] X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , R 1 , R 2 , R 4 , R 5’ , R 6 , R 7 , R 8 and R 9 As defined in the present invention. In an optional embodiment of the present invention, the compound represented by formula (I) has the structural formula (I-5):

[0150]

[0151] in,

[0152] Q and Q1 are independently -C(=O)-, -O-, -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-, wherein -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl- are each independently optionally substituted by 1 or 2 halogens;

[0153] Preferably, Q and Q1 are independently -C(=O)-, -O-, -CR b R b -, -cyclopropyl-, -cyclobutyl-, -oxetanyl-, or -azetidinyl;

[0154] Further preferably, Q and Q1 are independently -C(=O)-, -O-, -CH2-, -CF2-,

[0155] h, h', r and r' are independently 0, 1, 2, 3, 4, 5, or 6;

[0156] R b is H, F, Cl or Br;

[0157] R ex is H, F, Cl, Br or OH;

[0158] R e -C(=O)-R e1 、-S(=O)-R e1 、-S(=O)2-R e1 , 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, wherein the 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl and 5-6 membered heteroaryl are each independently optionally substituted by 1, 2, 3 or 4 R;

[0159] Preferably, R e H, F, Cl, Br, OH, COOH, -S(=O)2-OH, -S(=O)2-NH-C(=O)-CH3 or

[0160] g、X 1 , X 4 , R a , R, R e1 , R 2 , R 4 , R x5 , R x6 and R x7 As defined in the present invention.

[0161] In an optional embodiment of the present invention, the compound represented by formula (I) has the structural formula (I-4):

[0162]

[0163] in,

[0164] Q and Q1 are independently -C(=O)-, -O-, -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-, wherein -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl- are each independently optionally substituted by 1 or 2 halogens;

[0165] Preferably, Q and Q1 are independently -C(=O)-, -O-, -CR b R b -, -cyclopropyl-, -cyclobutyl-, -oxetanyl-, or -azetidinyl;

[0166] Further preferably, Q and Q1 are independently -C(=O)-, -O-, -CH2-, -CF2-,

[0167] h, h', r and r' are independently 0, 1, 2, 3, 4, 5, or 6;

[0168] R b is H, F, Cl or Br;

[0169] R ex is H, F, Cl, Br or OH;

[0170] R e -C(=O)-R e1 、-S(=O)-R e1 、-S(=O)2-R e1 , 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, wherein the 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl and 5-6 membered heteroaryl are each independently optionally substituted by 1, 2, 3 or 4 R;

[0171] Preferably, R e H, F, Cl, Br, OH, COOH, -S(=O)2-OH, -S(=O)2-NH-C(=O)-CH3 or

[0172] g、X 1 , X 4 , R a , R, R e1 , R 4 , R x5 , R x6 and Rx7 As defined in the present invention.

[0173] In an optional embodiment of the present invention, Q and Q1 are independently -C(=O)-, -O-, -CR b R b -, -cyclopropyl-, -cyclobutyl-, -oxetanyl- or -azetidinyl, wherein R b is H, F, Cl or Br.

[0174] In an optional embodiment of the present invention, Q and Q1 are independently -C(=O)-, -O-, -CH2-, -CF2-,

[0175] In an optional embodiment of the present invention, R e H, F, Cl, Br, OH, COOH, -S(=O)2-OH, -S(=O)2-NH-C(=O)-CH3 or

[0176] In an optional embodiment of the present invention, the compound represented by formula (I) has the structural formula (I-1A) or (I-2A):

[0177]

[0178] in,

[0179] Q and Q1 are independently -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-;

[0180] h, h', r and r' are independently 0, 1, 2, 3, 4, 5, or 6;

[0181] m, g, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , R a , R 2 , R 4 , R 5’ , R 6 , R 7 , R 8 and R 9 As defined in the present invention.

[0182] In an optional embodiment of the present invention, the compound represented by formula (I) has the structural formula (I-1A1) or (I-2A1):

[0183]

[0184] in,

[0185] Q and Q1 are independently -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-;

[0186] h, h', r and r' are independently 0, 1, 2, 3, 4, 5, or 6;

[0187] m, g, n, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , R a , R e , R 2 , R 4 , R 5’ , R 6 , R 7 , R 8 and R 9 As defined in the present invention.

[0188] In an optional embodiment of the present invention, X 1 , X 2 , X 3 C, X 4 is N.

[0189] In an optional embodiment of the present invention, X 5 , X 6 , X 7 For C.

[0190] In an optional embodiment of the present invention, the compound represented by formula (I) has the structural formula (I-3):

[0191]

[0192] in,

[0193] Q and Q1 are independently -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-;

[0194] h, h', r and r' are independently 0, 1, 2, 3, 4, 5, or 6;

[0195] g、X 1 , X 4 , R a , R e , R 2 , R x5 , R x6 and R x7 As defined in the present invention.

[0196] In an optional embodiment of the present invention, the compound represented by formula (I) has the structural formula (I-4):

[0197]

[0198] in,

[0199] Q and Q1 are independently -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-;

[0200] h, h', r and r' are independently 0, 1, 2, 3, 4, 5, or 6;

[0201] R ex is H, F, Cl, Br or OH;

[0202] R e -C(=O)-R e1 、-S(=O)-R e1 、-S(=O)2-R e1 , 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, wherein the 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl and 5-6 membered heteroaryl are each independently optionally substituted by 1, 2, 3 or 4 R;

[0203] g、X 1 , X 4 , R a , R, R e1 , R x5 , R x6 and R x7 As defined in the present invention.

[0204] In an optional embodiment of the present invention, the compound represented by formula (I) has the structural formula (I-3A):

[0205]

[0206] in,

[0207] Q and Q1 are independently -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-;

[0208] h, h', r and r' are independently 0, 1, 2, 3, 4, 5, or 6;

[0209] g、X 1 , X 4 , R a , R e , R x5 , R x6 and R x7 As defined in the present invention.

[0210] In an optional embodiment of the present invention, the compound represented by formula (I) has the structural formula (I-5A):

[0211]

[0212] in,

[0213] Q and Q1 are independently -C(=O)-, -O-, -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-, wherein -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl- are each independently optionally substituted by 1 or 2 halogens;

[0214] h, h', r and r' are independently 0, 1, 2, 3, 4, 5, or 6;

[0215] R ex is H, F, Cl, Br or OH;

[0216] R e -C(=O)-R e1 、-S(=O)-R e1 、-S(=O)2-R e1 , 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, wherein the 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl and 5-6 membered heteroaryl are each independently optionally substituted by 1, 2, 3 or 4 R;

[0217] g、X 1 , X 4 , R a , R, R e1 , R 2 , R x5 , R x6 and R x7 As defined in the present invention.

[0218] In an optional embodiment of the present invention, the compound represented by formula (I) has the structural formula (I-4A):

[0219]

[0220] in,

[0221] Q and Q1 are independently -C(=O)-, -O-, -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-, wherein -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl- are each independently optionally substituted by 1 or 2 halogens;

[0222] h, h', r and r' are independently 0, 1, 2, 3, 4, 5, or 6;

[0223] R ex is H, F, Cl, Br or OH;

[0224] R e -C(=O)-R e1 、-S(=O)-R e1 、-S(=O)2-R e1 , 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, wherein the 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl and 5-6 membered heteroaryl are each independently optionally substituted by 1, 2, 3 or 4 R;

[0225] g、X 1 , X 4 , R a , R, R e1 , R x5 , R x6 and R x7 As defined in the present invention.

[0226] In an optional embodiment of the present invention, the compound represented by formula (I) has the structural formula (I-4A):

[0227]

[0228] in,

[0229] Q and Q1 are independently -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-;

[0230] h, h', r and r' are independently 0, 1, 2, 3, 4, 5, or 6;

[0231] R ex is H, F, Cl, Br or OH;

[0232] R e -C(=O)-R e1、-S(=O)-R e1 、-S(=O)2-R e1 , 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, wherein the 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl and 5-6 membered heteroaryl are each independently optionally substituted by 1, 2, 3 or 4 R;

[0233] g、X 1 , X 4 , R a , R, R e1 , R 2 , R x5 , R x6 and R x7 As defined in the present invention.

[0234] In an optional embodiment of the present invention, X 1 C, X 4 is N.

[0235] In an optional embodiment of the present invention, R x5 , R x6 and R x7 For H.

[0236] In an optional embodiment of the present invention, R a For H.

[0237] In an optional embodiment of the present invention, R ex It is H or F.

[0238] In an optional embodiment of the present invention, R e It is COOH, -S(=O)2-OH, -S(=O)2-NH-C(=O)-CH3, imidazole, triazole or tetrazole.

[0239] In an optional embodiment of the present invention, the compound represented by formula (I) has the structural formula (I-5B):

[0240]

[0241] in,

[0242] Q and Q1 are independently -C(=O)-, -O-, -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-, wherein -CH2- is optionally substituted by 1 or 2 halogens; at least one of Q and Q1 is -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-;

[0243] h, h', r and r' are independently 0, 1, 2, 3, 4, 5, or 6;

[0244] R ex is H, F, Cl, Br or OH;

[0245] R e -C(=O)-R e1 、-S(=O)-R e1 、-S(=O)2-R e1 , 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl or 5-6 membered heteroaryl;

[0246] R e1 Each independently represents H, OH, -CH3 or -NH-C(=O)-CH3;

[0247] g、X 1 , X 4 , R a , R 2 , R x5 , R x6 and R x7 As defined in the present invention;

[0248] Preferably, at least one of Q and Q1 is

[0249] In an optional embodiment of the present invention, the compound represented by formula (I) has the structural formula (I-5C):

[0250]

[0251] in,

[0252] Q1 is -C(=O)-, -O-, -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-, wherein the -CH2- is optionally substituted by 1 or 2 halogens;

[0253] Q is -C 3-6 Cycloalkyl, preferably

[0254] h, h', r and r' are independently 0, 1, 2, 3, 4, 5, or 6;

[0255] R ex is H, F, Cl, Br or OH;

[0256] R e -C(=O)-R e1 、-S(=O)-R e1 、-S(=O)2-R e1 , 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl or 5-6 membered heteroaryl;

[0257] Re1 Each independently represents H, OH, -CH3 or -NH-C(=O)-CH3;

[0258] g、X 1 , X 4 , R a , R 2 , R x5 , R x6 and R x7 As defined in the present invention.

[0259] In an optional embodiment of the present invention, the compound represented by formula (I) has the structural formula (I-5D):

[0260]

[0261] in,

[0262] Q1 is -C(=O)-, -O-, -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-, wherein the -CH2- is optionally substituted by 1 or 2 halogens; preferably -CH2-;

[0263] Q is -C 3-6 Cycloalkyl, preferably

[0264] h, h', r and r' are independently 0, 1, 2, 3 or 4;

[0265] R ex is H, F, Cl, Br or OH;

[0266] R e -COOH, -S(=O)2-OH, -S(=O)2-NH-C(=O)-CH3 or Preferably -COOH;

[0267] g is 1, 2, or 3;

[0268] X 1 for CH;

[0269] X 4 is CH or N;

[0270] R a are independently H, halogen or C 1-3 alkyl;

[0271] R 2 H, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 Deuterated alkyl;

[0272] R x5 , R x6 and R x7 are independently H, F or Cl.

[0273] In an optional embodiment of the present invention, the compound is selected from any of the following compounds or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

[0274]

[0275]

[0276]

[0277] In an optional embodiment of the present invention, the compound is selected from any of the following compounds or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

[0278]

[0279]

[0280]

[0281]

[0282] In an optional embodiment of the present invention, the pharmaceutically acceptable salt is hydrochloride.

[0283] In a second aspect of the present invention, a pharmaceutical composition is provided, characterized in that it comprises the above-mentioned compound or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug.

[0284] In an optional embodiment of the present invention, the above-mentioned pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

[0285] The second aspect of the present invention is the use of the compound described in the first aspect of the present invention 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.

[0286] The second aspect of the present invention is a method for treating or preventing infections and diseases caused by Acinetobacter baumannii using the compound described in the first aspect of the present invention or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition described in the second aspect of the present invention.

[0287] Terms and Definitions

[0288] Unless otherwise specified, the terms and definitions used in this application, including the specification and claims, are as follows.

[0289] Those skilled in the art will appreciate that, according to the conventions used in the art, in the structural formula of the present application, Used to depict chemical bonds, which are the points at which a moiety or substituent is attached to a core or backbone structure.

[0290] Unless otherwise specified, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, 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.

[0291] Unless otherwise specified, the term "pharmaceutically acceptable salt" refers to salts of pharmaceutically acceptable non-toxic acids or bases including salts of inorganic acids and bases, and organic acids and bases.

[0292] In addition to pharmaceutically acceptable salts, other salts are contemplated by the present invention. These may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or may be useful in the identification, characterization or purification of the compounds of the present invention.

[0293] 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 the administration of a compound to an organism.

[0294] 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 can enhance the handling characteristics of a pharmaceutical formulation, i.e., make the formulation more suitable for direct compression by increasing fluidity and / or adhesion.

[0295] Unless otherwise specified, the term "prodrug" refers to a compound of the present invention that can be converted into a biologically active compound under physiological conditions or by solvolysis. The prodrug of the present invention is prepared by modifying the functional groups in the compound, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. The prodrug includes a compound formed by connecting a hydroxyl or amino group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group and a free amino group, respectively.

[0296] Unless otherwise specified, the term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, and includes cis-trans isomers, enantiomers, diastereomers and conformational isomers.

[0297] 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 a pure optical isomer, or as a mixture of isomers, such as a racemic and diastereomeric mixture, depending on the number of asymmetric carbon atoms. When describing optically active compounds, prefixes D and L or R and S are used to represent 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 symbols for the rotation of plane polarized light caused by the specified compound, where (–) or L indicates that the compound is left-handed. Compounds prefixed with (+) or D are right-handed. For 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 generally referred to as mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. Many geometric isomers of olefins, C=N double bonds, etc. may also exist in the compounds described herein, and all such stable isomers are contemplated in 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 the cis- or trans- configuration.

[0298] When the bonds to the chiral carbon in the formula of the present invention are depicted as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and the enantiomerically pure compounds and mixtures thereof produced therefrom are included within the scope of the general formula. The graphic representation of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, the absolute configuration of a stereocenter is indicated by a wedge-shaped bond and a dashed bond.

[0299] 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. Exemplary methods include fractional recrystallization using a chiral resolution 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 diastereomeric 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, the selection of chromatographic columns can be selected by those skilled in the art according to the structure of the compound and the test results. Further, optically pure starting materials or reagents of known configurations can also be used to obtain any enantiomer or diastereomer of the compounds described in the present invention through stereo organic synthesis.

[0300] Unless otherwise specified, the term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom in a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in 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 separate 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 characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form is predominant; while in phenols, the enol form is predominant. The present invention includes all tautomeric forms of the compounds.

[0301] Unless otherwise specified, the key is a solid wedge-shaped key ( ) and dotted wedge bonds ( ) represents the absolute configuration of a stereocenter, and

[0302] Straight solid line key ( ) and straight dashed bonds ( ) indicates the relative configuration of the stereocenter.

[0303] The compounds of the present invention may contain non-natural ratios of atomic isotopes on one or more of the atoms constituting the compounds. For example, radioactive isotope labeled compounds may be used, such as deuterium (2H), tritium (3H), iodine-125 (125I) or C-14 (14C). All isotopic changes of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0304] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. For oral dosage forms of the present invention, an "effective amount" of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0305] 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.

[0306] 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., =O), it means that two hydrogen atoms are replaced. Keto substitution does not occur on aromatic groups.

[0307] 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.

[0308] The term "optionally substituted" means that the group may be substituted or unsubstituted, and unless otherwise specified, the type and number of the substituents may be any on the basis of what is chemically feasible.

[0309] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition in each case 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 case of R has an independent option. In addition, combinations of substituents and / or their variants are permitted only if such combinations result in stable compounds. In addition, when multiple rings (paracyclic, spirocyclic, or bridged rings) are substituted with substituents, it means that each hydrogen atom on the ring may be substituted, for example Represents Ra It can replace hydrogen on the pyrrole ring or on the benzene ring.

[0310] Unless otherwise specified, the term “C 1-6 "Alkyl" is used to refer to 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). Examples of C1-6 alkyl 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, etc.

[0311] Unless otherwise specified, the term “C 1-3 "Alkyl" is used to refer to 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 may 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.

[0312] The term "halo" by itself or as part of another substituent is used interchangeably with the term "halogen-substituted."

[0313] Unless otherwise specified, "haloalkyl" or "halogen-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.

[0314] Unless otherwise specified, the term “C 1-6 "Alkoxy" refers to those alkyl groups containing 1 to 6 carbon atoms which are attached to the rest of the molecule via an oxygen atom. 1-6 Alkoxy includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6, C5, C4 and C3 alkoxy, etc. 1-6Examples 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.

[0315] 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. 1-3 Alkoxy includes 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.

[0316] Unless otherwise specified, the term “C 1-6 "Alkylamino" refers to those alkyl groups containing 1 to 6 carbon atoms which are linked to the rest of the molecule via a hydrogen atom. 1-6 Alkylamino groups include C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6, C5, C4 and C3 alkylamino, etc. 1-6 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH(CH3) 2、 -NHCH2CH(CH3)2, etc.

[0317] Unless otherwise specified, the term “C 1-3 "Alkylamino" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule through an amino group. 1-3 Alkylamino groups include C 1-2 , C3 and C2 alkylamino, etc. 1-3 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, and the like.

[0318] 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 includes 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.

[0319] 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 includes 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.

[0320] 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 system. 3-6 Cycloalkyl includes C 3-5 , C 4-5 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-6 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0321] Unless otherwise specified, Cn-n+m or Cn-Cn+m includes any specific case of n to n+m carbons, for example, C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 , 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 Etc.; similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and also includes any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 6-7-membered ring, 6-8-membered ring, and 6-10-membered ring, etc.

[0322] 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 may be 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, paracyclic and bridged rings. In addition, with respect to the "3-12 membered heterocycloalkyl", heteroatoms may occupy the position where the heterocycloalkyl is connected to the rest of the molecule. For example, 3-12 membered heterocycloalkyl includes, but is not limited to, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 3-10, 3-8, 4-6, 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.

[0323] Unless otherwise specified, the term "3-8 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 6 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 may be 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 "3-8 membered heterocycloalkyl", heteroatoms may occupy the position where the heterocycloalkyl is connected to the rest of the molecule. For example, 3-8 membered heterocycloalkyl includes, but is not limited to, 3, 4, 5, 6, 7, and 8 members. Examples of 3-8 membered heterocycloalkyl groups 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.

[0324] Unless otherwise specified, the terms "5-12 membered heteroaromatic ring" and "5-12 membered heteroaryl" of the present invention can be used interchangeably, and the term "5-12 membered heteroaryl" means a cyclic group with a conjugated π electron system consisting of 5 to 12 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. It can be a monocyclic, fused bicyclic or fused tricyclic system, wherein each ring is aromatic. Wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). The 5-12 membered heteroaryl can be connected to the rest of the molecule via a heteroatom or a 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, etc. Examples of the 5-12 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), 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) oxazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-1pyridyl, 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.).

[0325] Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" of the present invention can be used interchangeably, and the term "5-6 membered heteroaryl" means 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 rest are carbon atoms. Wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). The 5-6 membered heteroaryl can be connected to the rest of the molecule through a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), 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.), furanyl (including 2-furanyl and 3-furanyl, 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.).

[0326] Unless otherwise specified, the term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0327] Unless otherwise specified, the term "carboxylic acid and its bioisostere" refers to carboxylic acid (-COOH), and a group or substituent with similar physical and chemical properties in a biological sense to carboxylic acid (-COOH), and a substance having substantially similar or related biological activity. In some embodiments, "carboxylic acid and its bioisostere" are selected from the carboxylic acid bioisosteres and derivatives described in P. Lassalas et al., J. Med. Chem. 2016, 59, 3183-3203 (DOI: 10.1021 / acs.jmedchem.5b01963). In some embodiments, "carboxylic acid and its bioisostere" include but are not limited to -C(=O)-R e1 、-C(=O)NH-R e1 、-N(R e1 )C(=O)-R e1 、-ON(R e1 )C(=O)-R e1 、-S(=O)-Re1 、-S(=O)2-R e1 、-NH-S(=O)2-R e1 、-C(=O)-NH-S(=O)2-R e1 、-NH-C(=O)-NH-S(=O)2-R e1 、-NH-C(=O)-NH-C(=O)-R e1 、-P(=O)(-R e1 2. C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl, C 6-12 Aryl or 5-12 membered heteroaryl, the C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl, C 6-12 The aryl group and the 5-12 membered heteroaryl group are each independently optionally substituted by 1, 2, 3 or 4 R; wherein each R e1 are independently H, -OH, NH2, -ONa, -OK (potassium ion), C 1-6 Alkyl, C 1-6 Alkoxy, -NH-C 1-6 Alkyl, -N(-C 1-6 Alkyl)2, -NH-C(=O)C 1-6 Alkyl, C 6-12 Aryl or 5-12 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, -NH-C 1-6 Alkyl, -N(-C 1-6 Alkyl)2, -NH-C(=O)C 1-6 Alkyl, C 6-12 The aryl and 5-12 membered heteroaryl are each independently optionally substituted by 1, 2, 3 or 4 R; wherein each R is independently H, halogen, OH, NH2, CN, =O, =S, COOH or C 1-6 The carboxylic acid and its bioisostere are independently preferably -COOH, -S(=O)2-OH, -S(=O)2-NH-C(=O)-CH3 or

[0328] In addition, it should be noted that, unless otherwise clearly indicated, the description method "...independently" used in the present invention should be understood in a broad sense, meaning that the individuals described are independent of each other and can be independently the same or different specific groups. In more detail, the description method "...independently" can mean that in different groups, the specific options expressed by the same symbols do not affect each other, and can also mean that in the same group, the specific options expressed by the same symbols do not affect each other.

[0329] 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.

[0330] Unless otherwise specified, the term "therapeutically effective amount" refers to the amount of an active compound or drug that elicits 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) Preventing disease: e.g., preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but does not yet experience or develop the pathology or symptoms of the disease. (2) Inhibiting disease: e.g., inhibiting a disease, disorder or condition (i.e., preventing 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) Alleviating disease: e.g., alleviating a disease, disorder or condition (i.e., reversing the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition.

[0331] As used herein, the term "treatment" and other similar synonyms include the following meanings:

[0332] (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;

[0333] (ii) inhibiting a disease or condition, i.e. arresting its development;

[0334] (iii) alleviate the disease or condition, that is, cause regression of the disease or condition; or

[0335] (iv) alleviating the symptoms caused by the disease or condition.

[0336] Beneficial Effects

[0337] According to the embodiments of the present invention, the present invention has at least one of the following technical effects:

[0338] The present invention provides a novel compound, and its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug has excellent pharmacokinetic properties, good efficacy and drugability, and can be used to effectively treat or prevent infections and diseases caused by Acinetobacter baumannii; the compound of the present invention has a strong inhibitory effect on Acinetobacter baumannii. DETAILED DESCRIPTION

[0339] The present invention is 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. On the basis of a full understanding of the present invention, the experimental methods in the following examples that do not specify specific conditions are usually 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 solution of the present invention, and such changes should be deemed to be included in the scope of protection of the present invention.

[0340] Preparation of intermediate A1:

[0341]

[0342] The synthetic route of intermediate A1 is as follows:

[0343]

[0344] The synthesis steps are as follows:

[0345] Synthesis Table 1:

[0346] Table 1: Synthesis conditions and steps

[0347]

[0348] 1.1 Operation steps:

[0349] 1.1.1 Weigh 60 g of 2-CTC resin (1.197 mmol / g) into a reactor, 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.

[0350] 1.1.2 Drain and rinse with 10V DMF 6 times, blowing nitrogen for 30 seconds each time.

[0351] 1.1.3 Add 10V 20% Pip / DMF (1st: 10min; 2nd: 10min)*2 into the reactor.

[0352] 1.1.4 After the reaction was completed, the resin was washed 6 times with 10V DMF, and the ninhydrin / tetrachlorobenzoquinone test was positive.

[0353] 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.

[0354] 1.1.6 After the reaction is completed, the ninhydrin / chloranil test is negative. The reaction solution is removed and the resin is washed 6 times with 10V DMF.

[0355] 1.1.7 Repeat steps 1.1.2-1.1.5 according to Table 1 to sequentially condense the above amino acids 1-3.

[0356] 1.1.8 Wash the resin twice with MeOH and twice with MTBE, and then drain the resin into fine sand to obtain compound A1.

[0357] 1.2 Reductive amination:

[0358] 1.2.1 Weigh the peptide resin (A1-4) and put it into a flask. Add 10V 49.7% trimethyl orthoformate / 49.7% NMP / 0.6% acetic acid and 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, the time needs to be extended).

[0359] 1.2.2 Drain and rinse with 10V DMF 6 times, blowing nitrogen for 30 seconds each time.

[0360] 1.2.3 Add 10V 20% Pip / DMF (1st: 10min; 2nd: 10min)*2 into the reactor.

[0361] 1.2.4 After the reaction was completed, the resin was washed 6 times with 10V DMF, and the ninhydrin / tetrachlorobenzoquinone test was positive.

[0362] 1.2.5 Wash the resin twice with MeOH and twice with MTBE, and then drain the resin to obtain compound A1-6.

[0363] 1.3 Cutting, cracking and condensation ring closure:

[0364] 1.3.1 Weigh the peptide resin (Compound A1-6) and put it into a centrifuge tube, add 10V 30% HFIP / 70% DCM reagent, cleave at room temperature for 2.5 hours, filter, and spin-dry the filtrate to obtain a crude product.

[0365] 1.3.2 The crude product was dissolved in 10V DMF, 1.5eq HATU and 2eq DIEA were added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was poured into ice water to quench, extracted with ethyl acetate 3 times, extracted with saturated brine 3 times, dried over anhydrous sodium sulfate, concentrated and dried, and separated and purified by column chromatography (EA:PE = 80% to 100%) to obtain the product intermediate A1.

[0366] Preparation of intermediate B1:

[0367] 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(1-((tert-butoxycarbonyl)amino)cyclopropyl)pentanoic acid

[0368]

[0369] The synthetic route of intermediate B1 is as follows:

[0370]

[0371] Step 1: Synthesis of tert-butyl N-(1-formylcyclopropyl)carbamate (Intermediate B1-2)

[0372]

[0373] Oxalyl chloride (51.79g, 240.87mmol) is dissolved in DCM (600mL). The solution is stirred and cooled to -60°C under a nitrogen atmosphere, then dimethyl sulfoxide (42.77g, 547.44mmol) is added dropwise to the solution within 30 minutes, and then tert-butyl N-[1-(hydroxymethyl)cyclopropyl]carbamate (41g, 218.98mmol) is added to the solution. After 30 minutes, triethylamine (110.58g, 1.09mmol) is added to the solution. The reaction mixture is stirred for 2 hours at 25°C under a nitrogen atmosphere. The desired product is detected by TLC (PE:EA=2:1, Rf=0.45). The solution is extracted with dichloromethane (250mL*3), washed with brine, and dried over anhydrous sodium sulfate. The filtrate is concentrated under vacuum, and the residue is dissolved in petroleum ether to form a white solid, which is filtered. The solid was concentrated under vacuum to give crude product tert-butyl N-(1-formylcyclopropyl)carbamate (Intermediate B1-2) (40.00 g, crude product) as a white solid, which was used directly in the next step.

[0374] Step 2: Synthesis of ethyl (E)-3-(1-((tert-butyloxycarbonyl)amino)cyclopropyl)acrylate (Intermediate B1-3)

[0375]

[0376] NaH (7.77g, 323.94mmol) was dissolved in THF (600mL), and then ethyl 2-ethoxyphosphoryl acetate (72.62g, 323.904mmol) was slowly added to the reaction solution at 0°C. The reaction mixture was stirred for 30 minutes at 0°C under a nitrogen atmosphere. The solution was then cooled to -78°C, and tert-butyl N-(1-formylcyclopropyl)carbamate (intermediate B1-2) (40g, 215.96mmol) was added dropwise to the solution. The reaction mixture was stirred at 25°C for 2 hours. The desired product was detected by TLC. The solution was quenched with aqueous ammonium chloride, extracted with ethyl acetate (200mL*3), washed with brine, and dried over anhydrous sodium sulfate. The filtrate was concentrated under vacuum and the residue was purified by normal phase purification (EA:PE=15-45%) to give (E)-3-[1-(tert-butoxycarbonylamino)cyclopropyl]prop-2-enoic acid ethyl ester (Intermediate B1-3) (31.20 g, 122.20 mmol, 56.59% yield) as a white solid.

[0377] Step 3: Synthesis of tert-butyl N-[1-(3-hydroxypropyl)cyclopropyl]carbamate

[0378]

[0379] (E)-3-[1-(tert-butoxycarbonylamino)cyclopropyl]prop-2-enoic acid ethyl ester (intermediate B1-3) (31.2g, 122.20mmol) was dissolved in tetrahydrofuran (500mL), and then lithium borohydride (6.72g, 305.51mmol) was added to the solution. The reaction mixture was stirred at 25°C under a nitrogen atmosphere for 12 hours. The desired product was detected by TLC (PE:EA=5:1). The solution was quenched with 1M aqueous hydrochloric acid solution, extracted with ethyl acetate (300mL*3), washed with brine, and dried over anhydrous sodium sulfate. The filtrate was concentrated under vacuum, and the residue was purified by normal phase purification (EA:PE=25-50%) to obtain tert-butyl N-[1-(3-hydroxypropyl)cyclopropyl]carbamate (intermediate B1-4) (7.28g, 33.82mmol, 27.67% yield).

[0380] Step 4: Synthesis of tert-butyl N-[1-(3-oxypropyl)cyclopropyl]carbamate (Intermediate B1-5)

[0381]

[0382] Oxalyl chloride (3.24g, 25.55mmol) is dissolved in dichloromethane (70mL). The solution is stirred and cooled to -78 ° C and continued for 5 minutes, then dimethyl sulfoxide (4.54g, 58.06mmol) is added dropwise to the solution. The solution is stirred at -78 ° C under a nitrogen atmosphere for 30 minutes, and then N-[1-(3-hydroxypropyl) cyclopropyl] tert-butyl carbamate (intermediate B1-4) (5g, 23.22mmol) is added dropwise to the solution. After 30 minutes, triethylamine (11.73g, 116.12mmol) is added to the solution. The solution is stirred at 25 ° C for 1 hour. The desired product is detected by LCMS. The solution is extracted with dichloromethane (30mL*3), washed with brine, and dried over anhydrous sodium sulfate. The filtrate was concentrated under vacuum to give the crude product tert-butyl N-[1-(3-oxopropyl)cyclopropyl]carbamate (Intermediate B1-5) (4.80 g, crude product) as a pale yellow oil, which was used directly in the next step.

[0383] LC-MS(ESI)[M+H-56] + =158

[0384] Step 5: Synthesis of (E)-2-(benzyloxycarbonylamino)-5-[1-(tert-butoxycarbonylamino)cyclopropyl]pent-2-enoic acid methyl ester (Intermediate B1-6)

[0385]

[0386] 2-(Benzyloxycarbonylamino)-2-dimethoxyphosphorylated methyl ester (14.91g, 45.01mmol) and DBU (7.54g, 49.51mmol) were dissolved in dichloromethane (60mL). The reaction mixture was stirred at 0°C for 5 minutes, and then tert-butyl N-[1-(3-oxopropyl)cyclopropyl]carbamate (intermediate B1-5) (4.8g, 22.51mmol) was added to the solution. The solution was stirred at 25°C under a nitrogen atmosphere for 2 hours. LCMS detected the desired product. The solution was extracted with dichloromethane (50mL*3), washed with brine, and dried over anhydrous sodium sulfate. The filtrate was concentrated under vacuum and the residue was purified by normal phase purification (EA:PE=25-50%) to give (E)-2-(benzyloxycarbonylamino)-5-[1-(tert-butoxycarbonylamino)cyclopropyl]pent-2-enoic acid methyl ester (Intermediate B1-6) (5.90 g, 14.10 mmol, 62.64% yield) as a colorless oil.

[0387] LC-MS (ESI) [M+H+23] + =441.3

[0388] Step 6: Synthesis of (2-amino-5-[1-(tert-butoxycarbonylamino)cyclopropyl]pentanoic acid methyl ester (Intermediate B1-7)

[0389]

[0390] (E)-2-(Benzyloxycarbonylamino)-5-[1-(tert-butoxycarbonylamino)cyclopropyl]pent-2-enoic acid methyl ester (intermediate B1-6) (5.9 g, 14.10 mmol) was dissolved in methanol (70 mL), and palladium / charcoal (149.44 mg, 1.41 mmol) was added to the solution. The reaction mixture was stirred at 25 ° C under a hydrogen atmosphere for 4 hours. The desired product was detected by LCMS. The solution was passed through diatomaceous earth and washed with methanol (50 mL*3). The filtrate was concentrated under vacuum to give a light yellow oily crude product 2-amino-5-[1-(tert-butoxycarbonylamino)cyclopropyl]pentanoic acid methyl ester (intermediate B1-7) (4.00 g, crude product), which was used directly in the next step. LC-MS (ESI) [M+H] + =287.2

[0391] Step 7: Synthesis of 2-amino-5-[1-(tert-butoxycarbonylamino)cyclopropyl]pentanoic acid (Intermediate B1-8)

[0392]

[0393] 2-amino-5-[1-(tert-butoxycarbonylamino)cyclopropyl]pentanoic acid methyl ester (intermediate B1-7) (4g, 13.97mmol) was dissolved in tetrahydrofuran (40mL): methanol (10mL): water (10mL) = 4:1:1, and then lithium hydroxide (2.93g, 69.84mmol) was dissolved in water and added to the solution. The reaction mixture was stirred at 25°C for 12 hours. The desired product was detected by LCMS. The pH was adjusted to 8 with 1M aqueous hydrochloric acid solution and concentrated directly under vacuum to obtain the crude product 2-amino-5-[1-(tert-butoxycarbonylamino)cyclopropyl]pentanoic acid (intermediate B1-8) (3.80g, crude product) which was directly used in the next step. LC-MS (ESI) [M+H] + =273.2

[0394] Step 8: Synthesis of 5-[1-(tert-butoxycarbonylamino)cyclopropyl]-2-(9H-fluoren-9-ylmethoxycarbonylamine)pentanoic acid (Intermediate B1)

[0395]

[0396] 2-Amino-5-[1-(tert-butoxycarbonylamino)cyclopropyl]pentanoic acid (Intermediate B1-8) (3.8 g, 13.95 mmol) was dissolved in a solution of acetone (30 mL): water (30 mL), and then FmocOsu (4.71 g, 13.95 mmol) was added to the solution. The reaction mixture was stirred at 25°C for 12 hours. The desired product was detected by LCMS. The solution was extracted with ethyl acetate (50 mL*3), combined with the organic layer, and dried over anhydrous sodium sulfate. The filtrate was concentrated under vacuum, and the residue was purified by normal phase purification (DCM:PE=100% to MeOH:DCM=0~10%) to give 5-[1-(tert-butoxycarbonylamino)cyclopropyl]-2-(9H-fluoren-9-ylmethoxycarbonylamine)pentanoic acid (Intermediate B1) (2.53 g, 5.12 mmol, 36.67% yield).

[0397] 1 HNMR (400MHz, DMSO-d6) δ12.52(s,1H),7.90(d,J=7.2Hz,2H),7.73(d,J=7.2Hz,2H),7.60(d,J=7.6Hz,1H),7.42(t,J=7.2Hz,2H) ,7.36-7.31(m,2H),7.07(s,1H),4.28-4.20(m,3H),3.88(dd,J=12.4,9.2Hz,1H),1.73-1.35(m,15H),0.55(s,2H),0.45(s,2H). LC-MS(ESI)[M+23] + =517.3

[0398] Preparation of intermediate A2:

[0399]

[0400] The preparation of intermediate A2 refers to the preparation of intermediate A1.

[0401] Example 1: Preparation of target compound 1

[0402] 4-[(11S,14S,17S)-14-[3-(1-aminocyclopropyl)propyl]-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaazatricyclo[19.4.0.03,8]pentacosa-1(21),3,5,7,22,24-hexen-22-yl]benzoic acid (Compound 1)

[0403]

[0404] The synthetic route of compound 1 is as follows:

[0405]

[0406] Step 1: Synthesis of tert-butyl 3-[[(11S, 14S, 17S)-14-[3-[1-(tert-butoxycarbonylamino)cyclopropyl]propyl]-11-[3-(tert-butoxycarbonylamino)propyl]-22-(4-tert-butoxycarbonylphenyl)-16-methyl-12,15,18-trioxy-2-thio-4,10,13,16,19-pentaazatricyclo[19.4.0.03,8]pentacosa-1(21),3,5,7,22,24-hexen-17-yl]methyl]indole-1-carboxylate (Compound 1-2)

[0407]

[0408] 3-(((7S,10S,13S)-17-bromo-10-(3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)propyl)-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]thio Hetero[5,8,11,14]tetraazacycloheptadeca-13-yl)methyl)-1H-indole-1-carboxylic acid tert-butyl ester (100 mg, 92.92 μmol) and sodium carbonate (24.39 mg, 232.31 μmol) were dissolved in a solution of 1,4-dioxane (3 mL): water (0.5 mL), and then tetrakistriphenylphosphine palladium (21.45 mg, 18.58 μmol) was added to the solution. The reaction mixture was stirred and heated to 120°C in a microwave under a nitrogen atmosphere for 40 minutes. The desired product was detected by LCMS. The solution was concentrated under vacuum to give the crude product tert-butyl 3-[[(11S,14S,17S)-14-[3-[1-(tert-butoxycarbonylamino)cyclopropyl]propyl]-11-[3-(tert-butoxycarbonylamino)propyl]-22-(4-tert-butoxycarbonylphenyl)-16-methyl-12,15,18-trioxy-2-thio-4,10,13,16,19-pentaazatricyclo[19.4.0.03,8]pentacosa-1(21),3,5,7,22,24-hexen-17-yl]methyl]indole-1-carboxylate (109.04 mg, crude) which was used directly in the next step.

[0409] LC-MS(ESI)[M-300-56 / 2+H] + =431.0

[0410] Step 2: Synthesis of 4-[(11S,14S,17S)-14-[3-(1-aminocyclopropyl)propyl]-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaazatricyclo[19.4.0.03,8]pentacosa-1(21),3,5,7,22,24-hexen-22-yl]benzoic acid

[0411]

[0412] 3-[[(11S,14S,17S)-14-[3-[1-(tert-butoxycarbonylamino)cyclopropyl]propyl]-11-[3-(tert-butoxycarbonylamino)propyl]-22-(4-tert-butoxycarbonylphenyl)-16-methyl-12,15,18-trioxy-2-thio-4,10,13,16,19-pentaazatricyclo[19.4.0.03,8]pentacosa-1(21),3,5,7,22,24-hexen-17-yl]methyl]indole-1-carboxylic acid tert-butyl ester (109.04 mg, 92.92 μmol) was dissolved in trifluoroacetic acid (2 mL): dichloromethane (2 mL) solution. The reaction mixture was stirred at 25°C for 4 hours. The desired product was detected by LCMS. The solution was concentrated under vacuum, the residue was concentrated under vacuum, and the residue was purified by high performance liquid chromatography (0.1% formic acid, 0-30% 40 min) to give 4-[(11S,14S,17S)-14-[3-(1-aminocyclopropyl)propyl]-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaazatricyclo[19.4.0.03,8]pentacosa-1(21),3,5,7,22,24-hexen-22-yl]benzoic acid.

[0413] LC-MS(ESI)[M+H] + =817.1.

[0414] Example 2 Preparation of target compound 2

[0415] 4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-((1-(aminomethyl)cyclopropyl)methyl)-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)benzoic acid (Compound 2)

[0416]

[0417] The synthetic route of compound 2 is as follows:

[0418]

[0419] Step 1: Preparation of tert-butyl 3-(((7S,10S,13S)-17-bromo-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-((1-(((tert-butoxycarbonyl)amino)methyl)cyclopropyl)methyl)-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 2-1) Refer to the preparation method of intermediate A1.

[0420] Step 2: Synthesis of tert-butyl 3-(((7S,10S,13S)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-((1-(((tert-butoxycarbonyl)amino)methyl)cyclopropyl)methyl)-17-(4-(tert-butoxycarbonyl)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 2-2)

[0421]

[0422] To 3-(((7S,10S,13S)-17-bromo-10-(4-((tert-butyloxycarbonyl)amino)butyl)-7-((1-(((tert-butyloxycarbonyl)amino)methyl)cyclopropyl)methyl)-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]thiophene To a solution of hetero[5,8,11,14]tetraazacycloheptadecan-13-yl)methyl)-1H-indole-1-carboxylic acid tert-butyl ester (Compound 2-1) (14.84 mg, 48.79 μmol) and Na2CO3 (8.54 mg, 81.31 μmol) in dioxane (3 mL) and H2O (0.5 mL) was added (PPh3)4 (7.51 mg, 6.50 μmol). The reaction mixture was stirred at 120°C in a microwave reactor for 40 minutes. LC-MS showed that the starting material disappeared and the product was detected. After vacuum concentration, the product was purified by high performance liquid chromatography (0.1% FA) to give tert-butyl 3-(((7S,10S,13S)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-((1-(((tert-butoxycarbonyl)amino)methyl)cyclopropyl)methyl)-17-(4-(tert-butoxycarbonyl)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 2-2).

[0423] LC-MS, M / Z(ESI):1173.5[M+H] +

[0424] Step 3: Synthesis of 4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-((1-(aminomethyl)cyclopropyl)methyl)-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)benzoic acid (Compound 2)

[0425]

[0426] A solution of tert-butyl 3-(((7S,10S,13S)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-((1-(((tert-butoxycarbonyl)amino)methyl)cyclopropyl)methyl)-17-(4-(tert-butoxycarbonyl)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 2-2) (18 mg, 15.34 μmol) and TFA (1 mL) in DCM (1 mL) 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 HPLC (0.1% FA in water) to give 4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-((1-(aminomethyl)cyclopropyl)methyl)-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)benzoic acid (Compound 2).

[0427] LC-MS, M / Z(ESI):817.4[M+H] +

[0428] Example 3 Preparation of target compound 3

[0429] 4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-((3-(aminomethyl)oxetan-3-yl)methyl)-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)benzoic acid (Compound 3)

[0430]

[0431] The synthetic route of compound 3 is as follows:

[0432]

[0433] Step 1: Preparation of tert-butyl 3-(((7S,10S,13S)-17-bromo-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-((3-(((tert-butoxycarbonyl)amino)methyl)oxetan-3-yl)methyl)-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 3-1) Refer to the preparation method of intermediate A1.

[0434] Step 2: Synthesis of tert-butyl 3-(((7S,10S,13S)-10-(4-((tert-butyloxycarbonyl)amino)butyl)-7-((3-(((tert-butyloxycarbonyl)amino)methyl)oxetane-3-yl)methyl)-17-(4-(tert-butyloxycarbonyl)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 3-2)

[0435]

[0436] To 3-(((7S,10S,13S)-17-bromo-10-(4-((tert-butyloxycarbonyl)amino)butyl)-7-((3-(((tert-butyloxycarbonyl)amino)methyl)oxetan-3-yl)methyl)-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 3-1) (120 mg, 109.88 μmol), (4-tert-butoxycarbonylphenyl) boronic acid (60.99 mg, 274.69 μmol) and Na2CO3 (29.11 mg, 274.69 μmol) in dioxane (4 mL) and H2O (1 mL) were added Pd(PPh3)4 (25.39 mg, 21.98 μmol), and the reaction mixture was stirred at 120 ° C. in a microwave reactor for 40 minutes. LC-MS showed that the starting material disappeared and the product was detected. Water was added to the mixture, extracted twice with EA (20 mL), and washed once with brine (20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product. The residue was purified by silica gel column chromatography (EA / PE=80%) to give tert-butyl 3-(((7S,10S,13S)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-((3-(((tert-butoxycarbonyl)amino)methyl)oxetan-3-yl)methyl)-17-(4-(tert-butoxycarbonyl)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 3-2) (60 mg, yield 41%).

[0437] LC-MS, M / Z(ESI):1189.5[M+H] +

[0438] Step 3: Synthesis of 4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-((3-(aminomethyl)oxetane-3-yl)methyl)-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)benzoic acid (Compound 3)

[0439]

[0440] Tert-butyl 3-(((7S,10S,13S)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-((3-(((tert-butoxycarbonyl)amino)methyl)oxetan-3-yl)methyl)-17-(4-(tert-butoxycarbonyl)phenyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecanede

[0441] A solution of 1H-indole-1-carboxylate (compound 3-2) (0.06 g, 50.44 μmol) and TFA (1 mL) in DCM (1 mL) was stirred at 25 ° C for 2 hours. LC-MS showed that the starting material was completely consumed and the product was detected. The mixture was concentrated in vacuo to obtain a crude product. The crude product was purified by HPLC (A = 0.5% FA in H2O, B = ACN, B / A = 30%) to give 4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-((3-(aminomethyl)oxetane-3-yl)methyl)-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)benzoic acid (Compound 3).

[0442] LC-MS, M / Z(ESI):833.4[M+H] +

[0443] Example 4: Preparation of target compound 4

[0444] 4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(2-(1-(aminomethyl)cyclopropyl)ethyl)-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)benzoic acid (Compound 4)

[0445]

[0446] The synthetic route of compound 4 is as follows:

[0447]

[0448] Step 1: 3-(((7S,10S,13S)-17-bromo-10-(2-(1-(((tert-butyloxycarbonyl)amino)methyl)cyclopropyl)ethyl)-7-(3-((tert-butyloxycarbonyl)

[0449] The synthesis of tert-butyl 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 4-1) refers to the preparation method of intermediate A1.

[0450] Step 2: Synthesis of tert-butyl 3-(((7S,10S,13S)-10-(2-(1-(((tert-butoxycarbonyl)amino)methyl)cyclopropyl)ethyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-17-(4-(tert-butoxycarbonyl)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 4-2)

[0451]

[0452] 3-(((7S,10S,13S)-17-bromo-10-(2-(1-(((tert-butyloxycarbonyl)amino)methyl)cyclopropyl)ethyl)-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-13-yl)methyl)-1H -Indole-1-carboxylic acid tert-butyl ester (Compound 4-1) (80 mg, 0.074 mmol) and [4-(tert-butyloxycarbonyl)phenyl]boric acid (33.3 mg, 0.15 mmol) were dissolved in dioxane (1.2 mL) and water (0.25 mL), potassium carbonate (35.8 mg, 0.26 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (8.4 mg, 0.01 mmol) were added, argon was replaced three times, and the temperature was raised to 90 ° C for 16 hours. Water (30 mL) was added to the reaction solution for dilution, 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 3-(((7S,10S,13S)-10-(2-(1-(((tert-butoxycarbonyl)amino)methyl)cyclopropyl)ethyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-17-(4-(tert-butoxycarbonyl)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-carboxylic acid tert-butyl ester (compound 4-2).

[0453] LC-MS, M / Z(ESI):1173.7[M+H] +

[0454] Step 3: Synthesis of 4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(2-(1-(aminomethyl)cyclopropyl)ethyl)-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)benzoic acid (Compound 4)

[0455]

[0456] 3-(((7S,10S,13S)-10-(2-(1-(((tert-butoxycarbonyl)amino)methyl)cyclopropyl)ethyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-17-(4-(tert-butoxycarbonyl)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-carboxylic acid tert-butyl ester (Compound 4-2) (30 mg, 0.026 mmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.2 mL) was added at 0°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 4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(2-(1-(aminomethyl)cyclopropyl)ethyl)-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)benzoic acid (Compound 4).

[0457] LC-MS, M / Z(ESI):817.5[M+H] +

[0458] Test example:

[0459] Antibiotic Minimal Inhibitory Concentration (MIC) Testing

[0460] The in vitro antibacterial activity of antibiotics was tested by the minimum inhibitory concentration experiment. The test bacteria was Acinetobacter baumannii (ATCC19606), and the culture medium was sterile cation-regulated MH II broth (BD, catalog number 212322). The test compound was dissolved in the cation-regulated MH II broth culture medium and prepared into a working solution with a maximum concentration of 64 μg / mL. The culture medium was used for two-fold serial dilution, and the diluted culture medium was transferred to a sterile 96-well culture plate, 100 μL per well, and a control well without the compound was set up. Subsequently, Acinetobacter baumannii was prepared with the culture medium to a final concentration of ~1×10 6 CFU / mL working solution, add this working solution to each well of the 96-well plate, 100 μL per well, and set up blank wells without compounds and bacteria. After mixing, place the 96-well plate in a 37°C incubator for 16 hours. After the culture is completed, transfer the 96-well plate to a microplate reader (Molecular Devices, SpectraMax iD5), detect the absorbance at OD600 of each well, and calculate the inhibition rate of bacterial growth under different compound concentrations. The lowest concentration when the compound has an inhibition rate of ≥80% on bacteria is the minimum inhibitory concentration of the compound.

[0461] Table 2: Minimum inhibitory concentration of the compounds of the present invention against Acinetobacter baumannii

[0462]

[0463] Experimental conclusion, as shown in Table 2, the compounds of the present invention have a strong inhibitory effect on Acinetobacter baumannii.

Claims

1. A compound represented by formula (I), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, in, X 1 N or C (-L x1 -R x1 ); X 2 N or C (-L x2 -R x2 ); X 3 N or C (-L x3 -R x3 ); X 4 N or C (-L x4 -R x4 ); X 5 N or C (-L x5 -R x5 ); X 6 N or C (-L x6 -R x6 ); X 7 N or C (-L x7 -R x7 ); X 8 N or C (-L x8 -R x8 ); R 1 -(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; R 3 For -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-NH-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 , the R 3 Further 0, 1, 2, 3 or 4 R b replace; R 2 H, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 3-8 Cycloalkyl; R 4 , R 6 and R 9 H, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-8 Cycloalkyl; R 5 For -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-NH-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 , the R 5 Further 0, 1, 2, 3 or 4 R c replace; R 5’ H or C 1-6 alkyl; R 7 and R 8 H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-8 Cycloalkyl; R 31 , R 32 , R 51 and R 52 are independently H or C 1-6 alkyl; -L x1 -、-L x2 -、-L x3 -、-L x4 -、-L x5 -、-L x6 -、-L x7 -and-L x8 - are independently a single bond, -O-, -S-, -NH-, -C(=O)-, -S(=O)- or -S(=O)2-; 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 with 0, 1, 2, 3 or 4 R d replace; R x5 , R x6 and R x7 are independently H, F, Cl, Br, OH, NH2, CN, C 1-6 Alkyl, or carboxylic acid and its bioisostere, the C 1-6 The alkyl group is optionally substituted with 0, 1, 2, 3 or 4 R d replace; R x8 C 3-8 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 Aryl or 5-12 membered heteroaryl, the C 3-8 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 The aryl group and the 5-12 membered heteroaryl group are each independently optionally substituted by n R e replace; Each R a are independently H, halogen, OH, NH2, CN, COOH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-8 Cycloalkyl; Each R e are independently H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -SC 1-6 Alkyl or carboxylic acid and its bioisostere, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino and -SC 1-6 The alkyl group is optionally substituted with 1, 2, 3 or 4 R groups, each independently; R is independently H, halogen, OH, NH2, CN, =O, =S, COOH or C 1-6 alkyl; Each R b , R c and R d are independently F, Cl, Br, OH, NH2, CN, ═O, COOH or C 1-6 alkyl; m is 1, 2, 3 or 4; g is 1, 2, 3 or 4; n is 1, 2, 3 or 4; In addition, the R 3 and R 5 One of the following conditions is met: a) When R 3 For unsubstituted -C 0-10 Alkyl-NR 31 R 32 , and R 5 For -C 0-10 Alkyl-NR 51 R 52 or -C 0-10 Alkyl-C(=O)NR 51 R 52 When the R5 is further replaced by 1, 2, 3 or 4 R c replace; or, b) When R 3 For unsubstituted -C 0-10 Alkyl-NR 31 R 32 , and R 5 For -C 0-10 Alkyl-NR 51 R 52 -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-NH-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 When the R 5 Further 0, 1, 2, 3 or 4 R c replace; or, c) When R 3 is -C substituted with 1, 2, 3 or 4 F 0-10 Alkyl-NR 31 R 32 , R 5 For unsubstituted -C 0-10 Alkyl-NR 51 R 52 When R x5 Not Cl; or d) When R 5 For unsubstituted -C 0-10 Alkyl-NR 51 R 52 , and R 3 For -C 0-10 Alkyl-NR 31 R 32 When the R3 is further replaced by 1, 2, 3 or 4 R b replace; or, e) When R 5 For unsubstituted -C 0-10 Alkyl-NR 51 R 52 , and R 3 For -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-NH-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 , the R 3 Further 0, 1, 2, 3 or 4 R b replace.

2. The compound according to claim 1, characterized in that Each R a are independently H, halogen or C 1-3 alkyl; and / or, each R a are independently H or CH3; and / or, R 1 -(CH2) m -5-10 membered heteroaryl, the 5-10 membered heteroaryl is optionally substituted by g R a replace; and / or, R1 is -(CH2) m -benzo 5-membered heteroaryl, the benzo 5-membered heteroaryl is optionally substituted by g R a replace; and / or, R 1 -(CH2) m -5,6-diphenylamine heteroaryl, wherein the 5,6-diphenylamine heteroaryl is optionally substituted by g R a replace; and / or, R 1 -(CH2) m -pyrrolophenyl, the pyrrolophenyl optionally substituted by g R a replace; and / or, g is 1, 2, 3 or 4; and / or, m is 1, 2, 3 or 4; and / or, R 1 for and / or, R 1 for 3. The compound according to claim 1, characterized in that Each R b , R c and R d are independently F or Cl; and / or, R 31 and R 32 are independently H; and / or, R 3 For -C 1-6 Alkyl-NR 31 R 32 , -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-NH-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 , the R 3 Further 0, 1, 2, 3 or 4 R b replace; and / or, R 3 For -C 2-5 Alkyl-NH2, -C 0-3 Alkyl-C 3-6 Cycloalkyl-C 0-3 Alkyl -NH2 or -C 0-3 Alkyl-3-8 membered heterocycloalkyl-C 0-3 Alkyl-NH2, the R 3 Further 0, 1, 2, 3 or 4 R b replace; and / or, R 3 For -C 2-5 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, the R 3 Further 0, 1, 2, 3 or 4 R b replace; and / or, R 3 for The R 3 Further 0, 1, 2, 3 or 4 R b replace; and / or, R 3 for 4. The compound according to claim 1, characterized in that R 51 and R 52 are independently H; and / or, R 5 For -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-NH-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 , the R 5 Further 0, 1, 2, 3 or 4 R c replace; and / or, R 5 For -C 2-5 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, the R 5 Further 0, 1, 2, 3 or 4 R c replace; and / or, R 5 for The R 5 Further 0, 1, 2, 3 or 4 R c replace; and / or, R 5 for and / or, when R 3 for R 5 for When R x5 Not for Cl; and / or, when R 3 for When R 5 for 5. The compound according to claim 1, characterized in that Each R e are independently H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -SC 1-6 Alkyl, -C(=O)-R e1 、-C(=O)NH-R e1 、-N(R e1 )C(=O)-R e1 、-ON(R e1 )C(=O)-R e1 、-S(=O)-R e1 、-S(=O)2-R e1 、-NH-S(=O)2-R e1 、-C(=O)-NH-S(=O)2-R e1 、-NH-C(=O)-NH-S(=O)2-R e1 、-NH-C(=O)-NH-C(=O)-R e1 、-P(=O)(-R e1 2. C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl, C 6-12 Aryl or 5-12 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -SC 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 membered heteroaryl are each independently optionally substituted by 1, 2, 3 or 4 R; Each R e1 are independently H, OH, NH2, ONa, OK (potassium ion), C 1-6 Alkyl, C 1-6 Alkoxy, -NH-C 1-6 Alkyl, -N(-C 1-6 Alkyl)2, -NH-C(=O)C 1-6 alkyl, C6-12 aryl or 5-12 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, -NH-C 1-6 Alkyl, -N(-C 1-6 Alkyl)2, -NH-C(=O)C 1-6 Alkyl, C6-12 aryl and 5-12 membered heteroaryl are each independently optionally substituted by 1, 2, 3 or 4 R; R is independently H, halogen, OH, NH2, CN, =O, =S, COOH or C 1-6 alkyl; and / or, each R is independently H, F, Cl, OH, NH2, CN, =O, =S or -CH3; and / or, each R e1 are independently H, OH, -C 1-3 Alkyl, -NH-C 1-3 Alkyl or -NH-C(=O)C 1-3 alkyl; and / or, each R e1 Each independently represents H, OH, -CH3 or -NH-C(=O)-CH3; and / or, each R e are independently H, halogen, OH, NH2, CN, -C(=O)-R e1 、-S(=O)-R e1 、-S(=O)2-R e1 , C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, -SC 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl or 5-6 membered heteroaryl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, -SC 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl and 5-6 membered heteroaryl are each independently optionally substituted by 1, 2, 3 or 4 R; and / or, each R e are independently H, F, Cl, Br, OH, COOH, -S(=O)2-OH, -S(=O)2-NH-C(=O)-CH3 or and / or, R x8 C 6-10 Aryl or 5-6 membered heteroaryl, the C 6-10 The aryl group and the 5-6 membered heteroaryl group are each independently optionally substituted by n R e replace; and / or, R x8 is a phenyl group, the phenyl group is optionally substituted by n R e replace; and / or, n is 1, 2, 3 or 4; and / or, R x8 for 6. The compound according to claim 1, characterized in that R 2 H, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 Deuterated alkyl; and / or, R 2 CH3 or CD3; and / or, R 4 , R 6 and R 9 H, C 1-3 Alkyl or C 1-3 Haloalkyl; and / or, R 4 , R 6 and R 9 are independently H; and / or, R 5’ is H; and / or, R 7 and R 8 H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 3-6 Cycloalkyl; and / or, R 7 and R 8 are independently H; and / or, R x1 , R x2 , R x3 , R x4 , R x5 , R x6 and R x7 are each independently H, F or Cl.

7. The compound according to claim 1, characterized in that The compound represented by formula (I) satisfies one or more of the following conditions: (1) C 6-12 Aryl is independently phenyl or naphthyl, for example phenyl; (2) The heteroatom species of the 5-12 membered heteroaryl group are each independently selected from one or two of N, O and S, and the number of heteroatoms is each independently 1, 2, 3 or 4; preferably, the heteroatom species are each independently selected from one or two of N and O, and the number of heteroatoms is each independently 1 or 2; (3) The 5-12 membered heteroaryl group is independently a monocyclic or polycyclic ring, and the polycyclic rings may be fused rings; the polycyclic rings are bicyclic or tricyclic; preferably, the 5-12 membered heteroaryl group is independently a 5-7 membered monocyclic heteroaryl group or a 9-10 membered bicyclic heteroaryl group, preferably an indolyl group, for example (4) The heteroatom species of the 3-12 membered heterocycloalkyl group are each independently selected from one or two of N, O and S, and the number of heteroatoms is each independently 1, 2 or 3; preferably, the heteroatom species are each independently selected from one or two of N and O, and the number of heteroatoms is each independently 1 or 2; (5) The 3-12 membered heterocycloalkyl group may be independently monocyclic or polycyclic, and the polycyclic group may be bridged, fused or spirocyclic, and the polycyclic group may be bicyclic or tricyclic; preferably, the 3-12 membered heterocycloalkyl group may be independently 4-7 membered monocyclic heterocycloalkyl group, 8-10 membered bicyclic heterocycloalkyl group or 10-12 membered tricyclic heterocycloalkyl group; preferably, oxetane, for example (6) C 1-10 The alkyl groups are independently C 1-6 Alkyl, preferably C 1-3 Alkyl, for example methyl, ethyl, n-propyl or isopropyl, for example methyl; (7) C 0-10 The alkyl groups are independently C 0-6 Alkyl, preferably C 0-3 Alkyl, such as a single bond, methyl, ethyl, n-propyl or isopropyl, and also such as methyl; (8) C 3-8 The cycloalkyl groups are independently C 3-6 Cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example (9) C 1-6 The deuterated alkyl groups are independently C 1-3 Deuterated alkyl, such as -CD3; (10) C 1-6 The haloalkyl is independently C 1-3 Haloalkyl, for example -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl or -CH2CH2CF3; (11) C 1-6 The alkyl groups are independently C 1-3 alkyl, for example methyl, ethyl, n-propyl or isopropyl, for example methyl or ethyl; (12) The carboxylic acid and its bioisostere are independently -C(=O)-R e1 、-S(=O)2-R e1 or a 5-6 membered heteroaryl group, each R e1 Each independently represents H, OH, -CH3 or -NH-C(=O)-CH3; Preferably, the carboxylic acid and its bioisostere are independently -COOH, -S(=O)2-OH, -S(=O)2-NH-C(=O)-CH3 or (13) The halogen is independently selected from fluorine, chlorine, bromine or iodine; (14) C 1-6 The alkoxy groups are independently C 1-3 Alkoxy, for example methoxy, ethoxy, n-propoxy or isopropoxy, for example methoxy or ethoxy; and (15) C 1-6 The alkylamino groups are independently C 1-3 Alkylamino, for example -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3 or -NHCH(CH3)2.

8. The compound according to claim 1, characterized in that The compound represented by formula (I) has the structural formula (I-1) or (I-2): in, Q and Q1 are independently -C(=O)-, -O-, -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-, wherein -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl- are each independently optionally substituted by 1 or 2 halogens; h, h', r and r' are independently 0, 1, 2, 3, 4, 5, or 6; X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , R 1 , R 2 , R 4 , R 5’ , R 6 , R 7 , R 8 and R 9 As defined in claim 1.

9. The compound according to claim 1, characterized in that The compound represented by formula (Ⅰ) has the structural formula (Ⅰ-1A) or (Ⅰ-2A): in, Q and Q1 are independently -C(=O)-, -O-, -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-, wherein -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl- are each independently optionally substituted by 1 or 2 halogens; h, h', r and r' are independently 0, 1, 2, 3, 4, 5, or 6; m, g, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , R a , R 2 , R 4 , R 5’ , R 6 , R 7 , R 8 and R 9 As defined in claim 1.

10. The compound according to claim 1, characterized in that The compound represented by formula (Ⅰ) has the structural formula (Ⅰ-1A1) or (Ⅰ-2A1): in, Q and Q1 are independently -C(=O)-, -O-, -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-, wherein -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl- are each independently optionally substituted by 1 or 2 halogens; h, h', r and r' are independently 0, 1, 2, 3, 4, 5, or 6; m, g, n, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , R a , R e , R 2 , R 4 , R 5’ , R 6 , R 7 , R 8 and R 9 As defined in claim 1.

11. The compound according to claim 1, characterized in that The compound represented by formula (I) has the structural formula (I-4) or (I-5): or in, Q and Q1 are independently -C(=O)-, -O-, -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-, wherein -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl- are each independently optionally substituted by 1 or 2 halogens; Preferably, Q and Q1 are independently -C(=O)-, -O-, -CR b R b -, -cyclopropyl-, -cyclobutyl-, -oxetanyl-, or -azetidinyl; Further preferably, Q and Q1 are independently -C(=O)-, -O-, -CH2-, -CF2-, h, h', r and r' are independently 0, 1, 2, 3, 4, 5, or 6; R b is H, F, Cl or Br; R ex is H, F, Cl, Br or OH; R e -C(=O)-R e1 、-S(=O)-R e1 、-S(=O)2-R e1 , 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, wherein the 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl and 5-6 membered heteroaryl are each independently optionally substituted by 1, 2, 3 or 4 R; Preferably, R e H, F, Cl, Br, OH, COOH, -S(=O)2-OH, -S(=O)2-NH-C(=O)-CH3 or g、X 1 , X 4 , R a , R, R e1 , R 2 , R x5 , R x6 and R x7 As defined in claim 1.

12. The compound according to claim 11, characterized in that The compound represented by formula (Ⅰ) has the structural formula (Ⅰ-4A) or (Ⅰ-5A): in, Q and Q1 are independently -C(=O)-, -O-, -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-, wherein -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl- are each independently optionally substituted by 1 or 2 halogens; h, h', r and r' are independently 0, 1, 2, 3, 4, 5, or 6; R ex is H, F, Cl, Br or OH; R e -C(=O)-R e1 、-S(=O)-R e1 、-S(=O)2-R e1 , 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, wherein the 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl and 5-6 membered heteroaryl are each independently optionally substituted by 1, 2, 3 or 4 R; g、X 1 , X 4 , R a , R, R e1 , R 2 , R x5 , R x6 and R x7 As defined in claim 1.

13. The compound according to claim 1, characterized in that The compound represented by formula (I) satisfies one of the following schemes 1, 2, 3, 4 or 5: Solution 1: R 3 and R 5 At least one of them is -C 0-10 Alkyl-C 0-3 Halogenated alkyl-C 0-10 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 ; Option 2: The compound represented by formula (I) has the structural formula (I-5B): in, Q and Q1 are independently -C(=O)-, -O-, -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-, wherein -CH2- is optionally substituted by 1 or 2 halogens; at least one of Q and Q1 is -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-; h, h', r and r' are independently 0, 1, 2, 3, 4, 5, or 6; R ex is H, F, Cl, Br or OH; R e -C(=O)-R e1 、-S(=O)-R e1 、-S(=O)2-R e1 , 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl or 5-6 membered heteroaryl; R e1 Each independently represents H, OH, -CH3 or -NH-C(=O)-CH3; g、X 1 , X 4 , R a , R 2 , R x5 , R x6 and R x7 As defined in claim 1; Preferably, at least one of Q and Q1 is Option 3: The compound represented by formula (I) has the structural formula (I-5C): in, Q1 is -C(=O)-, -O-, -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-, wherein the -CH2- is optionally substituted by 1 or 2 halogens; Q is -C 3-6 Cycloalkyl, preferably h, h', r and r' are independently 0, 1, 2, 3, 4, 5, or 6; R ex is H, F, Cl, Br or OH; R e -C(=O)-R e1 、-S(=O)-R e1 、-S(=O)2-R e1 , 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl or 5-6 membered heteroaryl; R e1 Each independently represents H, OH, -CH3 or -NH-C(=O)-CH3; g、X 1 , X 4 , R a , R 2 , R x5 , R x6 and R x7 As defined in claim 1; Option 4: The compound represented by formula (I) has the structural formula (I-5D): in, Q1 is -C(=O)-, -O-, -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-, wherein the -CH2- is optionally substituted by 1 or 2 halogens; preferably -CH2-; Q is -C 3-6 Cycloalkyl, preferably h, h', r and r' are independently 0, 1, 2, 3 or 4; R ex is H, F, Cl, Br or OH; R e -COOH, -S(=O)2-OH, -S(=O)2-NH-C(=O)-CH3 or Preferably -COOH; g is 1, 2, or 3; X 1 for CH; X 4 is CH or N; R a are independently H, halogen or C 1-3 alkyl; R 2 H, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 Deuterated alkyl; R x5 , R x6 and R x7 are independently H, F or Cl; Option 5: The compound represented by formula (Ⅰ) has the structural formula (Ⅰ-1A2) or (Ⅰ-2A2): in, Q and Q1 are independently -CH2-, -C 3-6 Cycloalkyl- or -3-8 membered heterocycloalkyl-; h, h', r and r' are independently 0, 1, 2, 3, 4, 5, or 6; m, g, n, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , R a , R e , R 2 , R 4 , R 5’ , R 6 , R 7 , R 8 and R 9 As defined in claim 1.

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

15. The compound according to claim 14, characterized in that Selected from any of the following compounds or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

16. The compound according to claim 15, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The pharmaceutically acceptable salt is hydrochloride.

17. A pharmaceutical composition, characterized in that It comprises the compound according to any one of claims 1 to 16 or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug; Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

18. Use of a compound according to any one of claims 1 to 16 or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or a pharmaceutical composition according to claim 16 in the preparation of a medicament for treating or preventing infections and diseases caused by Acinetobacter baumannii.

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