Cephalosporin-based antimicrobial compounds and their pharmaceutical applications

Abstract

To provide cephalosporin compounds showing efficacy on gram-negative bacteria producing multiple types of β-lactamases.SOLUTION: The present invention provides a compound represented by formula (I-2), or a pharmaceutically acceptable salt, stereoisomer, rotamer, tautomer, or deuterated compound thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This disclosure belongs to the pharmaceutical field and specifically relates to cephalosporin-based antimicrobial compounds and their pharmaceutical applications. [Background technology]

[0002] The development of antifungal therapies remains an ongoing challenge facing modern society. Antimicrobial agents include various chemically synthesized drugs such as antibiotics, sulfonamides, imidazoles, nitroimidazoles, and quinolones, with β-lactam antibiotics being a particularly important category. To date, several β-lactamase inhibitors have been reported in the literature and are commercially available, and they have already become clinically important antimicrobial agents. However, the problem of drug resistance to β-lactamase inhibitors is becoming increasingly serious, with more and more bacteria producing β-lactamase and acquiring drug resistance by degrading β-lactamase inhibitors.

[0003] According to the Ambler molecular classification, β-lactamases are mainly divided into four types. Specifically, these include type A (TEM, SHV, CTX-M, KPC, etc.), type B (IMP, VIM, L-1, etc.), type C (AmpC), and type D (OXA, etc.). Of these types, types A, C, and D are mainly serine-β-lactamases, while type B is a metallobe-β-lactamase. Both types have different mechanisms of hydrolysis for β-lactamase inhibitors.

[0004] The emergence of Gram-negative bacteria that develop strong drug resistance to β-lactamase inhibitors (cephalosporins and carbapenems) presents a major clinical challenge. This drug resistance is caused by the production of serine β-lactamases of type A or D and metallobe β-lactamases of type B, which extend the substrate spectrum of the bacteria. Metallobe β-lactamases are known to be one of the causes of multidrug resistance in Gram-negative bacteria, and there is a need to develop more effective antimicrobial compounds. In particular, cephalosporin compounds that are effective against Gram-negative bacteria that produce multiple types of β-lactamases are currently a major challenge in the field of antimicrobial research.

[0005] According to a report in the literature (Antimicrob Agents Chemother. 1982, 22(2), 181-185.), cephalosporin compounds containing a catechol group in their molecule have high antibacterial activity against Gram-negative bacteria. This action is due to the interaction of the catechol group in the molecule with extracellular Fe. 3+ The compound forms a chelate, which allows the Fe on the cell membrane to 3+ The mechanism involves effective binding to the bacterial cell via a transport system (tonB-dependent transport system). This Trojan horse strategy leads to higher concentrations in the periplasmic space (the narrow space between the outer membrane and the cell wall), which then binds to the receptor and inhibits bacterial cell wall synthesis. Therefore, compounds with catechol or similar structures in the 3- or 7-position side chain of the cephalosporin skeleton have already been studied (EP0416410B1). Cefiderocol is a novel siderophore cephalosporin (WO2010050468, WO2017216765, Eur. J Med. Chem. 2018, 155, 847-868), and the FDA (U.S. Food and Drug Administration) has already approved Shionogi's Fetroja (cefiderocol) for the treatment of complicated urinary tract infections (cUTIs), including kidney infections caused by susceptible Gram-negative bacteria, in patients 18 years of age and older. [Overview of the Initiative]

[0006] The purpose of this disclosure is to provide a cephalosporin-based antimicrobial compound that can exhibit an effective antimicrobial spectrum against Gram-negative bacteria, particularly drug-resistant Gram-negative bacteria.

[0007] One aspect of the present disclosure provides a compound represented by formula (I-1) or a pharmaceutically acceptable salt thereof, stereoisomer, rotational isomer, tautomer, or deuterium compound, [ka] Eventually, X is selected from N, CH, or C-Cl. T is selected from S, S=O, CH2, and O. E is [ka] From which R1 and R2 are selected independently from hydrogen, halogen, phenyl group, alkylthio group and optionally an alkyl group substituted with a carbamoyl group (the alkyl group is preferably a C1-C6 alkyl group, the same applies hereinafter), 11 and R 12 Each of these is independently selected from hydrogen, a carboxyl group, and an alkyl group optionally substituted with a carbamoyl group, and m is an integer from 1 to 5. F is a single bond, A is selected from alkylene groups (preferably C1-C6 alkylene groups, the same applies hereinafter), alkenylene groups (preferably C2-C6 alkenylene groups, the same applies hereinafter), and alkynylene groups (preferably C2-C6 alkynylene groups, the same applies hereinafter). [ka] contains one or more N atoms and is a quaternary ammonium group selected from a heterocyclyl group (preferably 3- to 12-membered, more preferably 3- to 6-membered, the same hereinafter), a fused heterocyclyl group (preferably 6- to 14-membered, more preferably 7- to 10-membered, the same hereinafter), a heteroaryl group (preferably 5- to 12-membered, more preferably 5- to 8-membered, the same hereinafter), and a fused heteroaryl group (preferably 5- to 14-membered, more preferably 5- to 12-membered, the same hereinafter). Among them, the heterocyclyl group, the fused heterocyclyl group, the heteroaryl group, and the fused heteroaryl group are each independently optionally substituted with one or more substituents selected from an alkyl group, a halogen, a hydroxy group, a sulfhydryl group, -NR i R j , oxo, thio, -C(O)R k , -C(O)OR k , -C(S)R k , nitro group, cyano group, alkoxy group (preferably C1-C6 alkoxy group, the same hereinafter), alkylthio group (preferably C1-C6 alkylthio group, the same hereinafter), cycloalkyl group (preferably 3- to 12-membered, more preferably 3- to 6-membered, the same hereinafter), heterocyclyl group, aryl group (preferably 6- to 14-membered, more preferably 6- to 10-membered, the same hereinafter), and heteroaryl group, G1 is

Chemical formula

[0008] In the formula, "C" represents a carbon atom.

[0009] In one embodiment, E is [ka] Of these, R1 and R2 are independently selected from hydrogen, a halogen, and an alkyl group optionally substituted with a carbamoyl group.

[0010] In one embodiment, [ka] teeth [ka] Selected from, Of these, R8 is independently selected from halogen, hydroxyl group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 haloalkyl group, and C1-C6 haloalkoxy group. q is an integer between 0 and 5, independently of each other. r are each an independent integer between 0 and 5. Each of s is an independent integer between 0 and 3.

[0011] In one embodiment, [ka] teeth [ka] And, Of these, R8 is independently selected from halogen, hydroxyl group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 haloalkyl group, and C1-C6 haloalkoxy group, where q is an integer from 0 to 5 and r is an integer from 0 to 5.

[0012] In one embodiment, G1 is [ka] Selected from, Of these, R9 is independently selected from halogen, hydroxyl group, alkyl group, alkoxy group, haloalkyl group, and haloalkoxy group. k2 are integers from 1 to 6, each independently. k3 are each an integer from 0 to 3, and k4 are each an independent integer between 0 and 3.

[0013] In one embodiment, R9 is independently selected from halogen, hydroxyl group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 haloalkyl group, and C1-C6 haloalkoxy group. A1 is a single bond or a C1-C6 alkylene group, of which the alkylene group may optionally be a C1-C6 alkyl group, halogen, hydroxyl group, sulfhydryl group, or -NR i R j , oxo, thio, -C(O)R k , -C(O)OR k ,-C(S)R k , substituted with one or more substituents selected from nitro groups, cyano groups, C1-C6 alkoxy groups and C1-C6 alkylthio groups, A2 is a single bond or a C1-C6 alkylene group, of which the alkylene group may optionally be a C1-C6 alkyl group, halogen, hydroxyl group, sulfhydryl group, or -NR i R j , oxo, thio, -C(O)R k , -C(O)OR k ,-C(S)R k , substituted with one or more substituents selected from nitro groups, cyano groups, C1-C6 alkoxy groups and C1-C6 alkylthio groups, k2 are each an independent integer from 1 to 6, k3 are each an independent integer from 0 to 3, k4 are each an independent integer from 0 to 3, and x is an integer between 1 and 3.

[0014] In one embodiment, an example of ring D2 is [ka] Includes.

[0015] In one embodiment, C1 is -NR3-, -NR3-C(=O)-, -NR3-C(=S)-, -NR3-C(=NH)-, -NR3-C(=NH)-NR3-, -NR3-C(=S)-NR3- and [ka] They are selected from among them.

[0016] In one embodiment, R3 is selected from hydrogen, a hydroxyl group, a C1-C6 alkyl group, and a C1-C6 alkoxy group, of which the alkyl group and alkoxy group are independently and optionally selected from a C1-C6 alkyl group, a halogen, a hydroxyl group, and -NR. i R j , [ka] , oxo, -C(O)OR k and are substituted with one or more substituents selected from the cyano group, R n Each of these is independently selected from C1-C6 alkyl groups, hydroxyl groups, and halogens, and k5 is an integer from 0 to 5.

[0017] In one embodiment, [ka] teeth [ka] And R n Each of these is independently selected from C1-C6 alkyl groups, hydroxyl groups, and halogens, and k5 is an integer from 0 to 3.

[0018] In one embodiment, ring D1 is a phenyl group or a naphthyl group.

[0019] In one embodiment, the compound represented by formula I-1 is [ka] And, Among them, A, [ka] G1, C1, D1, R4, and n are as described above.

[0020] One aspect of this disclosure provides a compound represented by formula (I-2) or a pharmaceutically acceptable salt thereof, stereoisomer, rotational isomer, tautomer, or deuterium compound, [ka] Eventually, X is selected from N, CH, or C-Cl. T is selected from S, S=O, CH2, and O. E is [ka] From which R1 and R2 are selected independently from hydrogen, halogen, phenyl group, alkylthio group and optionally an alkyl group substituted with a carbamoyl group (the alkyl group is preferably a C1-C6 alkyl group, the same applies hereinafter), 11 and R 12 Each of these is independently selected from hydrogen, a carboxyl group, and an alkyl group optionally substituted with a carbamoyl group, and m is an integer from 1 to 5. F is a single bond, A is selected from alkylene groups (preferably C1-C6 alkylene groups, the same applies hereinafter), alkenylene groups (preferably C2-C6 alkenylene groups, the same applies hereinafter), and alkynylene groups (preferably C2-C6 alkynylene groups, the same applies hereinafter). [ka] This is a quaternary ammonium group comprising one or more N atoms and selected from heterocyclyl groups (preferably 3-12 members, more preferably 3-6 members, the same applies hereinafter), condensed heterocyclyl groups (preferably 6-14 members, more preferably 7-10 members, the same applies hereinafter), heteroaryl groups (preferably 5-12 members, more preferably 5-8 members, the same applies hereinafter), and condensed heteroaryl groups (preferably 5-14 members, more preferably 5-12 members, the same applies hereinafter), of which the heterocyclyl group, condensed heterocyclyl group, heteroaryl group, and condensed heteroaryl group can each be independently and optionally replaced with an alkyl group, halogen, hydroxyl group, sulfhydryl group, -NR i R j , oxo, thio, -C(O)R k , -C(O)OR k ,-C(S)R k , substituted with one or more substituents selected from nitro groups, cyano groups, alkoxy groups (preferably C1-C6 alkoxy groups, the same applies hereinafter), alkylthio groups (preferably C1-C6 alkylthio groups, the same applies hereinafter), cycloalkyl groups (preferably 3-12 members, more preferably 3-6 members, the same applies hereinafter), heterocyclyl groups, aryl groups (preferably 6-14 members, more preferably 6-10 members, the same applies hereinafter), and heteroaryl groups, G2 is G1 or an alkylene group, of which the alkylene group may optionally be an alkyl group, halogen, hydroxyl group, sulfhydryl group, or -NR i R j , oxo, thio, -C(O)R k , -C(O)OR k ,-C(S)R k , substituted with one or more substituents selected from nitro groups, cyano groups, alkoxy groups and alkylthio groups, and G1 is as described above. C2 is -NR 31 -C(=O)-, -NR3-C(=O)-R 33 -, -C(=O)-NR 31 -, -C(=O)-C(=O)-NR 31 -, -C(=N-OR 32 )-C(=O)-NR 31 -, -NR 31-C(=O)-C(=O)-, -NR 31 -C(=O)-C(=N-OR 32 )-, -NR3-C(=NH)-, -C(=NH)-NR3-, -NR3-C(=S)-, -C(=S)-NR3-, -NR3-C(=S)-NR3-, -NR3-C(=NH)-NR3-, -NR3- and

Chem.

Chem.

Chem.

[0021] In one embodiment, R 31 If it is an alkyl group, then it is an alkyl group, halogen, hydroxyl group, sulfhydryl group, -NR i R j , [ka] , oxo, thio, -C(O)R k , -C(O)OR k ,-C(S)R k It is substituted with one or more substituents selected from nitro, cyano, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups.

[0022] In one embodiment, E is [ka] R1 and R2 are independently selected from hydrogen, halogen, and optionally an alkyl group substituted with a carbamoyl group.

[0023] In one embodiment, [ka] teeth [ka] Selected from, Of these, R8 is independently selected from hydrogen, halogen, hydroxyl group, alkyl group, alkoxy group, haloalkyl group, and haloalkoxy group. q is an integer between 0 and 5, independently of each other. Each r is an integer from 0 to 5, and Each of s is an independent integer between 0 and 3.

[0024] In one embodiment, [ka] teeth [ka] And, Of these, R8 is independently selected from halogen, hydroxyl group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 haloalkyl group, and C1-C6 haloalkoxy group, where q is an integer from 0 to 5 and r is an integer from 0 to 5.

[0025] In one embodiment, G2 is [ka] Selected from, Of these, R9 is independently selected from halogen, hydroxyl group, alkyl group, alkoxy group, haloalkyl group, and haloalkoxy group. k2 are integers from 1 to 6, each independently. k3 are each an integer from 0 to 3, and k4 are each an independent integer between 0 and 3.

[0026] In one embodiment, R9 is independently selected from halogen, hydroxyl group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 haloalkyl group, and C1-C6 haloalkoxy group. A1 is a single bond or a C1-C6 alkylene group, of which the alkylene group may optionally be a C1-C6 alkyl group, halogen, hydroxyl group, sulfhydryl group, or -NR i R j , oxo, thio, -C(O)R k , -C(O)OR k ,-C(S)R k , substituted with one or more substituents selected from nitro groups, cyano groups, C1-C6 alkoxy groups and C1-C6 alkylthio groups, A2 is a single bond or a C1-C6 alkylene group, of which the alkylene group may optionally be a C1-C6 alkyl group, halogen, hydroxyl group, sulfhydryl group, or -NR i R j , oxo, thio, -C(O)R k , -C(O)OR k ,-C(S)R k , substituted with one or more substituents selected from nitro groups, cyano groups, C1-C6 alkoxy groups and C1-C6 alkylthio groups, k2 are each an independent integer between 1 and 6, k3 are each an independent integer between 0 and 3, and k4 are each an independent integer between 0 and 3. x is an integer between 1 and 3.

[0027] In one embodiment, G2 can optionally be a C1-C6 alkyl group, halogen, hydroxyl group, sulfhydryl group, -NR i R j , oxo, thio, -C(O)R k , -C(O)OR k ,-C(S)R k The C1-C6 alkylene group is substituted with one or more substituents selected from a nitro group, a cyano group, a C1-C6 alkoxy group, and a C1-C6 alkylthio group.

[0028] In one embodiment, C2 is -NR3-, -NR 31 -C(=O)-, -NR3-C(=S)-, -NR3-C(=NH)-, -NR3-C(=NH)-NR3-, -NR3-C(=S)-NR3- and [ka] Selected from, preferably -NR 31 It is either -C(=O)- or -NR3-C(=S)-.

[0029] In one embodiment, R3 is selected from hydrogen, a hydroxyl group, an alkyl group, and an alkoxy group, of which the alkyl group and alkoxy group are independently and optionally selected from an alkyl group, halogen, hydroxyl group, and -NR i R j , [ka] , oxo, -C(O)OR k and are substituted with one or more substituents selected from the cyano group, R n Each of these is independently selected from alkyl groups, hydroxyl groups, and halogens, and k5 is an integer from 0 to 5.

[0030] In one embodiment, R 31 The group is selected from hydroxyl groups, alkyl groups, and alkoxy groups, of which the alkyl and alkoxy groups can be independently and arbitrarily selected from alkyl groups, halogens, hydroxyl groups, and -NR groups. i R j , [ka] , oxo, -C(O)OR k and are substituted with one or more substituents selected from the cyano group, R n Each of these is independently selected from alkyl groups, hydroxyl groups, and halogens, and k5 is an integer from 0 to 5.

[0031] In one embodiment, R 31 The substituent is selected from a hydroxyl group, a substituted C1-C6 alkyl group, and optionally a substituted C1-C6 alkoxy group, wherein the substituent is a C1-C6 alkyl group, halogen, hydroxyl group, or -NR i R j , [ka] , oxo, -C(O)OR k and one or more selected from cyano groups.

[0032] In one embodiment, [ka] teeth [ka] And R n Each of these is independently selected from C1-C6 alkyl groups, hydroxyl groups, and halogens, and k5 is an integer from 0 to 3.

[0033] In one embodiment, ring D1 is a phenyl group or a naphthyl group.

[0034] In one embodiment, the compound represented by formula (I-2) [ka] And, Among them, A, [ka] G2, C2, D1, R4, and n are as described above.

[0035] One aspect of the present disclosure provides a compound represented by formula (I-3) or a pharmaceutically acceptable salt thereof, stereoisomer, rotational isomer, tautomer, or deuterium compound, [ka] Eventually, X is selected from N, CH, or C-Cl. T is selected from S, S=O, CH2, and O. E is [ka] From which R1 and R2 are selected independently from hydrogen, halogen, phenyl group, alkylthio group and optionally an alkyl group substituted with a carbamoyl group (the alkyl group is preferably a C1-C6 alkyl group, the same applies hereinafter), 11 and R 12 Each of these is independently selected from hydrogen, a carboxyl group, and an alkyl group optionally substituted with a carbamoyl group, and m is an integer from 1 to 5. F is a single bond, A is selected from alkylene groups (preferably C1-C6 alkylene groups, the same applies hereinafter), alkenylene groups (preferably C2-C6 alkenylene groups, the same applies hereinafter), and alkynylene groups (preferably C2-C6 alkynylene groups, the same applies hereinafter). [ka] This is a quaternary ammonium group comprising one or more N atoms and selected from heterocyclyl groups (preferably 3-12 members, more preferably 3-6 members, the same applies hereinafter), condensed heterocyclyl groups (preferably 6-14 members, more preferably 7-10 members, the same applies hereinafter), heteroaryl groups (preferably 5-12 members, more preferably 5-8 members, the same applies hereinafter), and condensed heteroaryl groups (preferably 5-14 members, more preferably 5-12 members, the same applies hereinafter), of which the heterocyclyl group, condensed heterocyclyl group, heteroaryl group, and condensed heteroaryl group can each be independently and optionally replaced with an alkyl group, halogen, hydroxyl group, sulfhydryl group, -NR i R j , oxo, thio, -C(O)R k , -C(O)OR k ,-C(S)R k, substituted with one or more substituents selected from nitro groups, cyano groups, alkoxy groups (preferably C1-C6 alkoxy groups, the same applies hereinafter), alkylthio groups (preferably C1-C6 alkylthio groups, the same applies hereinafter), cycloalkyl groups (preferably 3-12 members, more preferably 3-6 members, the same applies hereinafter), heterocyclyl groups, aryl groups (preferably 6-14 members, more preferably 6-10 members, the same applies hereinafter), and heteroaryl groups, G2 is G1 or an alkylene group, of which the alkylene group may optionally be an alkyl group, halogen, hydroxyl group, sulfhydryl group, or -NR i R j , oxo, thio, -C(O)R k , -C(O)OR k ,-C(S)R k , substituted with one or more substituents selected from nitro groups, cyano groups, alkoxy groups and alkylthio groups, G1 is [ka] And, Among them, x is an integer from 1 to 6, independently of each other. A1 is selected from a single bond, an alkylene group, an alkenylene group, and an alkynylene group, of which the alkylene group, alkenylene group, and alkynylene group can each be independently and optionally replaced with an alkyl group, halogen, hydroxyl group, sulfhydryl group, or -NR. i R j , oxo, thio, -C(O)R k , -C(O)OR k ,-C(S)R k , substituted with one or more substituents selected from nitro groups, cyano groups, alkoxy groups and alkylthio groups, A2 is selected from a single bond, an alkylene group, an alkenylene group, and an alkynylene group, of which the alkylene group, alkenylene group, and alkynylene group can each be independently and optionally replaced with an alkyl group, halogen, hydroxyl group, sulfhydryl group, or -NR. i R j , oxo, thio, -C(O)R k , -C(O)OR k,-C(S)R k , substituted with one or more substituents selected from nitro groups, cyano groups, alkoxy groups and alkylthio groups, D3 is selected from cycloalkyl groups, condensed cycloalkyl groups, heterocyclyl groups, and condensed heterocyclyl groups. R9 is an alkyl group, halogen, hydroxyl group, sulfhydryl group, oxo, thio, -NR i R j , -C(O)R k , -C(O)OR k Selected from nitro groups, cyano groups, alkoxy groups, and alkylthio groups, of which the alkyl group, alkoxy group, and alkylthio group can each be independently and arbitrarily selected from alkyl groups, halogens, hydroxyl groups, sulfhydryl groups, and -NR groups. i R j , oxo, thio, -C(O)R k , -C(O)OR k ,-C(S)R k , substituted with one or more substituents selected from nitro groups, cyano groups, alkoxy groups, alkylthio groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups, k1 is an integer between 0 and 8. C1 is -O-, -C(=O)-, -C(=O)-C(=O)-, -OC(=O)-, -C(=O)-O-, -NR3-, -NR3-C(=O)-, -C(=O)-NR3-, -C(=O)-C(=O)-NR3-, -C(=N-OR 31 )-C(=O)-NR3-, -NR3-C(=O)-C(=O)-, -NR3-C(=O)-C(=N-OR 31 )-, -NR3-NR3-C(=O)-, -C(=O)-NR3-NR3-, -N=NC(=O)-, -C(=O)-N=N-, -C(=O)-NR3-C(=O)-, -NR3-C(=O)-NR3-, -S-, -S(=O)-, -SO2-, -SO2 -NR3-, -NR3-SO2-, -CH2-NR3-C(=O)-, -NR3-C(=NH)-, -C(=NH)-NR3-, -NR3-C(=S)-, -C(=S)-NR3-, -NR3-C(=S)-NR3-, -NR3-C(=NH)-NR3-, [Chemical formula] and -NR3-, wherein R3 is independently selected from hydrogen, hydroxy group, alkyl group and alkoxy group, and the alkyl group and alkoxy group are independently optionally substituted with one or more substituents selected from alkyl group, halogen, hydroxy group, sulfhydryl group, -NR i R j , [Chemical formula] , oxo, thio, -C(O)R k , -C(O)OR k , -C(S)R k , and is substituted with one or more substituents selected from nitro group, cyano group, alkoxy group, alkylthio group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, and R m is selected from hydrogen atom, alkyl group, hydroxy group, aryl group and heteroaryl group, wherein the alkyl group, aryl group and heteroaryl group are independently optionally substituted with one or more substituents selected from alkyl group, halogen, hydroxy group, sulfhydryl group, -NR i R j , carboxy group, nitro group, cyano group, alkoxy group, alkylthio group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, and R 31 is hydrogen or alkyl group, and ring D2 is as described above, R4 is independently selected from alkyl group, halogen, hydroxy group, sulfhydryl group, oxo, thio, -NR i R j , -C(O)R k , -C(O)OR k , and is selected from nitro group, cyano group, alkoxy group and alkylthio group, wherein the alkyl group, alkoxy group and alkylthio group are independently optionally substituted with one or more substituents selected from alkyl group, halogen, hydroxy group, sulfhydryl group, -NR i R j , oxo, thio, -C(O)R k , -C(O)ORk 、 -C(S)R k 、 substituted with one or more substituents selected from a nitro group, a cyano group, an alkoxy group, an alkylthio group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, n is an integer from 0 to 5, R i and R j are each independently selected from a hydrogen atom, a hydroxy group, a C1-C6 alkyl group, and a C1-C6 alkoxy group, and R k is a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxy group, and -NR i R j selected from, wherein the alkyl group and the haloalkyl group are each independently optionally substituted with an alkyl group, a halogen, a hydroxy group, a sulfhydryl group, -NR i R j 、 oxo, thio, carboxy group, nitro group, cyano group, alkoxy group, alkylthio group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group by one or more substituents selected.

[0036] In certain embodiments, E is

Chemical formula

[0037] In certain embodiments,

Chemical formula

Chemical formula

[0038] In one embodiment, [ka] teeth [ka] And, Of these, R8 is independently selected from halogen, hydroxyl group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 haloalkyl group, and C1-C6 haloalkoxy group, where q is an integer from 0 to 5 and r is an integer from 0 to 5.

[0039] In one embodiment, G2 is [ka] Selected from, Of these, R9 is independently selected from hydrogen, halogen, hydroxyl group, alkyl group, alkoxy group, haloalkyl group, and haloalkoxy group. k2 are integers from 1 to 6, each independently. k3 are each an integer from 0 to 3, and k4 are each an independent integer between 0 and 3.

[0040] In one embodiment, R9 is independently selected from halogen, hydroxyl group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 haloalkyl group, and C1-C6 haloalkoxy group. A1 is a single bond or a C1-C6 alkylene group, of which the alkylene group may optionally be a C1-C6 alkyl group, halogen, hydroxyl group, sulfhydryl group, or -NR i R j , oxo, thio, -C(O)R k, -C(O)OR k , -C(S)R k , substituted with one or more substituents selected from a nitro group, a cyano group, a C1-C6 alkoxy group, and a C1-C6 alkylthio group, A2 is a single bond or a C1-C6 alkylene group, wherein the alkylene group is optionally a C1-C6 alkyl group, a halogen, a hydroxy group, a sulfhydryl group, -NR i R j , oxo, thio, -C(O)R k , -C(O)OR k , -C(S)R k , substituted with one or more substituents selected from a nitro group, a cyano group, a C1-C6 alkoxy group, and a C1-C6 alkylthio group, k2 is independently an integer from 1 to 6, k3 is independently an integer from 0 to 3, k4 is independently an integer from 0 to 3, and x is an integer from 1 to 3.

[0041] In certain embodiments, G2 is optionally a C1-C6 alkyl group, a halogen, a hydroxy group, a sulfhydryl group, -NR i R j , oxo, thio, -C(O)R k , -C(O)OR k , -C(S)R k , a C1-C6 alkylene group substituted with one or more substituents selected from a nitro group, a cyano group, a C1-C6 alkoxy group, and a C1-C6 alkylthio group.

[0042] In certain embodiments, C1 is -NR3-, -NR3-C(=O)-, -NR3-C(=S)-, -NR3-C(=NH)-, -NR3-C(=NH)-NR3-, -NR3-C(=S)-NR3-,

Chemical Formula

[0043] In one embodiment, R3 is selected from hydrogen, a hydroxyl group, an alkyl group, and an alkoxy group, of which the alkyl group and alkoxy group are independently and optionally selected from an alkyl group, halogen, hydroxyl group, and -NR i R j , [ka] , oxo, -C(O)OR k and are substituted with one or more substituents selected from the cyano group, R n Each of these is independently selected from alkyl groups, hydroxyl groups, and halogens, and k5 is an integer from 0 to 5.

[0044] In one embodiment, [ka] teeth [ka] And R n Each of these is independently selected from C1-C6 alkyl groups, hydroxyl groups, and halogens, and k5 is an integer from 0 to 3.

[0045] In one embodiment, the compound represented by formula (I-3) [ka] And, Among them, A, [ka] G2, C1, R4, and n are as described above.

[0046] One aspect of the present disclosure provides a compound represented by formula (I-4) or a pharmaceutically acceptable salt thereof, stereoisomer, rotational isomer, tautomer, or deuterium compound, [ka] Eventually, X is selected from N, CH, or C-Cl. T is selected from S, S=O, CH2, and O. E is [ka] From which R1 and R2 are selected independently from hydrogen, halogen, phenyl group, alkylthio group and optionally an alkyl group substituted with a carbamoyl group (the alkyl group is preferably a C1-C6 alkyl group, the same applies hereinafter), 11 and R 12 Each of these is independently selected from hydrogen, a carboxyl group, and an alkyl group optionally substituted with a carbamoyl group, and m is an integer from 1 to 5. F is a single bond, A is selected from alkylene groups (preferably C1-C6 alkylene groups, the same applies hereinafter), alkenylene groups (preferably C2-C6 alkenylene groups, the same applies hereinafter), and alkynylene groups (preferably C2-C6 alkynylene groups, the same applies hereinafter). [ka] This is a quaternary ammonium group comprising one or more N atoms and selected from heterocyclyl groups (preferably 3-12 members, more preferably 3-6 members, the same applies hereinafter), condensed heterocyclyl groups (preferably 6-14 members, more preferably 7-10 members, the same applies hereinafter), heteroaryl groups (preferably 5-12 members, more preferably 5-8 members, the same applies hereinafter), and condensed heteroaryl groups (preferably 5-14 members, more preferably 5-12 members, the same applies hereinafter), of which the heterocyclyl group, condensed heterocyclyl group, heteroaryl group, and condensed heteroaryl group can each be independently and optionally replaced with an alkyl group, halogen, hydroxyl group, sulfhydryl group, -NR i R j , oxo, thio, -C(O)R k , -C(O)OR k ,-C(S)R k, substituted with one or more substituents selected from nitro groups, cyano groups, alkoxy groups (preferably C1-C6 alkoxy groups, the same applies hereinafter), alkylthio groups (preferably C1-C6 alkylthio groups, the same applies hereinafter), cycloalkyl groups (preferably 3-12 members, more preferably 3-6 members, the same applies hereinafter), heterocyclyl groups, aryl groups (preferably 6-14 members, more preferably 6-10 members, the same applies hereinafter), and heteroaryl groups, G2 is as described above. C3 is a single bond, -O-, -C(=O)-, -C(=O)-C(=O)-, -OC(=O)-, -C(=O)-O-, -NR3-, -NR3-C(=O)-, -C(=O)-NR3-, -C(=O)-C(=O)-NR3-, -C(=N-OR 31 )-C(=O)-NR3-, -NR3-C(=O)-C(=O)-, -NR3-C(=O)-C(=N-OR 31 )-, -NR3-NR3-C(=O)-, -C(=O)-NR3-NR3-, -N=NC(=O)-, -C(=O)-N=N-, -C(=O)-NR3-C(=O)-, -NR3-C(=O)-NR3-, -O-, -S-, -S(=O)-, -SO2-, -S O2-NR3-, -NR3-SO2-, -CH2-NR3-C(=O)-, -NR3-C(=NH)-, -C(=NH)-NR3-, -NR3-C(=S)-, -C(=S)-NR3-, -NR3-C(=S)-NR3-, -NR3-C(=NH)-NR3-, [ka] R3 is selected from -NR3-, where R3 is independently selected from hydrogen, a hydroxyl group, an alkyl group, and an alkoxy group, where the alkyl group and alkoxy group are independently and optionally selected from alkyl, halogen, hydroxyl group, sulfhydryl group, and -NR3-. i R j , [ka] , oxo, thio, -C(O)R k , -C(O)OR k ,-C(S)R k, substituted with one or more substituents selected from nitro, cyano, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, R m The group is selected from hydrogen atoms, alkyl groups, hydroxyl groups, aryl groups, and heteroaryl groups, of which the alkyl groups, aryl groups, and heteroaryl groups can each be independently and arbitrarily selected from alkyl groups, halogens, hydroxyl groups, sulfhydryl groups, and -NR groups. i R j , substituted with one or more substituents selected from carboxyl groups, nitro groups, cyano groups, alkoxy groups, alkylthio groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups, R 31 is hydrogen or alkyl group, and ring D2 is as described above. A3 is selected from alkylene groups, alkenylene groups, and alkynylene groups, of which the alkylene groups, alkenylene groups, and alkynylene groups can each be independently and optionally replaced with alkyl groups, halogens, hydroxyl groups, sulfhydryl groups, and -NR groups. i R j , oxo, thio, -C(O)R k , -C(O)OR k ,-C(S)R k , substituted with one or more substituents selected from nitro groups, cyano groups, alkoxy groups and alkylthio groups, R i and R j Each of these is independently a hydrogen atom or a C1-C6 alkyl group. R k These are, independently, a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyl group, and -NR. i R j Selected from, of which the alkyl group and haloalkyl group are independently and arbitrarily selected from alkyl groups, halogens, hydroxyl groups, sulfhydryl groups, and -NR groups. i R j It is substituted with one or more substituents selected from oxo, thio, carboxyl, nitro, cyano, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups.

[0047] In one embodiment, E is [ka] R1 and R2 are independently selected from hydrogen, halogen, and optionally an alkyl group substituted with a carbamoyl group.

[0048] In one embodiment, [ka] teeth [ka] Selected from, Of these, R8 is independently selected from hydrogen, halogen, hydroxyl group, alkyl group, alkoxy group, haloalkyl group, and haloalkoxy group. q is an integer between 0 and 5, independently of each other. Each r is an integer from 0 to 5, and Each of s is an independent integer between 0 and 3.

[0049] In one embodiment, C3 is a single bond, -NR3-, -NR3-C(=O)-, -NR3-C(=S)-, -NR3-C(=NH)-, -NR3-C(=NH)-NR3-, -NR3-C(=S)-NR3-, [ka] And selected from -NR3-.

[0050] In one embodiment, R3 is selected from hydrogen, a hydroxyl group, an alkyl group, and an alkoxy group, of which the alkyl group and alkoxy group are independently and optionally selected from an alkyl group, halogen, hydroxyl group, and -NR i R j , [ka] , oxo, -C(O)OR k and are substituted with one or more substituents selected from the cyano group, R n k5 is selected from a hydrogen atom, alkyl group, hydroxyl group, and halogen, and k5 is an integer from 0 to 5.

[0051] In one embodiment, formula [ka] teeth [ka] or [ka] And,

[0052] In one embodiment, the compound represented by formula (I-4) [ka] And, Among them, A, [ka] G2, C3, A3 and R k The above is true.

[0053] Another aspect of this disclosure provides a compound represented by formula (I-5) or a pharmaceutically acceptable salt thereof, stereoisomer, rotational isomer, tautomer, or deuterium compound, [ka] Eventually, X is selected from N, CH, or C-Cl. T is selected from S, S=O, CH2, and O. E is [ka] From which R1 and R2 are selected independently from hydrogen, halogen, phenyl group, alkylthio group and optionally an alkyl group substituted with a carbamoyl group (the alkyl group is preferably a C1-C6 alkyl group, the same applies hereinafter), 11 and R 12 Each of these is independently selected from hydrogen, a carboxyl group, and an alkyl group optionally substituted with a carbamoyl group, and m is an integer from 1 to 5. F is a single bond, R 13 is a hydrogen atom or a carboxyl group protecting group. R 14 is an optionally substituted aryl group or an optionally substituted heterocyclyl group, A is selected from alkylene groups, alkenylene groups, and alkynylene groups. Q is a heterocyclyl group that is optionally substituted (preferably a heterocyclyl group containing at least one N atom), Y1 is an arbitrarily substituted alkylene group, an arbitrarily substituted alkenylene group, an arbitrarily substituted alkynylene group, -N=CH-CH=N-, -N=CH-CH=NO-, -N=CH-CH2-, -N=CH(C=O)-, -N=CH(C=S)-, -NR 71 -C(=O)-, -NR 71 -C(=NH)-, -NR 71 -C(=S)-, -NR 71 -C(=O)CH2-, -NR 71 -C(=NH)CH2-, -NR 71 -C(=S)CH2-, -NR 71 C(=O)NR 71 -, -NR 71 C(=NH)NR 71 -, -NR 71 C(=S)NR 71 -, -NR 71 C(=O)NR 71 -O-, -NR 71 C(=NH)NR 71 -O-, -NR 71 C(=S)NR 71 -O-, -NR 71 C(=O)-C(=O)NR71 -, -NR 71 C(=NH)-C(=O)NR 71 -, -NR 71 C(=S)-C(=O)NR 71 -, -NR 71 C(=NH)-C(=NH)NR 71 -, -NR 71 C(=S)-C(=S)NR 71 -, -NR 71 CH2C(=O)-, -NR 71 CH2C(=S)-, -NR 71 S(=O)2NR 71 C(=O)-, -NR 71 S(=O)2NR 71 C(=NH)-, -NR 71 S(=O)2NR 71 C(=S)-, -NR 71 C(=O)NR 71 S(=O)²⁻, -NR 71 C(=NH)NR 71 S(=O)²⁻, -NR 71 C(=S)NR 71 Selected from S(=O)2- and single bonds, Each R 71 These may be independently selected from hydrogen, a hydroxyl group, an alkyl group, and an optionally substituted alkoxy group. Y2 is selected from a single bond, an optionally substituted alkylene group, an optionally substituted alkenylene group, and an optionally substituted alkynylene group. Y3 is -C(=O)-, -C(=S)-, -C(=O)-C(=O)-, -C(=S)-C(=O)-, -C(=S)-C(=S)-, -C(=O)-C(=NR 15 )-,-C(=S)-C(=NR 15 )- and -N=CR 16 -Selected from, of which, R 15 R is selected from a hydroxyl group, a ureido group, and an optionally substituted alkoxy group. 16 is a carbamoyl group optionally substituted or a carboxyl group optionally protected by a carboxyl protecting group or a salt thereof. Z1 is -NR 16 -, -N+ R 17 R 18 -, -NR 19 -C(=O)-NR 20 -, -NR 19 -C(=NH)-NR 20 -, -NR 19 -C(=S)-NR 20 - and single bonds are selected, of which R 16 R is selected from hydrogen, a carbamoyl group, an optionally substituted alkyl group, and an optionally hydroxyl group protected by a hydroxyl protecting group. 17 and R 18 Each is independently selected from an optionally substituted alkyl group, an optionally substituted alkylene group, and an optionally substituted alkenylene group, R 19 and R 20 Each is independently selected from hydrogen, an optionally substituted alkyl group, an optionally substituted hydroxyl group protected by an optionally substituted hydroxyl group protecting group, and an optionally substituted heterocyclyl group, Z2 is -NR 21 -or a single bond, of which R 21 The group is selected from hydrogen, optionally substituted alkyl groups, and optionally protected hydroxyl groups.

[0054] In one embodiment, Q does not contain a quaternary ammonium structure.

[0055] In one embodiment, the heterocyclyl group in Q is selected from pyrrolidinyl group, imidazolidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, dihydroimidazolyl group, dihydrofuranyl group, dihydropyrazolyl group, dihydropyrrolyl group, piperidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group and homopiperazinyl group, of which the heterocyclyl group may optionally be an alkyl group, halogen, hydroxyl group, sulfhydryl group, -NR i R j , oxo, thio, -C(O)R k , -C(O)OR k ,-C(S)R k, substituted with one or more substituents selected from nitro groups, cyano groups, alkoxy groups and alkylthio groups, preferred examples of Q [ka] Includes, for example, [ka] Even if that is the case, Of these, R8 is independently selected from hydrogen, halogen, hydroxyl group, alkyl group, alkoxy group, haloalkyl group and haloalkoxy group, and Each q is an independent integer between 0 and 5.

[0056] In one embodiment, R 14 teeth [ka] D4 is an aryl group or a heterocyclyl group, preferably a phenyl group or a naphthyl group, and R 41 These are, independently, alkyl groups, halogens, hydroxyl groups, sulfhydryl groups, oxo, thio, and -NR groups. i R j , -C(O)R k , -C(O)OR k Selected from nitro groups, cyano groups, alkoxy groups, and alkylthio groups, of which the alkyl group, alkoxy group, and alkylthio group can each be independently and arbitrarily selected from alkyl groups, halogens, hydroxyl groups, sulfhydryl groups, and -NR groups. i R j , oxo, thio, -C(O)R k , -C(O)OR k ,-C(S)R k It is substituted with one or more substituents selected from a nitro group, cyano group, alkoxy group, alkylthio group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group, where n is an integer from 0 to 8.

[0057] In one embodiment, the compound represented by formula (I-5) [ka] And, Among them, A, Q, Y1, Z1, Y2, Z2, Y3, R 13 and R 14 The above is true.

[0058] In one embodiment, the compound [ka] [ka] [ka] [ka] They are selected from among them.

[0059] The "alkyl group" described in this disclosure is preferably a C1-C6 alkyl group.

[0060] The "alkylene group" described in this disclosure is preferably a C1-C6 alkylene group.

[0061] The "alkenylene group" described in this disclosure is preferably a C2-C6 alkenylene group.

[0062] The "alkylylene group" described in this disclosure is preferably a C2-C6 alkylylene group.

[0063] The "alkoxy group" described in this disclosure is preferably a C1-C6 alkoxy group.

[0064] The "alkylthio group" described in this disclosure is preferably a C1-C6 alkylthio group.

[0065] The "cycloalkyl group" described herein is preferably a cycloalkyl group having 3 to 12 members, more preferably 3 to 6 members.

[0066] The “condensed cycloalkyl group” described herein is preferably a condensed cycloalkyl group having 6 to 14 members, more preferably 7 to 10 members.

[0067] The "heterocyclyl group" described herein is preferably a heterocyclyl group with 3 to 12 members, more preferably a heterocyclyl group with 3 to 6 members.

[0068] The “condensed heterocyclyl group” described herein is preferably a 6- to 14-membered, more preferably 7- to 10-membered condensed heterocyclyl group.

[0069] The “aryl group” described herein is preferably a 6- to 14-membered, more preferably a 6- to 10-membered aryl group.

[0070] The “condensed ring aryl group” described herein is preferably an 8- to 14-membered, more preferably an 8- to 12-membered condensed ring aryl group.

[0071] The "heteroaryl group" described herein is preferably a 5- to 12-membered heteroaryl group, more preferably a 5- to 8-membered heteroaryl group.

[0072] The “condensed heteroaryl group” described herein is preferably a 5- to 14-membered, more preferably 5- to 12-membered condensed heteroaryl group.

[0073] The "optionally substituted" group described in this disclosure is an alkyl group (preferably a C1-C6 alkyl group), a halogen, a deuterium, a hydroxyl group, a sulfhydryl group, or -NR. i R j , oxo, thio, -C(O)R k , -C(O)OR k ,-S(O)R k , -S(O)OR k ,-S(O)(O)R k , -S(O)(O)OR k,-C(S)R k It may also be substituted with one or more substituents selected from nitro groups, cyano groups, alkoxy groups (preferably C1-C6 alkoxy groups), alkylthio groups (preferably C1-C6 alkylthio groups), alkenyl groups (preferably C2-C6 alkenyl groups), alkynyl groups (preferably C2-C6 alkynyl groups), cycloalkyl groups (preferably 3-6 membered cycloalkyl groups), heterocyclyl groups (preferably 3-6 membered heterocyclyl groups), condensed cycloalkyl groups (preferably 7-10 membered condensed cycloalkyl groups), condensed heterocyclyl groups (preferably 7-10 membered condensed heterocyclyl groups), aryl groups (preferably 6-10 membered aryl groups), heteroaryl groups (preferably 5-10 membered heteroaryl groups), condensed ring aryl groups (preferably 8-12 membered condensed ring aryl groups), and condensed heteroaryl groups (preferably 5-12 membered condensed heteroaryl groups). i , R j and R k As stated above, the group of selectable substituents for each "optionally substituted" group may be homologous or different.

[0074] In one embodiment, the compound described herein has a Z configuration.

[0075] This disclosure further provides pharmaceutical compositions comprising at least one of the aforementioned compounds or a pharmaceutically acceptable salt thereof, or stereoisomers, rotational isomers, or tautomers thereof, or deuterium compounds, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0076] In one embodiment, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0077] In one embodiment, the pharmaceutical composition contains 0.01% to 99.99% of the compound, based on the total weight of the composition. In another embodiment, the pharmaceutical composition contains 0.1% to 99.9% of the compound. In yet another embodiment, the pharmaceutical composition contains 0.5% to 99.5% of the compound. In yet another embodiment, the pharmaceutical composition contains 1% to 99% of the compound. In yet another embodiment, the pharmaceutical composition contains 2% to 98% of the compound.

[0078] In one embodiment, based on the total weight of the composition, the pharmaceutical composition contains 0.01% to 99.99% of pharmaceutically acceptable carriers, diluents, or excipients. In one embodiment, the pharmaceutical composition contains 0.1% to 99.9% of pharmaceutically acceptable carriers, diluents, or excipients. In one embodiment, the pharmaceutical composition contains 0.5% to 99.5% of pharmaceutically acceptable carriers, diluents, or excipients. In one embodiment, the pharmaceutical composition contains 1% to 99% of pharmaceutically acceptable carriers, diluents, or excipients. In one embodiment, the pharmaceutical composition contains 2% to 98% of pharmaceutically acceptable carriers, diluents, or excipients.

[0079] This disclosure further relates to the use of the compounds described herein or their pharmaceutically acceptable salts, stereoisomers, rotational isomers, tautomers, or deuterium compounds, or pharmaceutical compositions containing them, in the preparation of agents for the prevention or treatment of diseases caused by pathogens in mammals, including humans.

[0080] This disclosure further relates to the use of the compounds described herein or their pharmaceutically acceptable salts, or their stereoisomers, rotational isomers, tautomers, or deuterium compounds, in the preparation of agents for the prevention or treatment of diseases caused by Gram-negative bacteria.

[0081] This disclosure further relates to a compound described herein that is a drug, or a pharmaceutically acceptable salt thereof, stereoisomer, rotational isomer, tautomer, or deuterium compound, or a pharmaceutical composition containing the same.

[0082] This disclosure further relates to the compounds described herein or pharmaceutically acceptable salts, stereoisomers, rotational isomers, tautomers, or deuterium compounds thereof, or pharmaceutical compositions containing them, for the prevention and treatment of diseases caused by pathogens in mammals, including humans.

[0083] This disclosure further relates to the compounds described herein or pharmaceutically acceptable salts, stereoisomers, rotational isomers, tautomers, or deuterium compounds thereof, or pharmaceutical compositions containing them, for the prevention or treatment of diseases caused by Gram-negative bacteria.

[0084] This disclosure further relates to a method for preventing and treating a disease caused by a pathogen, the method comprising administering to a patient in need a therapeutically effective dose of a compound described in this disclosure or a pharmaceutically acceptable salt, stereoisomer, rotational isomer, tautomer, or deuterium compound thereof, or a pharmaceutical composition containing the same.

[0085] The disclosure further relates to a method for preventing and treating a disease caused by Gram-negative bacteria, the method comprising administering to a patient in need a therapeutically effective dose of a compound described in the disclosure or a pharmaceutically acceptable salt, stereoisomer, rotational isomer, tautomer, or deuterium compound thereof, or a pharmaceutical composition containing the same.

[0086] In this specification, diseases caused by the aforementioned pathogenic bacteria or Gram-negative bacteria include, but are not limited to, respiratory tract infections, urinary tract infections, respiratory infections, sepsis, nephritis, cholecystitis, oral infections, endocarditis, pneumonia, meningomyelia, otitis media, enteritis, sinusitis, wound infections, and opportunistic infections.

[0087] In this specification, the Gram-negative bacteria are preferably intestinal Gram-negative bacteria (such as Escherichia coli, Klebsiella, Serratia, Enterobacter, Citrobacter, Morganella, Providencia, and Proteus), Gram-negative bacteria that reside in the respiratory system (such as Haemophilus and Moraxella), and glucose-non-fermenting Gram-negative bacteria (such as Pseudomonas aeruginosa, Pseudomonas other than P. aeruginosa, Stenotrophomonas, Burkholderia, and Acinetobacter).

[0088] This disclosure further provides the use of the compounds described herein or their pharmaceutically acceptable salts, stereoisomers, rotational isomers, tautomers, or deuterium compounds in agents for the prevention and treatment of diseases caused by Gram-positive bacteria.

[0089] In this specification, the mammal may be a human or a non-human mammal.

[0090] This disclosure further provides reagent kits comprising the compounds described herein or pharmaceutically acceptable salts, stereoisomers, rotational isomers, tautomers or deuterium compounds thereof, or pharmaceutical compositions.

[0091] Tests conducted using methods known in this field (e.g., WO2010050468) showed that the compounds relating to this disclosure exhibit inhibitory activity against Gram-negative bacteria and exhibit excellent efficacy.

[0092] Explanation of terms Unless otherwise specified, terms used in the specification and claims have the following meanings:

[0093] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group, which is a linear or branched group containing 1 to 20 carbon atoms, and preferably an alkyl group containing 1 to 12 carbon atoms. The non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl Syl group, 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2,3-dimethylhexyl group, 2,4-dimethylhexyl group, 2,5-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group, 2 This includes -ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 2-methyl-2-ethylpentyl group, 2-methyl-3-ethylpentyl group, n-nonyl group, 2-methyl-2-ethylhexyl group, 2-methyl-3-ethylhexyl group, 2,2-diethylpentyl group, n-decyl group, 3,3-diethylhexyl group, 2,2-diethylhexyl group, and various branched isomers thereof.More preferably, the alkyl group contains 1 to 6 carbon atoms, and non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, and the like. The alkyl group may be substituted or unsubstituted, and if substituted, the substituent may be substituted at any available connection site, and the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, or carboxylic acid ester groups.

[0094] The term "alkylene group" refers to a saturated linear or branched aliphatic hydrocarbon group having two residues derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane, and is a linear or branched group containing 1 to 20 carbon atoms, preferably containing 1 to 12 carbon atoms, and more preferably containing 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), etc. The alkylene group may be substituted or unsubstituted, and if substituted, the substituent may be substituted at any available connection site.

[0095] The term "alkenylene group" includes linear alkenyl groups having 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, and having at least one double bond at any position, such as vinylidene, allylene, propenylene, butenylene, prenylene, butadienylene, pentenylene, pentadienyldene, hexenylene, and hexadienylene groups.

[0096] The term "alkynylene group" refers to a linear alkylylene group having 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, and having at least one triple bond at any position, and includes, for example, ethynylene group, propynylene group, butynylene group, pentynylene group, hexynylene group, and the like.

[0097] The term "cycloalkyl group" refers to saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituents, where the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl groups, while polycyclic cycloalkyl groups include cycloalkyl groups of spiro rings, fused rings, and crosslinked rings.

[0098] The term "spirocycloalkyl group" refers to a polycyclic group in which 5-20 membered monorings share one carbon atom (referred to as a spiro atom), and may contain one or more double bonds, but does not have rings with a fully conjugated π-electron system. Preferably, it has 6-14 members, and more preferably 7-10 members. Spirocycloalkyl groups are classified into monospirocycloalkyl groups, bisspirocycloalkyl groups, or polyspirocycloalkyl groups depending on the number of spiro atoms shared between the rings, with monospirocycloalkyl groups and bisspirocycloalkyl groups being preferred. More preferably, they are 4-member / 4-membered, 4-member / 5-membered, 4-member / 6-membered, 5-member / 5-membered, or 5-member / 6-membered monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups are provided below. [ka] Includes.

[0099] The term "condensed cycloalkyl group" refers to a 5-20 member, all-carbon polycyclic group in which each ring in the system shares one adjacent pair of carbon atoms with the other rings in the system, and which may contain one or more double bonds, but which do not have rings with a fully conjugated π-electron system. Preferably, it has 6-14 members, and more preferably 7-10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic condensed cycloalkyl group, preferably bicyclic or tricyclic, and more preferably a 5-member / 5-member or 5-member / 6-member bicycloalkyl group. Non-limiting examples of condensed cycloalkyl groups are [ka] Includes.

[0100] The term "crosslinked cycloalkyl group" refers to a 5-20 membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly linked, and which may contain one or more double bonds but have no rings with a fully conjugated π-electron system. Preferably, it has 6-14 members, and more preferably 7-10 members. Depending on the number of rings it comprises, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic crosslinked cycloalkyl groups, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of crosslinked cycloalkyl groups include: [ka]

[0101] The cycloalkyl ring may be condensed with an aryl group, a heteroaryl group, or a heterocycloalkyl ring, of which the ring linked to the parent structure is a cycloalkyl group, and non-limiting examples include an indanyl group, a tetrahydronaphthyl group, a benzocycloheptane group, and the like. The cycloalkyl group may be optionally substituted or unsubstituted, and if substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, or carboxylic acid ester groups.

[0102] The term "heterocyclyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, of which one or more ring atoms are nitrogen, oxygen, or S(O). m The heteroatoms are selected from (where m is an integer from 0 to 2), but do not contain the -OO-, -OS-, or -SS- ring portion, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms, and more preferably 3 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl group, imidazolidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, dihydroimidazolyl group, dihydrofuranyl group, dihydropyrazolyl group, dihydropyrrolyl group, piperidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, homopiperazinyl group, etc., with piperidinyl group and pyrrolidinyl group being preferred. Polycyclic heterocyclyl groups include heterocyclyl groups of spiro rings, fused rings, and bridging rings.

[0103] The term "spiroheterocyclyl group" refers to a polycyclic heterocyclyl group in which 5-20 membered monocyclic rings share one atom (called a spiro atom), one or more of which ring atoms are nitrogen, oxygen, or S(O).m The ring atom is a heteroatom selected from (where m is an integer from 0 to 2), and the remaining ring atom is carbon. It may contain one or more double bonds, but there is no ring with a fully conjugated π-electron system. Preferably it is 6 to 14 members, more preferably 7 to 10 members. The spiroheterocyclyl group is divided into a monospiroheterocyclyl group, a bisspiroheterocyclyl group, or a polyspiroheterocyclyl group depending on the number of spiro atoms shared by the rings, preferably a monospiroheterocyclyl group and a bisspiroheterocyclyl group. More preferably it is a 4-member / 4, 4-member / 5-member, 4-member / 6-member, 5-member / 5-member, or 5-member / 6-member monospiroheterocyclyl group. Non-limiting examples of spiroheterocyclyl groups are [ka] Includes.

[0104] The term "condensed heterocyclyl group" refers to a polycyclic heterocyclyl group with 5 to 20 members, in which each ring in the system shares one pair of adjacent atoms with other rings in the system, and one or more rings may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system, and one or more of the ring atoms are nitrogen, oxygen, or S(O). m The heteroatom is selected from (where m is an integer from 0 to 2), and the remaining ring atom is carbon. Preferably, it has 6 to 14 members, and more preferably 7 to 10 members. Depending on the number of rings that make up the group, it can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl groups, preferably bicyclic or tricyclic, and more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl group. Non-limiting examples of fused heterocyclyl groups are [ka] Includes.

[0105] The term "bridged heterocyclyl group" refers to a polycyclic heterocyclyl group having 5 to 14 members in which any two rings share two atoms that are not directly linked, and which may contain one or more double bonds but lack rings with a fully conjugated π-electron system, of which one or more ring atoms are nitrogen, carbon, or S(O). m The heteroatom is selected from (where m is an integer from 0 to 2), and the remaining ring atom is carbon. Preferably, it has 6 to 14 members, and more preferably 7 to 10 members. Depending on the number of rings that make up the group, it can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic bridging heterocyclyl groups, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridging heterocyclyl groups are [ka] Includes.

[0106] The heterocyclyl ring may be condensed with an aryl group, a heteroaryl group, or a cycloalkyl ring, of which the ring linked to the parent structure is a heterocyclyl group, and a non-limiting example thereof is: [ka] This includes, among others.

[0107] The heterocyclyl group may be optionally substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, or carboxylic acid ester groups.

[0108] The term "aryl group" refers to a 6-14 member all-carbon monocyclic or condensed polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6-10 membered, such as a phenyl group and a naphthyl group. The aryl ring may be condensed with a heteroaryl group, a heterocyclyl group, or a cycloalkyl group, of which the ring linked to the parent structure is an aryl ring, and non-limiting examples include: [ka] Includes.

[0109] The aryl group may be substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylic acid ester groups, and is preferably a phenyl group.

[0110] The term "fused ring aryl group" may refer to an aromatic, unsaturated fused ring structure containing 8 to 14 ring atoms, formed by the sharing of two or more adjacent atoms between two or more cyclic structures, with 8 to 12 ring atoms being preferred. Examples include fully unsaturated fused ring aryl groups such as naphthalene and phenanthrene, and also partially saturated fused ring aryl groups such as benzo-3 to 8-membered saturated monocyclic cycloalkyl groups and benzo-3 to 8-membered partially saturated monocyclic cycloalkyl groups. Specific examples include, for example, 2,3-dihydro-1H-indenyl, IH-indenyl, 1,2,3,4-tetrahydronaphthyl, and 1,4-dihydronaphthyl.

[0111] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, of which the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 12 members, for example, an imidazolyl group, a furanyl group, a thienyl group, a thiazolyl group, a pyrazolyl group, an oxazolyl group, a pyrrolyl group, a tetrazolyl group, a pyridyl group, a pyrimidinyl group, a thiadiazolyl group, a pyrazinyl group, etc. Preferably an imidazolyl group, a pyrazolyl group, a pyrimidinyl group, or a thiazolyl group, and more preferably a pyrazolyl group or a thiazolyl group. The heteroaryl ring may be condensed with an aryl group, a heterocyclyl group, or a cycloalkyl ring, of which the ring linked to the parent structure is a heteroaryl ring, and non-limiting examples thereof are: [ka] Includes.

[0112] The heteroaryl group may be optionally substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylic acid ester groups.

[0113] The term "condensed heteroaryl group" refers to an aromatic, unsaturated condensed ring structure that contains 5 to 14 ring atoms (including at least one heteroatom), formed by two or more cyclic structures sharing two connecting atoms, and simultaneously contains oxo-substituted carbon, nitrogen, and sulfur atoms. Preferably, it is a "5-12 member condensed heteroaryl group," a "7-12 member condensed heteroaryl group," a "9-12 member condensed heteroaryl group," etc., such as a benzofuranyl group. These include benzoisofuranyl group, benzothiophenyl group, indolyl group, isoindolyl group, benzoxazolyl group, benzimidazolyl group, indazolyl group, benzotriazolyl group, quinolyl group, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolyl group, acridinyl group, phenantridinyl group, phthalazinyl group, phthalazinyl group, quinazolinyl group, quinoxalinyl group, phenazinyl group, pteridine group, prinyl group, naphthilidinyl group, phenazinyl group, phenothiazinyl group, etc.

[0114] The condensed heteroaryl group may be optionally substituted or unsubstituted, and if substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylic acid ester groups.

[0115] The term "alkoxy group" refers to -O-(alkyl group) and -O-(unsubstituted cycloalkyl group), of which alkyl groups are defined as described above. Non-exclusive examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy groups. Alkoxy groups may be optionally substituted or unsubstituted, and if substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylic acid ester groups.

[0116] The term "alkylthio group" refers to -S-(alkyl group) and -S-(unsubstituted cycloalkyl group), of which alkyl groups are defined as described above. Non-limiting examples of alkylthio groups include methylthio group, ethylthio group, propylthio group, butylthio group, cyclopropylthio group, cyclobutylthio group, cyclopentylthio group, and cyclohexylthio group. Alkylthio groups may be optionally substituted or unsubstituted, and if substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0117] The term "hydroxyalkyl group" refers to an alkyl group substituted with a hydroxyl group, and among these, alkyl groups are defined as described above.

[0118] The term "haloalkyl group" refers to an alkyl group substituted with a halogen, and the alkyl group is defined as described above.

[0119] The term "deuterated alkyl group" refers to an alkyl group substituted with a deuterium atom, and the alkyl group is defined as described above.

[0120] The term "hydroxyl group" refers to the -OH group.

[0121] The term "oxo" refers to an O group. For example, a carbon atom and an oxygen atom are linked by a double bond, forming a ketone or aldehyde group.

[0122] The term "thio" refers to the =S group. For example, a carbon atom and a sulfur atom are linked by a double bond to form a thiocarbonyl group -C(S)-.

[0123] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0124] The term "amino group" refers to -NH2.

[0125] The term "cyano group" refers to -CN.

[0126] The term "nitro group" refers to -NO2.

[0127] The term "carboxyl group" refers to -C(O)OH.

[0128] The term "aldehyde group" refers to -CHO.

[0129] The term "carboxylic acid ester group" refers to -C(O)O (alkyl group) or -C(O)O (cycloalkyl group), of which alkyl groups and cycloalkyl groups are defined as described above.

[0130] The term "acyl halogen" refers to compounds that contain the group -C(O)-halogen.

[0131] "Carboxylate protecting groups" are groups applied to the protection of carboxyl groups, as known in this field, as described in the literature ("Protective Groups in Organic Synthesis", 5 Th The carboxyl protecting group in Ed. TW Greene & PGM Wuts is referenced, and as an example, preferably the carboxyl protecting group is substituted or unsubstituted C 1-10 Linear or branched alkyl groups, substituted or unsubstituted C 2-10 A linear or branched alkenyl or alkynyl group, substituted or unsubstituted C 3-8 cyclic alkyl groups, substituted or unsubstituted C 5-10 an aryl group or heteroaryl group, or (C 1-8 It may also be an alkyl group or aryl group, or a 3-silyl group, preferably C 1-6 A linear or branched alkyl group, more preferably C 1-4 These are linear or branched alkyl groups. Examples include methyl, ethyl, allyl, isopentenyl, and trimethylsilylethyl groups.

[0132] "Amino protecting groups" are groups known in this field that are applied to the protection of amino groups, as seen in the reference ("Protective Groups in Organic Synthesis", 5 Th The amino protecting group in (Ed. TW Greene & PGM Wuts) is referenced, but preferably the amino protecting group is a (C) such as a formyl group, acetyl group, or benzoyl group. 1-10 (Alkyl or aryl group) It may also be an acyl group, (C 1-6 Alkyl alkyl group or C 6-10 It may also be an aryl group or a sulfonyl group, such as Boc or Cbz (C 1-6 Alkoxy group or C 6-10It may be an aryloxy group, a carbonyl group, or a substituted or unsubstituted alkyl group such as a trityl group (Tr), 2,4-dimethoxybenzyl (DMB), p-methoxybenzyl (PMB), or a benzyl group (Bn).

[0133] "Hydroxy protecting groups" are groups known in this field that are applied to the protection of hydroxyl groups, as seen in the reference ("Protective Groups in Organic Synthesis", 5 Th The hydroxyl protecting group in Ed. TW Greene & PGM Wuts is referenced. For example, preferably, the hydroxyl protecting group is a triethylsilyl group, triisopropylsilyl group, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, etc. (C 1-10 It may also be an alkyl group or aryl group, a 3-silyl group, or a C group such as a methyl group, tert-butyl group, allyl group, benzyl group, methoxymethyl group (MOM), ethoxyethyl group, or 2-tetrahydropyranyl (THP). 1-10 Alkyl alkyl groups or substituted alkyl groups, preferably alkyl groups substituted with alkoxy or aryl groups, more preferably C 1-6 C substituted with an alkoxy group 1-6 C substituted with alkyl or phenyl groups 1-6 Alkyl alkyl group, most preferably C 1-4 C substituted with an alkoxy group 1-4 It may be an alkyl group, such as a formyl group, acetyl group, or benzoyl group (C 1-10 (Alkyl group or aryl group) It may also be a syl group, (C 1-6 Alkyl alkyl group or C 6-10 (aryl group) may also be a sulfonyl group, (C 1-6 Alkoxy group or C 6-10 An aryloxy group may also be a carbonyl group.

[0134] The term "leaving group" refers to an atom or functional group that detaches from a larger molecule in a chemical reaction. Typical leaving groups include halogens, substituted sulfonyloxy groups, phosphoryloxy groups, amino groups, and R iR j N-, cyano group, R m There are S- and others.

[0135] The substituted sulfonyloxy group may be a C1-C6 alkylsulfonyloxy group, a perfluoroC1-C6 alkylsulfonyloxy group, an arylsulfonyloxy group, an aralkylsulfonyloxy group, or the like.

[0136] Specific examples of C1-C6 alkylsulfonyloxy groups include C1-C6 linear or branched alkylsulfonyloxy groups such as methylsulfonyloxy, ethylsulfonyloxy, n-propylsulfonyloxy, isopropylsulfonyloxy, n-butylsulfonyloxy, tert-butylsulfonyloxy, n-pentylsulfonyloxy, and n-hexylsulfonyloxy.

[0137] Specific examples of perfluoroC1-C6 alkylsulfonyloxy groups include C1-C6 linear or branched perfluoroalkylsulfonyloxy groups such as trifluoromethylsulfonyloxy, 1,1,2,2,2-pentafluoro-1-ethylsulfonyloxy, 1,1,2,2,3,3,3-heptafluoro-1-propylsulfonyloxy, and 1,1,2,2,3,3,4,4,4-nonafluoro-1-butylsulfonyloxy.

[0138] Examples of arylsulfonyloxy groups include phenylsulfonyloxy groups and naphthylsulfonyloxy groups having, optionally, 1 to 3 substituents selected from the group consisting of a C1-C6 linear or branched alkyl group, a C1-C6 linear or branched alkyl group, a nitro group, and a halogen atom on a benzene ring. Specific examples of optionally substituent-containing phenylsulfonyloxy groups include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-tolylphenylsulfonyloxy, 2-nitrophenylsulfonyloxy, and 3-chlorophenylsulfonyloxy. Specific examples of naphthylsulfonyloxy groups include α-naphthylsulfonyloxy and β-naphthylsulfonyloxy.

[0139] Examples of aralkylsulfonyloxy groups include C1-C6 linear or branched alkylsulfonyloxy groups substituted with a phenyl group (optionally having 1-3 substituents selected from a C1-C6 linear or branched alkyl group, a C1-C6 linear or branched alkyl group, a nitro group, and a halogen atom on a benzene ring), and C1-C6 linear or branched alkylsulfonyloxy groups substituted with a naphthyl group. Specific examples of alkylsulfonyloxy groups substituted with a phenyl group include benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-xylylsulfonyloxy, and 3-chlorobenzylsulfonyloxy. Specific examples of alkylsulfonyloxy groups substituted with a naphthyl group include α-naphthylmethylsulfonyloxy and β-naphthylmethylsulfonyloxy.

[0140] "Optional" or "optionally" means that the event or situation described below may occur, but is not necessarily so, and the expression includes cases where the event or situation occurs and cases where it does not. For example, "optionally alkyl-substituted heterocyclyl group" means that alkyl groups may be present, but is not necessarily so, and the expression includes cases where the heterocyclyl group is substituted with an alkyl group and cases where the heterocyclyl group is not substituted with an alkyl group.

[0141] "Substitutive" means that one or more hydrogen atoms in the group, preferably five or fewer, more preferably one to three hydrogen atoms, are substituted by a number of substituents that correspond independently to each other. Of course, substituents are only located at chemically possible sites, and those skilled in the art can identify possible or impossible substitutions (by experiment or theory) without excessive effort.

[0142] In the chemical structure of the compounds described in this disclosure, TIFF0007864220000093.tif15155 In the chemical structure of the compounds described herein, TIFF0007864220000094.tif12151 does not have a specified configuration; that is, it may be in Z configuration or E configuration, or it may contain both configurations simultaneously.

[0143] Tautomers are structural isomers of organic compounds that are readily interconverted by a chemical reaction called tautomerism. Such reactions always involve the transfer of hydrogen atoms or protons, with the transformation of single bonds and adjacent double bonds. Some common tautomer pairs are keto-enols and lactam-lactims. An example of lactam-lactim equilibrium is between A and B, as shown below. [ka]

[0144] All compounds in this disclosure can be depicted as either type A or type B. All tautomer forms are within the scope of this disclosure. The nomenclature of the compounds does not exclude any tautomer.

[0145] "Each independently" or "independently" means that substituents with the same selection range may be homologous or different groups at their respective locations, but the selection of the group at each location of the substituent is not affected by the selection of that substituent (or substituents with the same selection range) at other locations.

[0146] Compounds described herein or their pharmaceutically acceptable salts, or any isotopically labeled derivatives of their isomers, are covered by this disclosure. Atoms that can be isotoped include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine. Each of these is an isotope. 2 H(D), 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 It can be replaced by I, etc. Unless otherwise specified, when a position is identified as deuterium (D), it should be understood that the position contains deuterium at an abundance at least 3000 times higher than the natural abundance of deuterium (0.015%) (i.e., at least 45% deuterium is incorporated). [Modes for carrying out the invention]

[0147] The preparation of the compounds and pharmaceutically acceptable salts described herein will be further described below in conjunction with examples, but these examples are not intended to limit the scope of this disclosure.

[0148] Experimental methods in the examples of this disclosure that do not specify concrete conditions generally follow conventional conditions or conditions recommended by the raw material or product manufacturer. Reagents whose specific source is not specified are commercially available, common reagents.

[0149] The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (LCMS). The NMR shift (δ) is 10 -6 The values ​​are expressed in units of ppm. NMR measurements are performed using a Bruker AVANCE-400 nuclear magnetic resonance spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as the measurement solvents, and tetramethylsilane (TMS) as the internal standard. The stereochemistry of the optical isomers (isomers) of the compound is further confirmed by measuring single-crystal parameters.

[0150] HPLC measurements are performed using Waters ACQUITY ultra high performance LC, Shimadzu LC-20A systems, Shimadzu LC-2010HT series, or Agilent 1200 LC high-performance liquid chromatographs (ACQUITY UPLC BEH C18 1.7UM 2.1×50 mm chromatography column, Ultimate XB-C18 3.0×150 mm chromatography column, or Xtimate C18 2.1×30 mm chromatography column).

[0151] MS measurements are performed using a Waters SQD2 mass spectrometer, scanning in positive / negative ion mode with a mass scanning range of 100-1200.

[0152] Chiral HPLC analysis uses the following chromatography columns: Chiralpak IC-3 100×4.6 mm ID, 3 μm, Chiralpak AD-3 150×4.6 mm ID, 3 μm, Chiralpak AD-3 50×4.6 mm ID, 3 μm, Chiralpak AS-3 150×4.6 mm ID, 3 μm, Chiralpak AS-3 100×4.6 mm ID, 3 μm, ChiralCel OD-3 150×4.6 mm ID, 3 μm, Chiralcel OD-3 100×4.6 mm ID, 3 μm, ChiralCel OJ-H 150×4.6 mm ID, 5 μm, and Chiralcel OJ-3 150×4.6 mm ID, 3 μm.

[0153] For thin-layer chromatography, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used. The specifications for silica gel plates used in thin-layer chromatography (TLC) are 0.15 mm to 0.2 mm, and the specifications for separation and purification of products by thin-layer chromatography are 0.4 mm to 0.5 mm.

[0154] For flash column purification, Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage) are used.

[0155] Normal-phase column chromatography typically uses silica gel from Yantai Huanghai, with mesh sizes of 100-200, 200-300, or 300-400, as a support, or pre-packed ultra-high purity normal-phase silica gel columns from Changzhou Sandai (40-63 μm, 60, 12 g, 25 g, 40 g, 80 g, or other specifications).

[0156] Reverse-phase column chromatography typically uses pre-packed ultra-high purity C18 silica gel columns from Changzhou Sandai (20-45 μm, 100 Å, 40 g, 80 g, 120 g, 220 g, or other specifications).

[0157] For high-pressure column purification, Waters AutoP is used, along with either a Waters XBridge BEH C18 OBD Prep Column (130 Å, 5 μm, 19 mm × 150 mm) or an Atlantis T3 OBD Prep Column (100 Å, 5 μm, 19 mm × 150 mm).

[0158] For chiral preparative columns, DAIEL CHIRALPAK IC (250 mm × 30 mm, 10 μm) or Phenomenex-Amylose-1 (250 mm × 30 mm, 5 μm) are used.

[0159] The known starting materials relating to this disclosure may be synthesized by or in accordance with methods known in the art, or may be purchased from companies such as Shanghai Taitan Technology, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc.), and Darui Chemicals.

[0160] In the examples, unless otherwise specified, all reactions can be carried out under a nitrogen atmosphere.

[0161] An argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen balloon with a capacity of approximately 1 L.

[0162] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a capacity of approximately 1 L.

[0163] The pressurized hydrogenation reaction is carried out using a Parr 3916EKX type hydrogenator and a QL-500 type hydrogen generator or an HC2-SS type hydrogenator.

[0164] The hydrogenation reaction typically involves repeating the process of evacuating the system and filling it with hydrogen three times.

[0165] The microwave reaction will be carried out using a CEM Discover-S 908860 microwave reactor.

[0166] In the examples, unless otherwise specified, "solution" refers to an aqueous solution.

[0167] In the examples, unless otherwise specified, the reaction temperature is room temperature between 20°C and 30°C.

[0168] The reaction process in the examples was monitored by thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography to purify the compound, and the developing solvent system for thin-layer chromatography included A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system, D: petroleum ether / ethyl acetate / methanol, and E: petroleum ether / tetrahydrofuran system. The volume ratio of the solvents was adjusted according to the polarity of the compound, but it may also be adjusted by adding small amounts of basic or acidic reagents such as triethylamine and acetic acid.

[0169] Example 1 [ka]

[0170] Step 1 [ka] Compound 1-1 (2.46 g, 10 mmol) was dissolved in 86 mL of 5% aqueous sodium bicarbonate solution and stirred until clarified. Fmoc-OSu (3.37 g, 10 mmol, dissolved in 24 mL of dioxane) was added, and the mixture was reacted overnight. Most of the dioxane was evaporated under reduced pressure, the pH was adjusted with hydrochloric acid, and the mixture was extracted with ethyl acetate to separate the layers. The mixture was dried over magnesium sulfate, filtered, and evaporated to dryness to obtain compound 1-2 (5.2 g), which was then used directly in the next step. LC / MS (ESI): m / z 469.1 [M+H] +

[0171] Step 2 [ka] Compounds 1-2 (2.08 g, 4 mmol), EDCI (1.15 g, 6 mmol), and DMAP (49 mg, 0.4 mmol) were dissolved in dichloromethane (20 mL), then p-methoxybenzyl alcohol (828 mg, 6 mmol) was added and the mixture was reacted with stirring. After the reaction was complete, the mixture was concentrated under reduced pressure, methyl tert-butyl ether was added to form a slurry, and the mixture was filtered and the solvent removed under vacuum to obtain compound 1-3 (1.31 g, 2.23 mmol) with a yield of 56%. LC / MS (ESI): m / z 589.1[M+H] +

[0172] Step 3 [ka] Compound 1-3 (945 mg, 1.6 mmol) was dissolved in dichloromethane (10 mL), then DBU (243 mg, 1.6 mmol) was added and the mixture was stirred while reacting. After the reaction was complete, aqueous citric acid solution was added to quench the reaction, and the mixture was diluted with MTBE and separated into layers. The aqueous phase was adjusted to pH=8 with 1 N NaOH solution, extracted with dichloromethane, dried, and filtered to concentrate and obtain compound 1-4 (562 mg) in a yield of 96%. LC / MS (ESI): m / z 367.1 [M+H] +

[0173] Step 4 [ka] Compound 1-4 (534 mg, 1.46 mmol) was dissolved in acetonitrile (20 mL), and 1,4-dibromobutane (330 mg, 1.53 mmol) and N,N-diisopropylethylamine (395 mg, 3.06 mmol) were added. The mixture was heated under reflux for 6 hours. After the reaction was complete, aqueous citric acid solution was added to quench the reaction, and the mixture was diluted with methyl tert-butyl ether and separated into layers. The aqueous phase was extracted with dichloromethane, evaporated to dryness under reduced pressure, and the pH was further adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted with methyl tert-butyl ether, and the organic phases were combined. The mixture was then dried over anhydrous MgSO4, filtered, and concentrated to obtain compound 1-5 (400 mg) in a yield of 66%. LC / MS (ESI): m / z 421.1 [M+H] +

[0174] Step 5 [ka] Compound 1-5 (211 mg, 0.5 mmol), Compound 1-6 (360 mg, 0.45 mmol, obtained by the method of patent WO2016035847), and sodium iodide (225 mg, 1.5 mmol) were dissolved in N,N-dimethylformamide (0.8 mL), and the mixture was reacted while stirring. After the reaction was complete, the reaction solution was 0 o The mixture was cooled to 1C, and potassium iodide (523 mg, 3.15 mmol), N,N-dimethylformamide (1.6 mL), and acetyl chloride (177 mg, 2.25 mmol) were added. The mixture was stirred and reacted. After the reaction was complete, the reaction solution was added to a 5% aqueous solution of Na2S2O5, stirred, filtered, and the solvent was removed under vacuum to obtain compound 1-7 (540 mg). LC / MS (ESI): m / z 1164.2[M] +

[0175] Step 6 [ka] Compounds 1-7 (233 mg) were dissolved in anisole (0.5 mL) and trifluoroacetic acid (2 mL), and the reaction was carried out with stirring. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, the residue was dissolved in methyl t-butyl ether, washed with dilute hydrochloric acid, and the aqueous phase was combined and concentrated under reduced pressure to obtain 110 mg of crude product, which was then separated by HPLC to obtain 4 mg of compound 1. LC / MS (ESI): m / z 668.0[M+H] + 1 H-NMR(400 MHz,DMSO-d6)δ: 1.27-1.38(m,1H),1.44(s,3H),1.45(s,3H),1.56-1.80(m,4 H),1.82-1.96(m,1H),1.97-2.15(m,4H),3.04-3.20(m,3H),3.27-3.71(m,5H),3.92(d,1H),3.96-4.10(m,2H),4.65-4 .88(m,1H),5.27(d,1H),5.90-5.93(m,1H),6.71(s,1H),7.32(s,2H),8.06-8.56(m,2H),9.50(d,1H),12.62(brs,1H).

[0176] Example 2 [ka]

[0177] Step 1 [ka] Compound 2-1 (2.0 g, 10.69 mmol, 1 eq) was dissolved in dichloromethane (10 mL), triethylamine (3.24 g, 32.07 mmol, 3 eq) was added, and methanesulfonyl chloride (2.43 g, 21.38 mmol, 2 eq) was added dropwise. The reaction was allowed to proceed at room temperature. After the reaction was complete, the mixture was diluted with dichloromethane, washed with water, dried, filtered, and concentrated to obtain the crude product. 2.6 g of the crude product (approximately 8.96 mmol) was dissolved in acetonitrile (20 mL), and potassium carbonate (2.76 g, 20 mmol, 2.23 eq) and pyrrolidine (1.06 g, 15 mmol, 1.67 eq) were added. o The reaction was carried out overnight with stirring in 1C. After the reaction was complete, the solvent was evaporated under reduced pressure, the compound was dissolved in dichloromethane, washed with water, dried, filtered, concentrated under reduced pressure, and then separated by column chromatography to obtain 1.7 g of compound 2-2, with a yield of 79%.

[0178] Step 2 [ka] Compound 2-2 (300 mg, 1.25 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added, and the reaction was carried out with stirring. After the reaction was complete, the mixture was concentrated under reduced pressure, diluted with methanol, neutralized with potassium carbonate, and filtered to concentrate the mixture to obtain the crude product of compound 2-3, which was then used directly in the next step. LC / MS (ESI): m / z 141.1 [M+H] +

[0179] Step 3 [ka] The crude product of compound 2-3 obtained in the previous step, compound 2-4 (synthesized by the method of patent CN106661052A, 1.07 g, 2.5 mmol), and HATU (1.43 g, 3.75 mmol) were dissolved in N,N-dimethylformamide (10 mL), DIPEA (1.1 mL, 6.25 mmol) was added, and the mixture was reacted overnight with stirring. After the reaction was complete, aqueous sodium hydroxide solution was added and the mixture was stirred. The mixture was filtered, the filter cake was washed with water, and the solvent was removed under vacuum to obtain the crude product. This was separated by column chromatography to obtain compound 2-5 (600 mg, 1.09 mmol), with a two-step yield of 87%. LC / MS (ESI): m / z 555.1 [M+H] +

[0180] Step 4 [ka] Compounds 2-5 (219 mg, 0.4 mmol), 1-6 (398 mg, 0.5 mmol), sodium iodide (180 mg, 1.2 mmol), and boric acid (7.5 mg, 0.12 mmol) were dissolved in N-methylpyrrolidone (1 mL) and reacted with stirring. After the reaction was complete, the mixture was cooled in ice water, and KI (465 mg, 2.8 mmol), N-methylpyrrolidone (2 mL), and acetyl chloride (188 mg, 2.4 mmol) were added and reacted with stirring. After the reaction was complete, the reaction solution was directly added to a large amount of aqueous sodium pyrosulfite under ice bath, stirred, filtered, and the filter cake was washed with water to remove the solvent under vacuum to obtain compound 2-6 (635 mg). LC / MS (ESI): m / z 1294.4[M] +

[0181] Step 5 [ka] Compound 2-6 (200 mg) was dissolved in anisole (0.4 mL) and trifluoroacetic acid (1.6 mL), and the reaction was carried out with stirring. After the reaction was complete, MTBE (4 mL) was added to precipitate the solid, filtered, rinsed with MTBE, and dried to obtain 170 mg of crude product. After fractionation by HPLC, 4.2 mg of compound 2 was obtained. LC / MS (ESI): m / z 777.9[M+H] + 1 H-NMR(400 MHz,DMSO-d6)δ: 1.00-1.08(m,4H),1.44(s,3H),1.45(s,3H),1.91-2.14(m,4 H),3.36-3.44(m,2H),3.48-3.60(m,3H),3.60-3.74(m,3H),3.80(d,1H),4. 18(d,1H),5.01(d,1H),5.18-5.24(m,1H),5.67-5.82(m,1H),6.66-6.84(m, 3H),7.29(s,2H),8.76(s,1H),9.24-9.55(m,2H),10.26(br s,1H).

[0182] Example 3 [ka]

[0183] Step 1 [ka] Compound 3-1 (5 g, 29.40 mmol) and Compound 3-2 (3.68 g, 44.10 mmol) were dissolved in methanol (30 mL) and water (15 mL) and stirred. Potassium carbonate (14.22 g, 102.89 mmol) was added, and the mixture was heated under reflux to allow the reaction to proceed. After the reaction was complete, the mixture was cooled to room temperature, and MTBE and NaOH aqueous solution were added and separated. The aqueous phase was extracted with MTBE. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated until dry to obtain 0.7 g of Compound 3-3. LC / MS (ESI): m / z 145.1 [M+H] +

[0184] Step 2 [ka] Compound 2-4 (1.9 g, 4.43 mmol) was stirred in tetrahydrofuran (30 mL) under an ice bath, triethylamine (0.98 mL, 7.09 mmol) was added, and methanesulfonyl chloride (0.45 mL, 5.80 mmol) was added dropwise, after which the reaction was carried out under an ice bath. Compound 3-3 was dissolved in THF (10 mL) and added dropwise to the above reaction mixture, and after addition, the reaction mixture was heated to room temperature and the reaction was carried out. Ethyl acetate was added, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated until dry to obtain the crude product. The crude product was fractionated by HPLC to obtain 220 mg of compound 3-4. LC / MS (ESI): m / z 555.1 [M+H] +

[0185] Step 3 [ka] Compounds 1-6 (315 mg, 0.395 mmol), 3-4 (220 mg, 0.395 mmol), and sodium iodide (178 mg, 1.19 mmol) were added to N,N-dimethylformamide (0.9 mL) and reacted with stirring. After the reaction was complete, the reaction flask was cooled in an ice bath, and PBr3 (751 mg, 2.77 mmol) was added and reacted with stirring. After the reaction was complete, the reaction solution was added dropwise to an aqueous solution of NaHSO3, filtered, and the filter cake was washed with clean water and dried under vacuum to obtain 623 mg of crude product of compound 3-5. LC / MS (ESI): m / z 1298.1 [M] +

[0186] Step 4 [ka] Compounds 3-5 (200 mg, 0.154 mmol) were added to anisole (0.4 mL), trifluoroacetic acid (1.6 mL) was added, and the mixture was reacted at room temperature. Methyl tert-butyl ether was added, the mixture was stirred, and then the reaction was passed. The filtered cake was rinsed with MTBE and dried to obtain 112 mg of crude product. The crude product was fractionated by HPLC to obtain 7.1 mg of compound 3. LC / MS (ESI): m / z 781.9 [M+H] + 1 H-NMR(400 MHz,DMSO-d6)δ:1.43(s,3H),1.46(s,3H),1.94-2.09(m,3H),2.10-2.21(m,1H),3.43-3.56( m,8H),3.57-3.67(m,3H),3.67-3.83(m,2H),3.92-4.06(m,1H),4.07-4.36(m,3H),5.03-5.11 (m,1H),5.15(d,1H),5.69-5.75(m, 1H),6.71-6.82(m,3H),7.27(s,2H),8.15(s,1H).

[0187] Example 4 [ka]

[0188] Step 1 [ka] Compound 2-4 (3.0 g, 7.0 mmol) and triethylamine (0.85 g, 8.39 mmol) were added to toluene (50 mL), and diphenyl phosphate azide (2.31 g, 8.39 mmol) was gradually added dropwise. The mixture was then allowed to react overnight with stirring. o The reaction was carried out by raising the temperature to C, and then 9-fluorenylmethanol (2.06 g, 10.49 mmol) was added, followed by 110 oThe reaction was carried out with 1C, and after the reaction was complete, the temperature was lowered to room temperature. Piperidine (2.98 g, 34.97 mmol) was added, and the mixture was reacted overnight with stirring. Heating was stopped, the mixture was concentrated to remove toluene, dichloromethane and water were added, and the mixture was stirred and separated into layers. The aqueous phase was further extracted with dichloromethane, the organic phases were combined, dried, filtered, and concentrated to obtain the crude product. The crude product was directly subjected to column chromatography to obtain 462 mg of compound 4-1, with a yield of 17%. LC / MS(ESI): m / z 400.0[M+H] +

[0189] Step 2 [ka] Compound 4-1 (0.46 g, 1.15 mmol) was dissolved in dichloromethane (8 mL), and thiophosgene (0.40 g, 3.45 mmol) was added dropwise. o DMAP (0.70 g, 5.73 mmol) was added to 13C, and the mixture was heated to room temperature and stirred while reacting. After the reaction was complete, the reaction mixture was subjected to column chromatography to obtain 432 mg of compound 4-2, with a yield of 85%.

[0190] Step 3 [ka] Compound 4-2 (0.43 g, 1.01 mmol), compound 4-3 (0.13 g, 1.1 mmol), and DMAP (0.61 g, 5.0 mmol) were added to a reaction flask, and DMF (0.5 mL) was added. The mixture was then allowed to react overnight at room temperature with stirring. Water was added to the reaction mixture to precipitate a solid, which was then filtered. The filtered cake was collected and subjected to column chromatography to obtain 467 mg of compound 4-4, with a yield of 83%. LC / MS(ESI): m / z 556.0[M+H] +

[0191] Step 4 [ka] Compound 4-4 (200 mg, 0.36 mmol), Compound 1-6 (315 mg, 0.4 mmol), and sodium iodide (180 mg, 1.2 mmol) were dissolved in NMP (0.9 mL), and the mixture was reacted while stirring. After the reaction was complete, the reaction solution was 0 o The mixture was cooled to 1°C, PBr3 (650 mg, 2.4 mmol) was added, and the reaction was carried out with stirring. After the reaction was complete, the reaction mixture was added to an aqueous Na2S2O5 solution under ice bath, stirred, filtered, and the filter cake was washed with water to remove the solvent under vacuum to obtain compound 4-5 (515 mg). LC / MS (ESI): m / z 1299.0[M] +

[0192] Step 5 [ka] Compounds 4-5 (200 mg, 0.154 mmol) were placed in a reaction flask, anisole (0.4 mL) and trifluoroacetic acid (1.6 mL) were added, and the mixture was reacted with stirring. After the reaction was complete, MTBE was added, the mixture was filtered, and the filter cake was rinsed with MTBE and dried to obtain 68 mg of crude product. The crude product was fractionated by HPLC to obtain 4.4 mg of compound 4. LC / MS (ESI): m / z 782.9 [M+H] + 1 H-NMR(400 MHz,DMSO-d6)δ: 1.43(s,3H),1.44(s,3H),1.46-1.57(m,1H),1.78-2.11(m,4H),2.96(d,1H),3.41(d,2H),3.4 8-3.93(m,9H),4.57(s,1H),5.26(s,1H),5.38-5.45(m,1H),6.57(d,1H),6.64(d,1H),6.88(s, 1H),7.22-7.51(m,2H),9.05(s,1H),9.22-9.34(m,1H),9.36(s,1H),9.77(brs,1H).

[0193] Example 5: [ka]

[0194] Step 1 [ka] Compound 3-1 (50.0 g, 0.294 mol), hydroxylamine hydrochloride (40.8 g, 0.59 mol), sodium carbonate (62.3 g, 0.59 mol), ethanol (300 mL), and water (150 mL) were added to a three-necked flask. o The reaction was carried out in an oil bath of C. After the reaction was complete, the reaction solution was concentrated, isopropyl ether and water were added, and the mixture was stirred to separate the layers. The organic phase was washed with saturated brine, dried, and concentrated to obtain the crude product. Compound 5-1 (12.5 g) was obtained by vacuum distillation, with a yield of 33%. LC / MS (ESI): m / z 131.1 [M+H] +

[0195] Step 2 [ka] Compound 5-1 (1.0 g, 7.7 mmol), acetonitrile (10 mL), and sodium bicarbonate (1.3 g, 15.4 mmol) were added to a single-necked flask, cooled with ice water, and acetyl chloride (0.66 g, 8.5 mmol) was added dropwise. The reaction mixture was carried out in an ice water bath, and after the reaction was complete, dichloromethane and water were added and the mixture was stirred to separate the layers. The aqueous phase was extracted with dichloromethane, dried, and concentrated to obtain compound 5-2 (0.9 g, yield 68%). LC / MS (ESI): m / z 173.1 [M+H] +

[0196] Step 3 [ka] Compound 5-2 (510 g, 3 mmol), DCM (10 mL), and imidazole (410 mg, 6 mmol) were added to a single-necked flask. Tert-butyldiphenylchlorosilane (910 mg, 3.3 mmol) was added dropwise, and after the reaction was complete, DCM and H2O were added and the mixture was stirred to separate the layers. The aqueous phase was extracted with DCM. The organic phase was washed with saturated brine, dried, concentrated, and purified by column chromatography to obtain compound 5-3 (1.1 g) in 92% yield. LC / MS (ESI): m / z 411.1 [M+H] +

[0197] Step 4 [ka] Compound 5-4 (synthesized by the method of patent WO2016035847, 330 mg, 0.43 mmol), compound 5-3 (210 mg, 0.5 mmol), sodium iodide (194 mg, 1.3 mmol), and NMP (1.0 mL) were added to a single-necked flask and reacted at room temperature. After the reaction was complete, the reaction solution was added dropwise to a 5% aqueous sodium bisulfite solution, filtered, the filter cake was washed with water, and the solvent was removed under vacuum to obtain 230 mg of compound 5-5. LC / MS (ESI): m / z 1154.1 [M] +

[0198] Step 5 [ka] Compound 5-5 (200 mg, 0.164 mmol) was dissolved in anisole (0.4 mL) and trifluoroacetic acid (1.6 mL), and the mixture was reacted with stirring. After the reaction was complete, MTBE was added, the mixture was filtered, and the filter cake was rinsed with MTBE and dried to obtain 66 mg of crude product. The crude product was fractionated by HPLC to obtain 1.9 mg of compound 5. LC / MS (ESI): m / z 640.0 [M+H] + 1H-NMR(400 MHz,DMSO-d6)δ: 1.39(s,3H),1.45 (s,3H),1.89-2.16(m,4H),2.00(s,3H),3.41-3.90(m,12H),3.93-4.25(m ,2H),5.13-5.17(m,1H),5.70-5.80(m,1H),6.73(s,1H),7.22(s,2H),8.20 (s,1H).

[0199] Example 6: [ka]

[0200] Step 1 [ka] Compound 5-1 (0.5 g, 3.8 mmol), dichloromethane, and imidazole (0.8 g, 11.5 mmol) were added to a reaction flask, cooled with ice water, and tert-butyldiphenylchlorosilane (1.15 g, 4.3 mmol) was added dropwise. The reaction was carried out with stirring, and after the reaction was complete, dichloromethane and water were added and stirred to separate the layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried, concentrated, and purified by column chromatography to obtain compound 6-1 (1.2 g, yield 85%). LC / MS (ESI): m / z 369.1 [M+H] +

[0201] Step 2 [ka] Compound 2-4 (428 mg, 1.0 mmol) and N,N-dimethylacetamide (4 mL) were added to a three-necked flask. The reaction mixture was cooled in an ice salt bath, and then MsCl (126 mg, 1.1 mmol) and TEA (111 mg, 1.1 mmol) were added dropwise, and the reaction was carried out with stirring. Compound 6-1 (410 mg, 1.0 mmol) was added, and N-methylmorpholine (172 mg, 1.7 mmol) was added dropwise. After the reaction was complete, the reaction was quenched, and the aqueous phase was extracted with EA. The organic phases were combined, dried, concentrated, and purified by column chromatography to obtain compound 6-2 (240 mg, yield 30.8%). LC / MS (ESI): m / z 779.0 [M+H] +

[0202] Step 3 [ka] Compound 5-4 (270 mg, 0.35 mmol), compound 6-2 (240 mg, 0.31 mmol), sodium iodide (157 mg, 1.05 mmol), and NMP (0.81 mL) were added to a single-necked flask and reacted overnight at room temperature. The reaction mixture was then added dropwise to a 5% aqueous solution of sodium pyrosulfite, filtered, and the solvent was removed under vacuum to obtain 501 mg of compound 6-3. LC / MS (ESI): m / z 1523.1 [M] +

[0203] Step 4 [ka] Compound 6-3 (501 mg) was added to a reaction flask, TFA (4 mL) and anisole (1 mL) were added, and the mixture was reacted with stirring. After the reaction was complete, MTBE was added dropwise to the reaction mixture, filtered, and the filter cake was washed with MTBE to obtain 210 mg of crude product. The crude product was purified by reverse-phase column chromatography to obtain compound 6 (10 mg). LC / MS (ESI): m / z 767.8 [M+H] + 1 H-NMR (400 MHz,DMSO-d6)δ: 1.42(s,3H),1.48 (s,3H),1.85-2.25(m,4H),3.40-3.86(m,11H),3.88-4.07(m,2H),4.17-4.39 (m,1H),4.91-5.06 (m,1H),5.14-5.20(m,1H),5.74-5.83(m,1H),6.58-6.91 (m,3H),7.22(s,2H),10.65(br s,1H),11.60(br s,1H).

[0204] Example 7: [ka]

[0205] Step 1 [ka] Weigh compound 7-1 (0.40 g, 0.76 mmol) (synthesized according to known literature European Journal of Medicinal Chemistry, 2018, 155, 847-868) into a reaction flask, add anhydrous dichloromethane (4 mL) under nitrogen protection, and -40 o Cool to C, add pyridine (0.20 g, 2.5 mmol) dropwise, add trifluoromethanesulfonic acid anhydride (0.28 g, 0.99 mmol) dropwise, and -5 o The reaction was carried out by raising the temperature to C for 2 hours, then at room temperature for 2 hours, and then at -5 o The temperature was lowered again to 1C, ammonium sulfide was added dropwise, and the reaction was carried out at room temperature. After the reaction was complete, dichloromethane was added to dilute the mixture, it was washed with water, dried over anhydrous sodium sulfate, filtered, the solvent was removed by evaporation under reduced pressure, and the mixture was separated and purified using silica gel to obtain compound 7-2 (0.35 g, 0.65 mmol) in a yield of 85%. LC / MS (ESI): m / z 541.0 [M+H] +

[0206] Step 2 [ka] Compound 7-2 (350 mg, 0.65 mmol), compound 1-6 (647 mg, 0.81 mmol), and sodium iodide (369 mg, 2.46 mmol) were added to N,N-dimethylformamide (2 mL) and reacted with stirring. After the reaction was complete, the reaction flask was cooled in an ice bath, and PBr3 (360 mg, 1.33 mmol) was added and reacted with stirring. After the reaction was complete, the reaction mixture was added dropwise to an aqueous solution of NaHSO3. The mixture was filtered, the filter cake was washed with clean water, and then dried under vacuum to obtain 1.1 g of crude compound 7-3.

[0207] Step 3 [ka] Compound 7-3 (1.06 g, 0.824 mmol) was added to anisole (2 mL) and trifluoroacetic acid (8 mL), and the mixture was reacted at room temperature. Methyl tert-butyl ether was added, the mixture was stirred, and then filtered. The filtered cake was rinsed with MTBE and dried to obtain 550 mg of crude product. 50 mg of the crude product was taken and fractionated by HPLC to obtain 4.8 mg of compound 7. HRMS: 768.1334 [M+H] +

[0208] Example 8: [ka]

[0209] Step 1 [ka] Compound 8-1 (200 mg, 0.92 mmol) (synthesized according to known literature J. Med. Chem. 1997, 40, 1186-1194) was dissolved in DMF (10 mL) and PMBCl (503 mg, 3.21 mmol), K2CO3 (509 mg, 3.68 mmol), and NaI (138 mg, 0.92 mmol) were added. The reaction was heated to 50°C and carried out with stirring. After adding water to the reaction mixture, it was extracted with ethyl acetate, and the organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by reverse-phase silica gel column chromatography to obtain compound 8-2 (105 mg, yield 25%). 1 H-NMR (400 MHz,DMSO-d6) δ: 3.76 (s,6H),3.18 (s,3H),5.18 (s,2H),5.19 (s,2H),6.96 (d,4H),7.44 (d,4H),7.53 (s,1H),7.67 (s,1H),7.81 (s,2H),8.44 (s,1H).

[0210] Step 2 [ka] A mixed solution of compound 8-2 (105 mg, 0.23 mmol) in THF (3 mL) and MeOH (1.5 mL) was added to a solution of LiOH.H2O (20 mg, 0.46 mmol) in H2O (1.5 mL). The mixture was reacted at room temperature with stirring. After cooling the reaction solution to room temperature in an ice bath, it was neutralized with 2 M HCl, extracted with ethyl acetate, washed the organic phase sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain crude compound 8-3 (100 mg). 1 H-NMR (400 MHz,DMSO-d6) δ: 3.76 (s,6H),5.18 (s,2H),5.19 (s,2H),6.96 (d,4H),7.44 (d,4H),7.52 (s,1H),7.64 (s,1H),7.79 (s,2H),8.40 (s,1H),12.85 (br s,1H).

[0211] Step 3 [ka] A solution of compound 8-3 (100 mg, 0.23 mmol) in THF (3 mL) was cooled in an ice bath, protected with argon, and MsCl (53 mg, 0.46 mmol) and Et3N (70 mg, 0.69 mmol) were added. The reaction mixture was allowed to react at the same temperature with stirring. THF (1 mL) of compound 8-A (40 mg, 0.35 mmol) was added to the reaction mixture, and the reaction mixture was heated to room temperature and stirred. After adding water to the reaction mixture, it was extracted with EA, the organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel flash chromatography to obtain compound 8-4 (70 mg, 57%). LC / MS (ESI): m / z 541.1 [M+H] +

[0212] Step 4 [ka] Compound 8-4 (86 mg, 0.16 mmol), compound 1-6 (139 mg, 0.18 mmol), and sodium iodide (81 mg, 0.54 mmol) were added to N,N-dimethylformamide (0.5 mL) and reacted with stirring. After the reaction was complete, the reaction flask was cooled in an ice bath, and PBr3 (72 mg, 0.26 mmol) was added and reacted with stirring. After the reaction was complete, the reaction mixture was added dropwise to an aqueous solution of NaHSO3. The mixture was filtered, the filter cake was washed with clean water, and then dried under vacuum to obtain 150 mg of crude compound 8-5. LC / MS (ESI): m / z 1284.1[M] +

[0213] Step 5 [ka] Compound 8-5 (150 mg, 0.117 mmol) was placed in a single-necked flask, anisole (0.3 mL) and TFA (1.2 mL) were added, and the mixture was reacted with stirring. Then MTBE was added, and the mixture was filtered to obtain 78 mg of the crude product. The crude product was fractionated by HPLC to obtain 11.21 mg of compound 8. HRMS: 768.2109 [M+H] +

[0214] Example 9: [ka]

[0215] Step 1 [ka] To a solution of compound 2-4 (500 mg, 1.17 mmol) in DMF (12 mL), methyl iodide (5 g, 35.1 mmol) and potassium carbonate (323 mg, 2.34 mmol) were added and the mixture was allowed to react completely with stirring at room temperature. Water was added to the reaction mixture, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel flash chromatography to obtain compound 9-2 (505 mg, 97% yield). LC / MS (ESI): m / z 465.0 [M+Na] +

[0216] Step 2 [ka] A 1 M LiAlH4 (1.1 mL, 1.14 mmol) THF solution was added dropwise to a THF (4.2 mL) solution of compound 9-2 (505 mg, 1.14 mmol) cooled in ice water. The reaction was gradually heated to room temperature to allow complete reaction. After cooling the reaction mixture in an ice bath, Na2SO4.10H2O was added, the mixture was stirred at room temperature, filtered to remove the solid, and the resulting filtrate was concentrated under reduced pressure to obtain the crude product, compound 9-3. The crude product was used directly in the next step (465 mg, 98% yield). LC / MS (ESI): m / z 437.1 [M+Na] +

[0217] Step 3 [ka] Dess-Martin reagent (712 mg, 1.68 mmol) was added to a solution of compound 9-3 (465 mg, 1.12 mmol) in DCM (23 mL) cooled with ice / water. The reaction was gradually heated to room temperature to allow complete reaction. After quenching the reaction with H2O, the reaction was extracted with DCM, the organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel flash chromatography to obtain compound 9-4 (440 mg, 95% yield). LC / MS (ESI): m / z 412.9 [M+H] +

[0218] Step 4 [ka] A CH3CN (5 mL) solution of the mixture NH2OH.HCl (82 mg, 1.18 mmol) and Et3N (199 mg, 197 mmol) was stirred at room temperature. A CH3CN (5 mL) solution of compound 9-4 (405 mg, 0.98 mmol) was added dropwise, and the resulting mixture was stirred at room temperature. MsCl (280 mg, 2.45 mmol) and Et3N (104 mg, 1.03 mmol) were added to the reaction mixture, respectively. The mixture was stirred at room temperature until the reaction was complete. After quenching the reaction by adding H2O, the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel flash chromatography to obtain compound 9-5 (290 mg, 72% yield). LC / MS (ESI): m / z 432.0 [M+Na] +

[0219] Step 5 [ka] n-BuLi (0.64 mL, 1.02 mmol) was gradually added dropwise to a solution of compound 9-5 (210 mg, 0.51 mmol) in THF (5 mL) cooled with ice water. After adding a solution of compound 8-A (88 mg, 0.77 mmol) in THF (1 mL) to the reaction mixture, the reaction was further heated to room temperature and stirred. After the reaction was complete, saturated NH4Cl solution was added to the reaction mixture to quench the reaction. The reaction was extracted with EA, the organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel flash chromatography to obtain compound 9-6 (147 mg, yield 54%). LC / MS (ESI): m / z 524.2 [M+H] +

[0220] Step 6 [ka] Compound 9-6 (140 mg, 0.267 mmol), compound 1-6 (265 mg, 0.334 mmol), and sodium iodide (150 mg, 1 mmol) were added to N,N-dimethylformamide (0.8 mL) and reacted with stirring. After the reaction was complete, the reaction flask was cooled in an ice bath, and PBr3 (144 mg, 0.52 mmol) was added and reacted with stirring. After the reaction was complete, the reaction solution was added dropwise to an aqueous solution of NaHSO3, filtered, and the filter cake was washed with clean water and dried under vacuum to obtain 400 mg of crude product of compound 9-7. LC / MS (ESI): m / z 1267.1 [M] +

[0221] Step 7 [ka] Compound 9-7 (100 mg, 0.0788 mmol) was placed in a single-necked flask, anisole (0.3 mL) and TFA (1.2 mL) were added, and the mixture was reacted at room temperature. After the reaction was complete, MTBE was added, the mixture was filtered, and the crude product was fractionated by HPLC to obtain 4.4 mg of compound 9. HRMS: 751.1716 [M+H] +

[0222] Example 10: [ka]

[0223] Step 1 [ka] To a solution of compound 2-4 (1.5 g, 3.50 mmol) in DMF (35 mL), DMTMM (1.55 g, 5.26 mmol) and DIEA (905 mg, 7.0 mmol) were added. After protecting the reaction with argon and substituting three times, compound 10-A (525 mg, 7.0 mmol) was added to the reaction mixture, and the reaction was allowed to proceed at room temperature for 2 hours with stirring. The reaction mixture was gradually added to water, and the solid product was gradually precipitated. The solid product obtained by filtration was dissolved in DCM, extracted, and separated. The organic phase was then washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain compound 10-2 (1.6 g, yield 94%). LC / MS (ESI): m / z 486.1 [M+H] +

[0224] Step 2 [ka] A 10 mL solution of oxalyl chloride (1.05 g, 8.24 mmol) in DCM was cooled to -78°C in a dry ice / acetone bath. Under argon protection, DMSO (1.29 g, 16.5 mmol) was added dropwise, and the reaction was carried out with stirring. A 6 mL solution of compound 10-2 (1.6 g, 3.30 mmol) in DCM was gradually added dropwise to the reaction mixture, and the mixture was continuously stirred at -78°C. Et3N (3.34 g, 33.0 mmol) was then added, and the mixture was stirred at -78°C. The reaction was then gradually heated to 0°C until the reaction was complete. After quenching the reaction with H2O, the mixture was extracted with DCM, the organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel flash chromatography to obtain compound 10-3 (1.28 g, 80% yield). LC / MS (ESI): m / z 484.0 [M+H] +

[0225] Step 3 [ka] Compound 8-A (605 mg, 5.30 mmol) was added to a solution of compound 10-3 (1.28 g, 2.65 mmol) in DCM (26 mL). The reaction mixture was cooled in an ice bath, and then NaBH(OAc)3 (1.68 g, 7.95 mmol) was added. The reaction was carried out with stirring while the temperature was raised to room temperature. After the reaction was complete, the reaction mixture was quenched with NaHCO3, extracted with DCM, and the organic phase was washed sequentially with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel flash chromatography to obtain compound 10-4 (735 mg, 48% yield). LC / MS (ESI): m / z 582.1 [M+H] +

[0226] Step 4 [ka] To a solution of 2-4 (650 mg, 1.51 mmol) in DMF (13 mL), HATU (961 mg, 2.52 mmol) and DIEA (490 mg, 3.78 mmol) were added. The reaction was protected with argon and stirred at room temperature. 10-4 (735 mg, 1.26 mmol) was added to the reaction mixture, and the reaction was continued at room temperature with stirring. The reaction mixture was gradually added to water, filtered, and dried by suction to obtain product 10-5 (1.2 g, 96% yield). LC / MS (ESI): m / z 992.1 [M+H] +

[0227] Step 5 [ka] Compound 10-5 (546 mg, 0.55 mmol), compound 1-6 (398 mg, 0.5 mmol), and sodium iodide (225 mg, 1.5 mmol) were added to N,N-dimethylformamide (1.5 mL) and reacted with stirring. After the reaction was complete, the reaction flask was cooled in an ice bath, and PBr3 (360 mg, 1.33 mmol) was added and reacted with stirring. After the reaction was complete, the reaction solution was added dropwise to an aqueous solution of NaHSO3, filtered, and the filter cake was washed with clean water and dried under vacuum to obtain 1.13 g of crude compound 10-6. LC / MS (ESI): m / z 1737.1[M] +

[0228] Step 6 [ka] Compound 10-6 (1.13 g, 0.5 mmol) was added to anisole (2 mL) and trifluoroacetic acid (8 mL), and the mixture was reacted at room temperature. Methyl tert-butyl ether was added, the mixture was stirred, and then filtered. The filtered cake was rinsed with MTBE and dried to obtain 600 mg of crude product. After fractionation by HPLC, 4 mg of compound 10 was obtained. HRMS: 979.1874 [M+H] + 1 H-NMR (400 MHz,DMSO-d6)δ: 1.44(s,3H),1.46 (s,3H),1.66-2.06(m,6H),2.93-3.88 (m,14H),3.04-3.05 (m,2H),4.00-4.03 (m,2H),4.82-5.13 (m,1H),5.18(d,1H),5.74 (dd,1H),6.54 (d,1H),6.60 (d,1H),6.73-6.85 (m,3H),7.28(s,2H),8.05-8.33 (m,1H),9.46(br s,2H),10.26(br s,2H).

[0229] Example 11: [ka]

[0230] Step 1 [ka] Compound 11-1 (30.3 g, 174.1 mmol, 1.0 eq), 2,4-dimethoxybenzaldehyde (29.5 g, 177.6 mmol, 1.02 eq), methanol (300 mL), and anhydrous sodium sulfate (24.7 g, 174.1 mmol, 1.0 eq) were added to a reaction flask and the mixture was reacted at room temperature with stirring. The reaction mixture was then cooled in an ice bath, and sodium borohydride (3.3 g, 87.0 mmol, 0.5 eq) was added in several batches, and the mixture was reacted with stirring for 5 minutes, and then the reaction was continued at room temperature with stirring until complete. Glacial acetic acid (3.3 mL) was added, the mixture was stirred, filtered, and washed with ethyl acetate. The filtrate was concentrated, water and ethyl acetate were added to the residue, and the mixture was stirred to separate the layers. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a total of 58.0 g of compound 11-2 (yield: 102.8%). MS m / z 325.1[M+H] +

[0231] Step 2 [ka] Compound 11-2 (2.0 g, 6.2 mmol, 1.0 eq), S-epoxypropane (0.54 g, 9.3 mmol, 1.5 eq), and EtOH (20 mL) were added to a reaction flask and heated to 60°C to allow the reaction to proceed. The reaction was monitored by LC-MS to ensure that the starting materials had reacted completely. The reaction mixture was concentrated, and the crude product was purified by column chromatography to obtain a total of 1.2 g of compound 11-3, with a yield of 51.1%. MS m / z 383.2[M+H] +

[0232] Step 3 [ka] Compound 11-3 (1.2 g, 3.2 mmol, 1.0 eq), DCM (20 mL), and TEA (0.65 g, 6.4 mmol, 2.0 eq) were added to a reaction flask and cooled in an ice bath. MsCl (0.54 g, 4.7 mmol, 1.5 eq) was gradually added dropwise, and the reaction was carried out with stirring. The complete reaction of the starting materials was monitored by LC-MS. The reaction mixture was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product of compound 11-4 (1.34 g), which was used directly in the next step. MS m / z 461.1[M+H] +

[0233] Step 4 [ka] Crude product of compound 11-4 (1.34 g, 3.2 mmol, 1.0 eq), pyrrolidine (0.56 g, 8.0 mmol, 2.5 eq), MeCN (15 mL), and potassium carbonate (0.66 g, 4.8 mmol, 1.5 eq) were added to a reaction flask and reacted while heating to 40°C and stirring. The reaction was monitored by LC-MS to ensure that the starting materials had reacted completely. Water (30 mL) and EA (30 mL) were added to the reaction mixture and the mixture was stirred to separate the layers. The aqueous phase was washed with EA, the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography to obtain compound 11-5 (0.66 g, two-step yield: 48.5%). MS m / z 436.1[M+H] +

[0234] Step 5 [ka] Compound 11-5 (600 mg, 1.38 mmol) and TFA (10 mL) were added to the reaction flask and dissolved. The mixture was heated to 60°C and reacted until complete. The reaction mixture was concentrated until dry, MTBE (10 mL) was added, and the mixture was slurryed. The supernatant was poured out, and most of the solvent was removed from the resulting oily substance under vacuum. This mixture was then used directly in the next step of the reaction. MS m / z 186.1[M+H] +

[0235] Step 6 [ka] The crude product of compound 11-6 and compound 2-4 (1.31 g, 3.05 mmol) were dissolved in DCM (15 mL) and stirred at 0°C. DIPEA (2.02 mL, 12.22 mmol) and HATU (1.39 g, 3.67 mmol) were added. The reaction mixture was allowed to rise naturally to room temperature and continued until complete. After adding water (10 mL), the mixture was separated, the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated until dry. The crude product was separated by chromatography column (DCM:MeOH = 10:1) to obtain a total of 0.85 g of compound 11-7. MS m / z 1006.3 [M+H] +

[0236] Step 7 [ka] Compounds 1-6 (720 mg, 0.904 mmol), 11-7 (650 mg, 0.645 mmol), sodium iodide (0.406 g, 2.71 mmol), and boric acid (17 mg, 0.271 mmol) were added to the reaction flask. After replacing the air with argon three times, NMP (2.1 mL) was added. The reaction mixture was allowed to react at room temperature until complete. The reaction mixture was used directly in the next step without any further treatment. MS m / z 1767.5 [M] +

[0237] Step 8 [ka] After adding NMP (0.7 mL) to the above reaction mixture, the reaction mixture was cooled to 0°C, phosphorus trichloride (0.103 mL, 1.17 mmol) was added, and the reaction was kept warm at 0°C until the reaction was complete. 5% aqueous sodium bisulfite solution (20 mL) was added to the reaction mixture, and it was slurryed under an ice bath. The mixture was filtered, the filtered cake was dissolved in DCM (20 mL), dried over anhydrous sodium sulfate, filtered again, and concentrated until dry to obtain a total of 1.21 g of compound 11-9. MS m / z 1751.4 [M] +

[0238] Step 9 [ka] Compound 11-9 (1.21 g, 0.69 mmol) was dissolved in anisole (0.2 mL) and trifluoroacetic acid (0.8 mL) and reacted at room temperature until the reaction was complete. After cooling to 0°C, MTBE (20 mL) was added, and the mixture was slurryed under an ice bath. The mixture was filtered, the filter cake was rinsed with MTBE, and then dried to obtain 0.82 g of crude product. Further fractionation by reverse-phase HPLC yielded a total of 107 mg of compound 11. MS m / z 993.1 [M+H] +

[0239] Biological evaluation The present disclosure will be further explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present disclosure.

[0240] Test Example 1: Antimicrobial Activity Test After gradient dilution of the test compound, MIC detection was performed on the test bacterial strains. The initial detection concentration was 32 μg / mL, which was then diluted 2-fold, resulting in 11 concentration points and a 2-concentration ratio. In addition, wells without the drug were set up as growth controls. The method for detecting the minimum inhibitory concentration (MIC) was performed in accordance with the guidelines of the American Council for Clinical Laboratory Standards (CLSI). 1. Preparation of bacterial inoculum After subculturing the cryopreserved bacterial strains, single colonies were selected and resuspended in physiological saline or sterile water tubes. The suspension was vortexed and shaken, and the bacterial suspension was adjusted to 0.5 McF at a wavelength of 530 nm using a spectrophotometer. The bacterial suspension was taken using a pipette, diluted in culture medium, and uniformly mixed before being inoculated onto bacterial detection plates. 2. Culture The bacterial detection plate was placed in an incubator and incubated at 35°C and 85% humidity for 24 hours, after which the MIC value was read. 3. Reading the MIC A disposable, sealed Parafilm was attached to a 96-well plate, and the mixture was shaken to ensure uniform mixing. Visual observation with a plate reader was performed, and the minimum concentration of the compound that inhibited bacterial growth compared to a growth control was defined as the MIC.

[0241] MIC results [Table 1]

[0242] As described above, the compounds relating to this disclosure have a broad antimicrobial spectrum, specifically an antimicrobial spectrum effective against anti-Gram-negative bacteria and / or efficacy against multidrug-resistant bacteria, and further exhibit high stability and resistance to β-lactamase-producing Gram-negative bacteria.

[0243] Test Example 2: Antimicrobial Activity Test 1. The test compound was dissolved in sterile saline, vortexed and shaken to mix uniformly, and then gradient-diluted with sterile saline to a total of 11 concentration points. The test concentration range was 32 to 0.031 μg / mL, with 2 wells per concentration. In addition, wells without the drug were set up as growth controls. 2. A 4 μL dilution was added to a 196 μL bacterial suspension in a 96-well plate (bacterial count in the suspension was 2-8 × 10⁶). 5 Colony-forming units / mL). 3. After incubating at 36 °C for 24 h, the MIC value was visually read. The detection method of the minimum inhibitory concentration (MIC) was operated according to the guidelines of the Clinical and Laboratory Standards Institute (CLSI) of the United States.

[0244]

Table 2

[0245] As described above, the compound according to the present disclosure has a broad antibacterial spectrum. Specifically, it has an antibacterial spectrum effective against Gram-negative bacteria and / or has the efficacy of resisting multi-drug resistant bacteria, and further shows high stability against Gram-negative bacteria producing β-lactamase.

[0246] Test Example 3: Pharmacokinetic Study in Cynomolgus Monkeys 1. Preparation of Samples An appropriate amount of the test compound was precisely weighed into a container. Under an ice bath, 0.9% sodium chloride injection and 0.2 M NaOH solution were added until the test compound was completely dissolved, and a sample solution with a concentration of 2 mg / mL was prepared and stored at 2 - 8 °C for use. 2. Test Animals Species and Race: Cynomolgus Monkey Animal Level: General Grade Source of Animals: Guangxi Xiongsen Primate Experimental Animal Breeding and Development Co., Ltd. Animal Use License Number: SYXK (Su) 2019 - 0012 3. Test Method Six cynomolgus monkeys were selected, with an equal number of males and females, and randomly divided into three groups, one animal per sex per group. Each monkey received a single intravenous infusion of the sample at a dose of 10 mg / kg. Blood samples were collected from each group before administration and at 5 min, 15 min, 0.5 h, 1 h, 2 h, 4 h, 6 h, and 8 h after administration. The concentration of each test compound in the cynomolgus monkey plasma was detected using LC-MS / MS methods, with a limit of quantification of 1 μg / mL for all plasma sample analyses. Plasma concentration data were analyzed using the non-compartmental model (NCA) method of the pharmacokinetic data analysis software WinNonlin to calculate pharmacokinetic parameters and investigate the pharmacokinetic characteristics of the test compounds in cynomolgus monkeys after administration. The results are shown in the table below. [Table 3] The compounds relating to this disclosure are superior to cefiderocol in terms of Cmax.

Claims

1. A compound represented by formula (I-2) or a pharmaceutically acceptable salt thereof, stereoisomer, rotational isomer, tautomer, or deuterium compound, 【Chemistry 1】 Eventually, X is selected from N, CH, or C-Cl. T is selected from S, S=O, and O. E is 【Chemistry 2】 And among them, R 1 and R 2 Each is independently selected from hydrogen, halogens, and optionally alkyl groups substituted with a carbamoyl group. F is a single bond, A is selected from alkylene groups, 【Transformation 3】 teeth, 【Chemistry 4】 And, Of these, R8 is independently selected from halogen, hydroxyl group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 haloalkyl group, and C1-C6 haloalkoxy group, where q is an integer from 0 to 5 and r is an integer from 0 to 5. G2 is an alkylene group, which is optionally substituted with one or more substituents selected from alkyl groups, halogens, hydroxyl groups, -NR i R j, cyano groups, and alkoxy groups. C 2 -NR 31 -C (=O)-, R 31 Each is independently selected from alkyl groups and alkoxy groups, and of these, the alkyl group and alkoxy group are independently 【Transformation 5】 Substituted with one or more substituents selected from, Ring D 1 It is selected from aryl groups, R 4 is independently selected from an alkyl group, a halogen, a hydroxy group, -NR i R j , a cyano group, and an alkoxy group and an alkylthio group, wherein the alkyl group and the alkoxy group are each independently optionally substituted with one or more substituents selected from an alkyl group, a halogen, a hydroxy group, -NR i R j , a cyano group, and an alkoxy group, n is an integer from 0 to 8. R i and R j These are, independently, a hydrogen atom, a hydroxyl group, and C 1 ~C 6 Alkyl and C 1 ~C 6 Selected from alkoxy groups, and R n Each of them is independently C 1 ~C 6 Selected from alkyl groups, hydroxyl groups, and hydrogen atoms, k5 is an integer between 0 and 5. A compound represented by formula (I-2), or a pharmaceutically acceptable salt thereof, stereoisomer, rotational isomer, tautomer, or deuterium compound. 【Request Item 2】 【Chemistry 6】 teeth 【Transformation 7】 And k5 is an integer between 0 and 3. The compound described in claim 1, or a pharmaceutically acceptable salt thereof, stereoisomer, rotational isomer, tautomer, or deuterium compound thereof. 【Request Item 3】 【Transformation 8】 teeth 【Chemistry 9】 That is, The compound described in claim 2, or a pharmaceutically acceptable salt thereof, stereoisomer, rotational isomer, tautomer, or deuterium compound thereof.

4. Ring D 1 is a phenyl group or a naphthyl group. The compound described in claim 1, or a pharmaceutically acceptable salt thereof, stereoisomer, rotational isomer, tautomer, or deuterium compound thereof.

5. G 2 C is an optional choice. 1 ~C 6 Alkyl groups, halogens, hydroxyl groups, -NR i R j , cyano group, and C 1 ~C 6 C substituted with one or more substituents selected from alkoxy groups 1 ~C 6 It is an alkylene group. The compound described in claim 1, or a pharmaceutically acceptable salt thereof, stereoisomer, rotational isomer, tautomer, or deuterium compound thereof.

6. The compound shown in formula (I-2) 【Chemistry 10】 And, Among them, A, 【Chemistry 11】 , G 2 , C 2 , D 1 , R 4 And n is as described in claim 1, The compound described in claim 1, or a pharmaceutically acceptable salt thereof, stereoisomer, rotational isomer, tautomer, or deuterium compound thereof.

7. the below described: 【Chemistry 12】 The compounds shown or their pharmaceutically acceptable salts, stereoisomers, rotational isomers, tautomers, or deuterium compounds.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, stereoisomer, rotational isomer, tautomer, or deuterium compound thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

9. The use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, stereoisomer, rotational isomer, tautomer, or deuterium compound, or the pharmaceutical composition according to claim 8, in the preparation of a drug for preventing or treating a disease caused by Gram-negative bacteria.

10. The use according to claim 9, wherein the disease is selected from respiratory tract infections, urinary tract infections, respiratory infections, sepsis, nephritis, cholecystitis, oral infections, endocarditis, pneumonia, meningomyelia, otitis media, enteritis, sinusitis, wound infections, and opportunistic infections.

11. The use according to claim 9, wherein the Gram-negative bacteria are Escherichia coli, Klebsiella, Serratia, Enterobacter, Citrobacter, Morganella, Providencia, Proteus, Haemophilus, Moraxella, Pseudomonas aeruginosa, Pseudomonas other than P. aeruginosa, Stenotrophomonas, Burkholderia, or Acinetobacter.

12. The use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, stereoisomer, rotational isomer, tautomer, or deuterium compound, or a pharmaceutical composition according to claim 8, in the preparation of a drug for preventing or treating diseases caused by pathogenic bacteria in mammals.

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