Cephalosporin antibacterial compounds and their medical applications

Abstract

Cephalosporin compounds represented by formula I-1, I-2 or I-3, pharmaceutical compositions containing the same, and uses as antibacterial agents. #imgabs0#

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to cephalosporin antibacterial compounds and their application in medicine. Background Art

[0002] The development of antimicrobial treatment options has become a continuous challenge facing today's society. Antimicrobial drugs include various antibiotics, sulfonamides, imidazoles, nitroimidazoles, quinolones and other chemically synthesized drugs, among which β-lactam antibiotics are a very important class. So far, literature research has reported or a variety of β-lactamase inhibitors have been marketed, which have become extremely important antimicrobial drugs in clinical practice. However, the problem of resistance to β-lactamase inhibitors is becoming more and more serious, and an increasing number of bacteria have acquired resistance by producing β-lactamases and degrading β-lactamase inhibitors.

[0003] According to the Ambler molecular classification, β-lactamases are mainly divided into 4 categories. Specifically, they are A-type (TEM type, SHV type, CTX-M type, KPC type, etc.), B-type (IMP type, VIM type, L-1 type, etc.), C-type (AmpC type) and D-type (OXA type, etc.). Among these types, A, C and D types are mainly divided into serine-β-lactamases, and B type is divided into metallo-β-lactamases, both of which have different mechanisms in hydrolyzing β-lactamase inhibitors.

[0004] The emergence of Gram-negative bacteria that have become highly resistant to β-lactamase inhibitors (including cephalosporins and carbapenems) has caused great clinical application problems. Such resistance is caused by the production of A or D type serine β-lactamases and B type metallo-β-lactamases that extend their substrate spectrum. Metallo-β-lactamases are known to be one of the reasons for the acquisition of multi-drug resistance in Gram-negative bacteria. However, the need to develop more effective antibacterial compounds, especially cephalosporin compounds that show effectiveness against Gram-negative bacteria that produce multiple β-lactamases, is a difficult problem in the current field of antibacterial drug research.

[0005] According to literature reports (Antimicrob Agents Chemother. 1982, 22 (2), 181-185.), cephalosporin compounds containing catechol groups in the molecule have high anti-Gram-negative bacterial activity. The role of the catechol group in the molecule is to bind to the extracellular Fe 3+ Forming chelates, the compounds pass through the Fe 3+The transport system (tonB-dependent transport system) is effectively combined into the bacteria. This Trojan horse strategy makes it more concentrated in the periplasmic space (the narrow space between the outer membrane and the cell wall) and binds to the receptor to inhibit the synthesis of the bacterial cell wall. Therefore, compounds with catechol or similar structures in the 3-side chain or 7-side chain of the cephalosporin skeleton have been studied (EP0416410B1). Cefiderocol is a new type of iron carrier cephalosporin (WO2010050468, WO2017216765, Eur.JMed.Chem.2018, 155, 847-868.). Currently, the FDA (U.S. Food and Drug Administration) has approved Fetroja (cefiderocol) of Shionogi Pharmaceutical for the treatment of complicated urinary tract infections (cUTI) in patients aged 18 years and above, including kidney infections caused by sensitive Gram-negative bacteria. Summary of the invention

[0006] The purpose of the present disclosure is to provide a cephalosporin antibacterial compound, which can present an effective antibacterial spectrum against Gram-negative bacteria, especially drug-resistant Gram-negative bacteria.

[0007] In one aspect, the present disclosure provides a compound represented by formula (I-1) or a pharmaceutically acceptable salt, stereoisomer, rotational isomer, tautomer or deuterated compound thereof,

[0008]

[0009] in,

[0010] X is selected from N, CH and C-Cl;

[0011] T is selected from S, S=O, CH2 and O;

[0012] E is selected from wherein R1 and R2 are each independently selected from hydrogen, halogen, phenyl, alkylthio and alkyl optionally substituted by carbamoyl (alkyl is preferably C1-C6 alkyl, the same below); R 11 and R 12 Each is independently selected from hydrogen, carboxyl and alkyl optionally substituted by carbamoyl; m is an integer from 1 to 5;

[0013] F is a single bond;

[0014] A is selected from alkylene (preferably C1-C6 alkylene, the same below), alkenylene (preferably C2-C6 alkenylene, the same below) and alkynylene (preferably C2-C6 alkynylene, the same below);

[0015] The quaternary ammonium group is a heterocyclic group (preferably 3 to 12 members, more preferably 3 to 6 members, the same below), a fused heterocyclic group (preferably 6 to 14 members, more preferably 7 to 10 members, the same below), a heteroaryl group (preferably 5 to 12 members, more preferably 5 to 8 members, the same below) and a fused heteroaryl group (preferably 5 to 14 members, more preferably 5 to 12 members, the same below) containing one or more N atoms, wherein the heterocyclic group, the fused heterocyclic group, the heteroaryl group and the fused heteroaryl group are each independently selected from alkyl, halogen, hydroxyl, thiol, -NR i R j , oxo, thio, -C(O)R k 、-C(O)OR k 、-C(S)R k , nitro, cyano, alkoxy (preferably C1-C6 alkoxy, the same below), alkylthio (preferably C1-C6 alkylthio, the same below), cycloalkyl (preferably 3 to 12 members, more preferably 3 to 6 members, the same below), heterocyclic group, aryl (preferably 6 to 14 members, more preferably 6 to 10 members, the same below) and heteroaryl;

[0016] G1 is

[0017] Where x is an integer from 1 to 6;

[0018] A1 is selected from a single bond, alkylene, alkenylene and alkynylene, wherein the alkylene, alkenylene and alkynylene are each independently selected from alkyl, halogen, hydroxyl, mercapto, -NR i R j , oxo, thio, -C(O)R k 、-C(O)OR k 、-C(S)R k , nitro, cyano, alkoxy and alkylthio;

[0019] A2 is selected from a single bond, alkylene, alkenylene and alkynylene, wherein the alkylene, alkenylene and alkynylene are each independently selected from alkyl, halogen, hydroxyl, mercapto, -NR i R j , oxo, thio, -C(O)R k 、-C(O)OR k 、-C(S)R k , nitro, cyano, alkoxy and alkylthio;

[0020] Ring D3 is selected from cycloalkyl, condensed cycloalkyl (preferably 6 to 14 members, more preferably 7 to 10 members, the same below), heterocyclic group and condensed heterocyclic group;

[0021] R9 is selected from alkyl, halogen, hydroxy, mercapto, oxo, thio, -NR i R j 、-C(O)R k 、-C(O)OR k , nitro, cyano, alkoxy and alkylthio, wherein the alkyl, alkoxy and alkylthio are each independently selected from alkyl, halogen, hydroxyl, mercapto, -NR i R j , oxo, thio, -C(O)R k 、-C(O)OR k 、-C(S)R k , nitro, cyano, alkoxy, alkylthio, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0022] k1 is an integer from 0 to 8;

[0023] C1 is selected from -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-, and -NR3-, wherein R3 is independently selected from hydrogen, hydroxy, alkyl and alkoxy, wherein the alkyl and alkoxy are independently selected from alkyl, halogen, hydroxy, mercapto, -NR i R j , Oxo, thio, -C(O)R k 、-C(O)OR k 、-C(S)R k , nitro, cyano, alkoxy, alkylthio, cycloalkyl, heterocyclic, aryl and heteroaryl; Rm is selected from hydrogen atom, alkyl, hydroxyl, aryl and heteroaryl, wherein the alkyl, aryl and heteroaryl are each independently selected from alkyl, halogen, hydroxyl, thiol, -NR i R j , carboxyl, nitro, cyano, alkoxy, alkylthio, cycloalkyl, heterocyclic, aryl and heteroaryl; R 31 is hydrogen or alkyl, and ring D2 is a heterocyclic group or a heteroaryl group;

[0024] Ring D1 is selected from aryl, fused aryl (preferably 8 to 14 members, more preferably 8 to 12 members, the same below), heterocyclic, fused heterocyclic, heteroaryl and fused heteroaryl;

[0025] R4 is independently selected from alkyl, halogen, hydroxy, thiol, oxo, thio, -NR i R j 、-C(O)R k 、-C(O)OR k , nitro, cyano, alkoxy and alkylthio, wherein the alkyl, alkoxy and alkylthio are each independently selected from alkyl, halogen, hydroxyl, mercapto, -NR i R j , oxo, thio, -C(O)R k 、-C(O)OR k 、-C(S)R k , nitro, cyano, alkoxy, alkylthio, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0026] n is an integer from 0 to 8;

[0027] R i and R j are each independently selected from a hydrogen atom, a hydroxyl group, a C1-C6 alkyl group and a C1-C6 alkoxy group; and

[0028] R k Each is independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxyl and -NR i R j wherein the alkyl, haloalkyl and alkoxy are each independently selected from alkyl, halogen, hydroxyl, mercapto, -NR i R j The group may be substituted by one or more substituents selected from the group consisting of , oxo, thio, carboxyl, nitro, cyano, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0029] "C" in the formula is a carbon atom.

[0030] In certain embodiments, E is wherein R1 and R2 are each independently selected from hydrogen, halogen and alkyl optionally substituted by carbamoyl.

[0031] In certain embodiments, Selected from:

[0032]

[0033] wherein R8 are each independently selected from halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy;

[0034] q is each independently an integer from 0 to 5;

[0035] r is each independently an integer from 0 to 5;

[0036] s is an integer of 0-3 for each independently.

[0037] In certain embodiments, for

[0038] Wherein R8 is independently selected from halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy, q is an integer of 0 to 5, and r is an integer of 0 to 5.

[0039] In certain embodiments, G1 is selected from

[0040]

[0041] wherein R9 are each independently selected from halogen, hydroxy, alkyl, alkoxy, haloalkyl and haloalkoxy;

[0042] k2 are each independently an integer from 1 to 6;

[0043] k3 are each independently an integer from 0 to 3; and

[0044] k4 is an integer of 0-3 independently.

[0045] In certain embodiments, R9 is each independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy;

[0046] A1 is a single bond or a C1-C6 alkylene group, wherein the alkylene group is optionally selected from C1-C6 alkyl, halogen, hydroxyl, mercapto, -NR i R j , oxo, thio, -C(O)R k 、-C(O)OR k、-C(S)R k , nitro, cyano, C1-C6 alkoxy and C1-C6 alkylthio;

[0047] A2 is a single bond or a C1-C6 alkylene group, wherein the alkylene group is optionally selected from C1-C6 alkyl, halogen, hydroxyl, mercapto, -NR i R j , oxo, thio, -C(O)R k 、-C(O)OR k 、-C(S)R k , nitro, cyano, C1-C6 alkoxy and C1-C6 alkylthio;

[0048] k2 is an integer of 1 to 6 independently; k3 is an integer of 0 to 3 independently; k4 is an integer of 0 to 3 independently; and

[0049] x is an integer from 1 to 3.

[0050] In certain embodiments, examples of ring D2 include

[0051]

[0052] In certain embodiments, C1 is selected from -NR3-, -NR3-C(=O)-, -NR3-C(=S)-, -NR3-C(=NH)-, -NR3-C(=NH)-NR3-, -NR3-C(=S)-NR3- and

[0053] In certain embodiments, R3 is selected from hydrogen, hydroxy, C1-C6 alkyl and C1-C6 alkoxy, wherein the alkyl and alkoxy are each independently selected from C1-C6 alkyl, halogen, hydroxy, -NR i R j , Oxo, -C(O)OR k and cyano are substituted with one or more substituents; R n Each is independently selected from C1-C6 alkyl, hydroxyl and halogen; k5 is an integer from 0 to 5.

[0054] In certain embodiments, wherein for R n Each is independently selected from C1-C6 alkyl, hydroxyl and halogen; k5 is an integer from 0 to 3.

[0055] In certain embodiments, Ring D1 is phenyl or naphthyl.

[0056] In certain embodiments, the compound represented by formula I-1 is

[0057]

[0058] Among them, A, G1, C1, D1, R4 and n are as described above.

[0059] In one aspect, the present disclosure provides a compound represented by formula (I-2) or a pharmaceutically acceptable salt, stereoisomer, rotational isomer, tautomer or deuterated compound thereof,

[0060]

[0061] in,

[0062] X is selected from N, CH and C-Cl;

[0063] T is selected from S, S=O, CH2 and O;

[0064] E is selected from wherein R1 and R2 are each independently selected from hydrogen, halogen, phenyl, alkylthio and alkyl optionally substituted by carbamoyl (alkyl is preferably C1-C6 alkyl, the same below); R 11 and R 12 Each is independently selected from hydrogen, carboxyl and alkyl optionally substituted by carbamoyl; m is an integer from 1 to 5;

[0065] F is a single bond;

[0066] A is selected from alkylene (preferably C1-C6 alkylene, the same below), alkenylene (preferably C2-C6 alkenylene, the same below) and alkynylene (preferably C2-C6 alkynylene, the same below);

[0067] The quaternary ammonium group is a heterocyclic group (preferably 3 to 12 members, more preferably 3 to 6 members, the same below), a fused heterocyclic group (preferably 6 to 14 members, more preferably 7 to 10 members, the same below), a heteroaryl group (preferably 5 to 12 members, more preferably 5 to 8 members, the same below) and a fused heteroaryl group (preferably 5 to 14 members, more preferably 5 to 12 members, the same below) containing one or more N atoms, wherein the heterocyclic group, the fused heterocyclic group, the heteroaryl group and the fused heteroaryl group are each independently selected from alkyl, halogen, hydroxyl, thiol, -NR i R j , oxo, thio, -C(O)R k 、-C(O)OR k 、-C(S)R k, nitro, cyano, alkoxy (preferably C1-C6 alkoxy, the same below), alkylthio (preferably C1-C6 alkylthio, the same below), cycloalkyl (preferably 3 to 12 members, more preferably 3 to 6 members, the same below), heterocyclic group, aryl (preferably 6 to 14 members, more preferably 6 to 10 members, the same below) and heteroaryl;

[0068] G2 is G1 or alkylene, wherein the alkylene is optionally selected from alkyl, halogen, hydroxyl, mercapto, -NR i R j , oxo, thio, -C(O)R k 、-C(O)OR k 、-C(S)R k , nitro, cyano, alkoxy and alkylthio; G1 is as described above;

[0069] C2 is selected from -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 wherein R3 is independently selected from hydrogen, hydroxy, alkyl and alkoxy, wherein the alkyl and alkoxy are independently selected from alkyl, halogen, hydroxy, mercapto, -NR i R j , Oxo, thio, -C(O)R k 、-C(O)OR k 、-C(S)R k , nitro, cyano, alkoxy, alkylthio, cycloalkyl, heterocyclic, aryl and heteroaryl; R m is selected from hydrogen atom, alkyl, hydroxyl, aryl and heteroaryl, wherein the alkyl, aryl and heteroaryl are each independently selected from alkyl, halogen, hydroxyl, thiol, -NR i R j, carboxyl, nitro, cyano, alkoxy, alkylthio, cycloalkyl, heterocyclic, aryl and heteroaryl; R 31 Each independently selected from hydroxy, alkyl and alkoxy, wherein the alkyl and alkoxy are each independently selected from alkyl, halogen, hydroxy, mercapto, -NR i R j , Oxo, thio, -C(O)R k 、-C(O)OR k 、-C(S)R k , nitro, cyano, alkoxy, alkylthio, cycloalkyl, heterocyclic, aryl and heteroaryl; R 32 is hydrogen or alkyl; ring D2 is as described above; R 33 is selected from optionally substituted alkylene, optionally substituted alkenylene, and optionally substituted alkynylene;

[0070] Ring D1 is selected from aryl, fused aryl (preferably 8 to 14 members, more preferably 8 to 12 members, the same below), heterocyclic, fused heterocyclic, heteroaryl and fused heteroaryl;

[0071] R4 is independently selected from alkyl, halogen, hydroxy, thiol, oxo, thio, -NR i R j 、-C(O)R k 、-C(O)OR k , nitro, cyano, alkoxy and alkylthio, wherein the alkyl, alkoxy and alkylthio are each independently selected from alkyl, halogen, hydroxyl, mercapto, -NR i R j , oxo, thio, -C(O)R k 、-C(O)OR k 、-C(S)R k , nitro, cyano, alkoxy, alkylthio, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0072] n is an integer from 0 to 8;

[0073] R i and R j are each independently selected from a hydrogen atom, a hydroxyl group, a C1-C6 alkyl group and a C1-C6 alkoxy group; and

[0074] R k Each is independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxyl and -NR i R j wherein the alkyl, haloalkyl and alkoxy are each independently selected from alkyl, halogen, hydroxyl, mercapto, -NRi R j The group may be substituted by one or more substituents selected from the group consisting of , oxo, thio, carboxyl, nitro, cyano, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0075] In certain embodiments, when R 31 When it is an alkyl group, it is selected from alkyl, halogen, hydroxyl, mercapto, -NR i R j , Oxo, thio, -C(O)R k 、-C(O)OR k 、-C(S)R k The radical may be substituted by one or more substituents selected from the group consisting of , nitro, cyano, alkoxy, alkylthio, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0076] In certain embodiments, E is wherein R1 and R2 are each independently selected from hydrogen, halogen and alkyl optionally substituted by carbamoyl.

[0077] In certain embodiments, wherein Selected from:

[0078]

[0079] wherein R8 are each independently selected from hydrogen, halogen, hydroxy, alkyl, alkoxy, haloalkyl and haloalkoxy;

[0080] q is each independently an integer from 0 to 5;

[0081] r is each independently an integer from 0 to 5; and

[0082] s is an integer of 0-3 for each independently.

[0083] In certain embodiments, for

[0084] Wherein R8 is independently selected from halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy, q is an integer of 0 to 5, and r is an integer of 0 to 5.

[0085] In certain embodiments, G2 is selected from

[0086]

[0087] wherein R9 are each independently selected from halogen, hydroxy, alkyl, alkoxy, haloalkyl and haloalkoxy;

[0088] k2 are each independently an integer from 1 to 6;

[0089] k3 are each independently an integer from 0 to 3; and

[0090] k4 is an integer of 0-3 independently.

[0091] In certain embodiments, R9 is each independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy;

[0092] A1 is a single bond or a C1-C6 alkylene group, wherein the alkylene group is optionally selected from C1-C6 alkyl, halogen, hydroxyl, mercapto, -NR i R j , oxo, thio, -C(O)R k 、-C(O)OR k 、-C(S)R k , nitro, cyano, C1-C6 alkoxy and C1-C6 alkylthio;

[0093] A2 is a single bond or a C1-C6 alkylene group, wherein the alkylene group is optionally selected from C1-C6 alkyl, halogen, hydroxyl, mercapto, -NR i R j , oxo, thio, -C(O)R k 、-C(O)OR k 、-C(S)R k , nitro, cyano, C1-C6 alkoxy and C1-C6 alkylthio;

[0094] k2 is an integer of 1 to 6 independently; k3 is an integer of 0 to 3 independently; k4 is an integer of 0 to 3 independently;

[0095] x is an integer from 1 to 3.

[0096] In certain embodiments, wherein G2 is optionally selected from C1-C6 alkyl, halogen, hydroxyl, thiol, -NR i R j , oxo, thio, -C(O)R k 、-C(O)OR k 、-C(S)R k C1-C6 alkylene substituted by one or more substituents selected from the group consisting of C1-C6 alkoxy, C1-C6 alkylthio, and C1-C6 alkylene.

[0097] In certain embodiments, C2 is selected from -NR3-, -NR 31-C(=O)-, -NR3-C(=S)-, -NR3-C(=NH)-, -NR3-C(=NH)-NR3-, -NR3-C(=S)-NR3- and Preferably -NR 31 -C(=O)- or -NR3-C(=S)-.

[0098] In certain embodiments, R3 is selected from hydrogen, hydroxy, alkyl and alkoxy, wherein the alkyl and alkoxy are each independently optionally selected from alkyl, halogen, hydroxy, -NR i R j , Oxo, -C(O)OR k and cyano are substituted with one or more substituents; R n Each is independently selected from alkyl, hydroxyl and halogen; k5 is an integer of 0-5.

[0099] In certain embodiments, R 31 is selected from hydroxy, alkyl, alkoxy, wherein the alkyl and alkoxy are each independently selected from alkyl, halogen, hydroxy, -NR i R j , Oxo, -C(O)OR k and cyano are substituted with one or more substituents; R n Each is independently selected from alkyl, hydroxyl and halogen; k5 is an integer of 0-5.

[0100] In certain embodiments, R 31 is selected from hydroxyl, C1-C6 alkyl substituted by a substituent and C1-C6 alkoxy optionally substituted by a substituent, wherein the substituent is selected from C1-C6 alkyl, halogen, hydroxyl, -NR i R j , Oxo, -C(O)OR k and one or more of a cyano group.

[0101] In certain embodiments, wherein for R n Each is independently selected from C1-C6 alkyl, hydroxyl and halogen; k5 is an integer from 0 to 3.

[0102] In certain embodiments, Ring D1 is phenyl or naphthyl.

[0103] In certain embodiments, the compound represented by formula (I-2) is

[0104]

[0105] Among them, A, G2, C2, D1, R4 and n are as described above.

[0106] In one aspect, the present disclosure provides a compound represented by formula (I-3) or a pharmaceutically acceptable salt, stereoisomer, rotational isomer, tautomer or deuterated compound thereof,

[0107]

[0108] in,

[0109] X is selected from N, CH and C-Cl;

[0110] T is selected from S, S=O, CH2 and O;

[0111] E is selected from wherein R1 and R2 are each independently selected from hydrogen, halogen, phenyl, alkylthio and alkyl optionally substituted by carbamoyl (alkyl is preferably C1-C6 alkyl, the same below); R 11 and R 12 Each is independently selected from hydrogen, carboxyl and alkyl optionally substituted by carbamoyl; m is an integer from 1 to 5;

[0112] F is a single bond;

[0113] A is selected from alkylene (preferably C1-C6 alkylene, the same below), alkenylene (preferably C2-C6 alkenylene, the same below) and alkynylene (preferably C2-C6 alkynylene, the same below);

[0114] The quaternary ammonium group is a heterocyclic group (preferably 3 to 12 members, more preferably 3 to 6 members, the same below), a fused heterocyclic group (preferably 6 to 14 members, more preferably 7 to 10 members, the same below), a heteroaryl group (preferably 5 to 12 members, more preferably 5 to 8 members, the same below) and a fused heteroaryl group (preferably 5 to 14 members, more preferably 5 to 12 members, the same below) containing one or more N atoms, wherein the heterocyclic group, the fused heterocyclic group, the heteroaryl group and the fused heteroaryl group are each independently selected from alkyl, halogen, hydroxyl, thiol, -NR i R j , oxo, thio, -C(O)R k 、-C(O)OR k 、-C(S)R k , nitro, cyano, alkoxy (preferably C1-C6 alkoxy, the same below), alkylthio (preferably C1-C6 alkylthio, the same below), cycloalkyl (preferably 3 to 12 members, more preferably 3 to 6 members, the same below), heterocyclic group, aryl (preferably 6 to 14 members, more preferably 6 to 10 members, the same below) and heteroaryl;

[0115] G2 is G1 or alkylene, wherein the alkylene is optionally selected from alkyl, halogen, hydroxyl, mercapto, -NR i R j , oxo, thio, -C(O)R k 、-C(O)OR k 、-C(S)R k , nitro, cyano, alkoxy and alkylthio;

[0116] G1 is

[0117] Wherein x is independently an integer from 1 to 6;

[0118] A1 is selected from a single bond, alkylene, alkenylene and alkynylene, wherein the alkylene, alkenylene and alkynylene are each independently selected from alkyl, halogen, hydroxyl, mercapto, -NR i R j , oxo, thio, -C(O)R k 、-C(O)OR k 、-C(S)R k , nitro, cyano, alkoxy and alkylthio;

[0119] A2 is selected from a single bond, alkylene, alkenylene and alkynylene, wherein the alkylene, alkenylene and alkynylene are each independently selected from alkyl, halogen, hydroxyl, mercapto, -NR i R j , oxo, thio, -C(O)R k 、-C(O)OR k 、-C(S)R k , nitro, cyano, alkoxy and alkylthio;

[0120] D3 is selected from cycloalkyl, fused cycloalkyl, heterocyclic and fused heterocyclic groups;

[0121] R9 is selected from alkyl, halogen, hydroxy, mercapto, oxo, thio, -NR i R j 、-C(O)R k 、-C(O)OR k , nitro, cyano, alkoxy and alkylthio, wherein the alkyl, alkoxy and alkylthio are each independently selected from alkyl, halogen, hydroxyl, mercapto, -NR i R j , oxo, thio, -C(O)R k 、-C(O)OR k 、-C(S)R k, nitro, cyano, alkoxy, alkylthio, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0122] k1 is an integer from 0 to 8;

[0123] C1 is selected from -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-, and -NR3-, wherein R3 is independently selected from hydrogen, hydroxy, alkyl and alkoxy, wherein the alkyl and alkoxy are independently selected from alkyl, halogen, hydroxy, mercapto, -NR i R j , Oxo, thio, -C(O)R k 、-C(O)OR k 、-C(S)R k , nitro, cyano, alkoxy, alkylthio, cycloalkyl, heterocyclic, aryl and heteroaryl; R m is selected from hydrogen atom, alkyl, hydroxyl, aryl and heteroaryl, wherein the alkyl, aryl and heteroaryl are each independently selected from alkyl, halogen, hydroxyl, thiol, -NR i R j , carboxyl, nitro, cyano, alkoxy, alkylthio, cycloalkyl, heterocyclic, aryl and heteroaryl; R 31 is hydrogen or alkyl; ring D2 is as described above;

[0124] R4 is independently selected from alkyl, halogen, hydroxy, thiol, oxo, thio, -NR i Rj 、-C(O)R k 、-C(O)OR k , nitro, cyano, alkoxy and alkylthio, wherein the alkyl, alkoxy and alkylthio are each independently selected from alkyl, halogen, hydroxyl, mercapto, -NR i R j , oxo, thio, -C(O)R k 、-C(O)OR k 、-C(S)R k , nitro, cyano, alkoxy, alkylthio, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0125] n is an integer from 0 to 5;

[0126] R i and R j are each independently selected from a hydrogen atom, a hydroxyl group, a C1-C6 alkyl group and a C1-C6 alkoxy group; and

[0127] R k Selected from hydrogen atom, alkyl group, halogenated alkyl group, hydroxyl group and -NR i R j wherein the alkyl and haloalkyl are each independently selected from alkyl, halogen, hydroxyl, thiol, -NR i R j The group may be substituted by one or more substituents selected from the group consisting of , oxo, thio, carboxyl, nitro, cyano, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0128] In certain embodiments, E is wherein R1 and R2 are each independently selected from hydrogen, halogen and alkyl optionally substituted by carbamoyl.

[0129] In certain embodiments, Selected from:

[0130]

[0131] wherein R8 are each independently selected from halogen, hydroxy, alkyl, alkoxy, haloalkyl and haloalkoxy;

[0132] q is each independently an integer from 0 to 5;

[0133] r is each independently an integer from 0 to 5; and

[0134] s is an integer of 0-3 for each independently.

[0135] In certain embodiments, for

[0136] Wherein R8 is independently selected from halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy, q is an integer of 0 to 5, and r is an integer of 0 to 5.

[0137] In certain embodiments, G2 is selected from

[0138]

[0139] wherein R9 are each independently selected from hydrogen, halogen, hydroxy, alkyl, alkoxy, haloalkyl and haloalkoxy;

[0140] k2 are each independently an integer from 1 to 6;

[0141] k3 are each independently an integer from 0 to 3; and

[0142] k4 is an integer of 0-3 independently.

[0143] In certain embodiments, R9 is each independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy;

[0144] A1 is a single bond or a C1-C6 alkylene group, wherein the alkylene group is optionally selected from C1-C6 alkyl, halogen, hydroxyl, mercapto, -NR i R j , oxo, thio, -C(O)R k 、-C(O)OR k 、-C(S)R k , nitro, cyano, C1-C6 alkoxy and C1-C6 alkylthio;

[0145] A2 is a single bond or a C1-C6 alkylene group, wherein the alkylene group is optionally selected from C1-C6 alkyl, halogen, hydroxyl, mercapto, -NR i R j , oxo, thio, -C(O)R k 、-C(O)OR k 、-C(S)R k , nitro, cyano, C1-C6 alkoxy and C1-C6 alkylthio;

[0146] k2 is an integer of 1 to 6 independently; k3 is an integer of 0 to 3 independently; k4 is an integer of 0 to 3 independently; and

[0147] x is an integer from 1 to 3.

[0148] In certain embodiments, G2 is optionally selected from C1-C6 alkyl, halogen, hydroxyl, thiol, -NR i R j , oxo, thio, -C(O)R k 、-C(O)OR k 、-C(S)R k C1-C6 alkylene substituted by one or more substituents selected from the group consisting of C1-C6 alkoxy, C1-C6 alkylthio, and C1-C6 alkylene.

[0149] In certain embodiments, C1 is selected from -NR3-, -NR3-C(=O)-, -NR3-C(=S)-, -NR3-C(=NH)-, -NR3-C(=NH)-NR3-, -NR3-C(=S)-NR3-,

[0150] In certain embodiments, R3 is selected from hydrogen, hydroxy, alkyl and alkoxy, wherein the alkyl and alkoxy are each independently optionally selected from alkyl, halogen, hydroxy, -NR i R j , Oxo, -C(O)OR k and cyano are substituted with one or more substituents; R n Each is independently selected from alkyl, hydroxyl and halogen; k5 is an integer of 0-5.

[0151] In certain embodiments, wherein for R n Each is independently selected from C1-C6 alkyl, hydroxyl and halogen; k5 is an integer from 0 to 3.

[0152] In certain embodiments, the compound represented by formula (I-3) is

[0153]

[0154] Among them, A, G2, C1, R4 and n are as described above.

[0155] In one aspect, the present disclosure provides a compound represented by formula (I-4) or a pharmaceutically acceptable salt, stereoisomer, rotational isomer, tautomer or deuterated compound thereof,

[0156]

[0157] in,

[0158] X is selected from N, CH and C-Cl;

[0159] T is selected from S, S=O, CH2 and O;

[0160] E is selected from wherein R1 and R2 are each independently selected from hydrogen, halogen, phenyl, alkylthio and alkyl optionally substituted by carbamoyl (alkyl is preferably C1-C6 alkyl, the same below); R 11 and R 12 Each is independently selected from hydrogen, carboxyl and alkyl optionally substituted by carbamoyl; m is an integer from 1 to 5;

[0161] F is a single bond;

[0162] A is selected from alkylene (preferably C1-C6 alkylene, the same below), alkenylene (preferably C2-C6 alkenylene, the same below) and alkynylene (preferably C2-C6 alkynylene, the same below);

[0163] The quaternary ammonium group is a heterocyclic group (preferably 3 to 12 members, more preferably 3 to 6 members, the same below), a fused heterocyclic group (preferably 6 to 14 members, more preferably 7 to 10 members, the same below), a heteroaryl group (preferably 5 to 12 members, more preferably 5 to 8 members, the same below) and a fused heteroaryl group (preferably 5 to 14 members, more preferably 5 to 12 members, the same below) containing one or more N atoms, wherein the heterocyclic group, the fused heterocyclic group, the heteroaryl group and the fused heteroaryl group are each independently selected from alkyl, halogen, hydroxyl, thiol, -NR i R j , oxo, thio, -C(O)R k 、-C(O)OR k 、-C(S)R k , nitro, cyano, alkoxy (preferably C1-C6 alkoxy, the same below), alkylthio (preferably C1-C6 alkylthio, the same below), cycloalkyl (preferably 3 to 12 members, more preferably 3 to 6 members, the same below), heterocyclic group, aryl (preferably 6 to 14 members, more preferably 6 to 10 members, the same below) and heteroaryl;

[0164] G2 as described above;

[0165] C3 is selected from 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-, and -NR3-, wherein R3 is independently selected from hydrogen, hydroxy, alkyl and alkoxy, wherein the alkyl and alkoxy are independently selected from alkyl, halogen, hydroxy, mercapto, -NR i R j , Oxo, thio, -C(O)R k 、-C(O)OR k 、-C(S)R k , nitro, cyano, alkoxy, alkylthio, cycloalkyl, heterocyclic, aryl and heteroaryl; R m is selected from hydrogen atom, alkyl, hydroxyl, aryl and heteroaryl, wherein the alkyl, aryl and heteroaryl are each independently selected from alkyl, halogen, hydroxyl, thiol, -NR i R j , carboxyl, nitro, cyano, alkoxy, alkylthio, cycloalkyl, heterocyclic, aryl and heteroaryl; R 31 is hydrogen or alkyl; ring D2 is as described above;

[0166] A3 is selected from alkylene, alkenylene and alkynylene, wherein the alkylene, alkenylene and alkynylene are each independently selected from alkyl, halogen, hydroxyl, mercapto, -NR i R j , oxo, thio, -C(O)R k 、-C(O)OR k 、-C(S)R k , nitro, cyano, alkoxy and alkylthio;

[0167] R i and R j Each is independently a hydrogen atom or a C1-C6 alkyl group;

[0168] R k Each is independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyl group and -NR i Rj wherein the alkyl and haloalkyl are each independently selected from alkyl, halogen, hydroxyl, thiol, -NR i R j The group may be substituted by one or more substituents selected from the group consisting of , oxo, thio, carboxyl, nitro, cyano, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0169] In certain embodiments, E is wherein R1 and R2 are each independently selected from hydrogen, halogen and alkyl optionally substituted by carbamoyl.

[0170] In certain embodiments, Selected from:

[0171]

[0172] wherein R8 are each independently selected from hydrogen, halogen, hydroxy, alkyl, alkoxy, haloalkyl and haloalkoxy;

[0173] q is each independently an integer from 0 to 5;

[0174] r is each independently an integer from 0 to 5; and

[0175] s is an integer of 0-3 for each independently.

[0176] In certain embodiments, C3 is selected from a single bond, -NR3-, -NR3-C(=O)-, -NR3-C(=S)-, -NR3-C(=NH)-, -NR3-C(=NH)-NR3-, -NR3-C(=S)-NR3-, and -NR3-.

[0177] In certain embodiments, R3 is selected from hydrogen, hydroxy, alkyl and alkoxy, wherein the alkyl and alkoxy are each independently optionally selected from alkyl, halogen, hydroxy, -NR i R j , Oxo, -C(O)OR k and cyano; Rn is selected from hydrogen atom, alkyl, hydroxyl and halogen; k5 is an integer from 0 to 5.

[0178] In certain embodiments, the formula -C3-A3-COOR k for

[0179] In certain embodiments, the compound represented by formula (I-4) is

[0180]

[0181] Among them, A, G2, C3, A3, and R k As mentioned before.

[0182] Another aspect of the present disclosure provides a compound represented by formula (I-5) or a pharmaceutically acceptable salt, stereoisomer, rotational isomer, tautomer or deuterated compound thereof,

[0183]

[0184] in,

[0185] X is selected from N, CH and C-Cl;

[0186] T is selected from S, S=O, CH2 and O;

[0187] E is selected from wherein R1 and R2 are each independently selected from hydrogen, halogen, phenyl, alkylthio and alkyl optionally substituted by carbamoyl (alkyl is preferably C1-C6 alkyl, the same below), R 11 and R 12 are each independently selected from hydrogen, carboxyl and alkyl optionally substituted by carbamoyl, and m is an integer from 1 to 5;

[0188] F is a single bond;

[0189] R 13 is a hydrogen atom or a carboxyl protecting group;

[0190] R 14 is an optionally substituted aryl group or an optionally substituted heterocyclic group;

[0191] A is selected from the group consisting of alkylene, alkenylene and alkynylene;

[0192] Q is an optionally substituted heterocyclic group (preferably a heterocyclic group containing at least one N atom);

[0193] Y1 is selected from optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, -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)NR71 -、-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)NR 71 -、-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 S(=O)2- and a single bond;

[0194] Each R 71 may be independently selected from hydrogen, hydroxy, alkyl, and optionally substituted alkoxy;

[0195] Y2 is selected from a single bond, optionally substituted alkylene, optionally substituted alkenylene and optionally substituted alkynylene;

[0196] Y3 is selected from -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 -, where R 15 is selected from hydroxy, urea and optionally substituted alkoxy, R 16 is an optionally substituted carbamoyl group or a carboxyl group optionally protected by a carboxyl protecting group, or a salt thereof;

[0197] Z1 is selected from -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 a single bond, where R 16 is selected from hydrogen, carbamoyl, optionally substituted alkyl and hydroxy optionally protected by a hydroxy protecting group, R 17 and R 18 are each independently selected from optionally substituted alkyl, optionally substituted alkylene and optionally substituted alkenylene, R 19 and R 20 are each independently selected from hydrogen, optionally substituted alkyl, hydroxy optionally protected by a hydroxy protecting group, and optionally substituted heterocyclyl; and

[0198] Z2 is -NR 21 - or a single bond, where R 21 is selected from hydrogen, optionally substituted alkyl and optionally protected hydroxy.

[0199] In certain embodiments, Q does not comprise a quaternary ammonium structure.

[0200] In certain embodiments, the heterocyclic group in Q is selected from pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and homopiperazinyl, wherein the heterocyclic group is optionally selected from alkyl, halogen, hydroxyl, thiol, -NR i R j , oxo, thio, -C(O)R k 、-C(O)OR k 、-C(S)R k , nitro, cyano, alkoxy and alkylthio; preferred examples of Q include

[0201]

[0202] For example it could be

[0203]

[0204] wherein R8 are each independently selected from hydrogen, halogen, hydroxy, alkyl, alkoxy, haloalkyl and haloalkoxy; and

[0205] q is an integer of 0-5 for each independently.

[0206] In certain embodiments, R 14 for

[0207] Wherein D4 is an aryl or heterocyclic group, preferably a phenyl or naphthyl group, R 41 Each is independently selected from alkyl, halogen, hydroxy, mercapto, oxo, thio, -NR i R j 、-C(O)R k 、-C(O)OR k , nitro, cyano, alkoxy and alkylthio, wherein the alkyl, alkoxy and alkylthio are each independently selected from alkyl, halogen, hydroxyl, mercapto, -NR i R j , oxo, thio, -C(O)R k 、-C(O)OR k 、-C(S)R k The radical is substituted by one or more substituents selected from the group consisting of , nitro, cyano, alkoxy, alkylthio, cycloalkyl, heterocyclic, aryl and heteroaryl, and n is an integer of 0 to 8.

[0208] In certain embodiments, the compound represented by formula (I-5) is

[0209]

[0210] Among them, A, Q, Y1, Z1, Y2, Z2, Y3, R 13 and R 14 As mentioned before.

[0211] In certain embodiments, the compound is selected from:

[0212]

[0213] The "alkyl group" described in the present disclosure is preferably a C1-C6 alkyl group.

[0214] The "alkylene group" described in the present disclosure is preferably a C1-C6 alkylene group.

[0215] The "alkenylene group" described in the present disclosure is preferably a C2-C6 alkenylene group.

[0216] The "alkynylene group" described in the present disclosure is preferably a C2-C6 alkynylene group.

[0217] The "alkoxy group" described in the present disclosure is preferably a C1-C6 alkoxy group.

[0218] The “alkylthio group” described in the present disclosure is preferably a C1-C6 alkylthio group.

[0219] The "cycloalkyl group" described in the present disclosure is preferably a 3- to 12-membered, more preferably a 3- to 6-membered cycloalkyl group.

[0220] The "fused cycloalkyl" described in the present disclosure is preferably a 6- to 14-membered, more preferably a 7- to 10-membered fused cycloalkyl.

[0221] The "heterocyclic group" described in the present disclosure is preferably a 3- to 12-membered, more preferably a 3- to 6-membered heterocyclic group.

[0222] The "fused heterocyclic group" described in the present disclosure is preferably a 6- to 14-membered, more preferably a 7- to 10-membered fused heterocyclic group.

[0223] The "aryl group" described in the present disclosure is preferably a 6- to 14-membered group, and more preferably a 6- to 10-membered aryl group.

[0224] The "fused ring aryl group" described in the present disclosure preferably has 8 to 14 members, and more preferably has 8 to 12 members.

[0225] The "heteroaryl group" described in the present disclosure is preferably a 5- to 12-membered group, and more preferably a 5- to 8-membered heteroaryl group.

[0226] The “fused heteroaryl group” described in the present disclosure is preferably a 5- to 14-membered, more preferably a 5- to 12-membered, fused heteroaryl group.

[0227] The "optionally substituted" group described in the present disclosure may be the group optionally selected from alkyl (preferably C1-C6 alkyl), halogen, deuterium, hydroxyl, mercapto, -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, nitro, cyano, alkoxy (preferably C1-C6 alkoxy), alkylthio (preferably C1-C6 alkylthio), alkenyl (preferably C2-C6 alkenyl), alkynyl (preferably C2-C6 alkynyl), cycloalkyl (preferably 3- to 6-membered cycloalkyl), heterocyclyl (preferably 3- to 6-membered heterocyclyl), condensed cycloalkyl (preferably 7- to 10-membered condensed cycloalkyl), condensed heterocyclyl (preferably 7- to 10-membered condensed heterocyclyl), aryl (preferably 6- to 10-membered aryl), heteroaryl (preferably 5- to 10-membered heteroaryl), condensed ring aryl (preferably 8- to 12-membered condensed ring aryl), condensed heteroaryl (preferably 5- to 12-membered condensed heteroaryl). R i , R j and R k As previously described, the set of optional substituents of each "optionally substituted" group may be the same or different.

[0228] In certain embodiments, the compounds described herein are in the Z configuration.

[0229] The present disclosure also provides a pharmaceutical composition, comprising at least one of the aforementioned compounds or pharmaceutically acceptable salts thereof, or stereoisomers, rotational isomers, tautomers or deuterated compounds thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

[0230] In certain embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0231] In certain embodiments, the pharmaceutical composition contains 0.01%-99.99% of the aforementioned compound based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of the aforementioned compound. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound.

[0232] In certain embodiments, the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable carrier, diluent or excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of a pharmaceutically acceptable carrier, diluent or excipient. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of a pharmaceutically acceptable carrier, diluent or excipient. In certain embodiments, the pharmaceutical composition contains 1%-99% of a pharmaceutically acceptable carrier, diluent or excipient. In certain embodiments, the pharmaceutical composition contains 2%-98% of a pharmaceutically acceptable carrier, diluent or excipient.

[0233] The present disclosure also relates to the use of the compound of the present disclosure or its pharmaceutically acceptable salt, stereoisomer, rotamer, tautomer or deuterated compound, or a pharmaceutical composition comprising the same, in the preparation of a medicament for preventing and treating diseases caused by pathogenic bacteria in mammals including humans.

[0234] The present disclosure also relates to use of the compound of the present disclosure or its pharmaceutically acceptable salt, or their stereoisomers, rotational isomers or tautomers or deuterated compounds in the preparation of drugs for preventing and treating diseases caused by Gram-negative bacteria.

[0235] The present disclosure also relates to the compounds of the present disclosure or their pharmaceutically acceptable salts, stereoisomers, rotamers, tautomers or deuterated compounds, or pharmaceutical compositions comprising the same, as drugs.

[0236] The present disclosure also relates to the compounds of the present disclosure or their pharmaceutically acceptable salts, stereoisomers, rotational isomers, tautomers or deuterated compounds, or pharmaceutical compositions comprising the same, which are used for preventing and treating diseases caused by pathogenic bacteria in mammals including humans.

[0237] The present disclosure also relates to the compound of the present disclosure or its pharmaceutically acceptable salt, stereoisomer, rotational isomer, tautomer or deuterated compound, or a pharmaceutical composition comprising the same, which is used for preventing and treating diseases caused by Gram-negative bacteria.

[0238] The present disclosure also relates to a method for preventing and treating diseases caused by pathogenic bacteria, which comprises administering to a patient in need thereof a therapeutically effective dose of the compound of the present disclosure or its pharmaceutically acceptable salt, stereoisomer, rotational isomer, tautomer or deuterated compound, or a pharmaceutical composition comprising the same.

[0239] The present disclosure also relates to a method for preventing and treating diseases caused by Gram-negative bacteria, which comprises administering to a patient in need thereof a therapeutically effective dose of the compound of the present disclosure or its pharmaceutically acceptable salt, stereoisomer, rotational isomer, tautomer or deuterated compound, or a pharmaceutical composition comprising the same.

[0240] In this article, the diseases caused by pathogens or diseases caused by Gram-negative bacteria include, but are not limited to, airway infections, urinary tract infections, respiratory infections, septicemia, nephritis, cholecystitis, oral infections, endocarditis, pneumonia, myelomyelitis, otitis media, enteritis, empyema, traumatic infections, opportunistic infections, etc.

[0241] Herein, the Gram-negative bacteria are preferably Gram-negative bacteria of intestinal bacteria (Escherichia coli, Klebsiella, Serratia, Enterobacter, Citrobacter, Morganella, Providencia, Proteus, etc.), Gram-negative bacteria living in the respiratory system (Haemophilus, Moraxella, etc.) and non-fermenting Gram-negative bacteria of glucose (Pseudomonas aeruginosa, Pseudomonas other than P.aeruginosa, Stenotrophomonas, Burkholderia, Acinetobacter, etc.).

[0242] The present disclosure also provides use of the compound of the present disclosure or its pharmaceutically acceptable salt, stereoisomer, rotational isomer, tautomer or deuterated compound in a drug for preventing and treating diseases caused by Gram-positive bacteria.

[0243] Herein, the mammal may be a human, or may be a non-human mammal.

[0244] The present disclosure further provides a kit comprising the compound described in the present disclosure or a pharmaceutically acceptable salt, stereoisomer, rotational isomer, tautomer or deuterated compound thereof, or a pharmaceutical composition.

[0245] According to the test method known in the art (eg, WO2010050468), it was determined that the compounds of the present disclosure have an inhibitory activity against Gram-negative bacteria with excellent effect.

[0246] Terminology explanation:

[0247] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0248] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. More preferred are alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0249] The term "alkylene" refers to a saturated straight or branched aliphatic hydrocarbon group having two residues derived from the same carbon atom or two different carbon atoms of a parent alkane by removing two hydrogen atoms, which is a straight or branched group containing 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, and more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene 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. Alkylene can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any available point of attachment.

[0250] The term "alkenylene" refers to a linear alkenyl 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 double bond at any position, including, for example, vinylene, allylene, propenylene, butenylene, prenylene, butadienylene, pentenylene, pentadienylene, hexenylene, hexadienylene, and the like.

[0251] The term "alkynylene" includes linear alkynylene 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 triple bond at any position, including, for example, ethynylene, propynylene, butynylene, pentynylene, hexynylene, and the like.

[0252] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include spirocyclic, fused and bridged cycloalkyls.

[0253] The term "spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (called a spiral atom) between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiral atoms shared between the rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl and a double spiral cycloalkyl. More preferably, it is a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral cycloalkyl. Non-limiting examples of spirocycloalkyl include:

[0254]

[0255] The term "condensed cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of condensed cycloalkyls include:

[0256]

[0257] The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic or tetracyclic, and more preferably a bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0258]

[0259] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0260] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O). m (wherein m is an integer from 0 to 2) heteroatoms, but does not include -OO-, -OS- or -SS- ring parts, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably piperidinyl, pyrrolidinyl. Polycyclic heterocyclic groups include spirocyclic, condensed ring and bridged heterocyclic groups.

[0261] The term "spiro heterocyclyl" refers to a polycyclic heterocyclic group in which the monocyclic rings of 5 to 20 members share one atom (called a spiro atom), wherein one or more of the ring atoms is selected from nitrogen, oxygen or S(O) m (wherein m is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of shared spiral atoms between rings, the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. More preferably, it is a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral heterocyclic group. Non-limiting examples of spiral heterocyclic groups include:

[0262]

[0263] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

[0264]

[0265] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system, and one or more of the ring atoms is selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0266]

[0267] The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0268] wait.

[0269] The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0270] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include:

[0271]

[0272] The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate, preferably phenyl.

[0273] The term "condensed ring aryl" may be an unsaturated aromatic condensed ring structure containing 8 to 14 ring atoms formed by two or more cyclic structures sharing two adjacent atoms, preferably 8 to 12 ring atoms. For example, it includes all unsaturated condensed ring aryl groups, such as naphthalene, phenanthrene, etc., and also includes partially saturated condensed ring aryl groups, such as benzo 3-8 membered saturated monocyclic cycloalkyl, benzo 3-8 membered partially saturated monocyclic cycloalkyl, and specific examples are 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, etc.

[0274] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl is preferably 5 to 12 members, such as imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, pyrazolyl, pyrimidyl or thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0275]

[0276] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0277] The term "fused heteroaryl" may be an unsaturated fused ring structure with aromaticity containing 5-14 ring atoms (including at least one heteroatom) which is formed by two or more ring structures sharing two adjacent atoms to form a structure, and the carbon atoms, nitrogen atoms and sulfur atoms may be oxidized, preferably "5-12 membered fused heteroaryl", "7-12 membered fused heteroaryl", "9-12 membered fused heteroaryl" and the like, for example, benzofuranyl, benzisofuranyl, benzothiophenyl, indolyl, isoindole, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, phenolazinyl, pteridinyl, purinyl, naphthyridinyl, phenazine, phenothiazine and the like.

[0278] The fused heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0279] The term "alkoxy" refers to-O-(alkyl) and-O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above. The non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0280] The term "alkylthio" refers to -S-(alkyl) and -S-(non-substituted cycloalkyl), wherein the definition of alkyl is as described above. Non-limiting examples of alkylthio include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio. Alkylthio can be optionally substituted or non-substituted, and when substituted, substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio and one or more substituents.

[0281] The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0282] The term "haloalkyl" refers to an alkyl group substituted with a halogen, wherein alkyl is as defined above.

[0283] The term "deuterated alkyl" refers to an alkyl group substituted with a deuterium atom, wherein alkyl is as defined above.

[0284] The term "hydroxy" refers to an -OH group.

[0285] The term "oxo" refers to a =0 group. For example, a carbon atom is connected to an oxygen atom via a double bond, wherein a ketone or aldehyde group is formed.

[0286] The term "thio" refers to a =S group. For example, a carbon atom is connected to a sulfur atom via a double bond to form a thiocarbonyl group -C(S)-.

[0287] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0288] The term "amino" refers to -NH2.

[0289] The term "cyano" refers to -CN.

[0290] The term "nitro" refers to -NO2.

[0291] The term "carboxy" refers to -C(O)OH.

[0292] The term "aldehyde" refers to -CHO.

[0293] The term "carboxylate" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

[0294] The term "acyl halide" refers to a compound containing the group -C(O)-halogen.

[0295] "Carboxyl protecting group" is a suitable group for protecting carboxyl group known in the art, see the literature ("Protective Groups in Organic Synthesis", 5 Th Ed.TWGreene & P.GMWuts) in the carboxyl protecting group, as an example, preferably, the carboxyl protecting group can be a substituted or unsubstituted C 1-10 A straight chain or branched alkyl, substituted or unsubstituted C 2-10 A straight-chain or branched alkenyl or alkynyl, substituted or unsubstituted C 3-8 Cyclic alkyl, substituted or unsubstituted C 5-10 aryl or heteroaryl, or (C 1-8 Alkyl or aryl) 3 silyl; preferably C 1-6 A straight or branched chain alkyl group, more preferably C 1-4 A straight chain or branched chain alkyl group, for example, methyl, ethyl, allyl, isopentenyl, trimethylsilylethyl, etc.

[0296] "Amino protecting group" is a suitable group for protecting amino group known in the art, see the literature ("Protective Groups in Organic Synthesis", 5 Th Ed.TWGreene & P.GMWuts) in the amino protecting group, preferably, the amino protecting group can be (C 1-10 alkyl or aromatic) acyl, such as formyl, acetyl, benzoyl, etc.; can be (C 1-6 Alkyl or C 6-10 Aryl)sulfonyl; can also be (C 1-6 Alkoxy or C 6-10It can also be a substituted or unsubstituted alkyl group, for example, trityl (Tr), 2,4-dimethoxybenzyl (DMB), p-methoxybenzyl (PMB) or benzyl (Bn).

[0297] "Hydroxy protecting group" is a suitable group for protecting hydroxyl group known in the art, see the literature ("Protective Groups in Organic Synthesis", 5 Th Ed.TWGreene & P.GMWuts) in the hydroxyl protecting group. As an example, preferably, the hydroxyl protecting group can be (C 1-10 alkyl or aryl) 3 silyl, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, etc.; it can be C 1-10 Alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C 1-6 Alkoxy substituted C 1-6 Alkyl or phenyl substituted C 1-6 Alkyl, most preferably C 1-4 Alkoxy substituted C 1-4 Alkyl, for example: methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), etc.; can be (C 1-10 alkyl or aromatic) acyl, such as formyl, acetyl, benzoyl, etc.; can be (C 1-6 Alkyl or C 6-10 Aryl)sulfonyl; can also be (C 1-6 Alkoxy or C 6-10 aryloxy)carbonyl.

[0298] The term "leaving group" refers to an atom or functional group that leaves a larger molecule in a chemical reaction. Representative leaving groups include halogen, substituted sulfonyloxy, phosphoryloxy, amino, R i R j N-, cyano, R m S-et al.

[0299] The substituted sulfonyloxy group may be a C1-C6 alkylsulfonyloxy group, a perfluoro C1-C6 alkylsulfonyloxy group, an arylsulfonyloxy group, an aralkylsulfonyloxy group or the like.

[0300] Specific examples of the C1-C6 alkylsulfonyloxy group include a C1-C6 linear or branched alkylsulfonyloxy group such as a methylsulfonyloxy group, an ethylsulfonyloxy group, an n-propylsulfonyloxy group, an isopropylsulfonyloxy group, an n-butylsulfonyloxy group, a tert-butylsulfonyloxy group, an n-pentylsulfonyloxy group and an n-hexylsulfonyloxy group.

[0301] Specific examples of the perfluoro C1-C6 alkylsulfonyloxy group 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.

[0302] Examples of arylsulfonyloxy groups include phenylsulfonyloxy and naphthylsulfonyloxy groups optionally having 1 to 3 substituents selected from the group consisting of C1-C6 straight or branched alkyl, C1-C6 straight or branched alkane, nitro and halogen atoms on the phenyl ring. Specific examples of the phenylsulfonyloxy group optionally having a substituent include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-tolylsulfonyloxy, 2-nitrophenylsulfonyloxy, 3-chlorophenylsulfonyloxy and the like. Specific examples of naphthylsulfonyloxy groups include α-naphthylsulfonyloxy, β-naphthylsulfonyloxy and the like.

[0303] Examples of the aralkylsulfonyloxy group include: a C1-C6 straight chain or branched chain alkylsulfonyloxy group substituted with a phenyl group (which optionally has 1 to 3 substituents selected from a C1-C6 straight chain or branched chain alkyl group, a C1-C6 straight chain or branched chain alkyl group, a nitro group and a halogen atom on the phenyl ring); and a C1-C6 straight chain or branched chain alkylsulfonyloxy group substituted with a naphthyl group. Specific examples of the alkylsulfonyloxy group substituted with a phenyl group include a benzylsulfonyloxy group, a 2-phenylethylsulfonyloxy group, a 4-phenylbutylsulfonyloxy group, a 4-methylbenzylsulfonyloxy group, a 2-methylbenzylsulfonyloxy group, a 4-nitrobenzylsulfonyloxy group, a 4-methylbenzylsulfonyloxy group, a 3-chlorobenzylsulfonyloxy group and the like. Specific examples of the alkylsulfonyloxy group substituted with a naphthyl group include an α-naphthylmethylsulfonyloxy group, a β-naphthylmethylsulfonyloxy group and the like.

[0304] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0305] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort.

[0306] In the chemical structures of the compounds disclosed herein, the bond No configuration is specified, i.e., the bond Can be or include both In the chemical structure of the compounds disclosed in the present invention, the bond The configuration is not specified, that is, it can be Z configuration or E configuration, or contain both configurations.

[0307] Tautomers are structural isomers of organic compounds that are easily interconvertible through a chemical reaction known as tautomerization. This reaction often results in the formal migration of hydrogen atoms or protons, accompanied by the conversion of single bonds and adjacent double bonds. Some common tautomeric pairs are: keto-enol, lactam-lactim. An example of a lactam-lactim equilibrium is between A and B as shown below.

[0308]

[0309] All compounds in the present disclosure can be drawn as either Form A or Form B. All tautomeric forms are within the scope of the present disclosure. The naming of the compounds does not exclude any tautomers.

[0310] "Each independently" or "independently" means that substituents with the same selection range can be the same or different groups at each occurrence, and the group selection of the substituent at each occurrence is not affected by the selection of the substituent (or substituents of the same selection range) at other positions.

[0311] Any isotope-labeled derivatives of the compounds or pharmaceutically acceptable salts thereof, or isomers thereof described in the present disclosure are covered by the present disclosure. Atoms that can be isotopically labeled include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, iodine, etc. They can be labeled with isotopes. 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 Unless otherwise indicated, when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (i.e., at least 45% deuterium incorporation) that is at least 3000 times greater than the natural abundance of deuterium, which is 0.015%. DETAILED DESCRIPTION

[0312] The preparation of the compounds and pharmaceutically acceptable salts described in the present disclosure is further described below in conjunction with examples, but these examples are not intended to limit the scope of the present disclosure.

[0313] The experimental methods in the examples of this disclosure that do not specify specific conditions are usually carried out under conventional conditions or under conditions recommended by raw material or product manufacturers. Reagents that do not specify specific sources are conventional reagents purchased from the market.

[0314] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (LCMS). -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the solvent, and tetramethylsilane (TMS) as the internal standard. The spatial configuration of the optical isomers (isomers) of the compound can be further confirmed by measuring the single crystal parameters.

[0315] HPLC determinations were performed using Waters ACQUITY ultra high performance LC, Shimadzu LC-20A systems, Shimadzu LC-2010HT series, or Agilent 1200 LC high pressure liquid chromatographs (ACQUITY UPLC BEH C18 1.7UM 2.1X50MM column, Ultimate XB-C18 3.0*150mm column, or Xtimate C18 2.1*30mm column).

[0316] MS was determined using a Waters SQD2 mass spectrometer in positive / negative ion mode with a mass scan range of 100-1200.

[0317] Chiral HPLC analysis was performed using Chiralpak IC-3 100×4.6mm ID, 3um, Chiralpak AD-3 150×4.6mm ID, 3um, Chiralpak AD-3 50×4.6mm ID, 3um, Chiralpak AS-3 150×4.6mm ID, 3um, Chiralpak AS-3 100×4.6mm ID, 3μm, ChiralCel OD-3 150×4.6mmI.D., 3um, Chiralcel OD-3 100×4.6mm ID, 3μm, ChiralCel OJ-H 150×4.6mm ID, 5um, Chiralcel OJ-3 150×4.6mm ID, 3um columns;

[0318] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0319] The flash column purification system used was Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).

[0320] Forward column chromatography generally uses Yantai Huanghai silica gel 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel as the carrier, or uses Changzhou Santai pre-filled ultra-pure normal phase silica gel column (40-63μm, 60, 12g, 25g, 40g, 80g or other specifications).

[0321] Reverse phase column chromatography generally uses Changzhou Santai pre-packed ultra-pure C18 silica gel column (20-45μm, 40g, 80g, 120g, 220g or other specifications).

[0322] The high-pressure column purification system uses Waters AutoP in combination with Waters XBridge BEH C18 OBDPrep Column. 5μm, 19mm X 150mm or Atlantis T3 OBD Prep Column, 5μm, 19mm X 150mm.

[0323] The chiral preparative column used was DAICEL CHIRALPAK IC (250 mm*30 mm, 10 um) or Phenomenex-Amylose-1 (250 mm*30 mm, 5 um).

[0324] The known starting materials in the present disclosure can be synthesized by methods known in the art, or can be purchased from Shanghai Titan Technology, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals and other companies.

[0325] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0326] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0327] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1L.

[0328] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.

[0329] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

[0330] The microwave reaction was carried out using a CEM Discover-S 908860 microwave reactor.

[0331] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0332] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0333] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the system of eluent for column chromatography used for purifying the compound and the developing solvent system for thin layer chromatography include: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system, D: petroleum ether / ethyl acetate / methanol, E: petroleum ether / tetrahydrofuran system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0334] Example 1

[0335]

[0336] first step

[0337]

[0338] Compound 1-1 (2.46 g, 10 mmol) was dissolved in 5% aqueous sodium bicarbonate solution (86 mL), stirred until dissolved, and Fmoc-OSu (3.37 g, 10 mmol, dissolved in 24 mL of dioxane) was added. After the addition, the reaction was allowed to react overnight, and most of the dioxane was evaporated under reduced pressure. The pH was adjusted with hydrochloric acid, and the layers were extracted with ethyl acetate. The layers were dried over magnesium sulfate, filtered and evaporated to dryness to obtain compound 1-2 (5.2 g), which was directly used in the next step.

[0339] LC / MS(ESI): m / z 469.1[M+H] +

[0340] Step 2

[0341]

[0342] Compound 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), and then p-methoxybenzyl alcohol (828 mg, 6 mmol) was added and stirred for reaction. After the reaction was completed, the mixture was concentrated under reduced pressure, methyl tert-butyl ether was added for slurrying, filtered, and the solvent was removed in vacuo to obtain compound 1-3 (1.31 g, 2.23 mmol) with a yield of 56%.

[0343] LC / MS(ESI): m / z 589.1[M+H] +

[0344] Step 3

[0345]

[0346] Compound 1-3 (945 mg, 1.6 mmol) was dissolved in dichloromethane (10 mL), and then DBU (243 mg, 1.6 mmol) was added and stirred for reaction. After the reaction was completed, citric acid aqueous solution was added to quench the reaction, MTBE was diluted and separated, and the aqueous phase was adjusted to pH = 8 with 1N NaOH solution, extracted with dichloromethane, dried, filtered and concentrated to obtain compound 1-4 (562 mg) with a yield of 96%.

[0347] LC / MS(ESI): m / z 367.1[M+H] +

[0348] Step 4

[0349]

[0350] Compound 1-4 (534 mg, 1.46 mmol) was dissolved in acetonitrile (20 mL), 1,4-dibromobutane (330 mg, 1.53 mmol) and N,N-diisopropylethylamine (395 mg, 3.06 mmol) were added, and the mixture was heated to reflux for 6 h. After the reaction, aqueous citric acid solution was added to quench the reaction, and the layers were diluted with methyl tert-butyl ether. The aqueous phase was extracted with dichloromethane, evaporated to dryness under reduced pressure, and then adjusted to pH = 8 with saturated sodium bicarbonate aqueous solution. The organic phases were combined and dried over anhydrous MgSO4, filtered and concentrated to obtain compound 1-5 (400 mg) with a yield of 66%.

[0351] LC / MS(ESI): m / z 421.1[M+H] +

[0352] Step 5

[0353]

[0354] Compound 1-5 (211 mg, 0.5 mmol), compound 1-6 (synthesized according to the method of patent WO2016035847, 360 mg, 0.45 mmol), and sodium iodide (225 mg, 1.5 mmol) were dissolved in N, N-dimethylformamide (0.8 mL), and stirred for reaction. After the reaction, the reaction solution was cooled to 0°C, potassium iodide (523 mg, 3.15 mmol), N, N-dimethylformamide (1.6 mL), and acetyl chloride (177 mg, 2.25 mmol) were added, and stirred for reaction. After the reaction, the reaction solution was added to a 5% Na2S2O5 aqueous solution, stirred and filtered, and the solvent was removed in vacuo to obtain compound 1-7 (540 mg).

[0355] LC / MS(ESI): m / z 1164.2[M] +

[0356] Step 6

[0357]

[0358] Compound 1-7 (233 mg) was dissolved in anisole (0.5 mL) and trifluoroacetic acid (2 mL), and the mixture was stirred for reaction. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in methyl tert-butyl ether, washed with dilute hydrochloric acid, and the combined aqueous phases were concentrated under reduced pressure to obtain 110 mg of a crude product, which was then prepared by HPLC to obtain 4 mg of compound 1.

[0359] LC / MS(ESI): m / z 668.0[M+H] +

[0360] 1H-NMR (400MHz, DMSO-d6) δ: 1.27-1.38 (m, 1H), 1.44 (s, 3H), 1.45 (s, 3H), 1.56-1.80 (m, 4H), 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).

[0361] Example 2

[0362]

[0363] first step

[0364]

[0365] 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 methylsulfonyl chloride (2.43 g, 21.38 mmol, 2 eq) was added dropwise, and the reaction was carried out at room temperature. After the reaction was completed, the mixture was diluted with dichloromethane, washed with water, dried, filtered, and concentrated to obtain a crude product. 2.6 g of the crude product (about 8.96 mmol) was dissolved in acetonitrile (20 mL), potassium carbonate (2.76 g, 20 mmol, 2.23 eq) and tetrahydropyrrole (1.06 g, 15 mmol, 1.67 eq) were added, and the reaction was stirred at 40 ° C overnight. After the reaction was completed, the solvent was evaporated under reduced pressure, the mixture was dissolved in dichloromethane, washed with water, dried, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 1.7 g of compound 2-2, with a yield of 79%.

[0366] Step 2

[0367]

[0368] Compound 2-2 (300 mg, 1.25 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred for reaction. After the reaction was completed, the mixture was concentrated under reduced pressure, and methanol was added for dilution. The mixture was neutralized with potassium carbonate, and the crude product of compound 2-3 was obtained by filtration and concentration and used directly in the next step.

[0369] LC / MS(ESI): m / z 141.1[M+H] +

[0370] Step 3

[0371]

[0372] The crude compound 2-3 obtained in the previous step, compound 2-4 (synthesized according to 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), and DIPEA (1.1 mL, 6.25 mmol) was added, and the reaction was stirred overnight. After the reaction was completed, sodium hydroxide aqueous solution was added and stirred, filtered, and the filter cake was washed with water and the solvent was removed in vacuo to obtain a crude product. Column chromatography was used to separate to obtain compound 2-5 (600 mg, 1.09 mmol), with a two-step yield of 87%.

[0373] LC / MS(ESI): m / z 555.1[M+H] +

[0374] Step 4

[0375]

[0376] Compound 2-5 (219 mg, 0.4 mmol), compound 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 the mixture was stirred for reaction. After the reaction, the mixture was cooled with ice water, and KI (465 mg, 2.8 mmol), N-methylpyrrolidone (2 mL), and acetyl chloride (188 mg, 2.4 mmol) were added, and the mixture was stirred for reaction. After the reaction, the reaction mixture was directly added to a large amount of sodium metabisulfite aqueous solution under ice bath, and filtered after stirring. The filter cake was washed with water and the solvent was removed in vacuo to obtain compound 2-6 (635 mg).

[0377] LC / MS(ESI): m / z 1294.4[M] +

[0378] Step 5

[0379]

[0380] Compound 2-6 (200 mg) was dissolved in anisole (0.4 mL) and trifluoroacetic acid (1.6 mL), and the reaction was stirred. After the reaction was completed, MTBE (4 mL) was added to precipitate a solid, which was filtered, washed with MTBE and dried to obtain 170 mg of a crude product. After HPLC preparation, 4.2 mg of compound 2 was obtained.

[0381] LC / MS(ESI): m / z 777.9[M+H]+

[0382] 1 H-NMR (400MHz, DMSO-d6) δ: 1.00-1.08 (m, 4H), 1.44 (s, 3H), 1.45 (s, 3H), 1. 91-2.14(m, 4H), 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).

[0383] Example 3

[0384]

[0385] first step

[0386]

[0387] 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 heated to reflux for reaction. After the reaction was completed, the mixture was cooled to room temperature, MTBE and NaOH aqueous solution were added for separation, and the aqueous phase was extracted with MTBE. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain 0.7 g of compound 3-3.

[0388] LC / MS(ESI): m / z 145.1[M+H] +

[0389] Step 2

[0390]

[0391] Compound 2-4 (1.9 g, 4.43 mmol) was stirred in tetrahydrofuran (30 mL) under ice-water bath, triethylamine (0.98 mL, 7.09 mmol) was added, and methylsulfonyl chloride (0.45 mL, 5.80 mmol) was added dropwise. After the addition was complete, the mixture was reacted under ice-water bath. Compound 3-3 was dissolved in THF (10 mL) and added dropwise to the above reaction solution. After the addition was complete, the reaction solution was warmed to room temperature for reaction. Ethyl acetate was added, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain a crude product. The crude product was prepared by HPLC to obtain 220 mg of compound 3-4.

[0392] LC / MS(ESI): m / z 555.1[M+H] +

[0393] Step 3

[0394]

[0395] Compound 1-6 (315 mg, 0.395 mmol), compound 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 stirred for reaction. After the reaction was completed, the reaction bottle was placed in an ice-water bath for cooling, PBr3 (751 mg, 2.77 mmol) was added, and the reaction was stirred for reaction. After the reaction was completed, the reaction solution was added dropwise to a NaHSO3 aqueous solution, filtered, and the filter cake was washed with clean water and vacuum dried to obtain 623 mg of a crude compound 3-5.

[0396] LC / MS(ESI): m / z 1298.1[M] +

[0397] Step 4

[0398]

[0399] Compound 3-5 (200 mg, 0.154 mmol) was added to anisole (0.4 mL) and trifluoroacetic acid (1.6 mL) and reacted at room temperature. Methyl tert-butyl ether was added and the mixture was stirred and filtered. The filter cake was rinsed with MTBE and dried to obtain 112 mg of a crude product. The crude product was subjected to HPLC preparation to obtain 7.1 mg of compound 3.

[0400] LC / MS(ESI): m / z 781.9[M+H] +

[0401] 1H-NMR (400MHz, 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).

[0402] Example 4

[0403]

[0404] first step

[0405]

[0406] Compound 2-4 (3.0 g, 7.0 mmol) and triethylamine (0.85 g, 8.39 mmol) were added to toluene (50 mL), and diphenylphosphoryl azide (2.31 g, 8.39 mmol) was slowly added dropwise. After the addition, the mixture was stirred and reacted overnight. The temperature was raised to 110°C for reaction. 9-fluorene methanol (2.06 g, 10.49 mmol) was added. After the addition, the mixture was reacted at 110°C. After the reaction was completed, the temperature was lowered to room temperature. Piperidine (2.98 g, 34.97 mmol) was added. The mixture was stirred and reacted overnight. The heating was stopped, the mixture was concentrated to remove toluene, dichloromethane and water were added and stirred, and the mixture was separated. The aqueous phase was extracted with dichloromethane, and the organic phases were combined, dried, filtered, and concentrated to obtain a crude product. The crude product was directly subjected to column chromatography to obtain 462 mg of compound 4-1, with a yield of 17%.

[0407] LC / MS(ESI): m / z 400.0[M+H] +

[0408] Step 2

[0409]

[0410] Compound 4-1 (0.46 g, 1.15 mmol) was dissolved in dichloromethane (8 mL), thiophosgene (0.40 g, 3.45 mmol) was added dropwise, DMAP (0.70 g, 5.73 mmol) was added at 0°C, and the mixture was heated to room temperature and stirred for reaction. After the reaction, the reaction solution was directly subjected to column chromatography to obtain compound 4-2, 432 mg, with a yield of 85%.

[0411] Step 3

[0412]

[0413] 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. After adding DMF (0.5 mL), the mixture was stirred at room temperature for overnight reaction. Water was added to the reaction solution to precipitate solids. The solids were filtered and the filter cake was collected. The filter cake was subjected to column chromatography to obtain 467 mg of compound 4-4 with a yield of 83%.

[0414] LC / MS(ESI): m / z 556.0[M+H] +

[0415] Step 4

[0416]

[0417] Compound 4-4 (200 mg, 0.36 mmol), compound 1-6 (315 mg, 0.4 mmol), sodium iodide (180 mg, 1.2 mmol), dissolved in NMP (0.9 mL), stirred for reaction, after the reaction, the reaction solution was cooled to 0°C, PBr3 (650 mg, 2.4 mmol) was added, stirred for reaction, after the reaction, the reaction solution was added to Na2S2O5 aqueous solution in an ice bath, stirred and filtered, the filter cake was washed with water and the solvent was removed in vacuo to obtain compound 4-5 (515 mg). LC / MS (ESI): m / z 1299.0 [M] +

[0418] Step 5

[0419]

[0420] Compound 4-5 (200 mg, 0.154 mmol) was placed in a reaction bottle, anisole (0.4 mL) and trifluoroacetic acid (1.6 mL) were added to stir and react, and after the reaction was completed, MTBE was added, filtered, and the filter cake was rinsed with MTBE and dried to obtain 68 mg of a crude product. The crude product was subjected to HPLC preparation to obtain 4.4 mg of compound 4.

[0421] LC / MS(ESI): m / z 782.9[M+H] +

[0422] 1H-NMR (400MHz, 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), 3.48-3.93(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), 7.2 2-7.51 (m, 2H), 9.05 (s, 1H), 9.22-9.34 (m, 1H), 9.36 (s, 1H), 9.77 (brs, 1H).

[0423] Embodiment 5:

[0424]

[0425] first step

[0426]

[0427] 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. The mixture was reacted in an oil bath at 50°C. After the reaction was completed, the reaction solution was concentrated, isopropyl ether and water were added, stirred and separated, and the organic phase was washed with saturated brine, dried, and concentrated to obtain a crude product, which was distilled under reduced pressure to obtain compound 5-1 (12.5 g) with a yield of 33%.

[0428] LC / MS(ESI): m / z 131.1[M+H] +

[0429] Step 2

[0430]

[0431] Compound 5-1 (1.0 g, 7.7 mmol), acetonitrile (10 mL), sodium bicarbonate (1.3 g, 15.4 mmol) were added to a single-mouth bottle, cooled with ice water, and acetyl chloride (0.66 g, 8.5 mmol) was added dropwise. The reaction solution was reacted in an ice-water bath. After the reaction was completed, dichloromethane and water were added, stirred and separated, and the aqueous phase was extracted with dichloromethane, dried, and concentrated to obtain compound 5-2 (0.9 g, yield 68%).

[0432] LC / MS(ESI): m / z 173.1[M+H] +

[0433] Step 3

[0434]

[0435] Compound 5-2 (510 g, 3 mmol), DCM (10 mL) and imidazole (410 mg, 6 mmol) were added to a single-mouth bottle, and tert-butyldiphenylsilyl chloride (910 mg, 3.3 mmol) was added dropwise. After the reaction was completed, DCM and H2O were added, stirred and separated, and 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) with a yield of 92%.

[0436] LC / MS(ESI): m / z 411.1[M+H] +

[0437] Step 4

[0438]

[0439] Compound 5-4 (synthesized according to 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-mouth bottle and reacted at room temperature. After the reaction was completed, the reaction solution was added dropwise to a 5% aqueous solution of sodium bisulfite, filtered, and the filter cake was washed with water. After the solvent was removed in vacuo, 230 mg of compound 5-5 was obtained.

[0440] LC / MS(ESI): m / z 1154.1[M] +

[0441] Step 5

[0442]

[0443] Compound 5-5 (200 mg, 0.164 mmol) was dissolved in anisole (0.4 mL) and trifluoroacetic acid (1.6 mL), stirred for reaction, and after the reaction was completed, MTBE was added, filtered, and the filter cake was rinsed with MTBE and dried to obtain 66 mg of a crude product. The crude product was subjected to HPLC preparation to obtain 1.9 mg of compound 5.

[0444] LC / MS(ESI): m / z 640.0[M+H] +

[0445] 1H-NMR (400MHz, 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, 1 2H), 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).

[0446] Embodiment 6:

[0447]

[0448] first step

[0449]

[0450] Compound 5-1 (0.5 g, 3.8 mmol), dichloromethane and imidazole (0.8 g, 11.5 mmol) were added to the reaction flask, cooled with ice water, tert-butyldiphenylsilyl chloride (1.15 g, 4.3 mmol) was added dropwise and stirred for reaction. After the reaction was completed, dichloromethane and water were added and stirred for separation, and 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%).

[0451] LC / MS(ESI): m / z 369.1[M+H] +

[0452] Step 2

[0453]

[0454] Compound 2-4 (428 mg, 1.0 mmol) and N, N-dimethylacetamide (4 mL) were added to a three-necked flask. The reaction solution was cooled in an ice-salt bath, and MsCl (126 mg, 1.1 mmol) and TEA (111 mg, 1.1 mmol) were added dropwise, and the mixture was stirred for reaction. Compound 6-1 (410 mg, 1.0 mmol) and N-methylmorpholine (172 mg, 1.7 mmol) were added dropwise. After the reaction was completed, the reaction was quenched, and the aqueous phase was extracted with EA. The organic phases were combined, dried, and purified by concentrated column chromatography to obtain compound 6-2 (240 mg, yield 30.8%).

[0455] LC / MS(ESI): m / z 779.0[M+H] +

[0456] Step 3

[0457]

[0458] 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 bottle and reacted overnight at room temperature. The reaction solution was added dropwise to a 5% aqueous solution of sodium metabisulfite, filtered, and the solvent was removed in vacuo to obtain 501 mg of compound 6-3.

[0459] LC / MS(ESI): m / z 1523.1[M] +

[0460] Step 4

[0461]

[0462] Compound 6-3 (501 mg) was added to the reaction flask, TFA (4 mL) and anisole (1 mL) were added, and the mixture was stirred for reaction. After the reaction was completed, MTBE was added dropwise to the reaction solution, and the mixture was filtered and the filter cake was washed with MTBE to obtain 210 mg of a crude product. The crude product was purified by reverse phase column chromatography to obtain compound 6 (10 mg).

[0463] LC / MS(ESI): m / z 767.8[M+H] +

[0464] 1 H-NMR (400MHz, 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).

[0465] Embodiment 7:

[0466]

[0467] first step

[0468]

[0469] Compound 7-1 (0.40 g, 0.76 mmol) was weighed in a reaction flask (synthesized according to the known literature European Journal of Medicinal Chemistry, 2018, 155, 847-868), anhydrous dichloromethane (4 mL) was added under nitrogen protection, the temperature was reduced to -40 ° C, pyridine (0.20 g, 2.5 mmol) was added dropwise, trifluoromethanesulfonic anhydride (0.28 g, 0.99 mmol) was added dropwise, the temperature was raised to -5 ° C for 2 hours, and then the temperature was lowered to -5 ° C again after reacting at room temperature for 2 hours, ammonium sulfide was added dropwise, and the reaction was carried out at room temperature. After the reaction was completed, dichloromethane was added to dilute, washed with water, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and silica gel was separated and purified to obtain compound 7-2 (0.35 g, 0.65 mmol) with a yield of 85%. LC / MS (ESI): m / z 541.0 [M+H] +

[0470] Step 2

[0471]

[0472] 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 stirred for reaction. After the reaction was completed, the reaction bottle was placed in an ice-water bath for cooling, PBr3 (360 mg, 1.33 mmol) was added, and the reaction was stirred for reaction. After the reaction was completed, the reaction solution was added dropwise to a NaHSO3 aqueous solution. Filter, wash the filter cake with clean water, and vacuum dry to obtain 1.1 g of crude compound 7-3.

[0473] Step 3

[0474]

[0475] Compound 7-3 (1.06 g, 0.824 mmol) was added to anisole (2 mL) and trifluoroacetic acid (8 mL) and reacted at room temperature. Methyl tert-butyl ether was added and the mixture was stirred and filtered. The filter cake was rinsed with MTBE and dried to obtain 550 mg of a crude product. 50 mg of the crude product was prepared by HPLC to obtain 4.8 mg of compound 7.

[0476] HRMS: 768.1334[M+H] +

[0477] Embodiment 8:

[0478]

[0479] first step

[0480]

[0481] PMBCl (503 mg, 3.21 mmol), K2CO3 (509 mg, 3.68 mmol), and NaI (138 mg, 0.92 mmol) were added to a DMF (10 mL) solution of compound 8-1 (200 mg, 0.92 mmol) (synthesized according to the known literature J. Med. Chem. 1997, 40, 1186-1194). The reaction was heated to 50°C and stirred. After adding water to the reaction solution, it was extracted with ethyl acetate, and the organic phase was washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered and evaporated to obtain a crude product. The crude product was purified by reverse phase silica gel column to obtain compound 8-2 (105 mg, yield 25%).

[0482] 1 H-NMR (400MHz, 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).

[0483] Step 2

[0484]

[0485] To a mixed solution of compound 8-2 (105 mg, 0.23 mmol) in THF (3 mL) and MeOH (1.5 mL) was added a solution of LiOH.H2O (20 mg, 0.46 mmol) in H2O (1.5 mL). The mixture was stirred at room temperature for reaction. The reaction solution was cooled to room temperature with an ice bath and adjusted to neutral with 2M HCl, extracted with ethyl acetate, and the organic phase was washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered and evaporated to give crude compound 8-3 (100 mg).

[0486] 1 H-NMR (400MHz, 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).

[0487] Step 3

[0488]

[0489] A solution of compound 8-3 (100 mg, 0.23 mmol) in THF (3 mL) was cooled in an ice-water bath, protected with argon, and MsCl (53 mg, 0.46 mmol) and Et3N (70 mg, 0.69 mmol) were added. The reaction mixture was stirred at this temperature. Compound 8-A (40 mg, 0.35 mmol) in THF (1 mL) was added to the above reaction solution, and the reaction mixture was heated to room temperature and stirred. After adding water to the reaction solution, it was extracted with EA, and the organic phase was washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered and evaporated to obtain a crude product. The crude product was purified by silica gel flash chromatography to obtain compound 8-4 (70 mg, 57%).

[0490] LC / MS(ESI): m / z 541.1[M+H] +

[0491] Step 4

[0492]

[0493] 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 stirred for reaction. After the reaction was completed, the reaction bottle was placed in an ice-water bath for cooling, PBr3 (72 mg, 0.26 mmol) was added, and the reaction was stirred. After the reaction was completed, the reaction solution was added dropwise to a NaHSO3 aqueous solution. Filter, wash the filter cake with clean water, and vacuum dry to obtain 150 mg of a crude compound 8-5.

[0494] LC / MS(ESI): m / z 1284.1[M] +

[0495] Step 5

[0496]

[0497] Compound 8-5 (150 mg, 0.117 mmol) was placed in a single-mouth bottle, anisole (0.3 mL) and TFA (1.2 mL) were added, stirred for reaction, and then MTBE was added and filtered to obtain 78 mg of a crude product. The crude product was subjected to HPLC preparation to obtain 11.21 mg of compound 8.

[0498] HRMS: 768.2109[M+H] +

[0499] Embodiment 9:

[0500]

[0501] first step

[0502]

[0503] To a DMF (12 mL) solution of compound 2-4 (500 mg, 1.17 mmol), iodomethane (5 g, 35.1 mmol) and potassium carbonate (323 mg, 2.34 mmol) were added, and the reaction was stirred at room temperature until the reaction was complete. Water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to obtain a crude product. The crude product was purified by silica gel flash chromatography to obtain compound 9-2 (505 mg, yield 97%).

[0504] LC / MS(ESI): m / z 465.0[M+Na] +

[0505] Step 2

[0506]

[0507] 1M LiAlH4 (1.1 mL, 1.14 mmol) in THF solution was added dropwise to a THF (4.2 mL) solution of compound 9-2 (505 mg, 1.14 mmol) cooled with ice water. The reaction was slowly heated to room temperature and the reaction was completed. The reaction mixture was cooled with an ice-water bath and then Na2SO4.10H2O was added. The mixture was stirred at room temperature and filtered to remove the solid. The filtrate was concentrated under reduced pressure to obtain a crude compound 9-3. The crude product was directly used in the next step (465 mg, yield 98%).

[0508] LC / MS(ESI): m / z 437.1[M+Na] +

[0509] Step 3

[0510]

[0511] Dess-Martin reagent (712 mg, 1.68 mmol) was added to an ice / water cooled DCM (23 mL) solution of compound 9-3 (465 mg, 1.12 mmol). The reaction was slowly heated to room temperature until complete. H2O was added to the reaction solution to quench the reaction, and then extracted with DCM. The organic phase was washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered and evaporated to give a crude product. The crude product was purified by silica gel flash chromatography to give compound 9-4 (440 mg, yield 95%).

[0512] LC / MS(ESI): m / z 412.9[M+H] +

[0513] Step 4

[0514]

[0515] A mixture of NH2OH.HCl (82 mg, 1.18 mmol) and Et3N (199 mg, 197 mmol) in CH3CN (5 mL) was stirred at room temperature, and a solution of compound 9-4 (405 mg, 0.98 mmol) in CH3CN (5 mL) 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 above reaction solution, respectively. The mixture was stirred at room temperature until the reaction was complete. After adding H2O to the reaction solution to quench the reaction, the reaction solution was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to obtain a crude product. The crude product was purified by silica gel flash chromatography to obtain compound 9-5 (290 mg, yield 72%).

[0516] LC / MS(ESI): m / z 432.0[M+Na] +

[0517] Step 5

[0518]

[0519] n-BuLi (0.64mL, 1.02mmol) was slowly added dropwise to a THF (5mL) solution of compound 9-5 (210mg, 0.51mmol) cooled with ice water. After adding a THF (1mL) solution of compound 8-A (88mg, 0.77mmol) to the above reaction solution, the reaction was slowly heated to room temperature and stirred. After the reaction was completed, a saturated NH4Cl solution was added to the reaction solution to quench the reaction. The organic phase was extracted with EA, washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered and evaporated to give a crude product. The crude product was purified by silica gel flash chromatography to give compound 9-6 (147mg, yield 54%).

[0520] LC / MS(ESI): m / z 524.2[M+H] +

[0521] Step 6

[0522]

[0523] 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 stirred for reaction. After the reaction was completed, the reaction bottle was placed in an ice-water bath for cooling, PBr3 (144 mg, 0.52 mmol) was added, and the reaction was stirred for reaction. After the reaction was completed, the reaction solution was added dropwise to a NaHSO3 aqueous solution, filtered, and the filter cake was washed with clean water and vacuum dried to obtain 400 mg of a crude compound 9-7.

[0524] LC / MS(ESI): m / z 1267.1[M] +

[0525] Step 7

[0526]

[0527] Compound 9-7 (100 mg, 0.0788 mmol) was placed in a single-mouth bottle, anisole (0.3 mL) and TFA (1.2 mL) were added and reacted at room temperature. After the reaction was completed, MTBE was added, filtered, and the crude product was subjected to HPLC to obtain 4.4 mg of compound 9.

[0528] HRMS: 751.1716[M+H] +

[0529] Embodiment 10:

[0530]

[0531] first step

[0532]

[0533] DMTMM (1.55 g, 5.26 mmol) and DIEA (905 mg, 7.0 mmol) were added to a DMF (35 mL) solution of compound 2-4 (1.5 g, 3.50 mmol). After the reaction was replaced three times with argon protection, compound 10-A (525 mg, 7.0 mmol) was added to the above reaction solution, and the reaction was stirred at room temperature for 2 h. The reaction solution was slowly added to water to gradually precipitate a solid product. The solid product obtained by filtration was dissolved in DCM, and after extraction and separation, the organic phase was washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered and evaporated to obtain compound 10-2 (1.6 g, yield 94%).

[0534] LC / MS(ESI): m / z 486.1[M+H] +

[0535] Step 2

[0536]

[0537] A solution of oxalyl chloride (1.05 g, 8.24 mmol) in DCM (10 mL) was cooled to -78 ° C with a dry ice / acetone bath, and DMSO (1.29 g, 16.5 mmol) was added dropwise under argon protection and stirred for reaction. A solution of compound 10-2 (1.6 g, 3.30 mmol) in DCM (6 mL) was slowly added dropwise to the above reaction solution and continued to stir at -78 ° C. Et3N (3.34 g, 33.0 mmol) was added and stirred at -78 ° C, and then the reaction was slowly raised to 0 ° C until the reaction was completed. After adding H2O to the reaction solution to quench the reaction, it was extracted with DCM, and the organic phase was washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered and evaporated to obtain a crude product. The crude product was purified by silica gel flash chromatography to obtain compound 10-3 (1.28 g, yield 80%).

[0538] LC / MS(ESI): m / z 484.0[M+H] +

[0539] Step 3

[0540]

[0541] Compound 8-A (605 mg, 5.30 mmol) was added to a DCM (26 mL) solution of compound 10-3 (1.28 g, 2.65 mmol), and the reaction solution was cooled in an ice-water bath, and NaBH (OAc) 3 (1.68 g, 7.95 mmol) was added. The reaction was stirred at room temperature. After the reaction was completed, the reaction solution was quenched with NaHCO 3 solution, and then extracted with DCM. The organic phase was washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered and evaporated to obtain a crude product. The crude product was purified by silica gel flash chromatography to obtain compound 10-4 (735 mg, yield 48%).

[0542] LC / MS(ESI): m / z 582.1[M+H] +

[0543] Step 4

[0544]

[0545] To a DMF (13 mL) solution of 2-4 (650 mg, 1.51 mmol), 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 above reaction solution and the reaction was stirred at room temperature. The reaction solution was slowly added to water, filtered, and dried to obtain the product 10-5 (1.2 g, yield 96%).

[0546] LC / MS(ESI): m / z 992.1[M+H] +

[0547] Step 5

[0548]

[0549] 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 stirred for reaction. After the reaction was completed, the reaction bottle was placed in an ice-water bath for cooling, PBr3 (360 mg, 1.33 mmol) was added, and the reaction was stirred for reaction. After the reaction was completed, the reaction solution was added dropwise to a NaHSO3 aqueous solution, filtered, and the filter cake was washed with clean water and vacuum dried to obtain 1.13 g of a crude product of compound 10-6.

[0550] LC / MS(ESI): m / z 1737.1[M] +

[0551] Step 6

[0552]

[0553] Compound 10-6 (1.13 g, 0.5 mmol) was added with anisole (2 mL) and trifluoroacetic acid (8 mL) and reacted at room temperature. Methyl tert-butyl ether was added, stirred and filtered. The filter cake was rinsed with MTBE and dried to obtain 600 mg of a crude product. After HPLC preparation, 4 mg of compound 10 was obtained.

[0554] HRMS: 979.1874[M+H] +

[0555] 1H-NMR (400MHz, 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).

[0556] Embodiment 11:

[0557]

[0558] first step

[0559]

[0560] Add 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), anhydrous sodium sulfate (24.7 g, 174.1 mmol, 1.0 eq) to the reaction bottle, and stir to react at room temperature. Then cool the reaction solution with an ice-water bath, add sodium borohydride (3.3 g, 87.0 mmol, 0.5 eq.) in batches, stir to react for 5 min, and then stir to react at room temperature until the end. Add glacial acetic acid (3.3 mL), stir, filter, and wash with ethyl acetate. The filtrate is concentrated, and water and ethyl acetate are added to the residue, stirred and separated, and the aqueous phase is extracted with ethyl acetate. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 58.0 g of compound 11-2 (yield: 102.8%)

[0561] MS m / z 325.1[M+H] +

[0562] Step 2

[0563]

[0564] Compound 11-2 (2.0 g, 6.2 mmol, 1.0 eq), S-propylene oxide (0.54 g, 9.3 mmol, 1.5 eq) and EtOH (20 mL) were added to a reaction flask and heated to 60°C for reaction. LC-MS monitored the complete reaction of the raw materials. The reaction solution was concentrated and the crude product was purified by column chromatography to obtain 1.2 g of compound 11-3 in a yield of 51.1%.

[0565] MS m / z 383.2[M+H] +

[0566] Step 3

[0567]

[0568] 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, cooled in an ice-water bath, and MsCl (0.54 g, 4.7 mmol, 1.5 eq) was slowly added dropwise, and stirred for reaction. LC-MS monitored that the raw material reaction was complete. The reaction solution was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude compound 11-4 (1.34 g), which was directly used for the next step reaction. MS m / z 461.1 [M+H] +

[0569] Step 4

[0570]

[0571] The crude product of compound 11-4 (1.34 g, 3.2 mmol, 1.0 eq), tetrahydropyrrole (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 heated to 40 ° C. and stirred for reaction. LC-MS monitored that the raw material reaction was complete. Water (30 mL) and EA (30 mL) were added to the reaction solution and stirred for stratification. The aqueous phase was washed with EA, and the organic phases were combined, washed with a 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%).

[0572] MS m / z 436.1[M+H] +

[0573] Step 5

[0574]

[0575] Compound 11-5 (600 mg, 1.38 mmol) and TFA (10 mL) were added to the reaction bottle to dissolve, and the reaction was heated to 60° C. The reaction solution was concentrated to dryness, MTBE (10 mL) was added, and the supernatant was poured out. The obtained oil was vacuum-dried to remove most of the solvent and directly used in the next step reaction.

[0576] MS m / z 186.1[M+H] +

[0577] Step 6

[0578]

[0579] Dissolve the crude compound 11-6 and compound 2-4 (1.31 g, 3.05 mmol) in DCM (15 mL) and stir at 0°C. Add DIPEA (2.02 mL, 12.22 mmol) and HATU (1.39 g, 3.67 mmol). The reaction solution is naturally warmed to room temperature and the reaction is completed. After adding water (10 mL), separate the liquids, wash the organic phase with water, dry it with anhydrous sodium sulfate, filter it, and concentrate it to dryness. The crude product is separated by chromatography column (DCM: MeOH = 10: 1) to obtain 0.85 g of compound 11-7.

[0580] MS m / z 1006.3[M+H] +

[0581] Step 7

[0582]

[0583] Compound 1-6 (720 mg, 0.904 mmol), compound 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 a reaction flask, and after the air was replaced by argon three times, NMP (2.1 mL) was added. The reaction solution was reacted at room temperature until completion. The reaction solution was used directly in the next step without treatment.

[0584] MS m / z 1767.5[M] +

[0585] Step 8

[0586]

[0587] After adding NMP (0.7 mL) to the above reaction solution, the reaction solution was cooled to 0°C, phosphorus trichloride (0.103 mL, 1.17 mmol) was added, and the reaction was kept at 0°C until the reaction was completed. A 5% sodium bisulfite aqueous solution (20 mL) was added to the reaction solution, and the mixture was slurried under an ice-water bath, filtered, and the filter cake was dissolved with DCM (20 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain 1.21 g of compound 11-9.

[0588] MS m / z 1751.4[M] +

[0589] Step 9

[0590]

[0591] 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 completed. After cooling to 0°C, MTBE (20 mL) was added, slurried in an ice-water bath, filtered, and the filter cake was rinsed with MTBE and dried to obtain 0.82 g of crude product. After reverse HPLC preparation, a total of 107 mg of compound 11 was obtained.

[0592] MS m / z 993.1[M+H] +

[0593] Biological evaluation

[0594] The present disclosure is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present disclosure.

[0595] Test Example 1: Antimicrobial Activity Test

[0596] After the test compound was diluted in series, the MIC of the test strain was tested. The starting test concentration was 32 μg / mL, 2-fold dilution, 11 concentration points, and double wells / concentration. A well without drug addition was set as a growth control. The minimum inhibitory concentration (MIC) test method was operated in accordance with the guidelines of the Clinical Laboratory Standards Institute (CLSI) of the United States.

[0597] 1. Preparation of Bacterial Inoculum

[0598] After subculturing the frozen strain, pick a single colony and resuspend it in physiological saline or sterile water, vortex and use a spectrophotometer to adjust the bacterial suspension to 0.5McF at a wavelength of 530nm. Use a pipette to take the bacterial solution, add it to the culture medium to dilute and mix, and inoculate it into the bacterial detection plate.

[0599] 2. Cultivation

[0600] The bacterial test plate was placed in an incubator at 35°C and 85% humidity, and the MIC value was read after incubation for 24 hours.

[0601] 3.MIC interpretation

[0602] A disposable sealing film was attached to the 96-well plate, and the plate was shaken to mix. The plate was read with the naked eye and the lowest concentration of the compound that could inhibit bacterial growth compared with the growth control was defined as MIC.

[0603] MIC results

[0604]

[0605] As shown above, the compounds of the present disclosure have a broad antibacterial spectrum, specifically have an effective antibacterial spectrum against Gram-negative bacteria, and / or have efficacy against multidrug-resistant bacteria, and further exhibit high stability against β-lactamase-producing Gram-negative bacteria.

[0606] Test Example 2: Antimicrobial Activity Test

[0607] 1. Dissolve the compound to be tested in sterile saline, vortex and mix, dilute it 2-fold with sterile saline, and test 11 concentration points in total. The test concentration range is 32-0.031 μg / mL, with two replicates per concentration. Set up a well without drug addition as a growth control.

[0608] 2. Add 4 μL of diluent to 196 μL of bacterial suspension in a 96-well plate (the number of bacteria in the bacterial suspension is 2 to 8X10 5 colony forming units / mL).

[0609] 3. After incubation at 36°C for 24 hours, read the MIC value by visual observation.

[0610] The minimum inhibitory concentration (MIC) detection method was performed according to the guidelines of the Clinical Laboratory Standards Institute (CLSI).

[0611]

[0612]

[0613] As shown above, the compounds of the present disclosure have a broad antibacterial spectrum, specifically have an effective antibacterial spectrum against Gram-negative bacteria, and / or have efficacy against multidrug-resistant bacteria, and further exhibit high stability against β-lactamase-producing Gram-negative bacteria.

[0614] Test Example 3: Pharmacokinetic test in cynomolgus monkeys

[0615] 1. Sample configuration

[0616] Accurately weigh appropriate amounts of the compounds to be tested into containers, add 0.9% sodium chloride injection and 0.2M NaOH solution under ice bath until the compounds to be tested are completely dissolved, prepare a sample solution with a concentration of 2 mg / mL, and store at 2-8°C for later use.

[0617] 2. Experimental Animals

[0618] Species and strain: Cynomolgus monkey

[0619] Animal level: Ordinary

[0620] Animal source: Guangxi Xiongsen Primate Experimental Animal Breeding Development Co., Ltd.

[0621] Animal use license number: SYXK(Su)2019-0012

[0622] 3. Test methods

[0623] Six cynomolgus monkeys, half male and half female, were selected and randomly divided into 3 groups, with 1 animal / sex in each group. The test samples were given to the cynomolgus monkeys by single intravenous infusion, and the dosage was 10 mg / kg. Blood samples were collected from each group of animals before medication and at 5min, 15min, 0.5h, 1h, 2h, 4h, 6h, and 8h after the end of medication. The experiment used LC-MS / MS method to detect the concentration of each test compound in the plasma of cynomolgus monkeys, and the quantitative lower limit of the plasma sample analysis method was 1μg / mL. The plasma concentration data was analyzed by the non-compartmental model method (NCA) of the metabolic kinetic data analysis software WinNonlin, and the pharmacokinetic parameters were calculated to investigate the pharmacokinetic characteristics of the test compounds in cynomolgus monkeys after medication. The results are shown in the following table

[0624]

[0625] The compounds disclosed in the present invention are superior to cefiderocol in terms of Cmax.

Claims

1. A compound represented by formula (II-2) or a pharmaceutically acceptable salt thereof, in, for q is 0, r is 1; A is selected from C1-C6 alkylene; G2 is C1-C6 alkylene, wherein the alkylene is optionally selected from C1-C6 alkyl, halogen, hydroxyl, -NR i R j , substituted by one or more substituents in C1-C6 alkoxy; C2 is selected from -NR 31 -C(=O)-, R 31 Selected from C1-C6 alkyl and C1-C6 alkoxy, wherein the alkyl and alkoxy are replaced by one or more replaced by; Ring D1 is an aryl group; R4 is independently selected from C1-C6 alkyl, halogen, hydroxyl, -NR i R j , C1-C6 alkoxy, wherein the alkyl and alkoxy are each independently selected from halogen, hydroxyl, -NR i R j is substituted by one or more substituents; n is an integer from 0 to 8; R i and R j Each is independently selected from a hydrogen atom, a hydroxyl group, a C1-C6 alkyl group and a C1-C6 alkoxy group; R n Each is independently selected from C1-C6 alkyl, hydroxyl and halogen; k5 is an integer from 0 to 5.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein for k5 is an integer from 0 to 3.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein for 4 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring D 1 is phenyl or naphthyl.

5. A compound as shown below or a pharmaceutically acceptable salt thereof, 6. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

7. Use of the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 6 in the preparation of a medicament for preventing and treating diseases caused by Gram-negative bacteria.

8. The method of claim 7, wherein the disease is selected from the group consisting of airway infectious diseases, urinary system infectious diseases, respiratory system infectious diseases, septicemia, nephritis, cholecystitis, oral infectious diseases, endocarditis, pneumonia, myelomeningomyelitis, otitis media, enteritis, empyema, traumatic infectious diseases and opportunistic infections.

9. The method according to claim 7, wherein the gram-negative bacteria is selected from the group consisting of Escherichia coli, Klebsiella, Serratia, Enterobacter, Citrobacter, Morganella, Providencia, Proteus, Haemophilus, Moraxella, Pseudomonas aeruginosa, Pseudomonas other than P. aeruginosa, Stenotrophomonas, Burkholderia and Acinetobacter.

10. Use of the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 6 in the preparation of a medicament for preventing and treating diseases caused by pathogenic bacteria in mammals.

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