Inhibitors of the p. aeruginosa virulence factor lasb

Abstract

The present invention relates to compounds of formula (Ia) and their use as inhibitors of the Pseudomonas aeruginosa virulence factor LasB. These compounds are useful in the treatment of bacterial infections, particularly infections caused by Pseudomonas aeruginosa.

Description

[0001] This invention relates to novel inhibitors of the virulence factor LasB from Pseudomonas aeruginosa. These compounds can be used to treat bacterial infections, particularly those caused by Pseudomonas aeruginosa.

[0002] Pseudomonas aeruginosa is a Gram-negative bacterium listed by the World Health Organization as one of the most important pathogens today (WHO. Global Priority List of Antibiotic-Resistant Bacteria to Guide New Antibiotic Research, Discovery and Development. WHO 2017). This opportunistic bacterium causes approximately 10% of hospital-acquired infections and has a high incidence in immunocompromised and cystic fibrosis patients (Magill, SS; Edwards, JR; Bamberg, W.; Beldavs, ZG; Dumyati, G.; Kainer, MA; Lynfield, R.; Maloney, M.; McAllister-Hollod, L.; Nadle, J. et al. N. Engl. J. Med. 2014, 370, 1198–1208; Richards, MJ; Edwards, JR; Culver, DH; Gaynes, R. P. Pediatrics 1999, 103, e39; Valenza, G.; Tappe, D.; Turnwald, D.; Frosch, M.). C.; Hebestreit, H.; Abele-Horn, MJ Cyst. Fibros. 2008, 7, 123–127; Sordé, R.; Pahissa, A.; Rello, J. Infect. Drug Resist. 2011, 4, 31–41. Due to the lack of effective treatments on the market, there is an urgent need to develop effective antibiotics (Mesaros, N.; Nordmann, P.; Plésiat, P.; Roussel-Delvallez, M.; Eldere, J. Van; Glupczynski, Y.; Laethem, Y. Van; Jacobs, F.; Lebecque, P.; Malfroot, A. et al. Clin. Microbiol. Infect. 2007, 13, 560–578; Taubes, G. Science 2008, 321, 356–361). This task is complicated by the high intrinsic resistance of pathogens (Hancock, REW; Speert, DPDrug Resist. Updat. 2000, 3, 247–255; Strateva, T.; Yordanov, DJ Med. Microbiol. 2009, 58, 1133–1148).

[0003] The outer membrane of Pseudomonas aeruginosa has particularly low permeability, which prevents antibiotics from entering the cell (Nikaido, H.; Yoshimura, FJ Bacteriol. 1982, 152, 636–642). Furthermore, its efflux pumps effectively transport unwanted antimicrobial agents out of the cell, and its inducible chromosomal β-lactamase can inactivate the corresponding β-lactam antibiotics (Pos, KMBiochim. Biophys. Acta-Proteins Proteomics 2009, 1794, 782–793; Moreira, MAS; Souza, ECde; Moraes, CAde. Brazilian J. Microbiol. 2004, 35, 19–28; Hancock, REW; Woodruff, WAClin. Infect. Dis. 1988, 10, 770–775; Li, XZ; Livermore, DM; Nikaido, H. Antimicrob. Agents Chemother. 1994, 38, 1732–1741). Another challenge is the increasing rate of mutant drug resistance in *Pseudomonas aeruginosa* strains (Thomson, JM; Bonomo, RACurr. Opin. Microbiol. 2005, 8, 518–524). For example, resistance to fluoroquinolones and aminoglycosides has reached 30% (Gasink, LB; Fishman, NO; Weiner, MG; Nachamkin, I.; Bilker, WB; Lautenbach, E. Am. J. Med. 2006, 119, 19–25; Poole, K. Antimicrob. Agents Chemother. 2005, 49, 479–487). Furthermore, resistance to almost all drugs used to treat Pseudomonas aeruginosa infections (e.g., cephalosporins and carbapenems) was described (Obritsch, MD; Fish, DN; MacLaren, R.; Jung, R. Pharmacotherapy 2005, 25, 1353–1364; ASCP Antimicrobial Susceptibility Testing Group. U.S. Geographical Bacterial Susceptibility Patterns. Am. J. Clin. Pathol. 1996, 106, 275–281). These facts underscore the urgent need for new treatment options.

[0004] In addition to traditional strategies targeting bacterial viability, recent research has focused on targeting bacterial virulence as an alternative approach to combating microbial infections (Dickey, SW; Cheung, GYC; Otto, M. Nat. Rev. Drug Discov. 2017, 16, 457–471; Rasko, DA; Sperandio, V. Nat. Rev. Drug Discov. 2010, 9, 117–128). Virulence factors are common in pathogenic bacteria and function by disrupting the host or evading its immune response (Strateva, T.; Mitov, I. Ann. Microbiol. 2011, 61, 717–732). Virulence factor inhibitors reduce bacterial virulence, thereby clearing the pathogen through the host's immune system or with the aid of antibiotics (Heras, B.; Scanlon, MJ; Martin, JLBr.J.Clin.Pharmacol.2015,79,208–215; Clatworthy, AE; Pierson, E.; Hung, DTNat.Chem.Biol.2007,3,541–548). Although only a few compounds have received clinical approval, numerous in vitro and in vivo studies support the effectiveness of this strategy (Wagner, S.; Sommer, R.; Hinsberger, S.; Lu, C.; Hartmann, RW; Emptting, M.; Titz, AJMed.Chem.2016,59,5929–5969). A major advantage of this novel approach is the reduction of selective pressure on bacteria, thus lowering the risk of resistance development. Furthermore, these antiviral agents do not harm symbiotic bacteria.

[0005] A well-known antiviral target of *Pseudomonas aeruginosa* is the elastase LasB. This extracellular zinc-containing protease plays a role in pathogenic invasion of tissues and is considered to be primarily involved during acute infection (Liu, PVJ Infect. Dis. 1974, 130, S94–S99). It has the ability to break down elastin, an important component of lung tissue and blood vessels (Morihara, K.; Tsuzuki, H.; Oka, T.; Inoue, H.; Ebata, MJ Biol. Chem. 1965, 240, 3295–3304). In addition, LasB can degrade fibrin, collagen, and surfactant proteins in the lungs, and also reduces host immunity by inactivating human immunoglobulins A and G, cytokines gamma-interferon and tumor necrosis factor α, and degrading the antimicrobial peptide LL-37 (Heck, LW; Morihara, K.; McRae, WB; Miller, EJ Infect. Immun. 1986, 51, 115–118; Heck, LW; Alarcon, PG; Kulhavy, RM; Morihara, K.; Mestecky, MW; Russell, JFJ Immunol. 1990, 144, 2253). –2257; Holder, IA; Wheeler, R. Can. J. Microbiol. 1984, 30, 1118–1124; Galloway, DRMol. ; Clabaugh, M.; Horvat, R.; Zhou, W. Infect. Immun. 1990, 58, 3009–3014; Mariencheck, WI; Alcorn, JF; Palmer, SM; Wright, JRAm. Mol. Biol. 2003, 28, 528–537; Schmidtchen, A. et al. Mol. Microbiol. 2002, 46, 157–168).

[0006] Because LasB is an attractive antiviral target, several LasB inhibitors have been described in the literature to date: natural products, such as the streptococcal metalloproteinase inhibitor TK-23 (SMPI) from *Streptomyces nigrescens* and phosphoramides (Oda, K.; Koyama, T.; Murao, S. Biochim. Biophys. Acta...). 1979, 571, 147–156; Nishino, N.; Powers, JCJ Biol. Chem. 1979, 255, 3482–19), small peptides containing metal chelating motifs such as thiols or isohydroxamic acid groups (Kessler, E.; Israel, M.; Landshman, N.; Chechick, A.; Blumberg, S. Infect. Immun. 1982, 38, 716–723; Cathcart, GRA; Quinn, D.; Greer, B.; Harriott, P.; Lynas, JF; Gilmore, BF; Walker, B. Antimicrob. Agents Chemother. 2011, 55, 2670–2678; Burns, FR; Paterson, CA; Gray, RD; Wells, JTA Antimicrob. Agents Chemother. 1990, 34, 2065–2069) and small synthetic molecules with isohydroxamic acid ester, thiol or mercaptoacetamide groups (Zhu, J.; Cai, X.; Harris, TL; Gooyit, M.; Wood, M.; Lardy, M.; Janda, KDChem. Biol. 2015, 22, 483–491; Adekoya, OA; S.; Wuxiuer, Y.; Bilto, I.; Marques, SM; Santos, MA; Nuti, E.; Cercignani, G.; Rossello, A.; Winberg, JO; et al. Eur. J. Med. Chem. 2015, 89, 340–348) and compounds based on cycloheptatrienolone (Fullagar, JL; Garner, AL; Struss, AK; Day, JA; Martin, DP; Yu, J.; Cai, X.; Janda, KD; Cohen, SMChem. Commun. 2013, 49, 3197–3199).

[0007] Recently, a group of N-arylthioacetamides has been described as potent LasB inhibitors (Kany, AM; Sikandar, A.; Haupenthal, J.; Yahiaoui, S.; Maurer, CK; Proschak, E.); J. Hartmann, RWACS Infect. Dis. 2018, 4, 988–997. The crystal structure of the most promising compound described therein (compound 36) revealed the presence of two molecules in the binding bag. A series of N-benzylamide / N-alkylamide derivatives were synthesized to allow a single molecule to occupy the active site. However, this approach failed to improve the inhibitory potency of the initial ligand.

[0008] The purpose of this invention is to provide a novel inhibitor of the virulence factor LasB in Pseudomonas aeruginosa.

[0009] This invention provides compounds of formula (Ia).

[0010]

[0011] in,

[0012] X is a triazole group with the formula -PO(OH)2, -SH, -C(=O)-NH-OH, or an optionally substituted triazole group, or -SR. 3 -PO(OH)(OR) 4 ) or -PO(OR 4 (OR) 5 ) group;

[0013] R 1 It is an optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, or optionally substituted aralkyl, or optionally substituted heteroaryl; or of the formula -CH(R 6 )-C(=O)-NH-R 7 Or the formula -C(Me)2-CH2-C(=O)-NH-R 7 、or formula -CH(R) 6 )-CH2-C(=O)-NH-R 7 、or formula -CH(R) 6 )-R 8 ;

[0014] R 2 It is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaryl, all of which may optionally be substituted;

[0015] R 3 It is a formula - COR 3aor -CON(R) 3b )2 group; wherein R 3a It is an alkyl, optionally substituted phenyl, or optionally substituted benzyl, and R 3b Independently selected from hydrogen or alkyl, optionally substituted phenyl or optionally substituted benzyl;

[0016] R 4 It is an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group;

[0017] R 5 It is an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group;

[0018] R 6 It is hydrogen or alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaryl, all of which may optionally be substituted;

[0019] R 7 It is an optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroaryl;

[0020] R 8 It is an optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, or optionally substituted heteroaryl; and

[0021] R 1a It is hydrogen, or, if R 1 It is the formula -CH(R) 6 )-C(=O)-NH-R 7 If the group is R, then R 1a and R 6 Together they are either -(CH2)3- or -(CH2)4-;

[0022] Or its pharmaceutically acceptable salt.

[0023] The present invention also provides compounds of formula (I).

[0024]

[0025] Wherein, X is a triazole group of the formula -PO(OH)2, -SH, -C(=O)-NH-OH, optionally substituted triazole group, or -SR. 3 -PO(OH)(OR) 4 ) or -PO(OR 4 (OR) 5 ) group;

[0026] R 1It is an optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, or optionally substituted aralkyl, or optionally substituted heteroaryl; or of the formula -CH(R 6 )-C(=O)-NH-R 7 Or the formula -C(Me)2-CH2-C(=O)-NH-R 7 、or formula -CH(R) 6 )-CH2-C(=O)-NH-R 7 、or formula -CH(R) 6 )-R 8 ;

[0027] R 2 It is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaryl, all of which may optionally be substituted;

[0028] R 3 It is a formula - COR 3a or -CON(R) 3b )2 group; wherein R 3a It is an alkyl, optionally substituted phenyl, or optionally substituted benzyl, and R 3b Independently selected from hydrogen or alkyl, optionally substituted phenyl or optionally substituted benzyl;

[0029] R 4 It is an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group;

[0030] R 5 It is an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group;

[0031] R 6 It is hydrogen or alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaryl, all of which may optionally be substituted;

[0032] R 7 It is an optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, or optionally substituted heteroaryl; and

[0033] R 8 It is an optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroaryl;

[0034] Or its pharmaceutically acceptable salt.

[0035] Preferably, X is a group of the formula -PO(OH)2, -SH, -C(=O)-NH-OH or triazole.

[0036] Furthermore, the present invention provides compounds of formula (I).

[0037]

[0038] in

[0039] X represents the formulas -SH, -PO(OH)2, and -SR. 3 , -PO(OH)(OR 4 ) or -PO(OR 4 (OR) 5 );

[0040] R 1 It is an aryl group with optional substitution or a heteroaryl group with optional substitution;

[0041] R 2 It is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaryl, all of which may optionally be substituted;

[0042] R 3 It is a formula - COR 3a or -CON(R) 3b )2 group; wherein R 3a It is an alkyl, optionally substituted phenyl, or optionally substituted benzyl, and R 3b Independently selected from hydrogen or alkyl, optionally substituted phenyl or optionally substituted benzyl;

[0043] R 4 It is an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group;

[0044] R 5 It is an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group;

[0045] Or its pharmaceutically acceptable salt.

[0046] According to another preferred embodiment, the present invention provides a compound of formula (II).

[0047]

[0048] Where R 1 and R 2 As defined above or below; or its pharmaceutically acceptable salt.

[0049] According to another preferred embodiment, the present invention provides a compound of formula (II).

[0050]

[0051] in

[0052] R 1 It is an optionally substituted aryl group or an optionally substituted heteroaryl group; and

[0053] R 2 It is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaryl, all of which may optionally be substituted;

[0054] Or its pharmaceutically acceptable salt.

[0055] According to another preferred embodiment, the present invention provides a compound of formula (III).

[0056]

[0057] Where R 1 and R 2 As defined above or below; or its pharmaceutically acceptable salt.

[0058] According to another preferred embodiment, the present invention provides a compound of formula (III).

[0059]

[0060] in

[0061] R 1 It is an aryl group with optional substitution or a heteroaryl group with optional substitution;

[0062] and

[0063] R 2 It is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaryl, all of which may optionally be substituted;

[0064] Or its pharmaceutically acceptable salt.

[0065] According to another preferred embodiment, the present invention provides a compound of formula (IV).

[0066]

[0067] Where R 1 and R 2 As defined above or below; or its pharmaceutically acceptable salt.

[0068] According to another preferred embodiment, the present invention provides a compound of formula (V).

[0069]

[0070] Where R 1 and R 2 As defined above or below; or its pharmaceutically acceptable salt.

[0071] According to another preferred embodiment, the present invention provides a compound of formula (VI).

[0072]

[0073] Where R 1 and R 2 As defined above or below; or its pharmaceutically acceptable salt.

[0074] The following preferred embodiments are independently applicable to compounds of formulas (I), (Ia), (II), (III), (IV), (V), and (VI):

[0075] Preferably, R 1 It is an optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, or optionally substituted heteroaryl.

[0076] More preferably, R 1 It is an aryl group that is optionally substituted or a heteroaryl group that is optionally substituted.

[0077] Furthermore, preferably, R 1 It is an optionally substituted phenyl, optionally substituted naphthyl, or optionally substituted heteroaryl group, which contains one or two rings and 5 to 10 ring atoms selected from C, O, N, and S.

[0078] Particularly preferred, R 1 It is an optionally substituted phenyl or optionally substituted heteroaryl group containing one or two rings and 5, 6, 9 or 10 ring atoms selected from C, O, N and S.

[0079] More preferably, R 1 It is a heteroaryl group containing 5 or 6 ring atoms selected from C, O, N and S with optional substitution.

[0080] More preferably, R 1 It is an optional substituted phenyl group.

[0081] More preferably, R 1 Cy is a formula 1 -L-Cy 2 The group, of which Cy 1It is an optionally substituted cycloalkylene group containing one or two rings and three to seven carbon ring atoms, an optionally substituted heterocycloalkylene group containing one or two rings and three to seven ring atoms selected from C, N, O and S, an optionally substituted phenylene group, or an optionally substituted heteroarylene group containing five or six ring atoms selected from C, N, O and S; cy 2 It is a cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaryl, all of which may optionally be substituted; L is a bond or -O-, -S-, -NH-, -CH2-, -CO-, -NHCO-, -CO-NH-, -CH2-CO-NH-, -NH-CO-CH2-, -CH2-O-CO-NH-, -NH-CO-O-CH2-, -O-CO-NH-, -NH-CO-O-, -NHSO2-, -SO2NH-, -CH2-SO2-NH-, -NH-SO2-CH2-, -S-CH2-, -CH2-S-, -NH-CH2-, -CH2-NH-, -O-CH2-, or -CH2-O-.

[0082] Preferably, Cy 2 It is an optionally substituted phenyl, optionally substituted biphenyl, optionally substituted naphthyl, optionally substituted heteroaryl, containing one or two rings and 5, 6, 9 or 10 ring atoms selected from C, O, N and S, optionally substituted cycloalkyl containing 3 to 7 ring atoms, optionally substituted heterocycloalkyl containing 3 to 7 ring atoms selected from C, N, O and S, optionally substituted heterocycloalkylaryl containing 9 or 10 ring atoms selected from C, N, S and O, or of the formula -CH(CH2Ph)Ph.

[0083] More preferably, L is a bond or -NHCO-, -CO-NH-, -CH2-CO-NH-, -NH-CO-CH2-, -NHSO2- or -SO2NH-.

[0084] Furthermore, preferably, Cy 1 It is 1,4-phenylene.

[0085] More preferably, R 1 It is the formula -CH(R) 6 )-C(=O)-NH-R 7 . group.

[0086] Furthermore, preferably, R 1 It is the formula -CH(R) 6 )-R 8 . group.

[0087] More preferably, R 6 Is it hydrogen or C? 1-6 Alkyl, C3-7 Cycloalkyl, heterocycloalkyl containing 3-7 ring atoms selected from C, N, O and S, phenyl or heteroaryl containing 5 or 6 ring atoms selected from C, N, S and O, or of the formula -CH2-R 6a The group, wherein R 6a It is C 3-7 Cycloalkyl, heterocycloalkyl containing 3 to 7 ring atoms selected from C, N, O and S, phenyl or heteroaryl containing 5 or 6 ring atoms selected from C, N, S and O.

[0088] Particularly preferred, R 6 It is a group with the formula -CH(CH3)2.

[0089] Furthermore, preferably, R 7 It is an optionally substituted phenyl or an optionally substituted C 3-7 Cycloalkyl; especially optionally substituted phenyl.

[0090] More preferably, R 8 It is an optionally substituted benzimidazole group, an optionally substituted triazole group, or an optionally substituted imidazole group.

[0091] Furthermore, preferably, R 8 It is a group of the following formula:

[0092]

[0093] Each of them Each can independently represent a single or double bond, with at least one in each ring. It is a double bond;

[0094] A1 and A2 each independently represent CH, N, NH, O, or S;

[0095] B is R B1 or -YR B2 The groups, in which

[0096] R B1 It consists of hydrogen atoms, halogen atoms, CN, CF3, CH2-OH; NR T1 R T2 ; or alkyl, alkenyl, ynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaryl, all of which may be optionally substituted;

[0097] R T1 and R T2 Each of these groups independently represents a hydrogen atom or a (C1-C3) alkyl group, which may be substituted by one or more identical or different groups selected from halogen atoms, OH, =O, and NH2;

[0098] Y is -O- or -S-; and

[0099] R B2 It is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroarylalkyl, all of which may optionally be substituted.

[0100] More preferably, R 8 Groups that are the following:

[0101]

[0102] Each of them Each can independently represent a single bond or a double bond, at least one of which... It is a double bond;

[0103] C1 and C3 each independently represent C or N;

[0104] C2, C4, and C5 each independently represent CH, N, NH, O, or S;

[0105] D is an optionally substituted aryl group or an optionally substituted heteroaryl group (particularly preferably, D is an optionally substituted phenyl group).

[0106] More preferably, R 2 It is C 1-6 Alkyl; heteroalkyl containing 1-6 carbon atoms and 1, 2, 3 or 4 heteroatoms selected from O, S and N; C 4-10 alkylcycloalkyl; or C 7-12 Aryl alkyl groups; all of these can be optionally substituted.

[0107] Particularly preferred, R 2 It is C 1-6 Alkyl; heteroalkyl containing 1-6 carbon atoms and 1, 2, 3 or 4 heteroatoms selected from O, S and N; or of the formula -CH2-R 21 The group, wherein R 21 It is C 3-7 Cycloalkyl, COOH, COOMe, or optionally substituted phenyl groups.

[0108] Furthermore, particularly preferably, R 2 It is C 1-4 Alkyl; or -CH2-R 21 The group, wherein R 21 It is C 3-6 Cycloalkyl, OMe, COOH, COOMe, or optionally substituted phenyl groups. Preferably, R 21It is an unsubstituted phenyl group or a phenyl group substituted with one or two substituents independently selected from OH, NO2, and Me; more preferably, R 21 It is an unsubstituted phenyl group.

[0109] More preferably, R 2 It is an optionally substituted benzyl group (i.e., a group of the formula -CH2-Ph that may be optionally substituted). Furthermore, preferably, R 2 It is an unsubstituted benzyl group.

[0110] More preferably, R 2 It is an isobutyl group (i.e., a group with the formula -CH2CH(CH3)2).

[0111] The term "optionally substituted" refers to a group that is unsubstituted or substituted by one or more (especially one, two or three; preferably one or two) substituents.

[0112] If group R 1 and / or group R 2 If more than one substituent is included, these substituents are chosen independently; that is, they can be the same or different.

[0113] If group R 1 and / or group R 2 If replaced by a cyclic group, such as a cycloalkyl or heterocycloalkyl group, the cyclic group can be bonded to group R via a single or double bond. 1 and / or group R 2 Above, or the cyclic group can be cyclized or fused to group R. 1 and / or group R 2 Above. Indigo is an example of a substituted phenyl group.

[0114] Examples of substituents include fluorine, chlorine, bromine, and iodine, as well as OH, SH, NH2, -SO3H, -SO2NH2, -COOH, -COOMe, -COMe(Ac), -NHSO2Me, -SO2NMe2, -CH2NH2, -NHAc, -SO2Me, -CONH2, -CN, -NHCONH2, -NHC(NH)NH2, -NOHCH3, -N3, and -NO2 groups. Other examples of substituents are C1-C... 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne group, C1-C 10 Heteroalkyl, C3-C 18 cycloalkyl, C1-C 17 Heterocyclic alkyl, C4-C 20 Alkyl cycloalkyl, C1-C 19 Heteroalkylcycloalkyl, C6-C 18 Aryl, C1-C17 heteroaryl, C7-C 20 Araneyl and C1-C 19 Heteroalkyl groups; particularly C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 heteroalkyl, C3-C 10 Cycloalkyl, C1-C9 heterocycloalkyl, C4-C 12 alkylcycloalkyl, C1-C 11 Heteroalkylcycloalkyl, C6-C 10 Aryl, C1-C9 heteroaryl, C7-C 12 Araneyl and C1-C 11 Heteroalkyl, more preferably C1-C6 alkyl and C1-C6 heteroalkyl.

[0115] Preferred substituents are halogen atoms (such as F, Cl, Br, I) and the formula -OH, -OC. 1-6 Alkyl groups (such as -OMe, -OEt, -O-nPr, -O-iPr, -O-nBu, -O-iBu and -O-tBu), -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups: -2, -COOH, -COOMe, -COCF3, -NHSO2Me, -SO2NMe2, -SO3H, -SO2NH2, -CONH2, -CH2NH2, -CN, -C 1-6 Alkyl groups (such as -Me, -Et, -nPr, -iPr, -nBu, -iBu, -tBu, and -CF3), -SH, -S-CO-C 1-6 Alkyl, -SC 1-6 Alkyl, -NHAc, -NO2, -C≡CH, -NHCONH2, -SO2Me, -SO2CF3, phenyl, -C 3-6 Cycloalkyl groups (such as cyclopropyl and cyclobutyl) and heterocyclic alkyl groups containing 3-6 ring atoms selected from C, N, S and O.

[0116] Further preferred substituents are halogen atoms (such as F, Cl, Br) and the formula -OH, -OC. 1-6 Alkyl groups (such as -OMe, -OEt, -O-nPr, -O-iPr, -O-nBu, -O-iBu and -O-tBu), -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups: -2, -COOH, -COOMe, -COMe, -NHSO2Me, -SO2NMe2, -SO3H, -SO2NH2, -CONH2, -CH2NH2, -CN, -C 1-6Alkyl groups (such as -Me, -Et, -nPr, -iPr, -nBu, -iBu, -tBu, and -CF3), -SH, -S-CO-C 1-6 Alkyl, -SC 1-6 Alkyl, -NHAc, -NO2, -C≡CH, -NHCONH2, -SO2Me and cyclopropyl.

[0117] The substituents are particularly preferably selected independently from halogens (especially F and Cl), -Me, -CF3, -OMe, -OH, -COOH, -CONH2, -COOMe, -COMe and -NO2.

[0118] The substituents are further particularly preferably selected independently from halogens (especially F and Cl), -Me, -CF3, -OMe, -OH, -COOH, -COOMe and -NO2.

[0119] The most preferred compounds of this invention are the compounds disclosed in the examples or their salts.

[0120] Further preferred embodiments of the invention are combined in any desired manner (e.g., R). 1 Any implementation can be used with R 2 (any combination of implementation methods).

[0121] For example, the suffix "-ene" in "phenylene" refers to the corresponding divalent group.

[0122] The term alkyl refers to a saturated, straight-chain or branched hydrocarbon group containing 1 to 20 carbon atoms, preferably 1 to 15 carbon atoms, and particularly 1 to 10 (e.g., 1, 2, 3 or 4) carbon atoms, such as methyl (Me, CH3), ethyl (Et), n-propyl (nPr), isopropyl (iPr), n-butyl (nBu), isobutyl (iBu), sec-butyl (sBu), tert-butyl (tBu), n-pentyl, isopentyl, n-hexyl, 2,2-dimethylbutyl or n-octyl.

[0123] The particularly preferred alkyl group is C. 1-6 Alkyl; and preferably C10 alkyl. 1-4 alkyl.

[0124] C 1-6 Alkyl groups refer to saturated, straight-chain, or branched hydrocarbon groups containing 1-6 carbon atoms. C 1-4 Alkyl groups are saturated, straight-chain, or branched hydrocarbon groups containing 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0125] The terms alkenyl and ynyl refer to at least partially unsaturated, straight-chain or branched hydrocarbon groups containing 2-20 carbon atoms, preferably 2-15 carbon atoms, particularly 2-10 (e.g., 2, 3, or 4) carbon atoms, such as vinyl, allyl, isopropenyl, butenyl, ethynyl, propynyl (e.g., propynyl), butynyl, isoprene, or 2-hexenyl. Preferably, the alkenyl group has one or two (particularly preferred, one) double bonds, and the ynyl group has one or two (particularly preferred, one) triple bonds.

[0126] In addition, the terms alkyl, alkenyl, and alkynyl refer to groups in which one or more hydrogen atoms have been replaced by halogen atoms (preferably F or Cl), such as 2,2,2-trichloroethyl or trifluoromethyl.

[0127] The term heteroalkyl refers to an alkyl, alkenyl, or alkynyl group in which one or more (preferably 1 to 8; particularly preferably 1, 2, 3, or 4) carbon atoms are substituted with oxygen, nitrogen, phosphorus, boron, selenium, silicon, or sulfur atoms (preferably oxygen, sulfur, or nitrogen atoms) or with an SO or SO2 group. Furthermore, heteroalkyl also refers to a carboxylic acid or a group derived from a carboxylic acid, such as acyl, acylalkyl, alkoxycarbonyl, acyloxy, acyloxyalkyl, carboxylamide, or alkoxycarbonyloxy. Additionally, the term heteroalkyl refers to a group in which one or more hydrogen atoms are substituted with a halogen atom (preferably F or Cl).

[0128] Preferably, the heteroalkyl group comprises 1 to 12 carbon atoms and 1 to 8 heteroatoms selected from oxygen, nitrogen, and sulfur (especially oxygen and nitrogen). Particularly preferably, the heteroalkyl group comprises 1 to 6 (e.g., 1, 2, 3, or 4) carbon atoms and 1, 2, 3, or 4 (especially 1, 2, or 3) heteroatoms selected from oxygen, nitrogen, and sulfur (especially oxygen and nitrogen). Terms C1-C 10 A heteroalkyl group is defined as a heteroalkyl group containing 1-10 carbon atoms and 1, 2, 3, 4, 5, or 6 heteroatoms selected from O, S, and / or N (especially O and / or N). The terms C1-C6 heteroalkyl groups refer to heteroalkyl groups containing 1-6 carbon atoms and 1, 2, 3, or 4 heteroatoms selected from O, S, and / or N (especially O and / or N). The terms C1-C4 heteroalkyl groups refer to heteroalkyl groups containing 1-4 carbon atoms and 1, 2, or 3 heteroalkyl groups selected from O, S, and / or N (especially O and / or N).

[0129] Further preferably, heteroalkyl means an alkyl group (straight-chain or branched) as defined above, wherein one or more (preferably 1 to 6; particularly preferably 1, 2, 3 or 4) carbon atoms are substituted with oxygen, sulfur or nitrogen atoms or CO groups or SO groups or SO2 groups; the group preferably comprises 1 to 6 (e.g. 1, 2, 3 or 4) carbon atoms and 1, 2, 3 or 4 (particularly 1, 2 or 3) heteroatoms selected from oxygen, nitrogen and sulfur (particularly oxygen and nitrogen); the group may preferably be substituted with one or more (preferably 1 to 6; particularly preferably 1, 2, 3 or 4) fluorine, chlorine, bromine or iodine atoms or OH, =O, SH, =S, NH2, =NH, N3, CN or NO2 groups.

[0130] Examples of heteroalkyl groups are groups of the following formula: R a -OY a -、R a -SY a -、R a -SO-Y a -、R a -SO2-Y a -、R a -N(R b )-SO2-Y a -、R a -SO2-N(R b )-Y a -、R a -N(R b )-Y a -、R a -CO-Y a -、R a -O-CO-Y a -、R a -CO-OY a -、R a -CO-N(R b )-Y a -、R a -N(R b )-CO-Y a -、R a -O-CO-N(R b )-Y a -、R a -N(R b )-CO-OY a -、R a -N(R b )-CO-N(R c )-Y a -、R a -O-CO-OY a -、R a -N(Rb )-C(=NR d )-N(R c )-Y a -、R a -CS-Y a -、R a -O-CS-Y a -、R a -CS-OY a -、R a -CS-N(R b )-Y a -、R a -N(R b )-CS-Y a -、R a -O-CS-N(R b )-Y a -、R a -N(R b )-CS-OY a -、R a -N(R b )-CS-N(R c )-Y a -、R a -O-CS-OY a -、R a -S-CO-Y a -、R a -CO-SY a -、R a -S-CO-N(R b )-Y a -、R a -N(R b )-CO-SY a -、R a -S-CO-Y a -、R a -O-WHAT-SY a 、R a -S-CO-SY a -、R a -S-CS-Y a -、R a -CS-SY a -、R a -S-CS-N(R b )-Y a -、R a -N(R b )-CS-SY a -、R a -S-CS-OY a-、R a -O-CS-SY a -, where R a It is a hydrogen atom, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; R b It is a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, or a C2-C6 alkynyl group; R c It is a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, or a C2-C6 alkynyl group; R d It is a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, or a C2-C6 alkynyl group, Y a It is a bond, C1-C6 alkylene, C2-C6 alkenyl or C2-C6 ynyl, wherein each heteroalkyl group contains at least one carbon atom and one or more hydrogen atoms may be substituted by fluorine or chlorine atoms.

[0131] Specific examples of heteroalkyl groups are methoxy, trifluoromethoxy, ethoxy, n-propoxy, isopropyloxy, n-butoxy, tert-butoxy, methoxymethyl, ethoxymethyl, -CH2CH2OH, -CH2OH, SO2Me, -NHAc, methoxyethyl, 1-methoxyethyl, 1-ethoxyethyl, 2-methoxyethyl or 2-ethoxyethyl, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, isopropylethylamino, methylaminomethyl, ethylaminomethyl, diisopropylaminoethyl, methylthio, ethylthio, isopropylthio, enol ether, dimethylaminomethyl, dimethylaminoethyl, acetyl, propionyl, butyryloxy, acetoxy, methoxycarbonyl, ethoxycarbonyl, propionyloxy, acetamino or propionylamino, carboxymethyl, carboxyethyl or carboxypropyl, N-ethyl-N-methylcarbamoyl or N-methylcarbamoyl. Other examples of heteroalkyl groups are nitrile (-CN), isonitrile, cyanate, thiocyanate, isocyanate, isothiocyanate, and alkylnitrile.

[0132] The term cycloalkyl refers to a cyclic group that is saturated or partially unsaturated (e.g., cycloalkenyl) and contains one or more rings (preferably 1 or 2) and 3 to 14 cyclic carbon atoms, preferably 3 to 10 (especially 3, 4, 5, 6 or 7) cyclic carbon atoms. Furthermore, cycloalkyl also refers to a group in which one or more hydrogen atoms are replaced by fluorine, chlorine, bromine or iodine atoms or by OH, =O, SH, =S, NH2, =NH, N3 or NO2 groups; thus, for example, cycloketones such as cyclohexanone, 2-cyclohexenone or cyclopentanone. Other specific examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, spiro[4,5]decyl, norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decahydronaphthyl, bicyclo[4,3,0]nonyl, tetrahydronaphthyl, cyclopentylcyclohexyl, fluorocyclohexyl or cyclohex-2-enyl. Preferably, the term cycloalkyl refers to a saturated cyclic group comprising one or more rings (preferably 1 or 2) and containing 3 to 14 cyclic carbon atoms, preferably 3 to 10 (especially 3, 4, 5, 6 or 7) cyclic carbon atoms.

[0133] The term heterocyclic alkyl refers to a cycloalkyl group as defined above, wherein one or more (preferably 1, 2, or 3) cyclic carbon atoms are substituted with oxygen, nitrogen, silicon, selenium, phosphorus, or sulfur atoms (preferably oxygen, sulfur, or nitrogen atoms) or SO or SO2 groups. Heterocyclic alkyl groups preferably have 1 or 2 rings and 3 to 10 (particularly 3, 4, 5, 6, or 7) cyclic atoms (preferably selected from C, O, N, and S). Furthermore, heterocyclic alkyl also refers to groups substituted with fluorine, chlorine, bromine, or iodine atoms or with OH, =O, SH, =S, NH2, =NH, N3, or NO2 groups. Examples are piperidinyl, prolyl, imidazoalkyl, piperazine, morpholinyl (e.g., -N(CH2CH2)2O), hexamethylenetetramine, pyrrolidinyl, tetrahydrothiophene, tetrahydropyranyl, tetrahydrofuranyl, or 2-pyrazolinyl, as well as lactams, lactones, cyclic imides, and cyclic anhydrides.

[0134] The term alkylcycloalkyl refers to a group that simultaneously contains a cycloalkyl group and an alkyl, alkenyl, or ynyl group as defined above, such as alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkenyl, alkenylcycloalkyl, and ynylcycloalkyl. Alkylcycloalkyl preferably comprises a cycloalkyl group containing one or two rings and 3 to 10 (particularly 3, 4, 5, 6, or 7) cyclic carbon atoms, and one or two alkyl, alkenyl, or ynyl groups (particularly alkyl) having 1 or 2 to 6 carbon atoms.

[0135] The term heteroalkylcycloalkyl refers to an alkylcycloalkyl group as defined above, wherein one or more (preferably 1, 2, or 3) carbon atoms are substituted with oxygen, nitrogen, silicon, selenium, phosphorus, or sulfur atoms (preferably oxygen, sulfur, or nitrogen atoms), or an SO group or an SO2 group. The heteroalkylcycloalkyl group preferably comprises 1 or 2 rings having 3 to 10 (particularly 3, 4, 5, 6, or 7) ring atoms, and 1 or 2 alkyl, alkenyl, ynyl, or heteroalkyl (particularly alkyl or heteroalkyl) groups having 1 or 2 to 6 carbon atoms. Examples of these groups are alkylheterocycloalkyl, alkylheterocyclic alkenyl, alkenylheterocycloalkyl, ynylheterocycloalkyl, heteroalkylcycloalkyl, heteroalkylheterocycloalkyl, and heteroalkylheterocyclic alkenyl, wherein the cyclic groups are saturated or mono, di, or triunsaturated.

[0136] The term aryl refers to an aromatic group containing one or more rings and 6 to 14 ring carbon atoms, preferably 6 to 10 (especially 6) ring carbon atoms. Aryl also refers to a group substituted with fluorine, chlorine, bromine, or iodine atoms, or with OH, SH, NH2, N3, or NO2 groups. Examples include phenyl (Ph), naphthyl, biphenyl, 2-fluorophenyl, aniline, 3-nitrophenyl, or 4-hydroxyphenyl.

[0137] The term heteroaryl refers to an aromatic group comprising one or more rings and 5 to 14 ring atoms, preferably 5 to 10 (particularly 5, 6, 9, or 10) ring atoms, containing one or more (preferably 1, 2, 3, or 4) oxygen, nitrogen, phosphorus, or sulfur ring atoms (preferably O, S, or N). The expressed heteroaryl also refers to a group substituted with fluorine, chlorine, bromine, or iodine atoms or with OH, SH, N3, NH2, or NO2 groups. Examples include pyridyl (e.g., 4-pyridyl), imidazole (e.g., 2-imidazole), phenylpyrrolyl (e.g., 3-phenylpyrrolyl), thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, indole, indazole, tetrazolyl, pyrazinyl, pyrimidinyl, pyrazinyl, 4-hydroxypyridinyl (4-pyridinone), 3,4-hydroxy Pyridyl (3,4-pyridone), oxazolyl, isoxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazole, indolyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, pyridazinyl, quinolinyl, isoquinolinyl, pyrroleyl, purinyl, carbazolyl, acridineyl, pyrimidinyl, 2,3′-bisfuranyl, pyrazolyl (e.g., 3-pyrazolyl), and isoquinolinyl.

[0138] The term aralkyl refers to a group containing both an aryl group as defined above and an alkyl, alkenyl, alkynyl, and / or cycloalkyl group, such as arylalkyl, arylalenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylarylcycloalkyl, and alkylarylcycloalkenyl. Specific examples of aralkyl groups are phenylcyclopentyl, cyclohexylphenyl, and groups derived from toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, 1H-indanone, tetrahydronaphthalene, dihydronaphthalene, indanone, cumene, fluorene, and indanone. Aralkyl groups preferably comprise one or two aromatic ring systems (especially one or two rings), each containing 6 to 10 carbon atoms and one or two alkyl, alkenyl, and / or alkynyl groups containing 1 or 2 to 6 carbon atoms, and / or cycloalkyl groups containing 3, 4, 5, 6, or 7 ring carbon atoms.

[0139] The term heteroarylene refers to a group that simultaneously contains aryl and / or heteroaryl groups as defined above, as well as alkyl, alkenyl, ynyl and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl groups. A heteroarylene preferably comprises one or two aromatic ring systems (especially one or two rings), each aromatic ring containing 5 or 6 to 9 or 10 ring atoms (preferably selected from C, N, O, and S), and one or two alkyl, alkenyl, and / or ynyl groups containing 1 or 2 to 6 carbon atoms, and / or one or two heteroalkyl groups containing 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms selected from O, S, and N, and / or one or two cycloalkyl groups each containing 3, 4, 5, 6, or 7 ring carbon atoms, and / or one or two heterocycloalkyl groups each containing 1, 2, 3, or 4 oxygen, sulfur, or nitrogen atoms and 3, 4, 5, 6, or 7 ring atoms.

[0140] Examples include arylheteroalkyl, arylheterocycloalkyl, arylheterocycloalkenyl, arylalkylheterocycloalkyl, arylalenylheterocycloalkyl, arylynylheterocycloalkyl, arylalkylheterocycloalkenyl, heteroarylalkyl, heteroarylenyl, heteroarylynyl, heteroarylheteroalkyl, heteroarylcycloalkyl, heteroarylcycloalkenyl, heteroarylheterocycloalkyl, heteroarylalkylcycloalkenyl, heteroarylalkylcycloalkyl, heteroarylalkylcycloalkyl, heteroarylalkylcycloalkenyl, and heteroarylheteroalkylheterocycloalkyl, where the cyclic group is saturated or mono, di, and triunsaturated. Specific examples include tetrahydroisoquinolinyl, benzoyl, phthalic acid, 2- or 3-ethylindolyl, 4-methylpyridinyl, 2-, 3- or 4-methoxyphenyl, 4-ethoxyphenyl, and 2-, 3- or 4-carboxyphenylalkyl.

[0141] As mentioned above, the terms cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, and heteroaryl also refer to groups substituted by fluorine, chlorine, bromine, or iodine atoms or by OH, =O, SH, =S, NH2, =NH, N3, or NO2 groups.

[0142] The term halogen refers to F, Cl, Br, or I.

[0143] When aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl, or heteroaryl contains more than one ring, these rings may be bonded to each other by single or double bonds, or these rings may be cyclic, fused, or bridged.

[0144] Due to their substitution, the compounds of the present invention may contain one or more chiral centers. Therefore, the present invention includes all pure enantiomers and all pure diastereomers, as well as mixtures thereof in any mixing ratio. Furthermore, the present invention includes all cis / trans isomers of the compounds of the present invention and mixtures thereof. Additionally, the present invention includes all tautomeric forms of the compounds of the present invention.

[0145] The present invention further provides pharmaceutical compositions comprising one or more compounds described herein or pharmaceutically acceptable salts, solvates, or hydrates thereof, optionally in combination with one or more carrier substances and / or one or more adjuvants. The pharmaceutical compositions of the present invention may contain additional antibacterial compounds.

[0146] The compounds or pharmaceutical compositions of the present invention can be administered in combination with other antibacterial compounds.

[0147] The present invention also provides compounds or pharmaceutical compositions as described herein for treating bacterial infections, particularly those caused by Pseudomonas aeruginosa.

[0148] The present invention further provides compounds as described herein or pharmaceutical compositions as defined herein for the preparation of medicaments for the treatment of bacterial infections, particularly bacterial infections caused by Pseudomonas aeruginosa.

[0149] Examples of pharmacologically acceptable salts of sufficiently basic compounds are salts of physiologically acceptable inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; or salts of organic acids, such as methanesulfonic acid, p-toluenesulfonic acid, lactic acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid, and salicylic acid. Furthermore, sufficiently acidic compounds can form alkali metal or alkaline earth metal salts, such as sodium, potassium, lithium, calcium, or magnesium salts; ammonium salts; or organic base salts, such as methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, meglumine, piperidine, morpholine, tri-(2-hydroxyethyl)amine, lysine, or arginine salts; all of these are further examples of salts of the compounds described herein.

[0150] The compounds described herein may be solvated, especially hydrated. Solvation / hydration may occur during production or due to the hygroscopicity of compounds that are initially anhydrous. Solvates and / or hydrates may exist, for example, in solid or liquid form.

[0151] The therapeutic uses of the compounds described herein, their pharmacologically acceptable salts, solvates and hydrates, as well as formulations and pharmaceutical compositions thereof, are also within the scope of this invention.

[0152] Typically, the compounds and pharmaceutical compositions described herein will be administered using established and acceptable modes of administration known in the art.

[0153] For oral administration, such therapeutic agents can be administered via one of the following routes: oral, such as tablets, sugar-coated pills, coated tablets, pellets, semi-solids, soft or hard capsules, such as soft and hard gelatin capsules, aqueous or oily solutions, emulsions, suspensions or syrups; parenteral injection, including intravenous, intramuscular and subcutaneous injection, such as as injectable solutions or suspensions; rectal suppositories; by inhalation or blowing, such as as powder formulations; as microcrystals or sprays (e.g., liquid aerosols); transdermal, such as through transdermal drug delivery systems (TDDS), such as ointments containing the active ingredient; or intranasal administration. To produce such tablets, pellets, semi-solids, coated tablets, pills and hard capsules, such as gelatin capsules, therapeutically useful products can be mixed with pharmaceutically inert inorganic or organic excipients, such as lactose, sucrose, glucose, gelatin, malt, silica gel, starch or derivatives thereof, talc, stearic acid or its salts, dry skim milk, etc. For the production of soft capsules, excipients such as vegetable oils, petroleum, animal oils or synthetic oils, waxes, fats, and polyols can be used. For the production of liquid solutions, emulsions or suspensions or syrups, excipients such as water, alcohols, brine, glucose solutions, polyols, glycerol, lipids, phospholipids, cyclodextrins, vegetable oils, petroleum, animal oils, or synthetic oils can be used. Lipids are particularly preferred, and phospholipids (preferably of natural origin; particularly preferred with a particle size between 300 and 350 nm) are preferred, preferably in phosphate-buffered saline (pH = 7 to 8, preferably 7.4). For suppositories, excipients such as vegetable oils, petroleum, animal oils or synthetic oils, waxes, fats, and polyols can be used. For aerosol formulations, compressed gases suitable for the purpose, such as oxygen, nitrogen, and carbon dioxide, can be used. Pharmaceutically useful reagents may also contain additives for preservation and stabilization, such as UV stabilizers, emulsifiers, sweeteners, flavorings, salts that alter osmotic pressure, buffers, coating additives, and antioxidants.

[0154] Generally, for oral or parenteral administration to an adult weighing approximately 80 kg, a daily dose of approximately 1 mg to approximately 10,000 mg, preferably approximately 5 mg to approximately 1,000 mg, is appropriate, although the upper limit may be exceeded when indicated. The daily dose may be administered as a single dose or in divided doses, or for parenteral administration, by continuous infusion or subcutaneous injection.

[0155] According to another preferred embodiment, the present invention provides a method for inhibiting the virulence factor LasB of Pseudomonas aeruginosa in a subject, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0156] According to another preferred embodiment, the present invention provides a method for treating bacterial infections, comprising administering to a subject requiring such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0157] According to another preferred embodiment, the present invention provides a method for treating bacterial infections, comprising administering to a subject requiring such treatment a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0158] Gram-positive pathogens such as *Clostridium histolyticum* (recently renamed *Hathevaya histolytica*), *C. tetani*, and *Bacillus cereus* produce collagenases ColH and ColG (*Clostridium histolyticum*), ColT (*C. tetani*), and ColQ1 (*Bacillus cereus* strain Q1) as virulence factors, making them attractive targets for the treatment of these bacterial infections. E.;Kany,AM;Haupenthal,J.;Hüsecken,K.;Hoppe,IJ;Voos,K.;Yahiaoui,S.; B.; Ducho, C.; Brandstetter, H.; Hartmann, RWJAm. Chem. Soc. 2017, 139, 12696–12703). The compounds of the present invention are also effective inhibitors of these collagenases. Example

[0159] I. General Procedures:

[0160] Option 1 Synthesis of α-substituted-N-arylthioacetamide and α-substituted-N-heteroarylthioacetamide

[0161]

[0162] (a) Sodium nitrite, 6M HCl, -5°C to room temperature; (b) EDC.HCl, DCM, room temperature or ClCO2Et, Et3N, THF, room temperature; (c) Potassium thioacetate, acetone, room temperature; (d) NaOH, MeOH, room temperature.

[0163] General Procedure A: Synthesis of 2-Chloroalkyl Acids (1)

[0164] Amino acids (1.0 equivalent) were dissolved in 6 M hydrochloric acid (2 mL / mmol or until mostly dissolved) under a nitrogen atmosphere and cooled to -5 °C. Sodium nitrite (3.5 equivalent) was dissolved in water (0.3 mL / mmol amino acids) and added slowly dropwise. The mixture was stirred overnight while being heated to room temperature. The reaction mixture was extracted with EtOAc / THF (3:1, 3-fold). The combined organic extracts were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na₂SO₄, and filtered. The solvent was removed under reduced pressure to give the crude product, which required no further purification for the next step.

[0165] General Procedure B-1: Synthesis of N-acetyl-2-halo-2-alkylacetamide derivatives (3)

[0166] 2-Haloalkyl acids (1.2 equivalents) (2-chloroalkyl acid (1) being crude or commercially available 2-bromoalkyl acid (2)) and EDC.HCl (1.2 equivalents) were added to a solution of the corresponding aniline (1.0 equivalent) in DCM. The resulting mixture was stirred at room temperature until the starting aniline was consumed (monitored by TLC or LC-MS). The resulting solution was washed with 1M HCl and a saturated aqueous solution of NaCl. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide the crude product. The obtained crude product was used for the next step without further purification, or purified using column chromatography.

[0167] General Procedure B-2: Synthesis of N-acetyl-2-halo-2-alkylacetamide derivatives (3)

[0168] 2-Haloalkyl acids (1.0 equivalent) (2-chloroalkyl acid (1) as crude or commercially available 2-bromoalkyl acid (2)) were dissolved in THF. Et3N (1.0 equivalent) was added to this solution at room temperature, followed by the dropwise addition of ethyl chloroformate (1.1 equivalent). A solution of the corresponding heterocyclic amine (0.8 equivalent) dissolved in THF was added dropwise to the mixture. The reaction was stirred overnight at room temperature. The THF was evaporated, the crude solid was dissolved in DCM, and the solution was washed with an aqueous solution of KHCO3 (10 wt%) and water. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide the crude product. The obtained crude product was purified by rapid chromatography.

[0169] General Program C: N-aryl -2-Thioacetyl-2-alkylacetamide derivatives and N-heteroaryl-2-thioacetyl Synthesis of alkyl-2-alkylacetamide derivatives (4)

[0170] An N-aryl-2-halo-2-alkylacetamide derivative or an N-heteroaryl-2-chloro-2-alkylformamide derivative (1.0 equivalent) ((3) purified or used as crude) was dissolved in acetone, and potassium thioacetate (2.0 equivalent) was added to the solution. The resulting mixture was stirred at room temperature until complete conversion was achieved (monitored by TLC or LC-MS). After concentration under vacuum, the resulting residue was diluted with H2O and extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The crude residue was purified by column chromatography.

[0171] General Program D: Synthesis N-aryl -2-Mercapto-2-alkylacetamide derivatives and N-heteroaryl-2-mercapto-2-alkyl Acetamide derivatives (II)

[0172] Under an argon atmosphere, NaOH (3.0 equivalents) was added to a MeOH solution of compound 4 (1.0 equivalents). The reaction mixture was stirred at room temperature. The reaction mixture was acidified with 2M HCl and extracted with EtOAc. The resulting organic layer was washed with 0.5M HCl solution and saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. In the case of heterocyclic derivatives, the pH was adjusted to acidic using an Amberlite IR-120 instead of HCl. The product was obtained as a pure product or purified using column chromatography or preparative HPLC.

[0173] Option 2 Synthesis of phosphonic acid derivatives

[0174]

[0175] (a) EDC·HCl, DCM, room temperature; (b) P(OEt)3, pure, 150℃; (c) i) TMSBr, DCM, room temperature; ii) MeOH, room temperature.

[0176] General Procedure E: Synthesis of Diethyl Phosphonate Derivatives (5)

[0177] The N-aryl-2-bromo-2-alkylacetamide derivative (3) (1.0 equivalent) was suspended in triethyl phosphite (10 equivalent) equipped with a reflux condenser, heated to 150°C and stirred for a total of 18 hours. Most of the unreacted triethyl phosphite was evaporated under vacuum, and the resulting oil was purified by column chromatography.

[0178] General Procedure F: Synthesis of Phosphonic Acid Derivatives (III)

[0179] Over a period of 15 minutes, trimethylbromosilane (5.0 equivalents) was added dropwise to a solution of diethyl phosphonate (5) (1.0 equivalent) in dry DCM. The reaction mixture was stirred overnight at room temperature. Then, MeOH was added and the mixture was stirred at room temperature for 30 minutes to cleave the previously formed TMS ester. The solvent was concentrated under vacuum, and the resulting oil was purified by preparative HPLC.

[0180] Option 3: Synthesis of α-phosphonic acid (2d)

[0181]

[0182] (a) HBr, NaNO2, H2O, 0℃-room temperature, 2h, quantitative; (b) EtOH, cat. H2SO4, reflux, 2h, 81%; (c) P(OEt)3, pure, 150℃; 48h, 44%; (d) NaOH, EtOH, 0℃-room temperature, 48h, 98%.

[0183] 2-Bromo-4-methylvaleric acid (2a)

[0184] 10.5 g of racemic leucine 1 (80.0 mmol, 1.0 equivalent) was dissolved in 48% HBr (80 mL) and 72 mL of distilled water. The mixture was cooled to 0 °C and a solution of NaNO2 (8.82 g, 128.0 mmol, 1.6 equivalent) dissolved in 20 mL of distilled water was added dropwise over 2 hours. Water was added dropwise. The mixture was heated to room temperature and stirred overnight. The mixture was then transferred to a separatory funnel and extracted with acetone (4 × 100 mL). The combined organic layers were washed with distilled water (400 mL) and a saturated aqueous solution of NaCl (400 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. A pale yellow liquid compound 2a (15.06 g, 80.0 mmol, quantified) was obtained and used in the next step without further purification.

[0185] Ethyl 2-bromo-4-methylvalerate (2b)

[0186] To α-bromic acid 2a (15.06 g, 80.0 mmol, 1.0 equivalent), a solution of concentrated sulfuric acid (30 μl / mmol) in ethanol (2 mL / mmol) was added, and the mixture was refluxed for 2 hours. The solution was then cooled to room temperature and concentrated under reduced pressure. Et₂O (150 mL) was added, and the organic layer was washed with a saturated aqueous solution of NaHCO₃ (150 mL), followed by a wash with a saturated aqueous solution of NaCl (150 mL). The organic layer was dried over MgSO₄, filtered, and concentrated under reduced pressure. Compound 2b (14.45 g, 64.7 mmol, 81% yield) was a pale yellow liquid and was used for the next step without further purification.

[0187] 2-(diethoxyphosphoryl)-4-methylvalerate (2c)

[0188] α-bromoester 2b (14.45 g, 64.7 mmol, 1.0 equivalent) and P(OEt)3 (22.41 mL, 129.4 mmol, 2.0 equivalent) were mixed and heated to 150 °C for 48 hours. The mixture was then cooled to room temperature and Et2O (350 mL) was added. The mixture was transferred to a separatory funnel and washed with saturated NaCl aqueous solution (2 × 350 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The product was purified using rapid chromatography (SiO2, hexane / EtOAc 1:1) to give compound 2c (7.93 g, 28.3 mmol, 44%) as a pale yellow oil. 1 H NMR (CDCl3, 500MHz) δppm: 4.18-4.24 (m, 2H), 4.11-4.17 (m, 4H), 3.00-3.07 (m, 1H), 1.95-2.07 (m, 1H), 1.55- 1.66 (m, 2H), 1.33 (dt, 6H, J=2.3, 7.0Hz), 1.28 (t, 3H, J=7.2Hz), 0.92 (d, 3H, J=6.1Hz), 0.89 (d, 3H, J=6.3Hz). 13 C NMR (CDCl3, 126MHz) δppm: 169.4 (d, J=5.5Hz), 62.7 (d, J=6.4Hz), 62.6 (d, J=6.4Hz), 61.3, 44.5, 43 .4, 35.5 (d, J = 5.5Hz), 26.9 (d, J = 14.7Hz), 22.9, 21.2, 16.4 (d, J = 3.7Hz), 16.3 (d, J = 3.7Hz), 14.1. 31 P NMR (CDCl3, 202MHz) δppm: 23.4.

[0189] HRMS(ESI+)C 12 H 26 O5P[M+1]+ calculates 281.1518, actual measurement is 281.1503.

[0190] 2-(diethoxyphosphoryl)-4-methylvaleric acid (2d)

[0191] Compound 2c (7.93 g, 28.3 mmol, 1.0 equivalent) was dissolved in EtOH (270 mL), and a solution of NaOH (2.15 g, 53.88 mmol, 2.0 equivalent) dissolved in distilled water (100 mL) was added. The mixture was stirred overnight at room temperature. Progress was monitored using LC-MS. After completion, the mixture was transferred to a separatory funnel. Distilled water (300 mL) and Et20 (400 mL) were added to separate the layers. The aqueous layer was acidified to pH 1 using HCl (6 M) and extracted with EtOAc (3 × 300 mL). The combined EtOAc-layer was washed with saturated aqueous solution (2 × 500 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. Compound 2d (6.63 g, 26.29 mmol, 98%) was obtained as a pale yellow oil, which was used without further purification. 1 H NMR (CDCl3, 500MHz) δppm: 8.33 (br s, 2H), 4.13-4.25 (m, 4H), 3.07 (ddd, 1H, J=3.1, 11.3, 23.0Hz), 1.99 (dddd, 1H, J=4.8, 8.5, 11.4, 13.5Hz), 1. 58-1.70 (m, 1H), 1.49-1.57 (m, 1H), 1.33 (dt, 6H, J=2.7, 7.1Hz), 0.92 (d, 3H, J=6.6Hz), 0.89 (d, 3H, J=6.6Hz). 13 C NMR (CDCl3, 126MHz) δppm: 171.9 (d, J=3.7Hz), 63.7 (d, J=6.4Hz), 62.9 (d, J=6.4Hz), 44.4, 43 .4, 35.6 (d, J=5.5Hz), 26.8 (d, J=13.8Hz), 23.0, 21.2, 16.3 (d, J=2.8Hz), 16.2 (d, J=2.8Hz). 31 P NMR (CDCl3, 202MHz) δppm: 24.3. HRMS(ESI+)C 10 H 22 O5P[M+1] + Calculated value: 253.1205; Actual measurement: 253.1191.

[0192] Option 4: Synthesis of bicyclic phosphonates

[0193]

[0194] L (connector): No connector, O, NH, S, CH2, CH2O, CH2S, SCH2, NHCH2, CO, NHCO, CONH, CH2CONH, NHSO2, SO2NH, CH2SO2NH

[0195] Ring 1: Aromatic or saturated six-membered ring

[0196] Ring 2: Aromatic or saturated six-membered ring or spiroalkyl

[0197] (a) 2d, EDC·HCl, DCM, room temperature or TBTU, NMM, DCM (or DMF), 0°C to room temperature;

[0198] (b) TMSBr, DCM, room temperature; ii) MeOH, room temperature.

[0199] General Procedure G: Synthesis of diethyl phosphonate derivatives (5a)

[0200] Aniline (commercially available, or synthesized according to conventional methods found in the literature, examples given in general procedures G-1, G-2, G-3, G-4 below) (1.0 equivalents) was dissolved in DCM or DMF with 2-(diethoxyphosphoryl)-4-methylpentanoic acid (2d) (1.2 equivalents) and N-methylmorpholine (2.5 equivalents). The reaction mixture was cooled in an ice bath and TBTU (1.5 equivalents) was added. The temperature was maintained for 30 minutes, then heated to room temperature. As an alternative route, EDC·HCl (2.0 equivalents), HOBt (2.0 equivalents), and DIPEA (2.5 equivalents) were used instead of TBTU / NMM. In both cases, the reaction mixture was stirred overnight and then washed with water and a saturated aqueous solution of NaCl. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide a crude product. The obtained crude product was used for the next step without further purification or purification by column chromatography.

[0201] General Procedure G-1: With amide connectors (CONH and CH) 2 Synthesis of CONH) aniline

[0202] The corresponding carboxylic acid (1.2 equivalents) was dissolved in DCM and EDC·HCl (1.2 equivalents) was added, followed by tert-butyl (4-aminophenyl)carbamate (1.0 equivalent). The reaction mixture was stirred at room temperature. If a precipitate formed, it was filtered and washed with DCM. When no precipitate formed, the reaction mixture was consumed, washed with 1M HCl (×2) and saturated NaCl aqueous solution (×1), and purified by column chromatography. The obtained product was suspended in a DCM / TFA mixture (3:1) at 0°C. The mixture was then stirred at room temperature for 2 hours. The solvent was evaporated. EtOAc was added and washed with 2.5M NaOH (×2) and saturated NaCl aqueous solution (×2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the desired aniline.

[0203] General Procedure G-2: Synthesis of Aniline with Sulfonamide Linkers (SO2NH and CH2SO2NH)

[0204] 1.0 equivalent of tert-butyl (4-aminophenyl)carbamate was dissolved in DCM and cooled to 0°C. Et3N (1.2 equivalents) was added, followed by the corresponding sulfonyl chloride (1.1 equivalents). The reaction mixture was stirred at room temperature for 8 hours. The precipitate was filtered, and the filtrate was purified by column chromatography. The resulting product was suspended at 0°C in a DCM / TFA mixture (3:1). The mixture was then stirred at room temperature for 2 hours. The solvent was evaporated. EtOAc was added, and the mixture was washed with 2.5 M NaOH (×2) and saturated aqueous NaCl solution (×2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the desired aniline.

[0205] General Procedure G-3: Synthesis of Aniline with an Ether Linker (CH2O)

[0206] 1.0 equivalent of tert-butyl (4-hydroxyphenyl)carbamate was dissolved in DMF. Potassium carbonate (2.0 equivalent) was added, and the reaction mixture was stirred for 15 minutes. The corresponding benzyl bromide was then added dropwise over 15 minutes, and the mixture was stirred overnight at room temperature. Water was added, and the mixture was extracted with EtOAc (×3), and the organic layer was washed with a saturated aqueous NaCl solution. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The obtained product was suspended in a DCM / TFA mixture (3:1) at 0 °C. The mixture was then stirred at room temperature for 2 hours. The solvent was evaporated. EtOAc was added, and the mixture was washed with 2.5 M NaOH (×2) and a saturated aqueous NaCl solution (×2). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the desired aniline.

[0207] General Procedure G-4: Synthesis of Linkageless Aniline

[0208] Arylamine (1.0 equivalent) was placed in a sealed tube, followed by a mixture of boric acid (1.5 equivalent), 2M NaOH, tetrakis(triphenylphosphine)palladium (0.02 equivalent), and dioxane / H₂O (4:1, v:v). The reaction mixture was washed with N₂ and subjected to microwave irradiation (150 °C, 150 W) for 20 min. After cooling to room temperature, a mixture of EtOAc / H₂O (1:1, v:v) was added to stop the reaction. The aqueous layer was extracted with EtOAc (×3). The organic layer was washed with saturated aqueous NaCl solution (1x) and water (1x), dried over MgSO₄, filtered, and concentrated under reduced pressure. The residues were purified by column chromatography.

[0209] Option 5: Synthesis of dipeptide derivatives with zinc phosphonate binding motifs

[0210]

[0211] (a) IBCF, NMM, -20℃ THF, 30 min; (b) i) HCl (4M in dioxane), room temperature, 12 h; ii) 2d, TBTU, NMM, DMF, 0℃–room temperature, 12 h; c) TMSBr, room temperature, 12 h. Preparative high performance liquid chromatography.

[0212] General Procedure H: Synthesis of Aniline-Substituted Derivatives (6)

[0213] The corresponding tert-butyloxycarbonyl-protected amino acid (1.0 equivalent) was dissolved in THF (0.1 M) and cooled to -20 °C. Then, NMM (2.5 equivalent) and isobutyl chloroformate (1.0 equivalent) were added dropwise. The reaction mixture was stirred at this temperature for 30 min, and then aniline (1.0 equivalent) dissolved in THF (1 M) was added. After the reaction mixture reached room temperature, it was diluted with EtOAc. The organic phase was washed with KHSO4 (1N) solution, saturated NaHCO3 solution, and saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Column chromatography purification yielded the corresponding peptide.

[0214] General Procedure I: Synthesis of Phospho-containing Dipeptide (5b)

[0215] A tert-butyloxycarbonyl-protected peptide (1.0 equivalent) was dissolved in DCM (0.1 M) and treated with HCl (10.0 equivalent, 4 M in dioxane) at 0 °C. The mixture was heated to room temperature and, after complete conversion (TLC), the solvent was removed under reduced pressure, resulting in a crystalline hydrochloride residue, which was subsequently dissolved in DMF (0.1 M). 2-(diethoxyphosphoryl)-4-methylpentanoic acid 2d (1.1 equivalent) was added to this solution, and the reaction mixture was cooled to 0 °C. Coupling was achieved via TBTU (1.1 equivalent) and NMM (2.5 equivalent). The reaction mixture was heated to room temperature and, after complete conversion (TLC), diluted with EtOAc and washed successively with 1 N KHSO4 solution, saturated NaHCO3 solution, and saturated NaCl aqueous solution. The organic layer was dried over anhydrous Na2SO4, filtered, and the residue was used for the next step without further purification.

[0216] Option 6: Synthesis of triazole derivatives

[0217]

[0218] (a) i) HCl (4M in dioxane), DCM, room temperature; 18h; ii) TBTU, NMM, DMF 0℃-room temperature, 22h; (b) CuSO4·5H2O, sodium ascorbate, tBuOH / H2O / MeOH (2:2:1) room temperature, 14h; (c) TMSBr, DCM, room temperature, overnight, preparative HPLC.

[0219] General Procedure J: Synthesis of alkynyl diethylphosphonate (8)

[0220] Alkyne component 7 (1.0 equivalent), as previously reported (https: / / doi.org / 10.1002 / anie.201601564), was dissolved in DCM (10 mL / mmol) and HCl (10.0 equivalent, 4 M in dioxane) was added at room temperature. The mixture was stirred for 18 hours and then concentrated under reduced pressure. Meanwhile, a mixture of compound 2d (1.1 equivalent) and TBTU (1.2 equivalent) in DMF (5 mL / mmol) was cooled to 0 °C and NMM (2.5 equivalent) was added. The reaction mixture was stirred for 30 minutes, and then the tert-butoxycarbonyl-deprotected alkenyl amino acid was dissolved in DMF (5 mL / mmol) and added dropwise at 0 °C. The mixture was stirred for 22 hours and then warmed to room temperature. After the addition of EtOAc, the organic layer was subsequently washed with saturated aqueous NaHCO3 solution, 1 M HCl, water, and saturated aqueous NaCl solution. The organic layer was dried over Na2SO4, filtered, concentrated under reduced pressure, and then discharged. The crude product was purified by automated combined flash purification (Teledyne ISCO).

[0221] General Procedure K: Synthesis of diethyl phosphonate (5c) containing 1H-1,2,3-triazole

[0222] According to (https: / / doi.org / 10.1016 / j.ejmech.2019.06.007), solutions of the corresponding alkenylphosphonate diethyl ester (1.0 equivalent) and azide (1.1 equivalent) were synthesized and purged with argon in tBuOH / H2O / MeOH (2:2:1, 10 mL / mmol). Sodium ascorbate (20 mol%) and CuSO4·5H2O (10 mol%) were added, and the reaction mixture was stirred at room temperature for 14 h. Then, a saturated EDTA solution was added, and the mixture was extracted with EtOAc (x3). The combined organic layers were washed with saturated aqueous NH4Cl and saturated aqueous NaCl solutions. After drying with anhydrous Na2SO4 and filtering, the solvent was removed under reduced pressure to give the title compound, which was used in the next step without further purification.

[0223] Option 7: Synthesis of imidazole derivatives

[0224]

[0225] (a) i) HCl (4M in dioxane), DCM, room temperature; 18h; ii) TBTU, NMM, DMF 0℃-room temperature, 22h; (b) TMSBr, DCM, room temperature, overnight, preparative HPLC.

[0226] Option 8: Synthesis of benzo[a]cyclopentadienyl 5-membered ring

[0227]

[0228] (a) TBTU, NMM, DMF, 0°C to room temperature, 2d; (b) HOAc / toluene (1:1), 110°C, 3h; (c) i) HCl (4M in 1,4-dioxane), DCM, 18h, room temperature; ii) TBTU, NMM, DMF, 0°C to room temperature, 21h; d) TMSBr, DCM, room temperature, 21h. Preparative high performance liquid chromatography.

[0229] General Procedure L: Synthesis of Benzocyclic Hetero-five-membered Rings (11)

[0230] The corresponding tert-butyloxycarbonyl-protected amino acid (1.0 equivalent) was dissolved in DMF (10 mL / mmol). After cooling to 0 °C, NMM (1.1 equivalent) and TBTU (1.1 equivalent) were added. The reaction mixture was stirred for 30 min, and the corresponding nucleophile (1.0) was added. After 3 days, a saturated NH4Cl aqueous solution was added, and the mixture was extracted with EtOAc (×3), followed by washing with a saturated NaHCO3 aqueous solution and a saturated NaCl aqueous solution. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was redissolved in toluene (5 mL), and HOAc (5 mL) was added. The mixture was heated under reflux for 3 h and quenched by the slow addition of a saturated NaHCO3 aqueous solution. After stirring for 20 min, the mixture was extracted with EtOAc (x3) and washed with 1 M HCl. It was then washed with a saturated NaHCO3 aqueous solution (x4) and a saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound, which was used in the next step without further purification.

[0231] Option 9: Synthesis of hydroxamic acid derivatives

[0232]

[0233] (a) i) NaOH, EtOH / H2O, room temperature; ii) EDC·HCl, DCM, room temperature; b) NH2OH, KCN, MeOH, room temperature

[0234] General Procedure M: Synthesis of Ethyl Ester Derivative (12)

[0235] Diethyl 2-alkylmalonate (1.0 equivalent) was dissolved in EtOH / H₂O (4:1), and NaOH (1.2 equivalent) was added. The reaction was stirred overnight at room temperature. EtOH was evaporated under reduced pressure, and a saturated aqueous solution of NaHCO₃ was added and extracted with DCM. The organic layer was discarded. The aqueous layer was acidified with 6M HCl and extracted with DCM. The organic layer was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na₂SO₄, filtered, and evaporated under reduced pressure. The obtained monobasic acid (1.2 equivalent) and EDC were added to a solution of the corresponding aniline (1.0 equivalent) in DCM with HCl (1.2 equivalent). The resulting mixture was stirred at room temperature until the starting aniline was consumed (monitored by TLC or LC-MS). The resulting solution was washed with 1M HCl and a saturated aqueous solution of NaCl. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to provide the crude product. The crude product was purified by column chromatography.

[0236] General Procedure N: Synthesis of Hydroxamic Acid Derivatives (IV)

[0237] Ethyl ester derivative 12 (1.0 equivalent) was dissolved in MeOH. 50% by weight of NH₂OH was added to H₂O (equal volume to methanol), followed by KCN (0.2 equivalent). The mixture was stirred overnight at room temperature. The solvent was concentrated under reduced pressure, and the resulting oil was purified by preparative HPLC.

[0238] Option 10: Synthesis of triazole derivatives

[0239]

[0240] a) 1H-1,2,3-triazole, K2CO3, acetone, 70℃

[0241] General procedure O: Synthesis of 1H-1,2,3-triazole (V) and 2H-1,2,3-triazole (VI) derivatives.

[0242] N-aryl-2-bromo-2-alkylacetamide derivative 3 (1.0 equivalent) was placed in a flask and dissolved in acetone. 1H-1,2,3-triazole (1.1 equivalent) and K₂CO₃ (1.1 equivalent) were added, and the mixture was heated to 70°C overnight. EtOAc was added, the organic layer was washed with water and a saturated aqueous solution of NaCl, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC.

[0243] II. Synthesis Examples

[0244] Example 1

[0245] 2-Chloro-3-phenylpropionic acid.

[0246]

[0247] NMR (500MHz, CDCl) 3 ) δppm: 7.37-7.24 (m, 5H), 4.51 (dd, J=7.8, 6.9Hz, 1H), 3.42 (dd, J=14.0, 6.7Hz, 1H), 3.21 (dd, J=14.1, 7.9Hz, 1H). MS(ESI - )m / z 183.25(MH) - 147.23 (MH-HCl) - .

[0248] 2-Chloro-N,3-Diphenylpropionamide.

[0249]

[0250] Purification was performed using hexane / EtOAc = 100:0 to 0:100. The resulting product was a white solid (404 mg, 31%). 11H NMR (500 MHz, DMSO-d6) δ ppm: 7.95 (s, 1H), 7.60 - 7.52 (m, 2H), 7.38 - 7.28 (m, 6H), 7.27 - 7.19 (m, 1H), 7.11 - 7.04 (m, 1H), 4.76 (t, J = 7.5 Hz, 1H), 3.41 (dd, J = 13.8, 7.2 Hz, 1H), 3.13 (dd, J = 13.9, 7.8 Hz, 1H). MS (ESI + ) m / z 260.08 (M + H) + .

[0251] S-(1-oxo-3-phenyl-1-(phenylamino)propyl-2-yl)ethyl sulfate.

[0252]

[0253] product. 1 1H NMR (500 MHz, CDCl3) δ ppm: 7.96 (brs, 1H), 7.46 (d, J = 8.2 Hz, 2H), 7.33 - 7.22 (m, 6H), 7.12 - 7.07 (m, 1H), 4.30 (t, J = 7.7 Hz, 1H), 3.46 (dd, J = 14.1, 8.5 Hz, 1H), 3.01 (dd, J = 14.1, 7.1 Hz, 1H), 2.38 (s, 3H), 1.59 (s, 3H). 13 13C NMR (126 MHz, CDCl3) δ ppm: 197.3, 168.3, 137.6, 137.6, 129.2, 128.9, 128.6, 127.0, 12④.4, 119.8, 48.5, 35.7, 30.4. MS (ESI + ) m / z 300.17 (M + H) + , 258.10 (M - Ac + 2H) + .

[0254] 2-Mercapto-N,3-Diphenylpropionamide (1).

[0255]

[0256] 43%). 1H NMR (500MHz, CDCl3) δppm: 8.02 (brs, 1H), 7.46 (d, J=8.1Hz, 2H), 7.36-7.29 (m, 4H), 7.29-7.23 (m, 4H), 7.14 (t, J=7.6H z, 1H), 3.72 (dd, J=14.8, 6.6Hz, 1H), 3.38 (dd, J=13.8, 6.5Hz, 1H), 3.24 (dd, J=13.8, 6.8Hz, 1H), 2.11 (d, J=8.9Hz, 1H). 13 C NMR (126MHz, CDCl3) δppm: 169.5, 137.3, 137.2, 129.4, 129.0, 128.6, 127.1, 124.8, 120.0, 45.9, 41.5. HRMS(ESI + C 15 H5NOS[M+H] + Calculated value: 258.0947; Actual value: 258.0943.

[0257] Example 2

[0258] S-(4-methyl-1-oxo-1-(p-tolylamino)pentan-2-yl)ethyl sulfate.

[0259]

[0260] EDC·HCl (172 mg, 0.90 mmol) and DCM (5 mL). The reaction was stirred at room temperature for 5 hours. The crude product obtained was used for the next step without further purification. The second step was carried out according to general procedure C, using potassium thioacetate (171 mg, 1.49 mmol) and acetone (7 mL). The reaction was stirred at room temperature for 2.5 hours. The crude product was purified by column chromatography (100% DCM). The product obtained was a beige solid (131 mg, 63% (after 2 steps)). 1 H NMR (500MHz, DMSO-d6) δppm: 10.23 (s, 1H), 7.46 (d, J = 8.0Hz, 2H), 7.10 (d, J = 8.0Hz, 2H), 4.27 (brt, J = 7.5Hz, 1H ), 2.35 (s, 3H), 2.24 (s, 3H), 1.88-1.75 (m, 1H), 1.62-1.40 (m, 2H), 0.95 (d, J=6.5Hz, 3H), 0.88 (d, J=6.5Hz, 3H). 13C NMR (126MHz, DMSO-d6) δppm: 194.5, 168.6, 136.2, 132.6, 129.1, 119.4, 46.4, 41.7, 30.3, 25.9, 22.5, 22.1, 20.5. HRMS(ESI + C 15 H 22 NO2S[M+H] + Calculated value: 280.1371; Actual value: 280.1358.

[0261] 2-Mercapto-4-methyl-N-(p-tolyl)pentanamide (2).

[0262]

[0263] Stir for 2 hours at room temperature. Purify the crude product using preparative HPLC (H2O(HCOOH 0.05%)-CH3CN(HCOOH 0.05%): 9.0-1.0 to 0.0-10.0). The product obtained is a beige solid (38 mg, 50%, MP = 90 °C). 1 H NMR (500MHz, DMSO-d6) δppm: 9.99 (s, 1H), 7.47 (d, J = 8.0Hz, 2H), 7.11 (d, J = 8.0Hz, 2H), 3.51 (brt, J = 7.8Hz, 1H), 2.93 (s, 1H), 2.25 (s, 3H), 1.84-1.73 (m, 1H), 1.67-1.56 (m, 1H), 1.54-1.43 (m, 1H), 0.91 (d, J=7.0Hz, 3H), 0.86 (d, J=6.5Hz, 3H). 13 C NMR (126MHz, DMSO-d6) δppm: 170.9, 136.5, 132.4, 129.2, 119.2, 44.4, 39.9, 25.8, 22.2, 22.1, 20.5. HRMS(ESI + C 13 H 20 NOS[M+H] + The calculated value is 238.1266, and the actual measured value is 238.1254.

[0264] Table 1: The following other compounds were prepared according to the above procedure:

[0265]

[0266]

[0267]

[0268]

[0269] Example 63

[0270] (4-Methyl-1-oxo-1-(p-tolylamino)pentan-2-yl)phosphonate diethyl ester.

[0271]

[0272] 1.02 mmol), EDC·HCl (196 mg, 1.02 mmol), and DCM (15 mL). The reaction was stirred at room temperature for 5 hours. The crude product obtained was used for the next step without further purification. The second step was carried out according to general procedure E, using the crude product obtained from the first step and triethyl phosphite (1.5 mL, 17.1 mmol). The crude product was purified by column chromatography (hexane / EtOAc = 1:1). The product obtained was a white solid (114 mg, 39% (after 2 steps)). 1 H NMR (500MHz, CDCl3) δppm: 8.41 (s, 1H), 7.39 (d, J=8.4Hz, 2H), 7.08 (d, J=8.4Hz, 2H), 4.21-4.08 (m, 4H), 2.97 (ddd, J=22.6, 11. 3, 3.5Hz, 1H), 2.28 (s, 3H), 2.09-1.99 (m, 1H), 1.77-1.68 (m, 1H), 1.61-1.52 (m, 1H), 1.32 (q, J=7.1Hz, 6H), 0.97-0.91 (m, 6H). 13 C NMR (126MHz, CDCl3) δppm: 165.6 (J=1.8Hz), 135.3, 133.8, 129.4, 119.8, 63.0 (J=7.4Hz), 62.8 (J=6.4Hz) , 45.2 (J=128.6Hz), 35.8 (J=4.6Hz), 26.6 (J=13.8Hz), 23.2, 21.2, 20.8, 16.4 (J=1.8Hz), 16.4 (J=2.8Hz). MS(ESI + )m / z342.2[M+H] + .

[0273] (4-Methyl-1-oxo-1-(p-tolylamino)pentane-2-yl)phosphonic acid (63).

[0274]

[0275] -1-(p-Tolylamino)pentan-2-yl)phosphonic acid. The reaction was stirred overnight at room temperature. Then, MeOH (10 mL) was added, the reaction mixture was stirred for another 30 minutes, and the solvent was evaporated under reduced pressure. The crude product was purified using preparative HPLC (CH3CN(HCOOH 0.05%)-H2O(HCOOH 0.05%): 1.0:9.0 to 10.0:0.0). The product was a white solid (56 mg, 71%). 1 H NMR (500MHz, DMSO-d6) δppm: 9.84 (s, 1H), 7.47 (d, J = 8.4Hz, 2H), 7.07 (d, J = 8.2Hz, 2H), 2.95 (ddd , J=22.4, 11.4, 2.9Hz, 1H), 2.22 (s, 3H), 1.99-1.89 (m, 1H), 1.51-1.34 (m, 2H), 0.87-0.82 (m, 6H). 13 C NMR (126MHz, DMSO-d6) δppm: 167.6 (J=4.6Hz), 137.0, 131.8, 129.0, 119.0, 46.0 (J=126.8Hz), 35.8 (J=3.7Hz), 26.5 (J=14.7Hz), 23.3, 21.4, 20.5. 31 P NMR (202MHz, DMSO-d6) δppm: 20.1. HRMS(ESI – C 13 H 19 NO4P[MH] - Calculated value: 284.1057; Actual value: 284.1058.

[0276] Example 95

[0277] Option 11: Synthesis of connectorless biphenyl derivatives.

[0278]

[0279] a) Pd(PPh3)4, dioxane / H2O (4:1, v:v, 3mL), NaOH (2M), microwave (150℃, 150W, 20min); b) EDC·HCl, DCM, room temperature, 2 hours; c) i) TMSBr, DCM, room temperature, overnight; ii) MeOH, room temperature.

[0280] (1-((2-(4-isopropoxyphenyl)pyrimidin-5-yl)amino)-4-methyl-1-oxopentane-2-yl)phosphonic acid diethyl ester.

[0281]

[0282] Diethyl phosphonate (4-methyl-1-oxopentan-2-yl)phosphonate. The crude product was purified by column chromatography (0% to 3% DCM / MeOH). The product was a white solid (84 mg, 69%). 1 H NMR (500MHz, CDCl3) δppm: 10.27 (s, 1H), 8.79 (s, 2H), 7.90 (d, J=8.8Hz, 2H), 6.69 (d, J =8.8Hz, 2H), 4.50 (hept, J = 6.0Hz, 1H), 4.32-4.17 (m, 2H), 4.10 (p, J = 7.2Hz, 2H), 3.34 ( ddd, J=22.8, 11.3, 2.8Hz, 1H), 2.17-2.06 (m, 1H), 1.60-1.52 (m, 1H), 1.43 (dtd, J=13.1 , 10.2, 2.9Hz, 1H), 1.31 (ddd, J=19.2, 12.6, 6.2Hz, 12H), 0.86 (dd, J=13.1, 6.5Hz, 6H). MS(ESI + )m / z 464[M+H] + .

[0283] (1-((2-(4-isopropoxyphenyl)pyrimidin-5-yl)amino)-4-methyl-1-oxopentane-2-yl)phosphonic acid (95).

[0284]

[0285] (Phenyl)pyrimidin-5-yl)amino)-4-methyl-1-oxopentane-2-yl)phosphonic acid (95). The reaction was stirred overnight at room temperature. Then, MeOH (4 mL) was added, the reaction mixture was stirred for another 30 minutes, and the solvent was evaporated under reduced pressure. The crude product was purified by preparative HPLC (CH3CN(HCOOH 0.05%)-H2O(HCOOH 0.05%)). The product was a white solid (41 mg, 72%). 1 H NMR (500MHz, DMSO-d6) δppm: 10.46 (s, 1H), 9.05 (s, 2H), 8.24 (d, J = 8.9Hz, 2H), 7.01 (d, J = 8.9Hz, 2H), 4.70 (dt, J = 12.1, 6.0Hz, 1H), 3.0 4 (ddd, J=22.4, 11.1, 2.3Hz, 1H), 2.00 (ddd, J=15.4, 10.0, 3.7Hz, 1H), 1.61-1.35 (m, 2H), 1.30 (d, J=6.0Hz, 6H), 0.88 (d, J=6.3Hz, 6H). 13C NMR (126MHz, DMSO-d6) δppm: 169.24, 169.20, 159.76, 158.52, 147.75, 132.71, 129.72, 129.36, 115.87, 69.75, 47.05, 46.05, 36.10, 36.06, 26.98, 26.87, 23.59, 22.28, 21.82. 31 P NMR (202MHz, DMSO-d6) δppm: 18.93.MS (ESI + )m / z 408[M+H] + .

[0286] Example 108

[0287] Option 12: Synthesis of biphenyl derivatives with sulfonamide joints.

[0288]

[0289] a) i) Et3N, DCM, 0℃-room temperature, 8h; ii) TFA, DCM, room temperature, 2h; b) EDC·HCl, DCM, room temperature, overnight; c) TMSBr, DCM, room temperature, overnight.

[0290] N-(4-Aminophenyl)-3,4-Dichlorobenzenesulfonamide.

[0291]

[0292] The mixture was stirred at room temperature for 8 hours. The precipitate was filtered and the filtrate was purified by column chromatography (hexane / EtOAc = 7 / 3) to give tert-butyl (4-((3,4-dichlorophenyl)sulfonamide)phenyl)carbamate (316 mg, 52%). The obtained tert-butyl (4-((3,4-dichlorophenyl)sulfonamide)phenyl)carbamate was suspended in 3.5 mL of DCM / TFA (3:1) and stirred at room temperature for 2 hours. After treatment, N-(4-aminophenyl)-3,4-dichlorobenzenesulfonamide (193 mg, 81%) was given as a beige solid. 1 HNMR (500MHz, DMSO-d6) δppm: 9.65 (brs, 1H), 7.81 (d, J = 8.4Hz, 1H), 7.77 (d, J = 2.0Hz, 1H) , 7.54 (dd, J=8.5, 2.1Hz, 1H), 6.66 (d, J=8.7Hz, 2H), 6.40 (d, J=8.7Hz, 2H), 5.01 (brs, 2H). MS(ESI - m / z 314.99 [MH] - .

[0293] (1-((4-((3,4-dichlorophenyl)sulfonamido)phenyl)amino)-4-methyl-1-oxopentane-2-yl)phosphonic acid di- Ethyl acetate.

[0294]

[0295] 0.52 mmol) and DIPEA (110 μl, 0.62 mmol) were added to DCM (5 mL). The crude product was purified by column chromatography (hexane / EtOAc = 3 / 7). The resulting product was a white foam (84 mg, 58%). 1 H NMR (500MHz, DMSO-d6) δppm: 10.27 (brs, 1H), 10.11 (s, 1H), 7.88 (d, J=2.1Hz, 1 H), 7.83 (d, J=8.4Hz, 1H), 7.61 (dd, J=8.4, 2.1Hz, 1H), 7.49-7.44 (m, 2H), 7.05- 7.00 (m, 2H), 4.06-3.95 (m, 4H), 3.15 (ddd, J=22.6, 11.3, 3.1Hz, 1H), 1.98-1.8 8 (m, 1H), 1.49-1.29 (m, 2H), 1.18 (dt, J=9.1, 7.1Hz, 6H), 0.85 (d, J=6.6Hz, 6H). MS(ESI + )m / z 551.12[M+H] + .

[0296] (1-((4-((3,4-dichlorophenyl)sulfonamido)phenyl)amino)-4-methyl-1-oxopentane-2-yl)phosphonic acid (108)。

[0297]

[0298] The mixture was stirred overnight. Then, MeOH (4 mL) was added, and the reaction mixture was stirred for another 30 minutes. The solvent was evaporated under reduced pressure. The crude product was purified using preparative HPLC (CH3CN(HCOOH 0.05%)-H2O(HCOOH 0.05%:1.0:9.0 to 10.0:0.0)). The product was a white solid (48 mg, 70%). 1H NMR (500MHz, DMSO-d6) δppm: 10.22 (s, 1H), 9.92 (s, 1H), 7.89 (d, J = 2.1Hz, 1H), 7.82 (d, J = 8.4Hz, 1H), 7.60 (dd, J = 8.4, 2.1Hz, 1H), 7. 51-7.46 (m, 2H), 7.01-6.97 (m, 2H), 2.93 (ddd, J=22.5, 11.3, 2.8Hz, 1H), 1.97-1.88 (m, 1H), 1.49-1.34 (m, 2H), 0.83 (d, J=6.4Hz, 6H). 13 C NMR (126MHz, DMSO-d6) δppm: 167.8 (d, J=5.5Hz), 139.66, 136.86, 135.99, 132.15, 131.73, 131.51, 128 .40, 126.85, 122.33, 119.82, 46.0 (d, J=126.8Hz), 35.7 (d, J=3.7Hz), 26.4 (d, J=14.7Hz), 23.2, 21.3. 31 P NMR (202MHz, DMSO-d6) δppm: 19.8. HRMS(ESI - C 18 H 20 Cl2N2O6PS[MH] - Calculated value: 493.0162; Actual value: 493.0156.

[0299] Example 147

[0300] Option 13: Synthesis of biphenyl derivatives with methylene joints.

[0301]

[0302] a) Et3N (3 equivalents), DCM, room temperature, 16h; b) TFA (5 equivalents), DCM, room temperature, 19h; c) EDC·HCl (1.2 equivalents), HOBt (1.2 equivalents), DIPEA (2.4 equivalents), DMF, room temperature, 18h; d) TMSBr (7 equivalents), DCM, room temperature, 23h.

[0303] (S)-(1-(4-chlorobenzyl)piperidin-3-yl)tert-butyl carbamate.

[0304]

[0305] (205.5 mg, 1 mmol, 1 equivalent) was dissolved in dry DCM (2.5 mL, 0.4 M), and then Et3N (303.6 mg, 418.1 μl, 3 mmol, 3 equivalents) was added under a nitrogen atmosphere. The reaction mixture was stirred at room temperature. After the reaction was complete (LCMS, 16 h), water (5 mL) was added, and the reaction mixture was extracted with DCM (3 × 10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and the volatiles were removed under reduced pressure to obtain the title compound (322 mg) as a white solid, which was used in the next step without further purification.

[0306] (S)-1-(4-chlorobenzyl)piperidine-3-amine.

[0307]

[0308] DCM (3 mL, 0.4 M). TFA (383 μl, 5 equivalents) was added to the resulting solution, and the reaction mixture was stirred at room temperature. After the reaction was complete (LCMS, 19 h), the solvent was removed under reduced pressure to obtain an oily residue, which was treated with 2 M NaOH solution and extracted with EtOAc (3 × 20 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and the volatiles were removed under reduced pressure to obtain the title compound in oil form (207 mg), which was used in the next step without further purification.

[0309] (1-(S)-1-(4-chlorobenzyl)piperidin-3-yl)amino)-4-methyl-1-oxopentane-2-yl)phosphonate diethyl ester.

[0310]

[0311] HOBt·H₂O (68.2 mg, 0.44 mmol, 2 equivalents) was dissolved in DMF (1.5 mL). EDC·HCl (85.3 mg, 0.44 mmol, 2 equivalents) and DIPEA (93 μl, 0.53 mmol, 2.4 equivalents) were added to the resulting solution, and the reaction was stirred at room temperature. After complete conversion (LCMS, 18 h), water (5 mL) and EtOAc (5 mL) were added to the reaction mixture. The organic phase was removed, and the aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic phases were passed through a pad of anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (55 mg), which was used in the next step without further purification.

[0312] (1-((S)-1-(4-chlorobenzyl)piperidin-3-yl)amino)-4-methyl-1-oxopentane-2-yl)phosphonic acid (147).

[0313]

[0314] Dry DCM (1 mL). Add bromotrimethylsilane (107 μl, 0.81 mmol, 7 equivalents) dropwise to the resulting solution, and stir the reaction at room temperature. After the reaction is complete (LCMS, 23 h), add MeOH (2 mL) and stir at room temperature for 30 min. Remove volatiles under reduced pressure, and purify the crude product by preparative HPLC to give the title compound (21 mg, 0.052 mmol, 45%) as a white amorphous solid.

[0315] Mixtures of diastereomers:

[0316] Major diastereomers: 1 H NMR (500MHz, DMSO-d6) δppm: 10.05 (s, 1H), 7.72-7.24 (m, 4H), 4.43-4.18 (m, 2H), 4.08-3.92 (m, 1H), 3.44-3.04 ( m, 2H), 3.00-2.30 (m, 3H), 1.98-1.80 (m, 2H), 1.80-1.62 (m, 2H), 1.54-1.27 (m, 3H), 0.81 (dd, J=6.4, 5.8Hz, 6H). 13 C NMR (126MHz, DMSO-d6) δ169.4, 158.6 (dd, J=31.2, 30.6Hz), 134.8, 133.8, 133.7, 129. 3, 58.7, 54.3, 51.0, 45.9 (d, J=124.0Hz), 43.9, 36.0, 26.9 (t, J=14.5Hz), 23.6, 21.8. 31 P NMR (202MHz, DMSO-d6) δppm: 19.7.

[0317] Secondary diastereomers: 1 H NMR (500MHz, DMSO-d6) δppm: 10.05 (s, 1H), 8.39-7.77 (m, 4H), 4.47-4.18 (m, 3H), 3.44-3.04 (m, 2H), 3. 00-2.30 (m, 3H), 1.98-1.80 (m, 2H), 1.80-1.62 (m, 2H), 1.54-1.27 (m, 3H), 0.81 (dd, J=6.4, 5.8Hz, 6H). 13C NMR (126MHz, DMSO-d6) δ169.7, 158.6 (dd, J=31.2, 30.6Hz), 134.9, 133.8, 133.7, 129. 2, 58.7, 54.3, 51.5, 45.6 (d, J=125.0Hz), 43.9, 27.8 (dd, J=33.1, 15.6Hz), 23.6, 21.8. 31 P NMR (202MHz, DMSO-d6) δppm: 19.6.

[0318] HRMS(ESI+)C 18 H 29 ClN2O4P[M+1] + The calculated value is 403.1553, and the actual measured value is 403.1537.

[0319] Example 151

[0320] (3-((3,4-dichlorophenyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)tert-butyl carbamate.

[0321]

[0322] [1.1.1]pentane-1-carboxylic acid (46.6 mg, 0.205 mmol, 1.0 equivalent) was dissolved in DMF (2 mL), cooled to 0 °C, and TBTU (73.0 mg, 0.23 mmol, 1.1 equivalent) was added, followed by NMM (24 μl, 0.23 mmol, 1.1 equivalent). The reaction mixture was stirred at the specified temperature for 1 hour, and then 3,4-dichloroaniline (33 mg, 0.205 mmol) was added. After stirring for 16 hours and warming to room temperature, EtOAc was added, followed by washing with saturated NaHCO3 solution, 1 M HCl, water, and saturated NaCl aqueous solution. The organic layer was dried on Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound as a colorless solid (42 mg, 0.113 mmol, 55%), which was used for the next step without further purification. 1 HNMR (CDCl3, 500MHz) δppm: 7.77-7.76 (m, 1H), 7.38-7.37 (m, 2H), 7.12 (bs, 1H), 5.00 (bs, 1H), 2.37 (s, 6H), 1.47 (s, 9H). 13 C NMR (CDCl3, 126MHz) δppm: 167.4, 136.8, 132.9, 130.6, 121.4, 118.8, 53.8, 45.1, 28.4. MS(ESI+):m / z[M+H] + =372.

[0323] (1-((3-((3,4-dichlorophenyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)amino)-4-methyl-1- Diethyl oxopentato-2-yl)phosphonate.

[0324]

[0325] 1.08 mmol (4 M in dioxane) was used for deprotection. 2-(diethoxyphosphoryl)-4-methylvaleric acid 2d (30 mg, 0.119 mmol), NMM (31 μl, 0.298 mmol), and TBTU (43 mg, 0.131 mmol) were used in peptide conjugation to give a yellow oily title compound (36.7 mg, 0.073 mmol, 67%) for the next step, without further purification. MS (ESI+): m / z [M+H] + =506.

[0326] (1-((3-((3,4-dichlorophenyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)amino)-4-methyl-1- oxypentane-2-yl)phosphonic acid (151).

[0327]

[0328] (36 mg, 0.071 mmol) and bromotrimethylsilane (47 μl, 0.356 mmol) were purified by preparative HPLC to give a colorless solid title compound (8.6 mg, 0.019 mmol, 27%).

[0329] Mixture of diastereomers 1 H NMR (500MHz, acetone-d6) δppm: 8.05 (d, J=2.3Hz, 1H), 7.62 (dd, J=8.9Hz, J=2.3Hz, 1H), 7.44 (d, J=8.9Hz, 1H), 3.0 2-2.94 (m, 1H), 2.40 (s, 6H), 2.01-1.98 (m, 1H), 1.65-1.61 (m, 1H), 1.59-1.53 ​​(m, 1H), 0.92 (d, J=6.3Hz, 6H). 13 C10 NMR (126MHz, acetone-d6) δppm: 169.9, 167.8, 138.9, 131.6, 130.4, 125.6, 121.0, 119.3, 53.8, 45.8, 45.0, 44.8, 38.2, 35.7, 26.7, 22.6, 21.0. 31 P NMR (202 MHz, acetone-d6) δppm: 24.7, 24.6. HRMS (ESI+) C 18 H 24 Cl2N2O5P[M+H] + The calculated value is 449.0794, and the actual measured value is 449.0798.

[0330] Example 152

[0331] (S)-(1-((3,4-dichlorophenyl)amino)-3-methyl-1-oxobutane-2-yl)carbamate tert-butyl ester.

[0332]

[0333] The reaction mixture was stirred at this temperature for 30 minutes, and then aniline (324 mg, 2 mmol, 1.0 equivalent) dissolved in THF (1 M) was added. After the reaction mixture reached room temperature, it was diluted with EtOAc. The organic phase was washed with KHSO4 (1 N) solution, saturated NaHCO3 aqueous solution, and saturated NaCl aqueous solution, dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification by column chromatography (SiO2, hexane / EtOAc 9:1) yielded the corresponding (S)-(1-(3,4-dichlorophenyl)amino)-3-methyl-1-oxobutane-2-yl)carbamate tert-butyl ester (523.8 mg, 1.44 mmol, 72% yield). 1 H NMR (500MHz, CDCl3) δppm: 8.85 (brs, 1H), 7.70 (brs, 1H), 7.2-7.3 (m, 2H), 5.27 (brd, 1H, J=8.2H z), 4.06 (brt, 1H, J=7.6Hz), 2.15 (brd, 1H, J=6.1Hz), 1.47 (s, 9H), 1.03 (dd, 6H, J=2.7, 6.7Hz). 13 C NMR (126MHz, CDCl3,) δppm: 170.7, 137.2, 132.5, 130.2, 121.2, 118.6, 61.1, 30.5, 28.3, 19.3, 18.4. HRMS(ESI+)C 16 H 23 Cl2N2O3[MH] + Calculated value: 361.1080; Actual measurement: 361.1080.

[0334] (1-(((S)-1-((3,4-dichlorophenyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-4-methyl- 1-Oxygen (152) pentane-2-yl)phosphonic acid.

[0335]

[0336] (Equivalent, 44 M in dioxane). The mixture was heated to room temperature and, after complete conversion (TLC), the solvent was removed under reduced pressure, resulting in a crystalline hydrochloride residue, which was subsequently dissolved in DMF (2.8 mL, 0.1 M). 2-(diethoxyphosphoryl)-4-methylpentanoic acid 2d (77.7 mg, 0.308 mmol, 1.1 equivalent) was added to this solution, and the reaction mixture was cooled to 0 °C. Coupling was achieved via TBTU (98.9 mg, 0.308 mmol, 1.1 equivalent) and NMM (0.08 mL, 2.5 equivalent). The reaction mixture was heated to room temperature and, after complete reaction (TLC), diluted with EtOAc and washed successively with 1 N KHSO4 solution, saturated NaHCO3 solution, and saturated NaCl aqueous solution. After drying under Na₂SO₄ and removing the solvent under reduced pressure, the residue (1-(S)-1-(3,4-dichlorophenyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)phosphonate diethyl ester (136.7 mg, 0.28 mmol, quantified) was used in the next step without further purification. Trimethylbromosilane (0.26 mL, 1.93 mmol) was added dropwise over 15 minutes to a solution of diethylphosphonate dipeptide (136.7 mg, 0.28 mmol) in DCM (0.1 M). The reaction mixture was stirred overnight at room temperature. MeOH was then added and the mixture was stirred at room temperature for 30 minutes to cleave the previously formed TMS ester. The solvent was removed under reduced pressure, and the crude product was purified by mass-triggered detection using a Phenomenex Gemini C18 column (250 × 4.6 mm, 5 μm particle size) via a Waters autophagy system (APS) to obtain dipeptide 152 (51.7 mg, 0.12 mmol, 43%) as a white amorphous solid.

[0337] Mixtures of diastereomers:

[0338] Major diastereomers: 1 H NMR (500MHz, MeOH-d4,) δppm: 8.04 (d, 1H, J=2.4Hz), 7.62 (dd, 1H, J=2.4, 8.9Hz), 7.42 (d, 1H, J=8.9Hz), 4.45 (d, 1H, J=5.0Hz), 3.24 (ddd, 1H, J=2.7, 11 .6, 23.3Hz), 2.42 (qd, 1H, J=6.9, 12.1Hz), 1.47-1.61 (m, 3H), 0.9-1.1 (m, 1 9H), 0.99 (d, 3H, J=7.02Hz), 0.98 (d, 3H, J=6.87Hz), 0.95 (d, 6H, J=6.56Hz). 13C NMR (126MHz, MeOH-d4) δppm: 172.7, 172.5 (d, J=4.6Hz), 139.6, 133.2, 131.5, 128.2, 123.5, 121.6, 60.7, 47.1, 46.0, 36.3 (d, J=4.6Hz), 31.2, 28.4 (d, J=15.6Hz), 23.7, 21.8, 19.9, 17.8 31 P NMR (202MHz, MeOH-d4) δppm: 22.7.

[0339] Secondary diastereomers: 1 H NMR (500MHz, MeOH-d4) δppm: 7.92 (dd, 1H, J=0.61, 1.83Hz), 7.44-7.46 (m, 1H), 4.27 (d, 1H, J=7.48Hz), 3.24 (ddd, 1H, J=2.7, 11.9, 22.4H z), 1.95-2.20 (m, 2H), 1.28-1.35 (m, 2H), 1.05 (d, 3H, J=6.71Hz), 1.00 (d, 3H, J=6.71Hz), 0.92 (d, 3H, J=6.10Hz), 0.90 (d, 3H, J=6.26Hz). 13 C NMR (126MHz, MeOH-d4) δppm: 172.6, 172.0 (d, J=4.6Hz), 139.7, 133.5, 131.7, 128.1, 122. 8, 120.8, 61.5, 46.8, 45.8, 37.3 (d, J=4.6Hz), 32.3, 28.1 (d, J=15.6Hz), 23.8, 21.9, 19.1. 31 P NMR (202MHz, MeOH-d4) δppm: 22.4. HRMS(ESI+)C 17 H 26 Cl2N2O5P[M+H] + Calculate 439.0956 and 439.0935.

[0340] Example 170

[0341] Option 14: The synthesis of triazole derivatives, taking compound 170 as an example.

[0342]

[0343] (a) i) HCl (4M in dioxane), DCM, room temperature, 18h; ii) TBTU, NMM, DMF 0℃-room temperature, 22h, 76% (2 steps); (b) CuSO4·5H2O, sodium ascorbate, tBuOH / H2O / MeOH (2:2:1) room temperature, 14h, 84%; (c) TMSBr, DCM, room temperature, 23h, preparative high performance liquid chromatography, 26%.

[0344] (4-Methyl-1-(((S)-4-methylpent-1-yn-3-yl)amino)-1-oxopentan-2-yl)phosphonate diethyl ester.

[0345]

[0346] 2.85 mL, 11.4 mmol, 4 M in dioxane) was used to obtain the corresponding tert-butyloxycarbonyl-deprotected alkanolamine hydrochloride. The mixture was stirred for 18 hours and then concentrated under reduced pressure. Meanwhile, a mixture of compound 2d (396 mg, 1.57 mmol) and TBTU (562 mg, 1.75 mmol) in DMF (7.5 mL) was cooled to 0 °C and NMM (0.91 mL, 3.58 mmol) was added. The reaction mixture was stirred for 30 minutes, and then the pre-prepared tert-butyloxycarbonyl-deprotected alkanolamine hydrochloride was dissolved in DMF (7.5 mL) and added dropwise at 0 °C. The mixture was stirred for 22 hours and then warmed to room temperature. After the addition of EtOAc, the organic layer was subsequently washed with saturated aqueous NaHCO3 solution, 1 M HCl, water, and saturated aqueous NaCl solution. The organic layer was dried on Na2SO4 and the solvent was removed under reduced pressure. The crude product was purified by automated combinatorial flash purification (Teledyne ISCO) to obtain 359 mg of (4-methyl-1-(S)-4-methylpent-1-yn-3-yl)amino)-1-oxopentane-2-yl)phosphonate diethyl ester (1.08 mmol, 2 steps 76%). 1 H NMR (500MHz, CDCl3) δppm: 6.68-6.58 (m, 1H), 4.67-4.64 (m, 1H), 4.18-4.09 (m, 4H), 2.87-2.80 (m, 1H), 2.24-2.23 (m, 1 H), 1.99-1.93 (m, 2H), 1.70-1.61 (m, 1H), 1.56-1.52 (m, 1H), 1.34-1.30 (m, 6H), 1.02-1.00 (m, 6H), 0.95-0.90 (m, 6H). MS(ESI+):m / z[M+H] + =332.

[0347] (1-(((S)-1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)-2-methylpropyl)amino)-4-methyl 1-Oxopentane-2-yl)phosphonate.

[0348]

[0349] A solution of phosphonate (293 mg, 0.89 mmol) and 4-azido-1,2-dichlorobenzene (170 mg, 0.904 mmol) was purged with argon. Sodium ascorbate (20 mol%) and CuSO4·5H2O (10 mol%) were added, and the reaction mixture was stirred at room temperature for 14 h. Then, a saturated EDTA solution was added, and the mixture was extracted with EtOAc (x3). The combined organic layers were washed with saturated aqueous NH4Cl and saturated aqueous NaCl solutions. After drying in Na2SO4 and filtering, the solvent was evaporated to yield the title compound (394 mg, 0.759 mmol, 84%, a mixture of diastereomers), which was used for the next step without further purification. MS (ESI+): m / z [M+H] + 520.

[0350] (1-(((S)-1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)-2-methylpropyl)amino)-4-methyl 170) phosphonic acid (170).

[0351]

[0352] The prepared compound was purified by HPLC to obtain the title compound (12 mg, 0.026 mmol, 26%, a mixture of diastereomers).

[0353] Major diastereomers: 1 H NMR (500MHz, MeOH-d4) δppm: 8.44 (s, 1H), 8.10-8.09 (m, 1H), 7.83-7.80 (m, 1H), 7.75-7.73 (m, 1H), 4.99-4.97 (m, 1H) ), 3.03-2.96 (m, 1H), 2.35-2.30 (m, 1H), 2.13-2.06 (m, 1H), 1.49-1.43 (m, 2H), 1.06-0.98 (m, 6H), 0.87-0.84 (m, 6H). 31 P NMR (202 MHz, MeOH-d4) δppm: 22.3. Minor diastereomers: 1 H NMR (500MHz, MeOH-d4) δppm: 8.58 (s, 1H), 8.10-8.09 (m, 1H), 7.83-7.80 (m, 1H), 7.73-7.70 (m, 1H), 5.08-5 .07 (m, 1H), 3.17-3.12 (m, 1H), 2.42-2.35 (m, 1H), 2.02-1.98 (m, 1H), 1.61-1.51 (m, 2H), 0.98-0.95 (m, 6H). 31P NMR (202MHz, MeOH-d4,) δppm: 22.3. HRMS(ESI+)C 18 H 26 Cl2N4O4P[M+H] + Calculated value: 463.1063; Actual value: 463.1065.

[0354] Example 171

[0355] Option 15: The synthesis of imidazole derivatives, taking compound 171 as an example.

[0356]

[0357] (a) i) Hydrochloric acid (4M in dioxane), DCM, room temperature, 18 hours; ii) TBTU, NMM, DMF 0℃–room temperature, 22 hours; (b) TMSBr, DCM, room temperature, overnight, preparative HPLC. 26%.

[0358] (1-(((S)-1-(5-(3,4-dichlorophenyl)-1H-imidazol-2-yl)-2-methylpropyl)amino)-4-methyl-1- Diethyl oxopentato-2-yl)phosphonate.

[0359]

[0360] (S)-(1-(5-(3,4-dichlorophenyl)-1H-imidazol-2-yl)-2-methylpropyl)carbamate tert-butyl ester. (S)-(1-(5-(3,4-dichlorophenyl)-1H-imidazol-2-yl)-2-methylpropyl)carbamate tert-butyl ester (77 mg, 0.200 mmol) was dissolved in DCM (2 mL) and HCl (0.25 mL, 1.00 mmol, 4 M in dioxane). After complete consumption of the starting material (LCMS), the solvent was evaporated to give (S)-1-(5-(3,4-dichlorophenyl)-1H-imidazol-2-yl)-2-methylpropyl-1-amine hydrochloride, which was used in the coupling step without further purification. The title compound was synthesized using Universal Procedure I with the above-mentioned (S)-1-(5-(3,4-dichlorophenyl)-1H-imidazol-2-yl)-2-methylpropyl-1-amine hydrochloride, compound 2d (51 mg, 0.200 mmol), TBTU (70.6 mg, 0.220 mmol), and NMM (53 μl, 0.500 mmol) in DMF (2 mL). The title compound (22 mg, 0.042 mmol, 21%) was obtained as a mixture of diastereomers using automated combinatorial flash purification (Teledyne ISCO). MS (ESI+): m / z [M+H] + 519.

[0361] Mixtures of diastereomers:

[0362] Major diastereomers:1 H NMR (500MHz, CDCl3) δppm: 7.88 (bs, 1H), 7.54 (dd, J=8.2Hz, J=1.8Hz, 1H), 7.39 (d, J=8.4H z, 1H), 7.25 (bs, 1H), 5.26-5.23 (m, 1H), 4.20-4.09 (m, 4H), 3.00-2.93 (m, 1H), 2.76-2.68 ( m, 1H), 2.18-2.11 (1H), 1.70-1.61 (m, 1H), 1.52-1.44 (m, 1H), 1.34 (dd, J=6.10Hz, 3H), 1. 30 (dd, J=7.1Hz, 3H), 1.02 (d, J=6.8Hz, 3H), 0.94 (dd, J=7.1Hz, 6H), 0.90 (d, J=6.7Hz, 3H). 31 P NMR (202MHz, CDCl3) δppm: 26.3.

[0363] Secondary diastereomers (selected signal): 1 H NMR (500MHz, CDCl3) δppm: 7.93 (dJ=1.8Hz, 1H), 7.64 (dd, J=8.4Hz, J=1.8Hz, 1H) , 7.41 (d, J=8.4Hz, 1H), 4.08-4.04 (m, 4H), 3.09-3.03 (m, 1H), 2.58-2.51 (m, 1H). 31 P NMR (202MHz, CDCl3) δppm: 26.5.

[0364] (1-(((S)-1-(5-(3,4-dichlorophenyl)-1H-imidazol-2-yl)-2-methylpropyl)amino)-4-methyl-1- Oxypentan-2-yl)phosphonic acid (171)

[0365]

[0366] (28 μl, 0.212 mmol). The title compound was purified by preparative HPLC as a colorless solid (5.2 mg, 0.011 mmol, 26%, a mixture of diastereomers).

[0367] Mixtures of diastereomers:

[0368] Major diastereomers: 1H NMR (500MHz, MeOH-d4) δppm: 8.09 (d, J=1.8Hz, 1H), 7.88 (s, 1H), 7.79 (dd, J=8.4Hz, J=1.7Hz, 1H), 7.62 (d, J=8.64Hz, 1H), 5.21 (d, J=5.0Hz,), 3 .33-3.25(m, 1H), 2.52-2.46(m, 1H), 2.10-2.04(m, 1H), 1.62-1.53(m, 2 H), 1.09 (d, J=6.9Hz, 3H), 1.01 (d, J=6.9Hz, 3H), 0.95 (dd, J=5.7Hz, 6H). 13 C NMR (126MHz, MeOH-d4) δppm: 174.3, 151.1, 134.5, 132.9, 132.5, 131.1, 128.9, 126.8, 117.6, 61.7, 54.1, 47.636.0, 32.3, 28.8, 23.5, 22.1, 19.4, 17.5, 14.6. 31 P NMR (202MHz, MeOH-d4) δppm: 19.7.

[0369] Secondary diastereomers (selected signal): 1 H NMR (500MHz, MeOH-d4) δppm: 8.04 (d, J=2.1Hz, 1H), 7.97 (d, J=1.8Hz, 1H), 7.89 (bs, 1H), 7.63 (d, J=7.6Hz, 1H), 3.18-3 .16 (m, 1H), 2.42-2.38 (m, 1H), 1.54-1.53 ​​(m, 2H), 1.13 (d, J=6.7Hz, 3H), 0.92 (d, J=6.4Hz, 3H), 0.90 (d, J=6.4hz, 3H). 13 C NMR (126MHz, MeOH-d4) δppm: 134.6, 132.7, 128.8, 126.9, 54.9, 32.7, 23.6, 22.0, 19.7.

[0370] Example 172

[0371] Option 16: The synthesis of benzimidazole derivatives, taking compound 172 as an example.

[0372]

[0373] (a) TBTU, NMM, DMF, 0℃–room temperature, 2d, quantitative; (b) HOAc / toluene (1:1), 110℃, 3h; (c) i) HCl (4M in 1,4-dioxane), DCM, room temperature, 18h; ii) TBTU, NMM, DMF, 0℃–room temperature, 21h, 97% (3 steps); d) TMSBr, DCM, room temperature, 21h, preparative HPLC, 1.2%.

[0374] (S)-(1-((2-amino-5-phenoxyphenyl)amino)-3-methyl-1-oxobutane-2-yl)carbamate tert- Butyl ester.

[0375]

[0376] 2.75 mmol). The reaction mixture was stirred at this temperature for 30 minutes, and 4-phenoxyphenyl-1,2-diamine (500 mg, 2.5 mmol) was added. The mixture was then heated to room temperature overnight, the reaction was quenched with a saturated aqueous solution of NaHCO3, and extracted with EtOAc (x3). The combined organic layers were then washed with 1 M HCl, water, and a saturated aqueous solution of NaCl, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was given as a brown foam (1.00 g, 2.50 mmol, quantitative) and used in the next step without further purification. 1 H NMR (500MHz, CDCl3) δppm: 7.62 (bs, 1H), 7.34-7.31 (m, 2H), 7.11-7.08 (m, 2H), 7.02-7.00 (m, 2H), 6.42-6.39 (m, 2H) , 5.11 (bs, 1H), 3.99-3.97 (m, 1H), 2.31-2.23 (m, 1H), 1.46 (s, 9H), 1.07 (dd, J=6.71Hz, 3H), 1.04 (dd, J=6.71Hz, 3H). MS(ESI+):m / z[M+H] + 400.

[0377] (S)-(2-methyl-1-(5-phenoxy-1H-benzo[d]imidazol-2-yl)propyl)tert-butyl carbamate.

[0378]

[0379] The solution was heated in HOAc (1:1) under reflux (preheated oil bath) for 3 hours. After cooling to room temperature, an aqueous solution of NaHCO3 was carefully added until pH = 9. The solution was then stirred for 20 minutes, extracted with EtOAc (x3), and washed with saturated aqueous solution of NaHCO3 (x4), water (x2), and saturated aqueous solution of NaCl. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as an orange solid (191 mg, 0.500 mmol, quantified), which was used for the next step without further purification. MS (ESI+): m / z [M+H] + 382.

[0380] (4-Methyl-1-(((S)-2-methyl-1-(5-phenoxy-1H-benzo[d]imidazol-2-yl)propyl)amino)-1- Diethyl oxopentato-2-yl)phosphonate.

[0381]

[0382] 18 hours. Then concentrated under reduced pressure. Meanwhile, a mixture of 2-(diethoxyphosphoryl)-4-methylpentanoic acid 2d (116 mg, 0.459 mmol) and TBTU (181 mg, 0.505 mmol) in DMF (2.5 mL) was cooled to 0 °C and NMM (121 μl, 1.15 mmol) was added. The reaction mixture was stirred for 30 minutes, and then a tert-butoxycarbonyl-deprotected benzimidazole amino acid derivative dissolved in DMF (2.5 mL) was added dropwise at 0 °C. After stirring for 21 hours, EtOAc and 1 M HCl were added, and the aqueous layer was extracted with EtOAc (x2). The combined organic layers were washed with water and a saturated aqueous NaCl solution. After drying in Na2SO4 and filtering, the solvent was removed under reduced pressure to give the title compound as a brown resin (208 mg, 0.405 mmol, 97%). The title compound was used for the next step without any further purification. MS (ESI+): m / z [M+H] + 516.

[0383] (4-Methyl-1-(((S)-2-methyl-1-(5-phenoxy-1H-benzo[d]imidazol-2-yl)propyl)amino)-1- oxypentane-2-yl)phosphonic acid (172).

[0384]

[0385] (1.74mg, 0.004mmol, 1.2%).

[0386] Mixture of diastereomers

[0387] Major diastereomers: 1H NMR (500MHz, DMSO-d6,) δppm: 8.14-8.12(m, 1H), 7.53-7.51(m, 1H), 7.37-7.33(m, 2H), 7.13-7.05(m, 2H), 6.97-6.95(m, 2H), 4.94-4.91(m ,1H),3.28-3.22(m,1H),2.32-2.26(m,1H),1.87-1.81(m,1H)1.50-1 .37(m, 2H), 0.98-0.96(m, 3H), 0.93-0.92(m, 3H), 0.87-0.86(m, 6H). 13 C NMR (126MHz, DMSO-d6) δppm: 169.8, 158.6, 156.2, 151.9, 130.5, 123.1, 118.1, 60.2, 53.7, 36.5, 32.4, 27.3 (d, J=14.7Hz), 23.5, 22.0, 19.8, 18.8. 31 P NMR (202MHz, DMSO-d6) δppm: 20.7. Minor diastereomers (selected signal): 1 H NMR (500MHz, DMSO-d6) δppm: 8.45-8.43 (m, 1H), 7.49-7.48 (m, 1H), 6.92-6.89 (m, 2H), 5.13-5.11 (m, 1H), 1.96-1.92 (m, 1H), 0.78-0.76 (m, 6H). 13 C NMR (126MHz, DMSO-d6) δppm: 170.71, 158.5, 157.4, 152.1, 123.4, 118.2, 115.1, 53.2, 34.9, 30.6, 26.8 (d, J=14.7Hz), 23.4, 21.9, 19.7, 17.4. 31 P NMR (202MHz, DMSO-d6) δppm: 20.9.

[0388] HRMS(ESI+)[M+H] + Calculated value: 460.1996, Actual measurement: 460.1982.

[0389] Example 173

[0390] Ethyl 4-methyl-2-(p-tolylcarbamoyl)valerate.

[0391]

[0392] EDC·HCl (515 mg, 2.68 mmol) was added to a solution of p-toluidine (240 mg, 2.23 mmol) in DCM (20 mL). The resulting mixture was stirred overnight at room temperature. Following treatment, the crude product was purified by column chromatography (Hex / EtOAc = 8 / 2). The product obtained was orange crystals (441 mg, 71%). 1 H NMR (500MHz, CDCl3) δppm: 8.45 (brs, 1H), 7.42 (d, J=8.1Hz, 2H), 7.13 (d, J=8.1Hz, 2H), 4.31-4.17 (m, 2H), 3.43 (t, J=7.7Hz, 1H), 2.32 (s, 3H), 1.94-1.80 (m, 2H), 1.69-1.61 (m, 1H), 1.35-1.28 (m, 3H), 0.96 (d, J=6.6Hz, 6H). 13 C NMR (126MHz, CDCl3) δppm: 173.2, 166.4, 135.0, 134.0, 129.4, 119.8, 61.7, 52.4, 40.8, 26.4, 22.5, 22.0, 20.9, 14.1. MS(ESI+):m / z[M+H] + =278.

[0393] N 1 -hydroxy-2-isobutyl-N 3 -(p-Tolyl)malonamide (173).

[0394]

[0395] The mixture was stirred overnight. The solvent was concentrated under vacuum, and the resulting oil was purified by preparative HPLC (CH3CN(HCOOH 0.05%)-H2O(HCOOH 0.05%): 1.0:9.0 to 10.0:0.0). The product was a white solid (49 mg, 52%). 1 H NMR (500MHz, DMSO-d6) δppm: 10.54 (s, 1H), 9.66 (s, 1H), 9.00 (s, 1H), 7.45 (d, J=8.4Hz, 2H), 7.10 (d, J=8.4Hz, 2H), 3.18 (t, J=7. 6Hz, 1H), 2.24 (s, 3H), 1.67 (t, J=7.2Hz, 2H), 1.47 (dquin, J=13.4, 6.7Hz, 1H), 0.87 (brd, J=6.6Hz, 3H), 0.87 (brd, J=6.6Hz, 3H). 13C NMR (126MHz, DMSO-d6) δppm: 167.6, 166.5, 136.3, 132.4, 129.2, 119.4, 49.9, 38.1, 25.8, 22.5, 22.3, 20.5. HRMS(ESI+)C 14 H 21 N₂O₃[M+H] + Calculated value: 265.1547; Actual value: 265.1545.

[0396] Examples 174 and 177

[0397] 4-Methyl-N-(p-tolyl)-2-(1H-1,2,3-triazol-1-yl)pentanamide (174) and 4-methyl-N-(p-tolyl) phenyl)-2-(2H-1,2,3-triazol-2-yl)pentanamide (177).

[0398] According to General Procedure O, 4-methyl-N-(p-tolyl)pentanamide (70 mg, 0.25 mmol) (synthesized according to General Procedure B-1), acetone (7 mL), 1H-1,2,3-triazole (18.7 mg, 0.27 mmol), and K2CO3 (37.4 mg, 0.27 mmol) were synthesized using 2-bromo-4-methyl-N-(p-tolyl)-2-(1H-1,2,3-triazol-1-yl)pentanamide (174) and 4-methyl-N-(p-tolyl)-2-(2H-1,2,3-triazol-2-yl)pentanamide (177). The crude product was purified by preparative HPLC (CH3CN(HCOOH 0.05%)-H2O(HCOOH 0.05%): 1.0: 9.0 to 10.0: 0.0) to obtain products 174 (20.3 mg, 30%) and 177 (30 mg, 45%), which were white solids.

[0399] 4-Methyl-N-(p-tolyl)-2-(1H-1,2,3-triazol-1-yl)pentanamide (174).

[0400]

[0401] 3H), 2.16-2.06 (m, 1H), 2.01-1.93 (m, 1H), 1.31-1.20 (m, 1H), 0.93 (d, J=6.8Hz, 3H), 0.90 (d, J=6.6Hz, 3H). 13 C NMR (126MHz, DMSO-d6) δppm: 166.6, 135.7, 133.3, 133.1, 129.3, 123.9, 119.5, 61.6, 40.4, 24.5, 22.4, 21.5, 20.5. HRMS(ESI + C 15 H 21 N4O[M+H] + Calculated value: 273.1710; Actual measurement: 273.1708.

[0402] 4-Methyl-N-(p-tolyl)-2-(2H-1,2,3-triazol-2-yl)pentanamide (177).

[0403]

[0404] J=13.8, 7.8, 6.2Hz, 1H), 1.47-1.36 (m, 1H), 0.91 (t, J=6.2Hz, 6H). 13 C NMR (126MHz, DMSO-d6) δppm: 166.2, 135.9, 134.5, 132.9, 129.2, 119.4, 65.8, 24.5, 22.5, 21.7, 20.5. HRMS(ESI + C 15 H 21 N4O[M+H] + Calculated value: 273.1710; Actual measurement: 273.1708.

[0405] III. Biological Evaluation

[0406] Anti-LasB activity:

[0407] The activity of the compounds of this invention is based on Kany, AM; Sikandar, A.; Haupenthal, J.; Yahiaoui, S.; Maurer, CK; Proschak, E.; The method described in J. Hartmann, RWACS Infect.Dis. 2018, 4, 988–997, is used for determination.

[0408] α-Benzylated derivatives:

[0409] Table 2: Activity of α-benzylthioacetamide on LasB.

[0410]

[0411] Enantiomer activity:

[0412] To clarify whether the configuration of the stereocenter affects activity, the enantiomers (E1 and E2, labeled according to their elution order from the chiral column) of the compounds in Examples 1 and 4 were separated using a chiral column equipped with preparative HPLC and detected independently. Although both enantiomers were active, a difference in activity was observed between the two configurations (Table 3). For both compounds, the E2 enantiomer showed higher activity.

[0413] Table 3. Activities of racemic mixtures and pure enantiomers in Examples 1 and 4.

[0414]

[0415] To ensure that racemization did not occur during the assay, the conformational stability in methanol and aqueous buffer (50 mM Tris, pH 7.2, 2.5 mM CaCl2) was tested. The CD spectrum remained unchanged for one hour, indicating that racemization did not occur during this period.

[0416] Selectivity:

[0417] Inhibition of zinc-containing human enzymes is often described as LasB inhibitors and has caused significant difficulties in the development of selective compounds. In particular, inhibition of matrix metalloproteinases (MMPs) should be avoided. To further investigate this issue, the selectivity of three derivatives (compounds of Examples 1, 5, and 8) for several human off-targets has been tested, including six MMPs, ADAM17 (TACE), HDAC-3, and HDAC-8 (Table 4). The compounds showed particularly high selectivity for MMPs and HDAC, while the inhibition of ADAM17 was much stronger.

[0418] Table 4. Off-target selectivity of Examples 1, 5 and 8 (ni = <10% inhibition).

[0419]

[0420] Cytotoxicity:

[0421] The compounds in Examples 1 and 5 were non-toxic to cell lines HepG2, HEK293, and A549 (Table 5). Additionally, the inhibitory activity against *Pseudomonas aeruginosa* PA14 was evaluated to rule out the antibacterial activity of the compounds of this invention. This is important because the target is bacterial virulence, not bacterial viability. The results showed that both compounds exhibited good inhibitory activity against PA14 and good cytotoxicity (IC50) in the cell lines. 50 The values ​​are all greater than 100 μM, so there is no problem.

[0422] Table 5. Cytotoxicity data and PA14 inhibition of Examples 1 and 5.

[0423]

[0424] α-alkylated derivatives:

[0425] In C α Compounds with alkyl substituents at the - position are highly favored for activity, and their IC50 is significantly higher. 50Values ​​(Tables 6 and 7) can reach submicromolar values. Among them, the compound with a 4-Me substituent and an isobutyl chain in the aromatic core in Example 2 proved to be one of the most promising compounds, and therefore its selectivity and cytotoxicity were further investigated (Table 8).

[0426] Table 6. α-alkylated derivatives and their corresponding activities with LasB.

[0427]

[0428]

[0429] 1 Compounds disclosed by Kany et al.

[0430] Table 7. Compounds with isobutyl groups at the α-position and their corresponding activities to LasB.

[0431]

[0432]

[0433] Table 8. Selectivity and cytotoxicity data of the compounds in Example 2. ni = inhibition <10%.

[0434]

[0435] Because the compounds of Example 2 had already demonstrated impressive activity and high selectivity for a broad spectrum of human enzymes in in vitro LasB inhibition assays, and showed no signs of cytotoxicity in vitro, they underwent further safety screening (Table 9). Regarding the IC50 for inhibition of hERG potassium channels... 50 Values ​​were determined to be >10 μM. Furthermore, determining the effect of the compounds of Example 2 on the five human CYP450 subtypes was particularly important, indicating weak or no inhibitory activity. Additionally, the compounds of Example 2 were analyzed using a mini-Ames inverse mutagenesis assay, and no genotoxicity was observed at a concentration of 125 μg / mL.

[0436] Table 9. Overview of the advanced safety profile of the compounds in Example 2: hERG / CYP inhibition and mini-Ames assay.

[0437] hERG CYP1A CYP2C9 CYP3A4 CYP2C19 CYP2D6 Miniature Ames <![CDATA[IC 50 [μM]]]> >10 >25 >25 15 1.0 22.3 No genotoxicity

[0438] In addition, the compounds of Example 2 were subjected to pharmacokinetic (PK) studies in mice (Table 10). Intravenous injection (IV) was administered at a dose of 10 mg / kg, detectable in the blood over 2 hours. Preliminary results indicated high clearance and low total exposure, but the volume of distribution could explain good tissue penetration.

[0439] Table 10. PK parameters of Example 2.

[0440] <![CDATA[C max [ng / mL]]> 200 <![CDATA[T max [min]]]> 15* <![CDATA[T 1 / 2 [min]]]> 50 CL / F [mL / min / kg] 505±119 <![CDATA[AUC 0-t [ng / mL*h]]> 241±22 V / F [L / kg] 45.5±2.8

[0441] *First measurement point

[0442] α-Carboxymethyl derivatives:

[0443] The compounds in Example 54 (Table 1) exhibit the following activities against LasB: IC 50 =3.9±0.4μM.

[0444] Heterocyclic derivatives:

[0445] Table 11. Heterocyclic derivatives and their corresponding anti-LasB activities.

[0446]

[0447]

[0448] Phosphonic acid derivatives:

[0449] Table 12. Phosphonic acid derivatives and their corresponding anti-LasB activities. Examples 63 to 89 were prepared according to the above procedure.

[0450]

[0451]

[0452]

[0453]

[0454] Table 13. Other phosphonic acid derivatives and their corresponding anti-LasB activities. Preparations were carried out according to the above procedures in Examples 90 to 151.

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464] Table 14: α-phosphonate dipeptides and their corresponding anti-LasB activities. Examples 152 to 169 were prepared according to the above procedure.

[0465]

[0466]

[0467]

[0468] All phosphonates exhibited excellent selectivity and cytotoxicity characteristics, and showed no inhibitory effect on the growth of PA14 bacteria (Tables 15, 17 and 18).

[0469] Table 15. Selectivity, cytotoxicity, and PA14 inhibition of compounds in Examples 63, 92, 108, and 152.

[0470] ni = Suppression <10%; nd = Undetermined

[0471]

[0472] Table 16: Examples of triazole, imidazole and benzimidazole as heteropentanes and benzo[a]heteropentanes.

[0473] Compounds 170 and 172 were prepared according to the above procedure.

[0474]

[0475] Table 17. Off-target selectivity of Examples 170 and 172.

[0476] (ni = <10% inhibition; nd = undetermined).

[0477]

[0478] Table 18. Cytotoxicity data and PA14 inhibition in Examples 170 and 172

[0479]

[0480] Because the compounds of Examples 63 and 170 exhibited impressive activity in in vitro LasB assays, high selectivity for a broad spectrum of human enzymes, and no signs of cytotoxicity in vitro, they underwent a more advanced safety screening (SafetyScreen44 plates, performed by EurofinsCEREP). This screening included 44 different targets, including GPCRs, transport proteins, ion channels, nuclear receptors, kinases, and other non-kinase enzymes. The compounds of Examples 63 and 170 showed no inhibition of control-specific binding to any of the tested targets (<22% inhibition at compound concentrations of 1.0E–0.5M).

[0481] Hydroxamic acid derivatives:

[0482] Table 19. Hydroxamic acid derivatives and their corresponding anti-LasB activities.

[0483] Example 173 was prepared according to the above procedure.

[0484]

[0485] Table 20. Selectivity, cytotoxicity, and PA14 inhibition of the compounds in Example 173.

[0486]

[0487] Triazole derivatives:

[0488] Table 21. Triazole derivatives and their corresponding anti-LasB activities.

[0489] Examples 174 to 178 were prepared according to the above procedure.

[0490]

[0491] *n=1

[0492] Table 22. Selectivity, cytotoxicity, and PA14 inhibition of the compounds in Examples 174 and 177.

[0493] ni = Suppression <10%; nd = Undetermined

[0494]

Claims

1. A compound of formula (III) or a pharmaceutically acceptable salt thereof: Where R 1 It is an optionally substituted phenyl, optionally substituted naphthyl, or optionally substituted heteroaryl group, containing one or two rings and 5 to 10 ring atoms selected from C, O, N, and S; or of the formula -CH(R 6 )-C(=O)-NH-R 7 The group, or formula -C(Me)2-CH2-C(=O)-NH-R 7 The group, or the formula -CH(R) 6 )-CH2-C(=O)-NH-R 7 The group, or the formula -CH(R) 6 )-R 8 The group; or the formula -Cy 1 -L-Cy 2 The group, of which Cy 1 It is an optionally substituted cycloalkylene containing one or two rings and three to seven carbon ring atoms, an optionally substituted heteroalkylene containing one or two rings and three to seven ring atoms selected from C, N, O and S, an optionally substituted phenylene, or an optionally substituted heteroarylene containing five or six ring atoms selected from C, N, O and S. Cy 2 It is an optionally substituted phenyl, an optionally substituted biphenyl, an optionally substituted naphthyl, an optionally substituted heteroaryl containing one or two rings and 5, 6, 9 or 10 ring atoms selected from C, O, N and S, an optionally substituted cycloalkyl containing 3 to 7 ring atoms, an optionally substituted heterocycloalkyl containing 3 to 7 ring atoms selected from C, N, O and S, an optionally substituted heterocycloalkylaryl containing 9 or 10 ring atoms selected from C, N, S and O, or of the formula -CH(CH2Ph)Ph; and L is a bond or -O-, -S-, -NH-, -CH2-, -CO-, -NHCO-, -CO-NH-, -CH2-CO-NH-, -NH-CO-CH2-, -CH2-O-CO-NH-, -NH-CO-O-CH2-, -O-CO-NH -, -NH-CO-O-, -NHSO2-, -SO2NH-, -CH2-SO2-NH-, -NH-SO2-CH2-, -S-CH2-, -CH2-S-, -NH-CH2-, -CH2-NH-, -O-CH2-, or -CH2-O-; R 2 It is a group of the formula -CH2CH(CH3)2; R 6 Is it hydrogen or C? 1-6 Alkyl, C 3-7 Cycloalkyl, heterocycloalkyl containing 3-7 ring atoms selected from C, N, O and S, phenyl or heteroaryl containing 5 or 6 ring atoms selected from C, N, S and O, or of the formula -CH2-R 6a The group, wherein R 6a It is C 3-7 Cycloalkyl, heterocycloalkyl containing 3 to 7 ring atoms selected from C, N, O and S, phenyl or heteroaryl containing 5 or 6 ring atoms selected from C, N, S and O; R 7 It is an optionally substituted phenyl or an optionally substituted C 3-7 cycloalkyl; and R 8 It is an optionally substituted benzimidazole group, an optionally substituted triazole group, or an optionally substituted imidazole group; in, The optional substituents are selected from halogen atoms and the formulas -OH, -OC. 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups: -2, -COOH, -COOMe, -COMe, -COCF3, -NHSO2Me, -SO2NMe2, -SO3H, -SO2NH2, -CONH2, -CH2NH2, -CN, -C 1-6 Alkyl, -Me, -Et, -nPr, -iPr, -nBu, -iBu, -tBu, -CF3, -SH, -S-CO-C 1-6 Alkyl, -SC 1-6 Alkyl, -NHAc, -NO2, -C≡CH, -NHCONH2, -SO2Me, -SO2CF3, phenyl, -C 3-6 Cycloalkyl groups and heterocyclic alkyl groups containing 3-6 cyclic atoms selected from C, N, S and O.

2. The compound according to claim 1, characterized in that, R 1 It is an optionally substituted phenyl, optionally substituted naphthyl, or optionally substituted heteroaryl group, which contains one or two rings and 5 to 10 ring atoms selected from C, O, N, and S.

3. The compound according to claim 1, characterized in that, R 1 It is an optional substituted phenyl group.

4. The compound according to claim 1, characterized in that, R 1 Cy is a formula 1 -L-Cy 2 The group, of which Cy 1 It is an optionally substituted cycloalkylene group containing one or two rings and three to seven carbon ring atoms; an optionally substituted heteroalkylene group containing one or two rings and three to seven ring atoms selected from C, N, O, and S; an optionally substituted phenylene group; or an optionally substituted heteroaryl group containing five or six ring atoms selected from C, N, O, and S; Cy 2 It is an optionally substituted phenyl, optionally substituted biphenyl, optionally substituted naphthyl, optionally substituted heteroaryl containing one or two rings and 5, 6, 9 or 10 ring atoms selected from C, O, N and S, optionally substituted cycloalkyl containing 3 to 7 ring atoms, optionally substituted heterocycloalkyl containing 3 to 7 ring atoms selected from C, N, O and S, optionally substituted heterocycloalkylaryl containing 9 or 10 ring atoms selected from C, N, S and O, or of the formula -CH(CH2Ph)Ph; L is a bond or -O-, -S-, -NH-, -CH2 -, -CO-, -NHCO-, -CO-NH-, -CH2-CO-NH-, -NH-CO-CH2-, -CH2-O-CO-NH-, -NH-CO-O-CH2-, -O-CO-NH-, -NH-CO-O- , -NHSO2-, -SO2NH-, -CH2-SO2-NH-, -NH-SO2-CH2-, -S-CH2-, -CH2-S-, -NH-CH2-, -CH2-NH-, -O-CH2- or -CH2-O-.

5. The compound according to claim 1, characterized in that, L is a bond or -NHCO-, -CO-NH-, -CH2-CO-NH-, -NH-CO-CH2-, -NHSO2-, or -SO2NH-.

6. The compound according to claim 1, characterized in that, Cy 1 It is 1,4-phenylene.

7. The compound according to claim 1, characterized in that, R 1 It is the formula -CH(R) 6 )-C(=O)-NH-R 7 The group or formula -CH(R) 6 )-R 8 . group.

8. The compound according to claim 1, characterized in that, R 6 It is a group with the formula -CH(CH3)2.

9. A pharmaceutical composition comprising a compound as described in any one of claims 1-8 and optionally one or more carrier substances and / or one or more adjuvants and / or one or more other antimicrobial compounds.

10. Use of the compound of any one of claims 1-8 or the pharmaceutical composition of claim 9 in the preparation of a medicament for treating bacterial infections.

11. Use of the compound of any one of claims 1-8 or the pharmaceutical composition of claim 9 in the preparation of a medicament for treating bacterial infections caused by Pseudomonas aeruginosa.

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