INHIBITORS OF PSEUDOMONAS AERUGINOSA VIRULENCE FACTOR LasB

Abstract

To provide the use of compounds for preparing pharmaceuticals for the treatment of bacterial infections caused by P. aeruginosa.SOLUTION: The use of a compound of general formula (Ia) or a pharmaceutically acceptable salt thereof is provided. (In the formula, X is a group of the formula -PO(OH)2.)SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to Pseudomonas aeruginosa ( Pseudomonas aeruginosa ) relates to novel inhibitors of the virulence factor LasB. These compounds are useful in the treatment of bacterial infections, particularly those caused by Pseudomonas aeruginosa. [Background technology]

[0002] Pseudomonas aeruginosa is a Gram-negative bacterium that is ranked by the WHO as one of the most important pathogens today (World Health Organization. Global Priority List of Antibiotic-Resistant Bacteria to Guide Research, Discovery, and Development of New Antibiotics. WHO 2017). This opportunistic bacterium causes approximately 10% of hospital-acquired infections, with a high incidence among 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, RP Pediatrics 1999, 103 , e39; Valenza, G.; Tappe, D.; Turnwald, D.; Frosch, M.; Koenig, C.; Hebestreit, H.; Abele-Horn, M. J. Cyst. Fibros. 2008, 7, 123-127; Sorde, R.; Pahissa, A.; Rello, J. Infect. Drug Resist. 2011, 4 , 31-41). The development of potent antibiotics is urgently needed due to the lack of efficient therapeutic drugs on the market (Mesaros, N.; Nordmann, P.; Plesiat, 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, DP Drug Resist. Update. 2000, 3 , 247-255; Strateva, T.; Yordanov, D. J. Med. Microbiol. 2009, 58 , 1133-1148).

[0003] Pseudomonas aeruginosa has an outer membrane with particularly low permeability, which prevents antibiotics from entering the cell (Nikaido, H.; Yoshimura, F. J. Bacteriol. 1982, 152 , 636-642). Furthermore, its efflux pumps efficiently transport unwanted antimicrobial agents out of the cell, and its inducible chromosomal β-lactamase can inactivate the corresponding β-lactam antibiotics (Pos, KM Biochim. Biophys. Acta - Proteins Proteomics 2009, 1794, 782-793; Moreira, MAS; Souza, EC de; Moraes, CA de. Brazilian J. Microbiol. 2004, 35 , 19-28; Hancock, REW; Woodruff, WA Clin. Infect. Dis. 1988, 10 , 770-775; Li, XZ; Livermore, DM; Nikaido, H. Antimicrob. Agents Chemother. 1994, 38 , 1732-1741). Even more challenging is the increasing rate of mutational resistance among P. aeruginosa strains (Thomson, JM; Bonomo, RA Curr. Opin. Microbiol. 2005, 8 , 518-524). For example, fluoroquinolone and aminoglycoside resistance has reached up to 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 nearly all drugs used to treat infections caused by P. aeruginosa (e.g., cephalosporins and carbapenems) has been described (Obritsch, MD; Fish, DN; MacLaren, R.; Jung, R. Pharmacotherapy 2005, 25 , 1353-1364; ASCP Susceptibility Testing Group. United States Geographic Bacteria Susceptibility Patterns. Am. J. Clin. Pathol. 1996, 106 , 275-281). These facts highlight the urgent need for new treatment options.

[0004] In addition to traditional strategies targeting bacterial viability, in recent years, special attention has been paid to targeting bacterial virulence as an alternative approach to combat 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 among pathogenic bacteria and act by damaging their host or evading its immune response (Strateva, T.; Mitov, I. Ann. Microbiol. 2011, 61 , 717-732). Inhibitors of virulence factors reduce bacterial virulence, thus allowing elimination of the pathogen by the host's immune system or with the aid of antibiotics (Heras, B.; Scanlon, MJ; Martin, JL Br. J. Clin. Pharmacol. 2015, 79 , 208-215; Clatworthy, AE; Pierson, E.; Hung, DT Nat. Chem. Biol. 2007, 3, 541-548). Although only a few compounds have reached clinical approval, numerous in vitro and in vivo studies support the effectiveness of this strategy (Wagner, S.; Sommer, R.; Hinsberger, S.; Lu, C.; Hartmann, R.W.; Empting, M.; Titz, A. J. Med. Chem . 2016, 59 , 5929-5969). The main advantage of this new approach is that it reduces the selective pressure on bacteria and therefore the risk of resistance development. Furthermore, these antipathogenic agents do not harm commensal bacteria.

[0005] A well-known antivirulence target of P. aeruginosa is the elastase LasB. This extracellular zinc-containing protease is thought to play a role in pathogenic invasion of tissues and is primarily relevant during acute infection (Liu, PV J. Infect. Dis. 1974, 130 , S94-S99). It has the ability to degrade elastin, an important component of lung tissue and blood vessels (Morihara, K.; Tsuzuki, H.; Oka, T.; Inoue, H.; Ebata, M. J. Biol. Chem. 1965, 240 , 3295-3304). Furthermore, LasB can degrade pulmonary fibrin, collagen, and surfactant proteins, and is involved in the inactivation of human immunoglobulins A and G, the cytokine gamma interferon, and tumor necrosis factor α, as well as the degradation of the antimicrobial peptide LL-37, thereby reducing host immunity (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, JF J. Immunol. 1990, 144 , 2253-2257; Holder, IA; Wheeler, R. Can. J. Microbiol. 1984, 30 , 1118-1124; Galloway, D.R. Mol. Microbiol. 1991, 5 , 2315-2321; Parmely, M.; Gale, A.; Clabaugh, M.; Horvat, R.; Zhou, W. Infect. Immun. 1990, 58 , 3009-3014; Mariencheck, WI; Alcorn, JF; Palmer, SM; Wright, JR Am. J. Respir. Cell Mol. Biol. 2003, 28 , 528-537; Schmidtchen, A. et al. Mol. Microbiol. 2002, 46 , 157-168).

[0006] Because LasB is an attractive antivirulence target, several LasB inhibitors have been described in the literature so far: Streptomyces nigrescens ( Streptomyces nigrescens ) and natural products such as Streptomyces metalloprotease inhibitor TK-23 (SMPI) and phosphoramidon (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 thiol or hydroxamate 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, JT Antimicrob. Agents Chemother. 1990, 34 , 2065-2069), as well as small synthetic molecules bearing hydroxamate, thiol, or mercaptoacetamide groups (Zhu, J.; Cai, X.; Harris, T.L.; Gooyit, M.; Wood, M.; Lardy, M.; Janda, K.D. Chem. Biol. 2015, 22 , 483-491; Adekoya, OA; Sjoeli, 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), as well as tropolone-based compounds (Fullagar, JL; Garner, AL; Struss, AK; Day, JA; Martin, DP; Yu, J.; Cai, X.; Janda, KD; Cohen, SM Chem. Commun. 2013, 49 , 3197-3199).

[0007] Recently, a potent LasB inhibitor, N -arylmercaptoacetamide groups have been described (Kany, A. M.; Sikandar, A.; Haupenthal, J.; Yahiaoui, S.; Maurer, C. K.; Proschak, E.; Koehnke, J.; Hartmann, R. W. ACS Infect. Dis. 2018, 4 , 988-997). The crystal structure of the most promising compound described in the paper (compound 36) revealed the presence of two molecules in the binding pocket. A single molecule must occupy the active site. N -benzylamide / N -Alkylamide derivatives have been synthesized. However, this approach failed to improve the inhibitory potency of the initial ligand. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] World Health Organization. Global Priority List of Antibiotic-Resistant Bacteria to Guide Research, Discovery, and Development of New Antibiotics. WHO 2017 [Non-patent document 2] Magill, SS; Edwards, JR; Bamberg, W.; Beldavs, ZG; Dumyati, G.; Kainer, MA; Lynfield, R.; Maloney, M.; McAllister-Hollod, L.; [Non-licensed document 3] Richards, MJ; Edwards, JR; Culver, DH; Gaynes, RP Pediatrics 1999, 103, e39

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[0009] An object of the present invention is to provide novel inhibitors of the Pseudomonas aeruginosa virulence factor LasB. [Means for solving the problem]

[0010] The present invention relates to compounds of general formula (Ia):

[0011] or a pharmaceutically acceptable salt thereof,

[0012] [ka]

[0013] In general formula (Ia),

[0014] X is a group of formula -PO(OH)2, -SH, -C(=O)-NH-OH, an optionally substituted triazolyl group, -SR 3 , -PO(OH)(OR 4 ) or -PO(OR 4 )(OR 5 ) group;

[0015] R 1 is an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group, or an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group; or a group of the general formula -CH(R 6 )-C(=O)-NH-R 7 or a group of the general formula -C(Me)2-CH2-C(=O)-NH-R 7 or a group of the general formula -CH(R 6 )-CH2-C(=O)-NH-R 7 or a group of the general formula -CH(R 6 )-R 8 is the basis of;

[0016] R 2 is an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group, or a heteroaralkyl group, all of which may be optionally substituted;

[0017] R 3 is represented by the general formula -COR 3a or -CON(R 3b )2 group; where R 3a is an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group, and R 3bare independently selected from a hydrogen atom, an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group;

[0018] R 4 is an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group;

[0019] R 5 is an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group;

[0020] R 6 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl group, all of which may be optionally substituted;

[0021] R 7 is an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group;

[0022] R 8 is an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group;

[0023] R 1a is a hydrogen atom or R 1 is represented by the general formula -CH(R 6)-C(=O)-NH-R 7 When R is a group 1a and R 6 together can be a group of formula -(CH2)3- or -(CH2)4-.

[0024] The present invention further provides compounds of general formula (I):

[0025] or a pharmaceutically acceptable salt thereof,

[0026] [ka]

[0027] In general formula (I),

[0028] X is a group of formula -PO(OH)2, -SH, -C(=O)-NH-OH, an optionally substituted triazolyl group, -SR 3 , -PO(OH)(OR 4 ) or -PO(OR 4 )(OR 5 ) group;

[0029] R 1 is an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group, or an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group; or a group of the general formula -CH(R 6 )-C(=O)-NH-R 7 or a group of the general formula -C(Me)2-CH2-C(=O)-NH-R 7 or a group of the general formula -CH(R 6 )-CH2-C(=O)-NH-R 7 or a group of the general formula -CH(R 6 )-R 8 is the basis of;

[0030] R 2is an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group, or a heteroaralkyl group, all of which may be optionally substituted;

[0031] R 3 is represented by the general formula -COR 3a or -CON(R 3b )2 group; where R 3a is an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group, and R 3b are independently selected from a hydrogen atom, an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group;

[0032] R 4 is an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group;

[0033] R 5 is an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group;

[0034] R 6 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl group, all of which may be optionally substituted;

[0035] R 7is an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group;

[0036] R 8 is an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group.

[0037] Preferably, X is a group of formula -PO(OH)2, -SH, -C(=O)-NH-OH, or a triazolyl group.

[0038] The present invention further provides compounds of general formula (I):

[0039] or a pharmaceutically acceptable salt thereof,

[0040] [ka]

[0041] In general formula (I),

[0042] X is a group of the formula -SH, -PO(OH)2, -SR 3 , -PO(OH)(OR 4 ) or -PO(OR 4 )(OR 5 ) group;

[0043] R 1 is an optionally substituted aryl group or an optionally substituted heteroaryl group;

[0044] R 2is an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group, or a heteroaralkyl group, all of which may be optionally substituted;

[0045] R 3 is represented by the general formula -COR 3a or -CON(R 3b )2 group; where R 3a is an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group, and R 3b are independently selected from a hydrogen atom, an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group;

[0046] R 4 is an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group;

[0047] R 5 is an alkyl group, an optionally substituted phenyl group or an optionally substituted benzyl group.

[0048] According to a further preferred embodiment, the present invention provides a compound of general formula (II):

[0049] or a pharmaceutically acceptable salt thereof,

[0050] [ka]

[0051] In general formula (II), R 1 and R 2 is as defined above or below.

[0052] According to a further preferred embodiment, the present invention provides a compound of general formula (II): or a pharmaceutically acceptable salt thereof,

[0053] [ka]

[0054] In the general formula (II),

[0055] R 1 is an optionally substituted aryl group or an optionally substituted heteroaryl group;

[0056] R 2 is an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group, or a heteroaralkyl group, all of which may be optionally substituted.

[0057] According to a further preferred embodiment, the present invention provides a compound of general formula (III):

[0058] or a pharmaceutically acceptable salt thereof,

[0059] [ka]

[0060] In general formula (III), R 1 and R 2 is as defined above or below.

[0061] According to a further preferred embodiment, the present invention provides a compound of general formula (III): or a pharmaceutically acceptable salt thereof,

[0062] [ka]

[0063] In general formula (III),

[0064] R 1 is an optionally substituted aryl group or an optionally substituted heteroaryl group;

[0065] R 2 is an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group, or a heteroaralkyl group, all of which may be optionally substituted.

[0066] According to a further preferred embodiment, the present invention provides a compound of general formula (IV): or a pharmaceutically acceptable salt thereof,

[0067] [ka]

[0068] In general formula (IV), R 1 and R 2 is as defined above or below.

[0069] According to a further preferred embodiment, the present invention provides a compound of general formula (V): or a pharmaceutically acceptable salt thereof,

[0070] [ka]

[0071] In general formula (V), R 1 and R 2 is as defined above or below.

[0072] According to a further preferred embodiment, the present invention provides a compound of general formula (VI): or a pharmaceutically acceptable salt thereof,

[0073] [ka]

[0074] In general formula (VI), R 1 and R 2 is as defined above or below. DETAILED DESCRIPTION OF THE INVENTION

[0075] The following preferred embodiments apply independently to compounds of general formulae (I), (Ia), (II), (III), (IV), (V) and (VI).

[0076] Preferably, R 1 is an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group, or an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group.

[0077] More preferably, R 1 is an optionally substituted aryl group or an optionally substituted heteroaryl group.

[0078] More preferably, R 1 is an optionally substituted phenyl group, an optionally substituted naphthyl group, or an optionally substituted heteroaryl group containing one or two rings and 5 to 10 ring atoms selected from C, O, N, and S.

[0079] Particularly preferably, R 1is an optionally substituted phenyl group or an optionally substituted heteroaryl group containing 1 or 2 rings and 5, 6, 9 or 10 ring atoms selected from C, O, N and S.

[0080] More preferably, R 1 is an optionally substituted heteroaryl group containing 5 or 6 ring atoms selected from C, O, N and S.

[0081] More preferably, R 1 is an optionally substituted phenyl group.

[0082] More preferably, R 1 is represented by the general formula -Cy 1 -L-Cy 2 where Cy is a group 1 is an optionally substituted cycloalkylene group having one or two rings and 3 to 7 carbon ring atoms, an optionally substituted heterocycloalkylene group having one or two rings and 3 to 7 ring atoms selected from C, N, O and S, an optionally substituted phenylene group, or an optionally substituted heteroarylene group having 5 or 6 ring atoms selected from C, N, O and S; Cy 2 is a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group, or a heteroaralkyl group, all of which are optionally substituted; L is a bond, or -O-, -S-, -NH-, -CH-, -CO-, -NHCO-, -CO-NH-, -CH-CO-NH-, -NH-CO-CH-, -CH-O-CO-NH-, -NH-CO-O-CH-, -O-CO-NH-, -NH-CO-O-, -NHSO-, -SONH-, -CH-SO-NH-, -NH-SO-CH-, -S-CH-, -CH-S-, -NH-CH-, -CH-NH-, -O-CH-, or -CH-O-.

[0083] Preferably, Cy 2 is an optionally substituted phenyl group, an optionally substituted biphenyl group, an optionally substituted naphthyl group, an optionally substituted heteroaryl group containing one or two rings and five, six, nine or ten ring atoms selected from C, O, N and S, an optionally substituted cycloalkyl group containing three to seven ring atoms, an optionally substituted heterocycloalkyl group containing three to seven ring atoms selected from C, N, O and S, an optionally substituted heterocycloalkylaryl group containing nine or ten ring atoms selected from C, N, S and O, or a group of the formula -CH(CHPh)Ph.

[0084] More preferably, L is a bond, or -NHCO-, -CO-NH-, -CH2-CO-NH-, -NH-CO-CH2-, -NHSO2- or -SO2NH-.

[0085] More preferably, Cy 1 is a 1,4-phenylene group.

[0086] More preferably, R 1 is a group having the general formula -CH(R 6 )-C(=O)-NH-R 7 It is based on.

[0087] More preferably, R 1 is a group having the general formula -CH(R 6 )-R 8 is the basis of

[0088] More preferably, R 6 is a hydrogen atom or C 1~6 Alkyl group, C 3~7 a cycloalkyl group, a heterocycloalkyl group containing 3 to 7 ring atoms selected from C, N, O and S, a phenyl group, or a heteroaryl group containing 5 or 6 ring atoms selected from C, N, S and O, or a group of the general formula -CH2-R6a where R 6a is C 3~7 It is a cycloalkyl group, a heterocycloalkyl group containing 3 to 7 ring atoms selected from C, N, O, and S, a phenyl group, or a heteroaryl group containing 5 or 6 ring atoms selected from C, N, S, and O.

[0089] Particularly preferably, R 6 is a -CH(CH3)2 group.

[0090] More preferably, R 7 is an optionally substituted phenyl group or an optionally substituted C 3~7 Cycloalkyl groups; in particular optionally substituted phenyl groups.

[0091] More preferably, R 8 is an optionally substituted benzimidazole group or an optionally substituted triazole group or an optionally substituted imidazole group.

[0092] More preferably, R 8 is a group of the general formula:

[0093] [ka]

[0094] wherein each "...." independently represents a single bond or a double bond, and at least one "...." in each ring is a double bond; A1 and A2 each independently represent CH, N, NH, O or S; B is R B1 or general formula -YR B2 where: R B1 is a hydrogen atom, halogen atom, CN, CF3, CH2-OH; NR T1 R T2or an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl group, all of which are optionally substituted: R T1 and R T2 each independently represents a hydrogen atom or a (C1-C3) alkyl group, which may be substituted with one or more identical or different groups selected from a halogen atom, OH, ═O, and NH2; Y is -O- or -S-; R B2 is a hydrogen atom, or an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group, or a heteroaralkyl group, all of which groups may be optionally substituted.

[0095] More preferably, R 8 is a group of the general formula:

[0096] [ka]

[0097] wherein each "...." independently represents a single bond or a double bond, and at least one "...." is a double bond; C1 and C3 each independently represent C or N; C2, C4 and C5 each independently represent CH, N, NH, O or S; D is an optionally substituted aryl group or an optionally substituted heteroaryl group (particularly preferably, D is an optionally substituted phenyl group).

[0098] More preferably, R2 is C 1~6 alkyl groups; heteroalkyl groups containing 1 to 6 carbon atoms and 1, 2, 3 or 4 heteroatoms selected from O, S and N; C 4~10 alkylcycloalkyl group; or C 7~12 and aralkyl groups; all of which may be optionally substituted.

[0099] Particularly preferably, R 2 is C 1~6 alkyl groups; heteroalkyl groups containing 1 to 6 carbon atoms and 1, 2, 3 or 4 heteroatoms selected from O, S and N; or groups of the general formula -CH2-R 21 where R 21 is C 3~7 It is a cycloalkyl group, COOH, COOMe or an optionally substituted phenyl group.

[0100] Furthermore, particularly preferably, R 2 is C 1-4 alkyl group; or a group of the general formula -CH2-R 21 where R 21 is C 3~6 A cycloalkyl group, OMe, COOH, COOMe or an optionally substituted phenyl group. Preferably, R 21 is a phenyl group that is unsubstituted or substituted with one or two substituents independently selected from OH, NO and Me; more preferably, R 21 is an unsubstituted phenyl group.

[0101] More preferably, R 2 is an optionally substituted benzyl group (i.e., an optionally substituted group of formula -CH2-Ph). More preferably, R 2 is an unsubstituted benzyl group.

[0102] More preferably, R 2 teeth, iso -butyl group (i.e., a group of formula -CH2CH(CH3)2).

[0103] The term "optionally substituted" refers to a group that is unsubstituted or substituted with one or more (especially 1, 2 or 3; preferably 1 or 2) substituents.

[0104] base R 1 and / or group R 2 When contains more than one substituent, the substituents are independently selected, ie, they can be the same or different.

[0105] base R 1 and / or group R 2 is substituted with a cyclic group such as a cycloalkyl group or a heterocycloalkyl group, the cyclic group is connected to the group R 1 and / or group R 2 or the cyclic group may be bonded to a group R 1 and / or group R 2 Isatin is an example of a substituted phenyl group.

[0106] Examples of substituents are fluorine, chlorine, bromine and iodine, as well as OH, SH, NH, -SOH, -SONH, -COOH, -COOMe, -COMe(Ac), -NHSOMe, -SONMe, -CHNH, -NHAc, -SOMe, -CONH, -CN, -NHCONH, -NHC(NH)NH, -NOHCH, -N and -NO groups. Further examples of substituents are C1-C 10 Alkyl groups, C2-C 10 Alkenyl groups, C2-C 10 Alkynyl groups, C1-C 10 Heteroalkyl groups, C3-C 18 Cycloalkyl groups, C1-C 17 Heterocycloalkyl groups, C4-C 20 Alkylcycloalkyl groups, C1-C 19 Heteroalkylcycloalkyl groups, C6-C 18 Aryl groups, C1-C17 Heteroaryl groups, C7-C 20 Aralkyl groups and C1-C 19 Heteroaralkyl groups; in particular, C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C1-C6 heteroalkyl groups, C3-C 10 Cycloalkyl groups, C1-C9 heterocycloalkyl groups, C4-C 12 Alkylcycloalkyl groups, C1-C 11 Heteroalkylcycloalkyl groups, C6-C 10 Aryl groups, C1-C9 heteroaryl groups, C7-C 12 Aralkyl groups and C1-C 11 Heteroaralkyl groups are more preferred, and C1-C6 alkyl groups and C1-C6 heteroalkyl groups are more preferred.

[0107] Preferred substituents are halogen atoms (e.g., F, Cl, Br, I) and groups of the formula -OH, -OC 1~6 Alkyl (e.g., -OMe, -OEt, -O- n Pr, -O- i Pr, -O- n Bu, -O- i Bu and -O- t Bu), -NH2, -NHC 1~6 Alkyl, -N(C 1~6 alkyl)2, -COOH, -COOMe, -COMe, -COCF3, -NHSO2Me, -SO2NMe2, -SO3H, -SO2NH2, -CONH2, -CH2NH2, -CN, -C 1~6 Alkyl (e.g., -Me, -Et, - n Pr, - i Pr, - n Bu, - i Bu, - t Bu and -CF3), -SH, -S-CO-C 1~6 Alkyl, -SC 1~6 Alkyl, -NHAc, -NO2, -C≡CH, -NHCONH2, -SO2Me, -SO2CF3, phenyl, -C 3~6Cycloalkyl (eg, cyclopropyl, cyclobutyl) and heterocycloalkyl groups containing 3 to 6 ring atoms selected from C, N, S, and O.

[0108] Further preferred substituents are halogen atoms (e.g., F, Cl, Br) and groups of the formula -OH, -OC 1~6 Alkyl (e.g., -OMe, -OEt, -O- n Pr, -O- i Pr, -O- n Bu, -O- i Bu and -O- t Bu), -NH2, -NHC 1~6 Alkyl, -N(C 1~6 alkyl)2, -COOH, -COOMe, -COMe, -NHSO2Me, -SO2NMe2, -SO3H, -SO2NH2, -CONH2, -CH2NH2, -CN, -C 1~6 Alkyl (e.g., -Me, -Et, - n Pr, - i Pr, - n Bu, - i Bu, - t Bu and -CF3), -SH, -S-CO-C 1~6 Alkyl, -SC 1~6 alkyl, -NHAc, -NO2, -C≡CH, -NHCONH2, -SO2Me and cyclopropyl groups.

[0109] The substituents are particularly preferably independently selected from halogen (especially F and Cl), -Me, -CF3, -OMe, -OH, -COOH, -CONH2, -COOMe, -COMe and -NO2.

[0110] The substituents are more particularly preferably independently selected from halogen (especially F and Cl), -Me, -CF3, -OMe, -OH, -COOH, -COOMe, -COMe and -NO2.

[0111] The most preferred compounds of the present invention are the compounds disclosed in the Examples or salts thereof.

[0112] It is further preferred to combine the preferred embodiments of the present invention in any desired manner (e.g., R 1 Any embodiment of R 2 (This can be combined with any of the embodiments of the above.)

[0113] The suffix "-ene", for example "phenylene", refers to the corresponding divalent radical.

[0114] The term alkyl refers to saturated, linear or branched hydrocarbon groups containing 1 to 20 carbon atoms, preferably 1 to 15 carbon atoms, in particular 1 to 10 (e.g. 1, 2, 3 or 4) carbon atoms, such as methyl (Me, CH3) groups, ethyl (Et) groups, n -propyl ( n Pr) group, iso -propyl ( i Pr) group, n -butyl( n Bu) group, iso -butyl( i Bu) group, sec -butyl( s Bu) group, tert -butyl( t Bu) group, n -pentyl group, iso -pentyl group, n -hexyl group, 2,2-dimethylbutyl group, or n -refers to the octyl group.

[0115] Particularly preferred alkyl groups are C 1~6 alkyl group; more preferred alkyl groups are C 1~4 It is an alkyl group.

[0116] C 1~6 The term alkyl refers to a saturated, straight-chain or branched hydrocarbon group containing 1 to 6 carbon atoms. 1~4 The term alkyl refers to saturated, straight-chain or branched hydrocarbon groups containing 1 to 4 carbon atoms. Examples include methyl, ethyl, n -propyl group, iso -propyl group, n -butyl group, iso -butyl group, sec -butyl group or tert -butyl group.

[0117] The terms alkenyl and alkynyl refer to at least partially unsaturated, linear or branched hydrocarbon groups containing 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, in particular 2 to 10 (e.g., 2, 3, or 4) carbon atoms, such as ethenyl (vinyl), propenyl (allyl), isopropenyl, butenyl, ethynyl (acetylenyl), propynyl (e.g., propargyl), butynyl, isoprenyl, or hex-2-enyl. Preferably, alkenyl groups have one or two (particularly preferably one) double bonds, and alkynyl groups have one or two (particularly preferably one) triple bonds.

[0118] Furthermore, the terms alkyl, alkenyl and alkynyl refer to groups in which one or more hydrogen atoms have been replaced by a halogen atom (preferably F or Cl), such as a 2,2,2-trichloroethyl or trifluoromethyl group.

[0119] 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 replaced by oxygen, nitrogen, phosphorus, boron, selenium, silicon, or sulfur atoms (preferably by oxygen, sulfur, or nitrogen atoms) or by SO or SO groups. The term heteroalkyl also refers to carboxylic acids or groups derived from carboxylic acids, such as acyl, acylalkyl, alkoxycarbonyl, acyloxy, acyloxyalkyl, carboxyalkylamide, or alkoxycarbonyloxy groups. Furthermore, the term heteroalkyl refers to groups in which one or more hydrogen atoms are replaced by halogen atoms (preferably F or Cl).

[0120] Preferably, the heteroalkyl group contains 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 contains 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). C1-C 10 The term heteroalkyl refers to a heteroalkyl group containing 1 to 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 term C1-C6 heteroalkyl refers to a heteroalkyl group containing 1 to 6 carbon atoms and 1, 2, 3 or 4 heteroatoms selected from O, S and / or N (especially O and / or N). The term C1-C4 heteroalkyl refers to a heteroalkyl group containing 1 to 4 carbon atoms and 1, 2 or 3 heteroatoms selected from O, S and / or N (especially O and / or N).

[0121] More preferably, the term heteroalkyl refers to an alkyl group (linear or branched) as defined above, in which one or more (preferably 1 to 6; particularly preferably 1, 2, 3 or 4) carbon atoms are replaced by oxygen, sulfur or nitrogen atoms or by CO, SO or SO groups; this group preferably contains 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); this group may preferably be substituted by one or more (preferably 1 to 6; particularly preferably 1, 2, 3 or 4) fluorine, chlorine, bromine or iodine atoms or by OH, ═O, SH, ═S, NH, ═NH, N, CN or NO groups.

[0122] Examples of heteroalkyl groups include those of the general 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-WHAT-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(R b )-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-OYa -, 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-OY a -, R a -O-CO-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 is a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, or a C2-C6 alkynyl group; R b is a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, or a C2-C6 alkynyl group; R c is a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, or a C2-C6 alkynyl group; R d is a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, or a C2-C6 alkynyl group, and Y ais a bond, a C1-C6 alkylene group, a C2-C6 alkenylene group, or a C2-C6 alkynylene group, and each heteroalkyl group contains at least one carbon atom, and one or more hydrogen atoms may be replaced by a fluorine atom or a chlorine atom.

[0123] Illustrative examples of heteroalkyl groups are methoxy, trifluoromethoxy, ethoxy, n -propyloxy, iso -propyloxy, n -butoxy, tert -butyloxy, 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, acetyloxy, methoxycarbonyl, ethoxycarbonyl, propionyloxy, acetylamino or propionylamino, carboxymethyl, carboxyethyl or carboxypropyl, N -ethyl- N -methyl-carbamoyl or N -methyl-carbamoyl. Further examples of heteroalkyl groups are nitrile (-CN), isonitrile, cyanate, thiocyanate, isocyanate, isothiocyanate and alkylnitrile groups.

[0124] The term cycloalkyl refers to saturated or partially unsaturated (e.g., cycloalkenyl) cyclic groups containing one or more rings (preferably one or two) and 3 to 14 ring carbon atoms, preferably 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms. The term cycloalkyl also refers to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, ═O, SH, ═S, NH, ═NH, N or NO groups, and thus to cyclic ketones such as, for example, cyclohexanone, 2-cyclohexenone or cyclopentanone. Further specific examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, spiro[4,5]decanyl, norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, bicyclo[4.3.0]nonyl, tetralin, cyclopentylcyclohexyl, fluorocyclohexyl or cyclohex-2-enyl. Preferably, the term cycloalkyl refers to saturated cyclic groups containing one or more (preferably one or two) rings and 3 to 14 ring carbon atoms, preferably 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms.

[0125] The term heterocycloalkyl refers to a cycloalkyl group as defined above in which one or more (preferably one, two or three) ring carbon atoms have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom) or by an SO or SO group. Heterocycloalkyl groups preferably have one or two rings and 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms (preferably selected from C, O, N and S). The term heterocycloalkyl further refers to groups substituted by a fluorine, chlorine, bromine or iodine atom or by an OH, ═O, SH, ═S, NH, ═NH, N or NO group. Examples are piperidyl, prolinyl, imidazolidinyl, piperazinyl, morpholinyl (e.g., —N(CHCH)O), urotropinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl or 2-pyrazolinyl groups, as well as lactams, lactones, cyclic imides and cyclic anhydrides.

[0126] The term alkylcycloalkyl refers to a cycloalkyl group as defined above, and a group containing both an alkyl group, an alkenyl group or an alkynyl group, such as alkylcycloalkyl group, cycloalkylalkyl group, alkylcycloalkenyl group, alkenylcycloalkyl group and alkynylcycloalkyl group. Alkylcycloalkyl groups preferably contain a cycloalkyl group containing one or two rings and 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms, and one or two alkyl, alkenyl or alkynyl groups (especially alkyl groups) having 1 or 2 to 6 carbon atoms.

[0127] The term "heteroalkylcycloalkyl" refers to an alkylcycloalkyl group as defined above in which one or more (preferably one, two, or three) carbon atoms have been replaced by oxygen, nitrogen, silicon, selenium, phosphorus, or sulfur atoms (preferably by oxygen, sulfur, or nitrogen atoms) or by an SO or SO group. Heteroalkylcycloalkyl groups preferably contain one or two rings with 3 to 10 (especially 3, 4, 5, 6, or 7) ring atoms and one or two alkyl, alkenyl, alkynyl, or heteroalkyl groups (especially alkyl or heteroalkyl groups) with 1 or 2 to 6 carbon atoms. Examples of such groups are alkylheterocycloalkyl groups, alkylheterocycloalkenyl groups, alkenylheterocycloalkyl groups, alkynylheterocycloalkyl groups, heteroalkylcycloalkyl groups, heteroalkylheterocycloalkyl groups, and heteroalkylheterocycloalkenyl groups, where the cyclic groups are saturated or mono-, di-, or tri-unsaturated.

[0128] 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. The term aryl also refers to groups substituted by fluorine, chlorine, bromine or iodine atoms or by OH, SH, NH, N or NO groups. Examples are phenyl (Ph), naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3-nitrophenyl or 4-hydroxyphenyl groups.

[0129] The term heteroaryl refers to aromatic groups containing one or more rings and 5 to 14 ring atoms, preferably 5 to 10 (especially 5 or 6 or 9 or 10) ring atoms, and containing one or more (preferably 1, 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N). The term heteroaryl further refers to groups substituted by fluorine, chlorine, bromine or iodine atoms, or by OH, SH, N, NH or NO groups. Examples include pyridyl groups (e.g., 4-pyridyl), imidazolyl groups (e.g., 2-imidazolyl), phenylpyrrolyl groups (e.g., 3-phenylpyrrolyl), thiazolyl groups, isothiazolyl groups, 1,2,3-triazolyl groups, 1,2,4-triazolyl groups, oxadiazolyl groups, thiadiazolyl groups, indolyl groups, indazolyl groups, tetrazolyl groups, pyrazinyl groups, pyrimidinyl groups, pyridazinyl groups, 4-hydroxypyridyl (4-pyridonyl) groups, 3,4-hydroxypyridyl (3,4 -pyridonyl), oxazolyl, isoxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indo-lyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, pyridazinyl, quinolinyl, isoquinolinyl, pyrrolyl, purinyl, carbazolyl, acridinyl, pyrimidyl, 2,3'-bifuryl, pyrazolyl (e.g., 3-pyrazolyl), and isoquinolinyl.

[0130] The term "aralkyl" refers to groups containing both aryl groups as defined above and alkyl, alkenyl, alkynyl and / or cycloalkyl groups, such as arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylarylcycloalkyl and alkylarylcycloalkenyl groups. Specific examples of aralkyl include phenylcyclopentyl, cyclohexylphenyl, and toluene, xylene, mesitylene, styrene, benzyl chloride, o -fluorotoluene, 1 H- radicals derived from indene, tetralin, dihydronaphthalene, indanone, cumene, fluorene and indane. The aralkyl group preferably contains 6 to 10 carbon atoms and one or two aromatic ring systems (especially one or two rings), each containing 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.

[0131] The term heteroaralkyl refers to groups containing both aryl and / or heteroaryl groups as defined above, and alkyl, alkenyl, alkynyl and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl groups. Heteroaralkyl groups preferably contain one or two aromatic ring systems (especially one or two rings) containing from 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 alkynyl 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 3, 4, 5, 6 or 7 ring atoms and 1, 2, 3 or 4 oxygen, sulfur or nitrogen atoms.

[0132] Examples are arylheteroalkyl groups, arylheterocycloalkyl groups, arylheterocycloalkenyl groups, arylalkylheterocycloalkyl groups, arylalkenylheterocycloalkyl groups, arylalkynylheterocycloalkyl groups, arylalkylheterocycloalkenyl groups, heteroarylalkyl groups, heteroarylalkenyl groups, heteroarylalkynyl groups, heteroarylheteroalkyl groups, heteroarylcycloalkyl groups, heteroarylcycloalkenyl groups, heteroarylheterocycloalkyl groups, heteroarylheterocycloalkenyl groups, heteroarylalkylcycloalkyl groups, heteroarylalkylheterocycloalkenyl groups, heteroarylheteroalkylcycloalkyl groups, heteroarylheteroalkylcycloalkenyl groups, and heteroarylheteroalkylheterocycloalkyl groups, wherein the cyclic groups are saturated or mono-, di-, or tri-unsaturated. Specific examples are tetrahydroisoquinolinyl, benzoyl, phthalidyl, 2-, or 3-ethylindolyl, 4-methylpyridino, 2-, 3-, or 4-methoxyphenyl, 4-ethoxyphenyl, and 2-, 3-, or 4-carboxyphenylalkyl groups.

[0133] As already mentioned above, the expressions cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl also refer to groups substituted by fluorine, chlorine, bromine or iodine atoms or by OH, ═O, SH, ═S, NH, ═NH, N or NO groups.

[0134] The term halogen refers to F, Cl, Br or I.

[0135] When an aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl, or heteroaralkyl group contains more than one ring, the rings may be joined to each other via single or double bonds, or the rings may be cyclized, fused, or bridged.

[0136] Due to their substitution, the compounds of the present invention may contain one or more centers of chirality. Therefore, the present invention includes both all pure enantiomers and all pure diastereomers, as well as mixtures thereof in any mixture ratio. The present invention also includes all cis / trans isomers of the compounds of the present invention and mixtures thereof. The present invention also includes all tautomeric forms of the compounds of the present invention.

[0137] 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 invention may also contain additional antibacterial compounds.

[0138] The compounds or pharmaceutical compositions of the invention may be administered in combination with an additional antibacterial compound.

[0139] The present invention further provides a compound or pharmaceutical composition as described herein for use in the treatment of a bacterial infection, particularly one caused by Pseudomonas aeruginosa.

[0140] The present invention further provides a compound as described herein or a pharmaceutical composition as defined herein for the preparation of a medicament for use in the treatment of a bacterial infection, particularly one caused by Pseudomonas aeruginosa.

[0141] Examples of pharmaceutically acceptable salts of sufficiently basic compounds are salts of physiologically acceptable mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; or 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 may form salts with alkali or alkaline earth metals, such as sodium, potassium, lithium, calcium, or magnesium; ammonium salts; or organic bases, such as methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, meglumine, piperidine, morpholine, tris-(2-hydroxyethyl)amine, lysine, or arginine, all of which are further examples of salts of the compounds described herein.

[0142] The compounds described herein may be solvated, particularly hydrated. Solvation / hydration may occur during the manufacturing process or as a result of the hygroscopic nature of compounds that do not initially contain water. Solvates and / or hydrates may exist, for example, in solid or liquid form.

[0143] Therapeutic uses of the compounds described herein, their pharmaceutically acceptable salts, solvates and hydrates, and formulations and pharmaceutical compositions are also within the scope of the present invention.

[0144] In general, the compounds and pharmaceutical compositions described herein are administered using established and accepted modes known in the art.

[0145] For oral administration, such therapeutically useful agents can be administered by one of the following routes: orally, for example, as tablets, dragees, coated tablets, pills, semisolids, soft or hard capsules, e.g., soft and hard gelatin capsules, aqueous or oily solutions, emulsions, suspensions, or syrups; parenterally, for example, by intravenous, intramuscular, and subcutaneous injection, for example, as injectable solutions or suspensions, rectally as suppositories; by inhalation or insufflation, for example, as powder formulations, microcrystals, or as sprays (e.g., liquid aerosols); transdermally, for example, via transdermal drug delivery systems (TDDS), such as patches containing the active ingredient, or intranasally. For the preparation of such tablets, pills, semisolids, coated tablets, dragees, and hard, e.g., gelatin, capsules, the therapeutically useful products can be mixed with pharmaceutically inert inorganic or organic excipients, such as, for example, lactose, sucrose, glucose, gelatin, malt, silica gel, starch or derivatives thereof, talc, stearic acid or its salts, dried skim milk, etc. For the preparation of soft capsules, excipients such as vegetable oils, petroleum, animal or synthetic oils, waxes, fats, and polyols can be used. For the preparation of liquid solutions, emulsions, suspensions, or syrups, excipients such as water, alcohol, saline, aqueous dextrose, polyols, glycerin, lipids, phospholipids, cyclodextrins, vegetable oils, petroleum, animal or synthetic oils can be used. Lipids are particularly preferred, and phospholipids (preferably of natural origin; particularly preferred are those with a particle size of 300-350 nm) in phosphate-buffered saline (pH = 7-8, preferably 7.4) are more preferred. For suppositories, excipients such as vegetable oils, petroleum, animal or synthetic oils, waxes, fats, and polyols can be used. For aerosol formulations, compressed gases suitable for this purpose, such as oxygen, nitrogen, and carbon dioxide, can be used. Pharmaceutically useful agents may also contain additives for preservation and stabilization, such as UV stabilizers, emulsifiers, sweeteners, flavoring agents, salts for changing osmotic pressure, buffers, coating additives, and antioxidants.

[0146] Generally, for oral or parenteral administration to an adult weighing approximately 80 kg, a daily dose of about 1 mg to about 10,000 mg, preferably about 5 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded if indicated. The daily dose can be administered as a single dose or divided doses, or, for parenteral administration, as continuous infusion or subcutaneous injection.

[0147] According to a further preferred embodiment, the present invention provides a method for inhibiting the Pseudomonas aeruginosa virulence factor LasB in a subject, comprising administering to the subject an effective amount of a compound of general formula (I) or a pharmaceutically acceptable salt thereof.

[0148] According to a further preferred embodiment, the present invention provides a method for treating a bacterial infection, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of general formula (I) or a pharmaceutically acceptable salt thereof.

[0149] According to a further preferred embodiment, the present invention provides a method for treating a bacterial infection, comprising administering to a subject in need of such treatment a pharmaceutical composition comprising a compound of general formula (I) or a pharmaceutically acceptable salt thereof.

[0150] The gram-positive pathogen Clostridium histolyticum ( Clostridium histolyticum )(Recently, Hazewaya histolytica ( Hathewaya histolytica ), C. tetani ( C. tetani ) and Bacillus cereus ( Bacillus cereus) produce collagenases ColH and ColG (Clostridium histolyticum), ColT (C. tetani), and ColQ1 (B. cereus strain Q1) as virulence factors, which are attractive targets for the treatment of infections originating from these bacteria (Schoenauer, E.; Kany, A.M.; Haupenthal, J.; Huesecken, K.; Hoppe, I.J.; Voos, K.; Yahiaoui, S.; Elsaesser, B.; Ducho, C.; Brandstetter, H.; Hartmann, R.W. J. Am. Chem. Soc. 2017, 139 , 12696-12703). The compounds of the present invention are also potent inhibitors of these collagenases. [Example]

[0151] I. General Procedure:

[0152] Scheme 1 :α-substitution- N -arylmercaptoacetamide and α-substituted- N Synthesis of heteroarylmercaptoacetamides

[0153] [ka]

[0154] (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

[0155] General Procedure A: Synthesis of 2-chloroalkanoic acids (1) The amino acid (1.0 equiv.) was 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 equiv.) was dissolved in water (0.3 mL / mmol amino acid) and slowly added dropwise. The mixture was stirred overnight while warming to room temperature. The reaction mixture was extracted with EtOAc / THF (3:1, 3x). The combined organic extracts were washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and filtered. The solvent was removed under reduced pressure to give the crude product, which was used in the next step without further purification.

[0156] General Procedure B-1: Synthesis of N-aryl-2-halo-2-alkylacetamide derivatives (3) 2-Haloalkanoic acid (1.2 equiv.) (crude 2-chloroalkanoic acid (1) or commercially available 2-bromoalkanoic acid (2)) and EDC·HCl (1.2 equiv.) were added to a DCM solution of the corresponding aniline (1.0 equiv.). 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 1 M HCl and saturated aqueous NaCl. The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The resulting crude product was used in the next step without further purification or purified using column chromatography.

[0157] General Procedure B-2: Synthesis of N-heteroaryl-2-halo-2-alkylacetamide derivatives (3) 2-Haloalkanoic acid (1.0 equiv.) (crude 2-chloroalkanoic acid (1) or commercially available 2-bromoalkanoic acid (2)) was dissolved in THF. EtN (1.0 equiv.) was added to this solution at room temperature, followed by dropwise addition of ethyl chloroformate (1.1 equiv.). A solution of the corresponding heterocyclic amine (0.8 equiv.) was dissolved in THF and added dropwise to this mixture. The reaction was stirred overnight at room temperature. THF was evaporated, the crude solid was dissolved in DCM, and the solution was washed with aqueous KHCO (10% wt.) and water. The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The resulting crude product was purified by flash chromatography.

[0158] General Procedure C: Synthesis of N-aryl-2-thioacetyl-2-alkylacetamide derivatives and N-heteroaryl-2-thioacetyl-2-alkylacetamide derivatives (4) N -aryl-2-halo-2-alkylacetamide derivatives or N The 2-heteroaryl-2-halo-2-alkylacetamide derivative (1.0 equiv.) ((3) purified or crude) was dissolved in acetone, and potassium thioacetate (2.0 equiv.) was added to the solution. The resulting mixture was stirred at room temperature until complete conversion (monitored by TLC or LC-MS). After concentration in vacuo, the resulting residue was diluted with HO and extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous NaSO, filtered, and evaporated under reduced pressure. The crude residue was purified using column chromatography.

[0159] General Procedure D: Synthesis of N-aryl-2-mercapto-2-alkylacetamide derivatives and N-heteroaryl-2-mercapto-2-alkylacetamide derivatives (II) NaOH (3.0 equiv.) was added to a solution of compound 4 (1.0 equiv.) in MeOH under an argon atmosphere. The reaction was stirred at room temperature. The reaction mixture was acidified with 2 M HCl and extracted with EtOAc. The resulting organic layer was washed with 0.5 M HCl solution and saturated aqueous NaCl, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. In the case of heterocyclic derivatives, the pH was adjusted to an acidic value using Amberlite IR-120 instead of HCl. The products were either obtained pure or purified using column chromatography or preparative HPLC.

[0160] Scheme 2 :Synthesis of phosphonic acid derivatives

[0161] [ka]

[0162] (a) EDC·HCl, DCM, room temperature; (b) P(OEt)3, neat, 150 °C; (c) i) TMSBr, DCM, room temperature; ii) MeOH, room temperature.

[0163] General Procedure E: Synthesis of diethylphosphonate derivatives (5) NThe -aryl-2-bromo-2-alkylacetamide derivative (3) (1.0 equiv.) was suspended in triethyl phosphite (10 equiv.), equipped with a reflux condenser, heated to 150° C., and stirred for a total of 18 h. Most of the unreacted triethyl phosphite was evaporated in vacuo, and the resulting oil was purified by column chromatography.

[0164] General Procedure F: Synthesis of Phosphonic Acid Derivatives (III) To a solution of diethylphosphonate (5) (1.0 equiv.) in dry DCM, bromotrimethylsilane (5.0 equiv.) was added dropwise over 15 min. The reaction mixture was stirred at room temperature overnight. MeOH was then added and stirred at room temperature for 30 min to cleave the previously formed TMS ester. The solvent was concentrated in vacuo, and the resulting oil was purified by preparative HPLC.

[0165] Scheme 3: Synthesis of α-phosphonic acid (2d)

[0166] [ka]

[0167] (a) HBr, NaNO2, H2O, 0 °C to room temperature, 2 hours, quantitative; (b) EtOH, catalytic H2SO4, reflux, 2 hours, 81%; (c) P(OEt)3, neat, 150 °C; 48 hours, 44%; (d) NaOH, EtOH, 0 °C to room temperature, 48 hours, 98%.

[0168] 2-Bromo-4-methylpentanoic acid (2a) 10.5 g of racemic leucine 1 (80.0 mmol, 1.0 equiv.) was dissolved in 48% HBr (80 mL) and 72 mL of distilled water. The mixture was cooled to 0 °C, and a solution of NaNO (8.82 g, 128.0 mmol, 1.6 equiv.) in 20 mL of distilled water was added dropwise over 2 h. The mixture was allowed to warm to room temperature and stirred overnight. It 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 saturated aqueous NaCl (400 mL), dried over MgSO, filtered, and concentrated under reduced pressure. Compound 2a (15.06 g, 80.0 mmol, quantitative) was obtained as a pale yellow liquid, which was used in the next step without further purification.

[0169] Ethyl 2-bromo-4-methylpentanoate (2b) To the α-bromo acid 2a (15.06 g, 80.0 mmol, 1.0 equiv.) was added a solution of concentrated sulfuric acid (30 μL / mmol) in ethanol (2 mL / mmol), and the mixture was refluxed for 2 h. The solution was then cooled to room temperature and concentrated under reduced pressure. EtO (150 mL) was added, and the organic layer was washed with saturated aqueous NaHCO (150 mL) followed by saturated aqueous NaCl (150 mL). The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. Compound 2b (14.45 g, 64.7 mmol, 81% yield) was used in the next step as a pale yellow liquid without further purification.

[0170] 2-(Diethoxyphosphoryl)-4-methylpentanoate (2c) The α-bromoester 2b (14.45 g, 64.7 mmol, 1.0 equiv.) and P(OEt) (22.41 mL, 129.4 mmol, 2.0 equiv.) were mixed and heated to 150 °C for 48 h. The mixture was then cooled to room temperature, and EtO (350 mL) was added. The mixture was transferred to a separatory funnel, washed with saturated aqueous NaCl (2 × 350 mL), dried over MgSO, filtered, and concentrated under reduced pressure. The product was purified using flash chromatography (SiO, hexane / EtOAc 1:1) to give compound 2c (7.93 g, 28.3 mmol, 44%) as a pale yellow oil. 1H NMR (CDCl3, 500 MHz) δ ppm: 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, 7.0 Hz), 1.28 (t, 3H, J = 7.2 Hz), 0.92 (d, 3H, J = 6.1 Hz), 0.89 (d, 3H, J = 6.3 Hz). 13 C NMR (CDCl3, 126 MHz) δ ppm: 169.4 (d, J = 5.5 Hz), 62.7 (d, J = 6.4 Hz), 62.6 (d, J = 6.4 Hz), 61.3, 44.5, 43.4, 35.5 (d, J = 5.5 Hz), 26.9 (d, J = 14.7 Hz), 22.9, 21.2, 16.4 (d, J = 3.7 Hz), 16.3 (d, J = 3.7 Hz), 14.1. 31 P NMR (CDCl3, 202 MHz) δ ppm: 23.4. HRMS (ESI+) calculated for C 12 H 26 O5P [M+1] + 281.1518, found: 281.1503.

[0171] 2-(Diethoxyphosphoryl)-4-methylpentanoic acid (2d) Compound 2c (7.93 g, 28.3 mmol, 1.0 equiv) was dissolved in EtOH (270 mL), and NaOH (2.15 g, 53.88 mmol, 2.0 equiv) and distilled HO (100 mL) were added. The mixture was stirred at room temperature overnight. LC-MS was used to monitor the progress. Upon completion, the mixture was transferred to a separatory funnel, distilled water (300 mL) and EtO (400 mL) were added, and the layers were separated. The aqueous layer was acidified to pH = 1 using HCl (6 M) and extracted with EtOAc (3 × 300 mL). The combined EtOAc layers were washed with saturated aqueous NaCl (2 × 500 mL), dried over MgSO, 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, 500 MHz) δ ppm: 8.33 (br s, 2H), 4.13-4.25 (m, 4H), 3.07 (ddd, 1H, J = 3.1, 11.3, 23.0 Hz), 1.99 (dddd, 1H, J = 4.8, 8.5, 11.4, 13.5 Hz), 1.58-1.70 (m, 1H), 1.49-1.57 (m, 1H), 1.33 (dt, 6H, J = 2.7, 7.1 Hz), 0.92 (d, 3H, J = 6.6 Hz), 0.89 (d, 3H, J = 6.6 Hz). 13 C NMR (CDCl3, 126 MHz) δ ppm: 171.9 (d, J = 3.7 Hz), 63.7 (d, J = 6.4 Hz), 62.9 (d, J = 6.4 Hz), 44.4, 43.4, 35.6 (d, J = 5.5 Hz), 26.8 (d, J = 13.8 Hz), 23.0, 21.2, 16.3 (d, J = 2.8 Hz), 16.2 (d, J = 2.8 Hz). 31P NMR (CDCl3, 202 MHz) δ ppm: 24.3. HRMS (ESI+) calculated for C 10 H 22 O5P [M+1] + 253.1205, found: 253.1191.

[0172] Scheme 4: Synthesis of bicyclic phosphonates

[0173] [ka]

[0174] (a) 2d, EDC·HCl, DCM, room temperature or TBTU, NMM, DCM (or DMF), 0° C. to room temperature; (b) TMSBr, DCM, room temperature; ii) MeOH, room temperature.

[0175] General Procedure G: Synthesis of diethylphosphonate derivatives (5a) Aniline (commercially available or synthesized according to conventional protocols that can be found in the literature or in the examples given in General Procedures G-1, G-2, G-3, G-4 below) (1.0 equivalent), 2-(diethoxyphosphoryl)-4-methylpentanoic acid (2d) (1.2 equivalents), and N N-methylmorpholine (2.5 equiv.) was dissolved in DCM or DMF. The reaction mixture was cooled in an ice bath, and TBTU (1.5 equiv.) was added. The temperature was maintained for 30 min and then warmed to room temperature. As another alternative route, EDC·HCl (2.0 equiv.), HOBt (2.0 equiv.), and DIPEA (2.5 equiv.) were used instead of TBTU / NMM. In both cases, the reaction mixture was stirred overnight and then washed with water and saturated aqueous NaCl. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The resulting crude product was used in the next step without further purification or purified using column chromatography.

[0176] General Procedure G-1: Amide Linker (CONH and CH 2 Synthesis of aniline using CONH The corresponding carboxylic acid (1.2 equiv.) was dissolved in DCM and EDC·HCl (1.2 equiv.) was added, followed by tert 4-Butyl (4-aminophenyl)carbamate (1.0 equiv.) was added. The reaction mixture was stirred at room temperature. If a precipitate formed, it was filtered and washed with DCM. If no precipitate formed, after consumption of the starting material, the reaction mixture was washed with 1 M HCl (×2) and saturated aqueous NaCl (×1) and purified by column chromatography. The resulting product was suspended in a DCM / TFA mixture (3:1) at 0 °C. The mixture was then stirred at room temperature for 2 h. The solvent was evaporated. EtOAc was added and washed with 2.5 M NaOH (×2) and saturated aqueous NaCl (×2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the desired aniline.

[0177] General Procedure G-2: Sulfonamide Linker (SO 2 NH and CH 2 SO 2 Synthesis of aniline using NH tert 4-Butyl (4-aminophenyl)carbamate (1.0 equiv.) was dissolved in DCM and cooled to 0 °C. EtN (1.2 equiv.) was added, followed by the corresponding sulfonyl chloride (1.1 equiv.). The reaction mixture was stirred at room temperature for 8 h. The precipitate was filtered, and the filtrate was purified by column chromatography. The resulting product was suspended in a DCM / TFA mixture (3:1) at 0 °C. The mixture was then stirred at room temperature for 2 h. The solvent was evaporated. EtOAc was added and washed with 2.5 M NaOH (×2) and saturated aqueous NaCl (×2). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the desired aniline.

[0178] General Procedure G-3: Ether Linker (CH 2 Synthesis of aniline using tert4-Butyl (4-hydroxyphenyl)carbamate (1.0 equiv.) was dissolved in DMF. Potassium carbonate (2.0 equiv.) was added and the reaction mixture was stirred for 15 min. The corresponding benzyl bromide was then added dropwise over 15 min and left stirring at room temperature overnight. Water was added, extracted with EtOAc (×3), and the organic layer was washed with saturated aqueous NaCl. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting product was suspended in a DCM / TFA mixture (3:1) at 0 °C. The mixture was then stirred at room temperature for 2 h. The solvent was evaporated. EtOAc was added and washed with 2.5 M NaOH (×2) and saturated aqueous NaCl (×2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the desired aniline.

[0179] General Procedure G-4: Synthesis of Anilines Without a Linker The arylamine (1.0 equiv.) was placed in a sealed tube, followed by the corresponding boronic acid (1.5 equiv.), 2M NaOH, tetrakis(triphenylphosphine)palladium (0.02 equiv.), and a mixture of dioxane / HO (4:1, v:v). The reaction mixture was flushed with N and subjected to microwave irradiation (150 °C, 150 W) for 20 min. After cooling to room temperature, the reaction was quenched by the addition of a mixture of EtOAc / HO (1:1, v:v). The aqueous layer was extracted with EtOAc (×3). The organic layer was washed with saturated aqueous NaCl (1×) and water (1×), dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified using column chromatography.

[0180] Scheme 5: Synthesis of dipeptide derivatives bearing a phosphonate zinc-binding motif

[0181] [ka]

[0182] (a) IBCF, NMM, -20 °C THF, 30 min, (b) i) HCl (4M in dioxane), room temperature, 12 h, ii) 2d, TBTU, NMM, DMF, 0 °C to room temperature, 12 h, c) TMSBr, room temperature, 12 h, preparative HPLC.

[0183] General Procedure H: Synthesis of aniline-substituted derivatives (6) The corresponding Boc-protected amino acid (1.0 equiv.) was dissolved in THF (0.1 M) and cooled to -20 °C. NMM (2.5 equiv.) and isobutyl chloroformate (1.0 equiv.) were then added dropwise. The reaction mixture was stirred at this temperature for 30 minutes, and then aniline (1.0 equiv.) 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 KHSO (1 N) solution, saturated NaHCO solution, and saturated aqueous NaCl solution, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. Column chromatography purification afforded the corresponding peptide.

[0184] General Procedure I: Synthesis of Fluorophore-Containing Dipeptide (5b) The Boc-protected peptide (1.0 equiv.) was dissolved in DCM (0.1 M) and treated with HCl (10.0 equiv., 4 M in dioxane) at 0 °C. The mixture was warmed to room temperature, and after complete conversion (TLC), the solvent was removed under reduced pressure to leave the crystalline hydrochloride salt, which was subsequently dissolved in DMF (0.1 M). 2-(Diethoxyphosphoryl)-4-methylpentanoic acid 2d (1.1 equiv.) was added to this solution, and the reaction mixture was cooled to 0 °C. Coupling was achieved with TBTU (1.1 equiv.) and NMM (2.5 equiv.). The reaction mixture was warmed to room temperature, and after complete conversion (TLC), it was diluted with EtOAc and washed successively with 1 N KHSO4 solution, saturated NaHCO3 solution, and saturated aqueous NaCl solution. The organic layer was dried over anhydrous Na2SO4, filtered, and the residue was used in the next step without further purification.

[0185] Scheme 6: Synthesis of triazole derivatives

[0186] [ka]

[0187] (a) i) HCl (4 M in dioxane), DCM, room temperature; 18 hours, ii) TBTU, NMM, DMF, 0 °C to room temperature, 22 hours; (b) CuSO4·5H2O, Na ascorbate, t BuOH / H2O / MeOH (2:2:1) RT, 14 h; (c) TMSBr, DCM, RT, overnight, preparative HPLC.

[0188] General Procedure J: Synthesis of Alkynyl Diethylphosphonates (8) The alkyne component 7 (1.0 equiv.), synthesized as previously reported (https: / / doi.org / 10.1002 / anie.201601564), was dissolved in DCM (10 mL / mmol) and HCl (10.0 equiv., 4 M in dioxane) was added at room temperature. The mixture was stirred for 18 h and then concentrated under reduced pressure. Meanwhile, a mixture of compound 2d (1.1 equiv.) and TBTU (1.2 equiv.) in DMF (5 mL / mmol) was cooled to 0 °C, and NMM (2.5 equiv.) was added. The reaction mixture was stirred for 30 min, and then the Boc-deprotected alkenyl amino acid was dissolved in DMF (5 mL / mmol) and added dropwise at 0 °C. The mixture was stirred for 22 h and allowed to warm to room temperature. After the addition of EtOAc, the organic layer was washed successively with saturated aqueous NaHCO3, 1 M HCl, water, and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by automated combiflash purification (Teledyne ISCO).

[0189] General Procedure K: Synthesis of 1H-1,2,3-triazole (5c) containing diethylphosphonate (https: / / doi.org / 10.1016 / j.ejmech.2019.06.007) of the corresponding alkenyl diethylphosphonate (1.0 equiv.) and azide (1.1 equiv.). tA solution of BuOH / HO / MeOH (2:2:1, 10 mL / mmol) was purged with argon. Sodium ascorbate (20 mol%) and CuSO4·5HO (10 mol%) were added, and the reaction mixture was stirred at room temperature for 14 h. Saturated EDTA solution was then added, and the mixture was extracted with EtOAc (×3). The combined organic layers were washed with saturated aqueous NH4Cl and saturated aqueous NaCl. After drying over anhydrous Na2SO4 and filtration, the solvent was removed under reduced pressure to give the title compound, which was used in the next step without further purification.

[0190] Scheme 7: Synthesis of imidazole derivatives

[0191] [ka]

[0192] (a) i) HCl (4 M in dioxane), DCM, room temperature; 18 hours, ii) TBTU, NMM, DMF, 0° C. to room temperature, 22 hours; (b) TMSBr, DCM, room temperature, overnight, preparative HPLC.

[0193] Scheme 8: Synthesis of benzene-annulated heteropentacycles

[0194] [ka]

[0195] (a) TBTU, NMM, DMF, 0 °C to RT, 2d; (b) HOAc / toluene (1:1), 110 °C, 3 h; (c) i) HCl (4 M in 1,4-dioxane), DCM, 18 h, RT; ii) TBTU, NMM, DMF, 0 °C to RT, 21 h; d) TMSBr, DCM, RT, 21 h, preparative HPLC.

[0196] General Procedure L: Synthesis of Benzene-Annulated Heteropentacycles (11) The corresponding Boc-protected amino acid (1.0 equiv.) was dissolved in DMF (10 mL / mmol). After cooling to 0 °C, NMM (1.1 equiv.) and TBTU (1.1 equiv.) were added sequentially. The reaction mixture was stirred for 30 min, and the corresponding nucleophile (1.0) was added. After 3 days, saturated aqueous NH4Cl was added, and the mixture was extracted with EtOAc (×3), followed by washing with saturated aqueous NaHCO3 and saturated aqueous NaCl. 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 saturated aqueous NaHCO3. After stirring for 20 min, the mixture was extracted with EtOAc (×3) and washed with 1 M HCl. After subsequent washing with saturated aqueous NaHCO3 (x4) and saturated aqueous NaCl, drying over anhydrous Na2SO4, filtration and concentration under reduced pressure, the title compound was obtained, which was used in the next step without further purification.

[0197] Scheme 9: Synthesis of hydroxamic acid derivatives

[0198] [ka]

[0199] (a) i) NaOH, EtOH / H2O, room temperature; ii) EDC·HCl, DCM, room temperature; b) NH2OH, KCN, MeOH, room temperature.

[0200] General Procedure M: Synthesis of ethyl ester derivative (12) Diethyl 2-alkylmalonate (1.0 equiv.) was dissolved in EtOH / HO (4:1) and NaOH (1.2 equiv.) was added. The reaction was stirred at room temperature overnight. EtOH was evaporated under reduced pressure, saturated aqueous NaHCO3 was added, and the mixture was extracted with DCM. The organic layer was discarded. The aqueous layer was acidified with 6 M HCl and extracted with DCM. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The resulting monoacid (1.2 equiv.) and EDC·HCl (1.2 equiv.) were added to a DCM solution of the corresponding aniline (1.0 equiv.). 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 1 M HCl and saturated aqueous NaCl. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified using column chromatography.

[0201] General Procedure N: Synthesis of Hydroxamic Acid Derivatives (IV) The ethyl ester derivative 12 (1.0 equiv.) was dissolved in MeOH. NHOH 50 wt.% in HO (same volume as methanol) was added, followed by KCN (0.2 equiv.). The mixture was stirred at room temperature overnight. The solvent was concentrated under reduced pressure, and the resulting oil was purified by preparative HPLC.

[0202] Scheme 10: Synthesis of triazole derivatives

[0203] [ka]

[0204] a)1 H -1,2,3-triazole, K2CO3, acetone, 70℃

[0205] General Procedure O: Synthesis of 1H-1,2,3-triazole (V) and 2H-1,2,3-triazole (VI) derivatives. N The 2-aryl-2-bromo-2-alkylacetamide derivative 3 (1.0 equivalent) was placed in a crimp vial and dissolved in acetone. H1,2,3-Triazole (1.1 equiv.) and K2CO3 (1.1 equiv.) were added, and the mixture was heated to 70 °C overnight. EtOAc was added, and the organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC.

[0206] II. Synthesis Examples Example 1 2-Chloro-3-phenylpropanoic acid.

[0207] [ka]

[0208] 2-Chloro-3-phenylpropanoic acid was prepared using D,L-phenylalanine (1.00 g, 6.0 mmol) and sodium nitrite (1.46 g, 21.2 mmol) according to general procedure A. The crude product was obtained as a pale yellow oil (1.05 g, 94%) and was used without further purification. 1 H NMR (500 MHz, CDCl3) δ ppm: 7.37-7.24 (m, 5H), 4.51 (dd, J = 7.8, 6.9 Hz, 1H), 3.42 (dd, J = 14.0, 6.7 Hz, 1H), 3.21 (dd, J = 14.1, 7.9 Hz, 1H). MS (ESI - ) m / z 183.25 (MH) - , 147.23 (MH-HCl) - .

[0209] 2-Chloro-N,3-diphenylpropanamide.

[0210] [ka]

[0211] 2-chloro- N,3-Diphenylpropanamide was prepared according to general procedure B-1 using 2-chloro-3-phenylpropanoic acid (934 mg, 5.06 mmol), EDC·HCl (786 mg, 5.06 mmol), and aniline (385 μL, 4.22 mmol). Purification was carried out by automated flash chromatography (hexane / EtOAc = 100:0 to 0:100). The product was obtained as a white solid (404 mg, 31%). 1 H NMR (500 MHz, DMSO- d 6) 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) + .

[0212] S-(1-oxo-3-phenyl-1-(phenylamino)propan-2-yl)ethanethioate.

[0213] [ka]

[0214] S -(1-oxo-3-phenyl-1-(phenylamino)propan-2-yl)ethanethioate with 2-chloro- N This compound was prepared according to general procedure C using 3-diphenylpropanamide (242 mg, 0.93 mmol) and potassium thioacetate (196 mg, 1.86 mmol). Purification was achieved by automated flash chromatography (hexane / EtOAc 100:0 to 0:100). The product was obtained as a colorless oil (127 mg, 46%). 1 H NMR (500 MHz, CDCl3) δ ppm: 7.96 (br s, 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 MS (ESI + ) m / z 300.17 (M+H) + , 258.10 (M-Ac+2H) + .

[0215] 2-Mercapto-N,3-diphenylpropanamide (1).

[0216] [ka]

[0217] 2-Mercapto- N ,3-diphenylpropanamide, S Prepared according to general procedure D using -(1-oxo-3-phenyl-1-(phenylamino)propan-2-yl)ethanethioate (127 mg, 0.42 mmol) and NaOH (50 mg, 1.3 mmol). Purification was carried out by automated flash chromatography (hexane / EtOAc = 100:0 to 0:100). The product was obtained as a white solid (46 mg, 43%). 1 H NMR (500 MHz, CDCl3) δ ppm: 8.02 ( br s, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.36-7.29 (m, 4H), 7.29-7.23 (m, 4H), 7.14 (t,J = 7.6 Hz, 1H), 3.72 (dd, J = 14.8, 6.6 Hz, 1H), 3.38 (dd, J = 13.8, 6.5 Hz, 1H), 3.24 (dd, J = 13.8, 6.8 Hz, 1H), 2.11 (d, J = 8.9 Hz, 1H). 13 C NMR (126 MHz, CDCl3) δ ppm: 169.5, 137.3, 137.2, 129.4, 129.0, 128.6, 127.1, 124.8, 120.0, 45.9, 41.5. HRMS (ESI + ) calculated for C 15 H 15 NOS [M+H] + 258.0947, found 258.0943.

[0218] Example 2 S-(4-methyl-1-oxo-1-(p-tolylamino)pentan-2-yl)ethanethioate.

[0219] [ka]

[0220] S -(4-methyl-1-oxo-1-( p (-tolylamino)pentan-2-yl)ethanethioate was synthesized in two steps. The first step was pThis reaction was carried out according to general procedure B-1 using 2-toluidine (80 mg, 0.75 mmol), 2-bromo-4-methylpentanoic acid (175 mg, 0.90 mmol), EDC·HCl (172 mg, 0.90 mmol), and DCM (5 mL). The reaction was stirred at room temperature for 5 hours. The resulting crude product was used in the next step without further purification. The second step was carried out according to general procedure C using the crude product from the first step, 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 using column chromatography (100% DCM). The product was obtained as a beige solid (131 mg, 63% over two steps). 1 H NMR (500 MHz, DMSO- d 6) δ ppm: 10.23 (s, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 4.27 ( br t, J = 7.5 Hz, 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 = 6.5 Hz, 3H), 0.88 (d, J = 6.5 Hz, 3H). 13 C NMR (126 MHz, DMSO- d 6) δ ppm: 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 + ) calculated for C 15 H 22 NO2S [M+H] + 280.1371, found 280.1358.

[0221] 2-Mercapto-4-methyl-N-(p-tolyl)pentanamide (2).

[0222] [ka]

[0223] 2-mercapto-4-methyl- N -( p -tolyl)pentanamide, S -(4-methyl-1-oxo-1-( p This compound was synthesized according to general procedure D using (-tolylamino)pentan-2-yl)ethanethioate (90 mg, 0.32 mmol), NaOH (39 mg, 0.97 mmol), and MeOH (5 mL). The reaction was stirred at room temperature for 2 h. The crude product was purified using preparative HPLC (HO(HCOOH 0.05%)-CHCN(HCOOH 0.05%): 9.0-1.0 to 0.0-10.0). The product was obtained as a beige solid (38 mg, 50%, MP=90°C). 1 H NMR (500 MHz, DMSO- d 6) δ ppm: 9.99 (s, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 3.51 (br t, J = 7.8 Hz, 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 = 7.0 Hz, 3H), 0.86 (d, J = 6.5 Hz, 3H). 13 C NMR (126 MHz, DMSO- d 6) δ ppm: 170.9, 136.5, 132.4, 129.2, 119.2, 44.4, 39.9, 25.8, 22.2, 22.1, 20.5. HRMS (ESI + ) calculated for C 13 H 20 NOS [M+H] + 238.1266, found 238.1254.

[0224] [Table 1]

[0225] TIFF2025148472000030.tif149159

[0226] TIFF2025148472000031.tif67159

[0227] Example 63 Diethyl (4-methyl-1-oxo-1-(p-tolylamino)pentan-2-yl)phosphonate.

[0228] [ka] Diethyl (4-methyl-1-oxo-1-( p (-tolylamino)pentan-2-yl)phosphonate was synthesized in two steps. The first step was p This was carried out according to general procedure B-1 using 2-toluidine (92 mg, 0.85 mmol), 2-bromo-4-methylpentanoic acid (200 mg, 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 resulting crude product was used in the next step without further purification. The second step was accomplished according to general procedure E using the crude product from the first step and triethyl phosphite (1.5 mL, 17.1 mmol). The crude product was purified using column chromatography (hexane / EtOAc = 1:1). The product was obtained as a white solid (114 mg, 39% over two steps). 1 H NMR (500 MHz, CDCl3) δ ppm: 8.41 (s, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 4.21-4.08 (m, 4H), 2.97 (ddd, J= 22.6, 11.3, 3.5 Hz, 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 = 7.1 Hz, 6H), 0.97-0.91 (m, 6H). 13 C NMR (126 MHz, CDCl3) δ ppm: 165.6 ( J = 1.8 Hz), 135.3, 133.8, 129.4, 119.8, 63.0 ( J = 7.4 Hz), 62.8 ( J = 6.4 Hz), 45.2 ( J = 128.6 Hz), 35.8 ( J = 4.6 Hz), 26.6 ( J = 13.8 Hz), 23.2, 21.2, 20.8, 16.4 ( J = 1.8 Hz), 16.4 ( J = 2.8 Hz). MS (ESI + ) m / z 342.2 [M+H] + .

[0229] (4-Methyl-1-oxo-1-(p-tolylamino)pentan-2-yl)phosphonic acid (63).

[0230] [ka]

[0231] (4-methyl-1-oxo-1-( p -tolylamino)pentan-2-yl)phosphonic acid with diethyl (4-methyl-1-oxo-1-( pThis compound was synthesized according to general procedure F using (-tolylamino)pentan-2-yl)phosphonate (110 mg, 0.32 mmol), bromotrimethylsilane (213 μL, 1.61 mmol), and DCM (6 mL). The reaction was stirred at room temperature overnight. MeOH (10 mL) was then added, the reaction mixture was stirred for an additional 30 minutes, and the solvent was evaporated under reduced pressure. The crude product was purified using preparative HPLC (CHCN(HCOOH 0.05%)-HO(HCOOH 0.05%): 1.0:9.0 to 10.0:0.0). The product was obtained as a white solid (56 mg, 71%). 1 H NMR (500 MHz, DMSO- d 6) δ ppm: 9.84 (s, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.2 Hz, 2H), 2.95 (ddd, J = 22.4, 11.4, 2.9 Hz, 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 (126 MHz, DMSO- d 6) δ ppm: 167.6 ( J = 4.6 Hz), 137.0, 131.8, 129.0, 119.0, 46.0 ( J = 126.8 Hz), 35.8 ( J = 3.7 Hz), 26.5 ( J = 14.7 Hz), 23.3, 21.4, 20.5. 31 P NMR (202 MHz, DMSO- d 6) δ ppm: 20.1. HRMS (ESI - ) calculated for C 13 H 19 NO4P [MH] - 284.1057, found 284.1058.

[0232] Example 95 Scheme 11:Synthesis of linker-free biphenyl derivatives.

[0233] [ka]

[0234] (a) Pd(PPh3)4, dioxane / H2O (4:1, v:v, 3 mL), NaOH (2M), microwave (150 °C, 150 W, 20 min); b) EDC·HCl, DCM, room temperature, 2 h; c) i) TMSBr, DCM, room temperature, overnight; ii) MeOH, room temperature.

[0235] Diethyl (1-((2-(4-isopropoxyphenyl)pyrimidin-5-yl)amino)-4-methyl-1-oxopentan-2-yl)phosphonate.

[0236] [ka]

[0237] Diethyl (1-((2-(4-isopropoxyphenyl)pyrimidin-5-yl)amino)-4-methyl-1-oxopentan-2-yl)phosphonate was synthesized according to general procedure G using 2-(4-isopropoxyphenyl)pyrimidin-5-amine (60 mg, 0.26 mmol), synthesized according to general procedure G-4, 2d (100 mg, 0.40 mmol), EDC·HCl (100 mg, 0.52 mmol) in DCM (5 mL). The crude product was purified using column chromatography (DCM / MeOH 0% to 3%). The product was obtained as a white solid (84 mg, 69%). 1 H NMR (500 MHz, CDCl3) δ ppm:10.27 (s, 1H), 8.79 (s, 2H), 7.90 (d, J = 8.8 Hz, 2H), 6.69 (d, J = 8.8 Hz, 2H), 4.50 (hept, J = 6.0 Hz, 1H), 4.32 - 4.17 (m, 2H), 4.10 (p, J = 7.2 Hz, 2H), 3.34 (ddd, J= 22.8, 11.3, 2.8 Hz, 1H), 2.17 - 2.06 (m, 1H), 1.60 - 1.52 (m, 1H), 1.43 (dtd, J = 13.1, 10.2, 2.9 Hz, 1H), 1.31 (ddd, J = 19.2, 12.6, 6.2 Hz, 12H), 0.86 (dd, J = 13.1, 6.5 Hz, 6H). MS (ESI + ) m / z 464 [M+H] + .

[0238] (1-((2-(4-isopropoxyphenyl)pyrimidin-5-yl)amino)-4-methyl-1-oxopentan-2-yl)phosphonic acid (95).

[0239] [ka]

[0240] (1-((2-(4-isopropoxyphenyl)pyrimidin-5-yl)amino)-4-methyl-1-oxopentan-2-yl)phosphonic acid (95) was synthesized according to general procedure F using diethyl (1-((2-(4-isopropoxyphenyl)pyrimidin-5-yl)amino)-4-methyl-1-oxopentan-2-yl)phosphonate (65 mg, 0.14 mmol), bromotrimethylsilane (100 μL, 0.72 mmol), and DCM (4 mL). The reaction was stirred at room temperature overnight. MeOH (4 mL) was then added, the reaction mixture was stirred for an additional 30 min, and the solvent was evaporated under reduced pressure. The crude product was purified using preparative HPLC (CHCN(HCOOH 0.05%)-HO(HCOOH 0.05%). The product was obtained as a white solid (41 mg, 72%). 1 H NMR (500 MHz, DMSO- d 6) δ ppm: 10.46 (s, 1H), 9.05 (s, 2H), 8.24 (d, J = 8.9 Hz, 2H), 7.01 (d, J = 8.9 Hz, 2H), 4.70 (dt, J= 12.1, 6.0 Hz, 1H), 3.04 (ddd, J = 22.4, 11.1, 2.3 Hz, 1H), 2.00 (ddd, J = 15.4, 10.0, 3.7 Hz, 1H), 1.61 - 1.35 (m, 2H), 1.30 (d, J = 6.0 Hz, 6H), 0.88 (d, J = 6.3 Hz, 6H). 13 C NMR (126 MHz, DMSO- d 6) δ ppm: 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 (202 MHz, DMSO- d 6) δ ppm: 18.93. MS (ESI + ) m / z 408 [M+H] + .

[0241] Example 108 Scheme 12: Synthesis of biphenyl derivatives bearing sulfonamide linkers.

[0242] [ka]

[0243] (a) i) Et3N, DCM, 0 °C–RT, 8 h; ii) TFA, DCM, RT, 2 h; b) EDC·HCl, DCM, RT, overnight; c) TMSBr, DCM, RT, overnight.

[0244] N-(4-aminophenyl)-3,4-dichlorobenzenesulfonamide.

[0245] [ka]

[0246] N -(4-Aminophenyl)-3,4-dichlorobenzenesulfonamide was synthesized according to general procedure G-2 using tert-butyl(4-aminophenyl)carbamate (300 mg, 1.44 mmol), EtN (240 μL, 1.73 mmol), and 3,4-dichlorobenzenesulfonyl chloride (250 μL, 1.58 mmol) in DCM (10 mL). The reaction 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). tert tert-butyl (4-((3,4-dichlorophenyl)sulfonamido)phenyl)carbamate (316 mg, 52%) was obtained. The obtained tert-butyl (4-((3,4-dichlorophenyl)sulfonamido)phenyl)carbamate was suspended in 3.5 mL of DCM / TFA (3:1) and stirred at room temperature for 2 hours. After workup, N -(4-aminophenyl)-3,4-dichlorobenzenesulfonamide (193 mg, 81%) was obtained as a beige solid. 1 H NMR (500 MHz, DMSO- d 6) δ ppm: 9.65 (br s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 8.5, 2.1 Hz, 1H), 6.66 (d, J = 8.7 Hz, 2H), 6.40 (d, J = 8.7 Hz, 2H), 5.01 (br s, 2H). MS (ESI - ) m / z 314.99 [MH] - .

[0247] Diethyl (1-((4-((3,4-dichlorophenyl)sulfonamido)phenyl)amino)-4-methyl-1-oxopentan-2-yl)phosphonate.

[0248] [ka]

[0249] Diethyl (1-((4-((3,4-dichlorophenyl)sulfonamido)phenyl)amino)-4-methyl-1-oxopentan-2-yl)phosphonate in DCM (5 mL) N This was synthesized according to general procedure G using 2d (100 mg, 0.40 mmol), EDC·HCl (100 mg, 0.52 mmol), HOBt (80 mg, 0.52 mmol), and DIPEA (110 μL, 0.62 mmol). The crude product was purified using column chromatography (hexane / EtOAc = 3 / 7). The product was obtained as a white foam (84 mg, 58%). 1 H NMR (500 MHz, DMSO- d 6) δ ppm: 10.27 (br s, 1H), 10.11 (s, 1H), 7.88 (d, J = 2.1 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.61 (dd, J = 8.4, 2.1 Hz, 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, 3.1 Hz, 1H), 1.98-1.88 (m, 1H), 1.49-1.29 (m, 2H), 1.18 (dt, J = 9.1, 7.1 Hz, 6H), 0.85 (d, J = 6.6 Hz, 6H). MS (ESI + ) m / z 551.12 [M+H] + .

[0250] (1-((4-((3,4-dichlorophenyl)sulfonamido)phenyl)amino)-4-methyl-1-oxopentan-2-yl)phosphonic acid (108).

[0251] [ka]

[0252] (1-((4-((3,4-dichlorophenyl)sulfonamido)phenyl)amino)-4-methyl-1-oxopentan-2-yl)phosphonic acid was synthesized according to general procedure F using diethyl (1-((4-((3,4-dichlorophenyl)sulfonamido)phenyl)amino)-4-methyl-1-oxopentan-2-yl)phosphonate (80 mg, 0.14 mmol), bromotrimethylsilane (100 μL, 0.72 mmol), and DCM (4 mL). The reaction was stirred at room temperature overnight. MeOH (4 mL) was then added, the reaction mixture was stirred for an additional 30 min, and the solvent was evaporated under reduced pressure. The crude product was purified using preparative HPLC (CHCN(HCOOH 0.05%)-HO(HCOOH 0.05%): 1.0:9.0 to 10.0:0.0). The product was obtained as a white solid (48 mg, 70%). 1 H NMR (500 MHz, DMSO- d 6) δ ppm: 10.22 (s, 1H), 9.92 (s, 1H), 7.89 (d, J = 2.1 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.60 (dd, J = 8.4, 2.1 Hz, 1H), 7.51-7.46 (m, 2H), 7.01-6.97 (m, 2H), 2.93 (ddd, J = 22.5, 11.3, 2.8 Hz, 1H), 1.97-1.88 (m, 1H), 1.49-1.34 (m, 2H), 0.83 (d, J = 6.4 Hz, 6H). 13 C NMR (126 MHz, DMSO- d 6) δ ppm: 167.8 (d, J = 5.5 Hz), 139.66, 136.86, 135.99, 132.15, 131.73, 131.51, 128.40, 126.85, 122.33, 119.82, 46.0 (d, J = 126.8 Hz), 35.7 (d, J = 3.7 Hz), 26.4 (d, J= 14.7 Hz), 23.2, 21.3. 31 P NMR (202 MHz, DMSO- d 6) δ ppm: 19.8. HRMS (ESI - ) calculated for C 18 H 20 Cl2N2O6PS [MH] - 493.0162, found 493.0156.

[0253] Example 147 Scheme 13: Synthesis of biphenyl derivatives with methylene linkers.

[0254] [ka]

[0255] (a) Et3N (3 eq.), DCM, room temperature, 16 h; b) TFA (5 eq.), DCM, room temperature, 19 h; c) EDC·HCl (1.2 eq.), HOBt (1.2 eq.), DIPEA (2.4 eq.), DMF, room temperature, 18 h; d) TMSBr (7 eq.), DCM, room temperature, 23 h.

[0256] Tert-butyl-(S)-(1-(4-chlorobenzyl)piperidin-3-yl)carbamate.

[0257] [ka]

[0258] In a heated and dried 50 mL Schlenk tube, S)-3-(Boc-amino)piperidine (200.3 mg, 1 mmol, 1 equiv.) and 4-chlorobenzyl bromide (205.5 mg, 1 mmol, 1 equiv.) were added and dissolved in dry DCM (2.5 mL, 0.4 mL), followed by the addition of EtN (303.6 mg, 418.1 μL, 3 mmol, 3 equiv.) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature, and upon completion of the reaction (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 NaSO, filtered, and the volatiles were removed under reduced pressure to give the title compound as an off-white solid (322 mg), which was used in the next step without further purification.

[0259] (S)-1-(4-chlorobenzyl)piperidin-3-amine.

[0260] [ka]

[0261] In a 50 mL Schlenk tube, tert -butyl-( S )-(1-(4-chlorobenzyl)piperidin-3-yl)carbamate (322 mg, ca. 0.99 mmol, 1 eq.) was dissolved in DCM (3 mL, 0.4 m). To the resulting solution was added TFA (383 μL, 5 eq.), and the reaction mixture was continued to stir at room temperature. After completion of the reaction (LCMS, 19 h), the solvent was removed under reduced pressure to give 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 NaSO, filtered, and the volatiles were removed under reduced pressure to give the title compound as an oil (207 mg), which was used in the next step without further purification.

[0262] Diethyl (1-(((S)-1-(4-chlorobenzyl)piperidin-3-yl)amino)-4-methyl-1-oxopentan-2-yl)phosphonate.

[0263] [ka]

[0264] In a 4 mL glass vial,S )-1-(4-Chlorobenzyl)piperidin-3-amine (50 mg, ca. 0.22 mmol, 1 equiv.), 2-(diethoxyphosphoryl)-4-methylpentanoic acid 2d (84.2 mg, 0.33 mmol, 1.5 equiv.), and HOBt·HO (68.2 mg, 0.44 mmol, 2 equiv.) were dissolved in DMF (1.5 mL). To the resulting solution, EDC·HCl (85.3 mg, 0.44 mmol, 2 equiv.) and DIPEA (93 μL, 0.53 mmol, 2.4 equiv.) were added, and the reaction was continued stirring at room temperature. After complete conversion (LCMS, 18 h), water (5 mL) and EtOAc (5 mL) were added to the reaction. The organic phase was removed, and the aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic phase was 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.

[0265] (1-(((S)-1-(4-chlorobenzyl)piperidin-3-yl)amino)-4-methyl-1-oxopentan-2-yl)phosphonic acid (147).

[0266] [ka]

[0267] In a heated and dried 25 mL Schlenk tube, add crude diethyl ether (1-((( S )-1-(4-chlorobenzyl)piperidin-3-yl)amino)-4-methyl-1-oxopentan-2-yl)phosphonate (53 mg, 0.115 mmol, 1 equiv.) and dry DCM (1 mL) were added under argon. To the resulting solution, bromotrimethylsilane (107 μL, 0.81 mmol, 7 equiv.) was added dropwise, and the reaction was continued to stir at room temperature. After completion of the reaction (LCMS, 23 h), MeOH (2 mL) was added and stirred at room temperature for 30 min. Volatiles were removed under reduced pressure, and the crude product was purified by preparative HPLC to afford the title compound as a white amorphous solid (21 mg, 0.052 mmol, 45%). Mixture of diastereomers: Main diastereomer: 1 H NMR (500 MHz, DMSO- d6) δ ppm: 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, 5.8 Hz, 6H). 13 C NMR (126 MHz, DMSO - d 6) δ 169.4, 158.6 (dd, J = 31.2, 30.6 Hz), 134.8, 133.8, 133.7, 129.3, 58.7, 54.3, 51.0, 45.9 (d, J = 124.0 Hz), 43.9, 36.0, 26.9 (t, J = 14.5 Hz), 23.6, 21.8. 31 P NMR (202 MHz, DMSO - d 6) δ ppm: 19.7. Minor diastereomer: 1 H NMR (500 MHz, DMSO - d 6) δ ppm: 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,​​​​​​​​​​​= 33.1, 15.6 Hz), 23.6, 21.8. 31 P NMR (202 MHz, DMSO- d 6) δ ppm: 19.6. HRMS (ESI+) calculated for C 18 H 29 ClN2O4P [M+1] + 403.1553, found 403.1537.

[0268] Example 151 Tert-butyl (3-((3,4-dichlorophenyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)carbamate.

[0269] [ka]

[0270] 3-(( tert (-Butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (46.6 mg, 0.205 mmol, 1.0 equiv.) was prepared as previously described (https: / / doi.org / 10.1002 / ejoc.201701296), dissolved in DMF (2 mL), cooled to 0 °C, and TBTU (73.0 mg, 0.23 mmol, 1.1 equiv.) was added, followed by NMM (24 μL, 0.23 mmol, 1.1 equiv.). The reaction mixture was stirred at the indicated temperature for 1 h, and then 3,4-dichloroaniline (33 mg, 0.205 mmol) was added. After stirring for 16 h and warming to room temperature, EtOAc was added, followed by washing with saturated NaHCO3 solution, 1 M HCl, water, and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound as a colorless solid (42 mg, 0.113 mmol, 55%), which was used in the next step without further purification. 1 H NMR (CDCl3, 500 MHz) δ ppm: 7.77-7.76 (m, 1 H), 7.38-7.37 (m, 2 H), 7.12 (bs, 1 H), 5.00 (bs, 1 H), 2.37 (s, 6 H), 1.47 (s, 9 H).13 C NMR (CDCl3, 126 MHz) δ ppm: 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

[0271] Diethyl (1-((3-((3,4-dichlorophenyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)amino)-4-methyl-1-oxopentan-2-yl)phosphonate.

[0272] [ka]

[0273] The title compound was prepared according to general procedure I. tert -butyl (3-((3,4-dichlorophenyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)carbamate (40 mg, 0.108 mmol) and HCl (0.27 mmol, 1.08 mmol, 4 M in dioxane) were used for deprotection. 2-(Diethoxyphosphoryl)-4-methylpentanoic acid 2d (30 mg, 0.119 mmol), NMM (31 μL, 0.298 mmol), and TBTU (43 mg, 0.131 mmol) were used for peptide coupling to give the title compound as a yellow oil (36.7 mg, 0.073 mmol, 67%), which was used in the next step without further purification. MS (ESI+): m / z [M+H] + =506.

[0274] (1-((3-((3,4-Dichlorophenyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)amino)-4-methyl-1-oxopentan-2-yl)phosphonic acid (151).

[0275] [ka]

[0276] The title compound was prepared according to general procedure F. Diethyl (1-((3-((3,4-dichlorophenyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)amino)-4-methyl-1-oxopentan-2-yl)phosphonate (36 mg, 0.071 mmol) and bromotrimethylsilane (47 μL, 0.356 mmol) were used to afford the title compound as a colorless solid (8.6 mg, 0.019 mmol, 27%) after purification by preparative HPLC. Mixture of diastereomers 1 H NMR (500 MHz, acetone- d 6) δ ppm: 8.05 (d, J = 2.3 Hz, 1 H), 7.62 (dd, J = 8.9 Hz, J = 2.3 Hz, 1 H), 7.44 (d, J = 8.9 Hz, 1 H), 3.02-2.94 (m, 1 H), 2.40 (s, 6 H), 2.01-1.98 (m, 1 H), 1.65-1.61 (m, 1 H), 1.59-1.53 ​​(m, 1 H), 0.92 (d, J = 6.3 Hz, 6 H). 13 C NMR (126 MHz, acetone- d 6) δ ppm: 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- d 6) δ ppm: 24.7, 24.6. HRMS (ESI+) calculated for C 18 H 24 Cl2N2O5P [M+H] + 449.0794, found: 449.0798.

[0277] Example 152 Tert-butyl (S)-(1-((3,4-dichlorophenyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate.

[0278] [ka]

[0279] ( tert (-butoxycarbonyl)-L-valine (434 mg, 2.0 mmol, 1.0 equiv.) was dissolved in THF (20 mL, 0.1 M) and cooled to -20 °C. NMM (0.55 mL, 2.5 equiv.) and isobutyl chloroformate (0.259 mL, 1.0 equiv.) were then added dropwise. The reaction mixture was stirred at this temperature for 30 min, and then aniline (324 mg, 2 mmol, 1.0 equiv.) 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 KHSO (1 N) solution, saturated aqueous NaHCO and saturated aqueous NaCl, dried over NaSO, filtered, and the solvent was removed under reduced pressure. Purification by column chromatography (SiO, hexane / EtOAc 9:1) gave the corresponding HCl (4.0%). tert -butyl( S )-(1-((3,4-dichlorophenyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (523.8 mg, 1.44 mmol, 72% yield). 1 H NMR (500 MHz, CDCl3) δ ppm: 8.85 (br s, 1H), 7.70 (br s, 1H), 7.2-7.3 (m, 2H), 5.27 (br d, 1H, J = 8.2 Hz), 4.06 (br t, 1H, J = 7.6 Hz), 2.15 (br d, 1H, J = 6.1 Hz), 1.47 (s, 9H), 1.03 (dd, 6H, J = 2.7, 6.7 Hz). 13 C NMR (126 MHz, CDCl3,) δ ppm: 170.7, 137.2, 132.5, 130.2, 121.2, 118.6, 61.1, 30.5, 28.3, 19.3, 18.4. HRMS (ESI+) calculated for C 16 H 23Cl2N2O3[M+H] + 361.1080, found 361.1080.

[0280] (1-(((S)-1-((3,4-dichlorophenyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)phosphonic acid (152).

[0281] [ka]

[0282] tert -butyl( S )-(1-((3,4-Dichlorophenyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (100.0 mg, 0.28 mmol, 1.0 equiv) was dissolved in DCM (0.1 M) and treated with HCl (0.69 mL, 10.0 equiv, 4 M in dioxane) at 0 °C. The mixture was warmed to room temperature, and after complete conversion (TLC), the solvent was removed under reduced pressure to leave the crystalline hydrochloride salt, 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 equiv) was added to this solution, and the reaction mixture was cooled to 0 °C. Coupling was achieved with TBTU (98.9 mg, 0.308 mmol, 1.1 equiv.) and NMM (0.08 mL, 2.5 equiv.). The reaction mixture was warmed to room temperature, and after complete reaction (TLC), it was diluted with EtOAc and washed successively with 1N KHSO4 solution, saturated NaHCO3 solution, and saturated aqueous NaCl solution. After drying over Na2SO4 and removing the solvent under reduced pressure, the residue diethyl (1-((( S)-1-((3,4-dichlorophenyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)phosphonate (136.7 mg, 0.28 mmol, quantitative) was used in the next step without further purification. To a solution of diethylphosphonate dipeptide (136.7 mg, 0.28 mmol) in DCM (0.1 M), bromotrimethylsilane (0.26 mL, 1.93 mmol) was added dropwise over 15 min. The reaction mixture was stirred at room temperature overnight. MeOH was then added and stirred at room temperature for 30 min to cleave the previously formed TMS ester. The solvent was removed under reduced pressure and the crude product was purified by a Waters Autopurifier System (APS) equipped with a Phenomenex Gemini C18 column (250 × 4.6 mm, 5 μm particle size) using mass-triggered detection to give dipeptide 152 (51.7 mg, 0.12 mmol, 43%) as a white amorphous solid. Mixture of diastereomers: Main diastereomer: 1 H NMR (500 MHz, MeOH- d 4,) δ ppm: 8.04 (d, 1H, J = 2.4 Hz), 7.62 (dd, 1H, J = 2.4, 8.9 Hz), 7.42 (d, 1H, J = 8.9 Hz), 4.45 (d, 1H, J = 5.0 Hz), 3.24 (ddd, 1H, J = 2.7, 11.6, 23.3 Hz), 2.42 (qd, 1H, J = 6.9, 12.1 Hz), 1.47-1.61 (m, 3H), 0.9-1.1 (m, 19H), 0.99 (d, 3H, J = 7.02 Hz), 0.98 (d, 3H, J = 6.87 Hz), 0.95 (d, 6H, J = 6.56 Hz). 13 C NMR (126 MHz, MeOH- d 4) δ ppm: 172.7, 172.5 (d,J = 4.6 Hz), 139.6, 133.2, 131.5, 128.2, 123.5, 121.6, 60.7, 47.1, 46.0, 36.3 (d, J = 4.6 Hz), 31.2, 28.4 (d, J = 15.6 Hz), 23.7, 21.8, 19.9, 17.8 31 P NMR (202 MHz, MeOH-d4) δ ppm: 22.7. Minor diastereomer: 1 H NMR (500 MHz, MeOH-<​​​​​​​​​​​​​​​​​​​​​​​​​​​​​Cl2N2O5P [M+H] + 439.0956, 439.0935.

[0283] Example 170 Scheme 14: Synthesis of triazole derivatives exemplified as compound 170.

[0284] [ka]

[0285] (a) i) HCl (4 M in dioxane), DCM, room temperature, 18 hours; ii) TBTU, NMM, DMF, 0 °C to room temperature, 22 hours, 76% (over two steps); (b) CuSO4·5H2O, Na ascorbate, t BuOH / H2O / MeOH (2:2:1) room temperature, 14 hours, 84%; (c) TMSBr, DCM, room temperature, 23 hours, preparative HPLC, 26%.

[0286] Diethyl (4-methyl-1-(((S)-4-methylpent-1-yn-3-yl)amino)-1-oxopentan-2-yl)phosphonate.

[0287] [ka]

[0288] The compound was synthesized as previously reported (https: / / doi.org / 10.1002 / anie.201601564). tert -butyl( S)-(4-Methylpent-1-yn-3-yl)carbamate (282 mg, 1.43 mmol) was dissolved in DCM (11 mL) and HCl (2.85 mL, 11.4 mmol, 4 M in dioxane) was added at room temperature to give the corresponding Boc-deprotected alkynylamine 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 previously prepared Boc-deprotected alkynylamine hydrochloride, dissolved in DMF (7.5 mL), was added dropwise at 0 °C. The mixture was stirred for 22 hours and allowed to warm to room temperature. After adding EtOAc, the organic layer was washed successively with saturated aqueous NaHCO3, 1 M HCl, water, and saturated aqueous NaCl. The organic layer was dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by automated combiflash purification (Teledyne ISCO) to give 359 mg of diethyl (4-methyl-1-((( S To obtain )-4-methylpent-1-yn-3-yl)amino)-1-oxopentan-2-yl)phosphonate (1.08 mmol, 76% over two steps). 1 H NMR (500 MHz, CDCl3) δ ppm: 6.68-6.58 (m, 1 H), 4.67-4.64 (m, 1 H), 4.18-4.09 (m, 4 H), 2.87-2.80 (m, 1 H), 2.24-2.23 (m, 1 H), MS (ESI+): m / z [M+H] + = 332.

[0289] Diethyl (1-(((S)-1-(1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)-2-methylpropyl)amino)-4-methyl-1-oxopentan-2-yl)phosphonate.

[0290] [ka]

[0291] 4-Azido-1,2-dichlorobenzene (170 mg, 0.904 mmol) and (4-methyl-1-((( S 2 mL of )-4-methylpent-1-yn-3-yl)amino)-1-oxopentan-2-yl)phosphonate (293 mg, 0.89 mmol) t A BuOH / HO / MeOH (2:2:1) solution was purged with argon. Na ascorbate (20 mol%) and CuSO4·5HO (10 mol%) were added, and the reaction mixture was stirred at room temperature for 14 h. Saturated EDTA solution was then added, the mixture was extracted with EtOAc (×3), and the combined organic layers were washed with saturated aqueous NH4Cl and saturated aqueous NaCl. After drying over Na2SO4 and filtration, the solvent was evaporated to give the title compound (394 mg, 0.759 mmol, 84%, mixture of diastereomers), which was used in the next step without further purification. MS (ESI+): m / z [M+H] + =520.

[0292] (1-(((S)-1-(1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)-2-methylpropyl)amino)-4-methyl-1-oxopentan-2-yl)phosphonic acid (170).

[0293] [ka]

[0294] The title compound was prepared according to general procedure F. 52 mg (0.100 mmol) of compound diethyl (1-((( S )-1-(1-(3,4-dichlorophenyl)-1 H -1,2,3-triazol-4-yl)-2-methylpropyl)amino)-4-methyl-1-oxopentan-2-yl)phosphonate to give the title compound after purification by preparative HPLC (12 mg, 0.026 mmol, 26%, Mixture of diastereomers: Main diastereomer: 1H NMR (500 MHz, MeOH- d 4) δ ppm: 8.44 (s, 1 H), 8.10-8.09 (m, 1 H), 7.83-7.80 (m, 1 H), 7.75-7.73 (m, 1 H), 4.99-4.97 (m, 1 H), 3.03-2.96 (m, 1 H), 2.35-2.30 (m, 1 H), 2.13-2.06 (m, 1 H), 1.49-1.43 (m, 2 H), 1.06-0.98 (m, 6 H), 0.87-0.84 (m, 6 H). 31 P NMR (202 MHz, MeOH- d 4) δ ppm: 22.3. Minor diastereomer: 1 H NMR (500 MHz, MeOH- d 4) δ ppm: 8.58 (s, 1 H), 8.10-8.09 (m, 1 H), 7.83-7.80 (m, 1 H), 7.73-7.70 (m, 1H), 5.08-5.07 (m, 1 H), 3.17-3.12 (m, 1 H), 2.42-2.35 (m, 1 H), 2.02-1.98 (m, 1 H), 1.61-1.51 (m, 2 H), 0.98-0.95 (m, 6 H). 31 P NMR (202 MHz, MeOH- d 4,) δ ppm: 22.3. HRMS (ESI+) calculated for C 18 H 26 Cl2N4O4P [M+H] + 463.1063, found: 463.1065.

[0295] Example 171 Scheme 15: Synthesis of imidazole derivatives exemplified as compound 171.

[0296] [ka]

[0297] (a) i) HCl (4M in dioxane), DCM, room temperature; 18 hours, ii) TBTU, NMM, DMF, 0°C to room temperature, 22 hours; (b) TMSBr, DCM, room temperature, overnight, preparative HPLC 26%.

[0298] Diethyl (1-(((S)-1-(5-(3,4-dichlorophenyl)-1H-imidazol-2-yl)-2-methylpropyl)amino)-4-methyl-1-oxopentan-2-yl)phosphonate.

[0299] [ka]

[0300] The corresponding imidazolyl amino acid derivatives tert -butyl( S )-(1-(5-(3,4-dichlorophenyl)-1 H -imidazol-2-yl)-2-methylpropyl)carbamate was synthesized as previously reported in the literature (https: / / doi.org / 10.1016 / j.ejmech.2016.08.070). tert -butyl( S )-(1-(5-(3,4-dichlorophenyl)-1 H (-imidazol-2-yl)-2-methylpropyl)carbamate (77 mg, 0.200 mmol) was dissolved in DCM (2 mL) and HCl (0.25 mL, 1.00 mmol, 4 M in dioxane) was added. After complete consumption of the starting material (LCMS), the solvent was evaporated to give ( S )-1-(5-(3,4-dichlorophenyl)-1 H (-imidazol-2-yl)-2-methylpropan-1-amine hydrochloride was obtained, which was used in the coupling step without further purification. S )-1-(5-(3,4-dichlorophenyl)-1 HThe title compound was synthesized using general procedure I with (-imidazol-2-yl)-2-methylpropan-1-amine hydrochloride, compound 2d (51 mg, 0.200 mmol), TBTU (70.6 mg, 0.220 mmol), and NMM (53 μL, 0.500 mmol). Automated combiflash purification (Teledyne ISCO) afforded the title compound (22 mg, 0.042 mmol, 21%) as a mixture of diastereomers. MS (ESI+): m / z [M+H] + =519. Mixture of diastereomers: Main diastereomer: 1 H NMR (500 MHz, CDCl3) δ ppm: 7.88 (bs, 1 H), 7.54 (dd, J = 8.2 Hz, J = 1.8 Hz, 1 H), 7.39 (d, J = 8.4 Hz, 1 H), 7.25 (bs, 1 H), 5.26-5.23 (m, 1 H), 4.20-4.09 (m, 4 H), 3.00-2.93 (m, 1 H), 2.76-2.68 (m, 1 H), 2.18-2.11 (1 H), 1.70-1.61 (m, 1 H), 1.52-1.44 (m, 1 H), 1.34 (dd, J = 6.10 Hz, 3 H), 1.30 (dd, J = 7.1 Hz, 3 H), 1.02 (d, J = 6.8 Hz, 3 H), 0.94 (dd, J = 7.1 Hz, 6 H), 0.90 (d, J = 6.7 Hz, 3 H). 31 P NMR (202 MHz, CDCl3) δ ppm: 26.3. Minor diastereomer (selected signal): 1 H NMR (500 MHz, CDCl3) δ ppm: 7.93 (d. J = 1.8 Hz, 1 H), 7.64 (dd, J = 8.4 Hz, J= 1.8 Hz, 1 H), 7.41 (d, J = 8.4 Hz, 1 H), 4.08-4.04 (m, 4 H), 3.09-3.03 (m, 1 H), 2.58-2.51 (m, 1 H). 31 P NMR (202 MHz, CDCl3) δ ppm: 26.5.

[0301] (1-(((S)-1-(5-(3,4-dichlorophenyl)-1H-imidazol-2-yl)-2-methylpropyl)amino)-4-methyl-1-oxopentan-2-yl)phosphonic acid (171)

[0302] [ka]

[0303] The title compound was prepared according to general procedure F. Diethyl (1-((( S )-1-(5-(3,4-dichlorophenyl)-1 H (-imidazol-2-yl)-2-methylpropyl)amino)-4-methyl-1-oxopentan-2-yl)phosphonate (22 mg, 0.042 mmol) and bromotrimethylsilane (28 μL, 0.212 mmol) were used. Purification by preparative HPLC afforded the title compound as a colorless solid (5.2 mg, 0.011 mmol, 26%, mixture of diastereomers). Mixture of diastereomers: Main diastereomer: 1 H NMR (500 MHz, MeOH- d 4) δ ppm: 8.09 (d, J = 1.8 Hz, 1 H), 7.88 (s, 1 H), 7.79 (dd, J = 8.4 Hz, J = 1.7 Hz, 1 H), 7.62 (d, J = 8.64 Hz, 1 H), 5.21 (d, J = 5.0 Hz, ), 3.33-3.25 (m, 1 H), 2.52-2.46 (m, 1 H), 2.10-2.04 (m, 1 H), 1.62-1.53 ​​(m, 2 H), 1.09 (d, J= 6.9 Hz, 3 H), 1.01 (d, J = 6.9 Hz, 3 H), 0.95 (dd, J = 5.7 Hz, 6 H). 13 C NMR (126 Mhz, MeOH- d 4) δ ppm: 174.3, 151.1, 134.5, 132.9, 132.5, 131.1, 128.9, 126.8, 117.6, 61.7, 54.1, 47.6 36.0, 32.3, 28.8, 23.5, 22.1, 19.4, 17.5, 14.6. 31 P NMR (202 MHz, MeOH- d 4) δ ppm: 19.7. Minor diastereomer (selected signal): 1 H NMR (500 MHz, MeOH- d 4) δ ppm: 8.04 (d, J = 2.1 Hz, 1 H), 7.97 (d, J = 1.8 Hz, 1 H), 7.89 (bs, 1 H), 7.63 (d, J = 7.6 Hz, 1 H), 3.18-3.16 (m, 1 H), 2.42-2.38 (m, 1 H), 1.54-1.53 ​​(m, 2 H), 1.13 (d, J =6.7 Hz, 3 H), 0.92 (d, J = 6.4 Hz, 3 H), 0.90 (d, J = 6.4 Hz, 3 H). 13 C NMR (126 MHz, MeOH- d 4) δ ppm: 134.6, 132.7, 128.8, 126.9, 54.9, 32.7, 23.6, 22.0, 19.7.

[0304] Example 172 Scheme 16: Synthesis of benzimidazole derivatives exemplified as compound 172.

[0305] [ka]

[0306] (a) TBTU, NMM, DMF, 0 °C–rt, 2d, quantitative; (b) HOAc / toluene (1:1), 110 °C, 3 h; (c) i) HCl (4 M in 1,4-dioxane), DCM, rt, 18 h; ii) TBTU, NMM, DMF, 0 °C–rt, 21 h, 97% (over 3 steps); d) TMSBr, DCM, rt, 21 h, preparative HPLC, 1.2%.

[0307] Tert-butyl (S)-(1-((2-amino-5-phenoxyphenyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate.

[0308] [ka]

[0309] The title compound was synthesized using general procedure L. Boc-Val-OH (543 mg, 2.50 mmol) was dissolved in DMF (25 mL) and NMM (302 μL, 2.75 mmol) was added, followed by TBTU (894 mg, 2.75 mmol) at 0 °C. The reaction mixture was stirred at this temperature for 30 min, and 4-phenoxybenzene-1,2-diamine (500 mg, 2.5 mmol) was added. After warming to room temperature overnight, the reaction was quenched with saturated aqueous NaHCO and extracted with EtOAc (×3). The combined organic layers were subsequently washed with 1 M HCl, water, and saturated aqueous NaCl, dried over NaSO, filtered, and concentrated in vacuo. The crude product was obtained as a brown foam (1.00 g, 2.50 mmol, quantitative) and used in the next step without further purification. 1 H NMR (500 MHz, CDCl3) δ ppm: 7.62 (bs, 1 H), 7.34-7.31 (m, 2 H), 7.11-7.08 (m, 2 H), 7.02-7.00 (m, 2 H), 6.42-6.39 (m, 2 H), 5.11 (bs, 1 H), 3.99-3.97 (m, 1 H), 2.31-2.23 (m, 1 H), 1.46 (s, 9 H), 1.07 (dd, J= 6.71 Hz, 3 H), 1.04 (dd, J = 6.71 Hz, 3 H). MS (ESI+): m / z [M+H] + = 400.

[0310] Tert-butyl (S)-(2-methyl-1-(5-phenoxy-1H-benzo[d]imidazol-2-yl)propyl)carbamate.

[0311] [ka]

[0312] The title compound was synthesized using general procedure L. tert -butyl( S )-(1-((2-amino-5-phenoxyphenyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (200 mg, 1.00 mmol) was dissolved in 5 mL of toluene / HOAc (1:1) and heated under reflux (preheated oil bath) for 3 h. After cooling to room temperature, saturated aqueous NaHCO3 was carefully added until pH = 9. The solution was then stirred for 20 min, extracted with EtOAc (x3), and washed with saturated aqueous NaHCO3 (x4), water (x2), and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound as an orange solid (191 mg, 0.500 mmol, quantitative), which was used in the next step without further purification. MS (ESI+): m / z [M+H] + =382.

[0313] Diethyl (4-methyl-1-(((S)-2-methyl-1-(5-phenoxy-1H-benzo[d]imidazol-2-yl)propyl)amino)-1-oxopentan-2-yl)phosphonate.

[0314] [ka]

[0315] tert -butyl( S )-(2-methyl-1-(5-phenoxy-1 H -Benzo[ d[Imidazol-2-yl)propyl]carbamate (159 mg, 0.417 mmol) was dissolved in DCM (4 mL), followed by the addition of HCl (4 M in 1,4-dioxane, 1.04 mL, 4.17 mmol). The reaction mixture was stirred at room temperature for 18 h and 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 min, followed by the dropwise addition of the Boc-deprotected benzimidazole amino acid derivative dissolved in DMF (2.5 mL) at 0 °C. After stirring for 21 h, EtOAc and 1 M HCl were added, and the aqueous layer was extracted with EtOAc (×2). The combined organic layers were washed with water and saturated aqueous NaCl. After drying over Na2SO4 and filtration, the solvent was removed under reduced pressure to give the title compound as a brownish resin (208 mg, 0.405 mmol, 97%). The title compound was used in the next step without further purification. MS (ESI+): m / z [M+H] + =516.

[0316] (4-Methyl-1-(((S)-2-methyl-1-(5-phenoxy-1H-benzo[d]imidazol-2-yl)propyl)amino)-1-oxopentan-2-yl)phosphonic acid (172).

[0317] [ka]

[0318] The title compound was prepared according to general procedure F. 166 mg (0.322 mmol) of diethyl (4-methyl-1-((( S )-2-methyl-1-(5-phenoxy-1 H -Benzo[ d ]imidazol-2-yl)propyl)amino)-1-oxopentan-2-yl)phosphonate was used to give the title compound after purification by preparative HPLC (1.74 mg, 0.004 mmol, 1.2%). Mixture of diastereomers: Main diastereomer: 1H NMR (500 MHz, DMSO- d 6,) δ ppm: 8.14-8.12 (m, 1 H), 7.53-7.51 (m, 1 H), 7.37-7.33 (m, 2 H), 7.13-7.05 (m, 2 H), 6.97-6.95 (m, 2 H), 4.94-4.91 (m, 1 H), 3.28-3.22 (m, 1 H), 2.32-2.26 (m, 1 H), 1.87-1.81 (m, 1 H) 1.50-1.37 (m, 2 H), 0.98-0.96 (m, 3 H), 0.93-0.92 (m, 3 H), 0.87-0.86 (m, 6 H). 13 C NMR (126 MHz, DMSO- d 6) δ ppm: 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 = 14.7 Hz), 23.5, 22.0, 19.8, 18.8. 31 P NMR (202 MHz, DMSO-d6) δ ppm: 20.7. Minor diastereomer (selected signals): 1 H NMR (500 MHz, DMSO- d 6) δ ppm: 8.45-8.43 (m, 1 H), 7.49-7.48 (m, 1 H), 6.92-6.89 (m, 2 H), 5.13-5.11 (m, 1 H), 1.96-1.92 (m, 1 H), 0.78-0.76 (m, 6 H). 13 C NMR (126 MHz, DMSO- d 6) δ ppm: 170.71, 158.5, 157.4, 152.1, 123.4, 118.2, 115.1, 53.2, 34.9, 30.6, 26.8 (d, J = 14.7 Hz), 23.4, 21.9, 19.7, 17.4. 31 P NMR (202 MHz, DMSO- d 6) δ ppm: 20.9. HRMS (ESI+) calculated for [M+H] + : 460.1996, found: 460.1982.

[0319] Example 173 Ethyl 4-methyl-2-(p-tolylcarbamoyl)pentanoate.

[0320] [ka]

[0321] Ethyl 4-methyl-2-( p (-tolylcarbamoyl)pentanoate was synthesized according to general procedure M using diethyl 2-alkylmalonate (645 mg, 2.98 mmol), EtOH / HO (30 mL, 4:1), and NaOH (143 mg, 3.58 mmol). The reaction was stirred at room temperature overnight. The resulting monoacid (505 mg, 2.68 mmol) and EDC·HCl (515 mg, 2.68 mmol) were added to p To a solution of -toluidine (240 mg, 2.23 mmol) in DCM (20 mL) was added. The resulting mixture was stirred at room temperature overnight. After workup, the crude product was purified using column chromatography (Hex / EtOAc = 8 / 2). The product was obtained as orange crystals (441 mg, 71%). 1 H NMR (500 MHz, CDCl3) δ ppm: 8.45 (br s, 1H), 7.42 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 4.31-4.17 (m, 2H), 3.43 (t, J = 7.7 Hz, 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 = 6.6 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ ppm: 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

[0322] N 1 -Hydroxy-2-isobutyl-N 3 -(p-Tolyl)malonamide (173).

[0323] [ka]

[0324] N 1 -hydroxy-2-isobutyl- N 3 -( p -tolyl)malonamide with ethyl 4-methyl-2-( p This compound was synthesized according to general procedure N using (-tolylcarbamoyl)pentanoate (100 mg, 0.36 mmol), MeOH (2 mL), NHOH 50 wt% in HO (2 mL), and KCN (4.7 mg, 0.07 mmol). The mixture was stirred at room temperature overnight. The solvent was concentrated in vacuo, and the resulting oil was purified by preparative HPLC (CHCN(HCOOH 0.05%)-HO(HCOOH 0.05%): 1.0:9.0 to 10.0:0.0). The product was obtained as a white solid (49 mg, 52%). 1 H NMR (500 MHz, DMSO- d 6) δ ppm: 10.54 (s, 1H), 9.66 (s, 1H), 9.00 (s, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 3.18 (t, J = 7.6 Hz, 1H), 2.24 (s, 3H), 1.67 (t, J= 7.2 Hz, 2H), 1.47 (dquin, J = 13.4, 6.7, 6.7, 6.7, 6.7 Hz, 1H), 0.87 (br d, J = 6.6 Hz, 3H), 0.87 (br d, J = 6.6 Hz, 3H). 13 C NMR (126 MHz, DMSO- d 6) δ ppm: 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 + ) calculated for C 14 H 21 N2O3[M+H] + 265.1547, found 265.1545.

[0325] Example 174 and Example 177 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). 4-Methyl- N -( p -Trill)-2-(1 H -1,2,3-triazol-1-yl)pentanamide (174) and 4-methyl- N -( p -Trill)-2-(2 H (1,2,3-triazol-2-yl)pentanamide (177) was reacted with 2-bromo-4-methyl- N -( p -tolyl)pentanamide (70 mg, 0.25 mmol) (synthesized according to General Procedure B-1), acetone (7 mL), 1 H This compound was synthesized according to general procedure 174 using 1,2,3-triazole (18.7 mg, 0.27 mmol) and KCO (37.4 mg, 0.27 mmol). The crude product was purified by preparative HPLC (CHCN(HCOOH 0.05%)-HO(HCOOH 0.05%): 1.0:9.0 to 10.0:0.0) to give product 174 (20.3 mg, 30%) and product 177 (30 mg, 45%) as a white solid.

[0326] 4-Methyl-N-(p-tolyl)-2-(1H-1,2,3-triazol-1-yl)pentanamide (174).

[0327] [Chemical]

[0328] 1 H NMR (500 MHz, DMSO- d 6) δ ppm: 10.53 (s, 1H), 8.30 (d, J J = 0.8 Hz, 1H), 7.77 (d, J J = 0.6 Hz, 1H), 7.47 (d, J J = 8.4 Hz, 2H), 7.16 (d, J J = 8.2 Hz, 2H), 5.61 (dd, J J = 9.8, 6.1 Hz, 1H), 2.25 (s, 3H), 2.16 - 2.06 (m, 1H), 2.01 - 1.93 (m, 1H), 1.31 - 1.20 (m, 1H),​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​1 H NMR (500 MHz, DMSO- d 6) δ ppm: 10.35 (s, 1H), 7.83 (s, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 5.46 (dd, J = 9.3, 6.0 Hz, 1H), 2.34-2.28 (m, 1H), 2.24 (s, 3H), 1.99 (ddd, J = 13.8, 7.8, 6.2 Hz, 1H), 1.47-1.36 (m, 1H), 0.91 (t, J = 6.2 Hz, 6H). 13 C NMR (126 MHz, DMSO- d 6) δ ppm: 166.2, 135.9, 134.5, 132.9, 129.2, 119.4, 65.8, 24.5, 22.5, 21.7, 20.5. HRMS (ESI + ) calculated for C 15 H 21 NO [M+H] + 273.1710, found 273.1708.

[0332] III. Biological Evaluation Activity against LasB: The activity of the compounds of the present invention was determined according to the methods described in Kany, AM; Sikandar, A.; Haupenthal, J.; Yahiaoui, S.; Maurer, CK; Proschak, E.; Koehnke, J.; Hartmann, RW ACS Infect. Dis . 2018, 4 , 988-997.

[0333] α-benzylated derivatives:

[0334] [Table 2]

[0335] Enantiomer activity: To elucidate whether the configuration of the stereocenter influences activity, the enantiomers of the compounds of Examples 1 and 4 (E1 and E2, labeled according to their elution order from the chiral column) were separated using preparative HPLC on a chiral column and tested independently. Both enantiomers were active, but differences in activity were observed between the two configurations (Table 3). For both compounds, the E2 enantiomer was more active.

[0336] [Table 3]

[0337] To ensure that no racemization occurred during the assay, configurational stability was tested in methanol and aqueous buffer (50 mM Tris, pH 7.2, 2.5 mM CaCl). The CD spectrum remained unchanged over 1 hour, indicating that no racemization occurred during this time.

[0338] Selectivity: Inhibition of zinc-containing human enzymes has been frequently described for LasB inhibitors, posing serious challenges to the development of selective compounds. In particular, inhibition of matrix metalloproteinases (MMPs) should be avoided. To further investigate this issue, three derivatives (compounds in Examples 1, 5, and 8) were tested for their selectivity against several human off-targets, including six MMPs, ADAM17 (TACE), HDAC-3, and HDAC-8 (Table 4). The selectivity of the compounds was particularly high for MMPs and HDACs, while the inhibition of ADAM17 was quite potent.

[0339] [Table 4]

[0340] Cytotoxicity: The compounds of Examples 1 and 5 were not toxic to the cell lines HepG2, HEK293, and A549 (Table 5). Furthermore, to exclude the antibacterial effect of the compounds of the present invention, their inhibitory effect against Pseudomonas aeruginosa PA14 was evaluated. This is important because the aim was to target the virulence of the bacteria rather than their viability. The results showed that for both compounds, the MIC values ​​against PA14 as well as the cytotoxicity in the cell lines (IC 50 value) was greater than 100 μM, indicating that there was no problem.

[0341] [Table 5]

[0342] α-Alkylated derivatives: C α Compounds with alkyl substituents at positions 1 and 2 are highly active, with submicromolar IC 50 Among these, the aromatic core and iso The compound of Example 2, which has a 4-Me substituent on the -butyl chain, proved to be one of the most promising compounds and was therefore further investigated for selectivity and cytotoxicity (Table 8).

[0343] [Table 6]

[0344] [Table 7]

[0345] [Table 8]

[0346] The compound of Example 2 exhibited impressive activity in the in vitro LasB inhibition assay, exhibited high selectivity against a broad range of human enzymes, and lacked signs of cytotoxicity in vitro, and was therefore subjected to more advanced safety screening (Table 9). 50 The inhibitory activity of Example 2 was determined to be >10 μM. Furthermore, the effect of the compound of Example 2 on five human CYP450 isoforms was determined and, of particular importance, demonstrated weak or no inhibition. Furthermore, when the compound of Example 2 was analyzed using a mini-Ames reversion assay, no genotoxicity was observed up to 125 μg / mL.

[0347] [Table 9]

[0348] Furthermore, the compound of Example 2 was subjected to a pharmacokinetic (PK) study in mice (Table 10). When injected intravenously (iv) at a dose of 10 mg / kg, it was detectable in the blood for 2 hours. Preliminary results indicate high clearance and low overall exposure, although the volume of distribution may account for good tissue penetration.

[0349] [Table 10]

[0350] α-Carboxymethyl derivatives: The compound of Example 54 (Table 1) exhibited the following activity against LasB: IC 50 =3.9±0.4μm.

[0351] Heterocyclic derivatives:

[0352] [Table 11]

[0353] Phosphonic acid derivatives:

[0354]

Table 12

[0355] TIFF2025148472000078.tif222168

[0356] TIFF2025148472000079.tif251164

[0357]

Table 13

[0358] TIFF2025148472000081.tif222170

[0359] TIFF2025148472000082.tif235170

[0360] TIFF2025148472000083.tif225170

[0361] TIFF2025148472000084.tif215170

[0362] TIFF2025148472000085.tif204170

[0363] TIFF2025148472000086.tif202170

[0364] TIFF2025148472000087.tif229170

[0365] TIFF2025148472000088.tif234170

[0366]

Table 14

[0367] TIFF2025148472000090.tif254166

[0368] All phosphonates exhibited excellent selectivity and cytotoxicity profiles and showed no inhibition of PA14 bacterial growth (Tables 15, 17 and 18).

[0369] [Table 15]

[0370] [Table 16]

[0371] [Table 17]

[0372] [Table 18]

[0373] Because the compounds of Examples 63 and 170 demonstrated impressive activity in the in vitro LasB assay, demonstrated high selectivity against a broad range of human enzymes, and showed no signs of cytotoxicity in vitro, they were subjected to a more advanced safety screening (SafetyScreen44 panel, Eurofins CEREP). This screening included 44 different targets, including GPCRs, transporters, ion channels, nuclear receptors, kinases, and other non-kinase enzymes. The compounds of Examples 63 and 170 showed no inhibition of control specific binding of all targets tested (less than 22% inhibition at compound concentrations between 1.0E and 0.5M).

[0374] Hydroxamic acid derivatives:

[0375] [Table 19]

[0376] Table 20

[0377] Triazole derivatives:

[0378] Table 21

[0379] Table 22

Claims

1. A compound of general formula (Ia) or a pharmaceutically acceptable salt thereof for use in the treatment of bacterial infections: (In general formula (Ia), X is a group of formula -PO(OH) ２ , —SH, —C(═O)—NH—OH, an optionally substituted triazolyl group, —SR ３ , -PO(OH)(OR ４ ) or -PO(OR ４ ) (OR ５ ) group; R １ is an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group, or an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group; or a group of the general formula -CH(R ６ )-C(=O)-NH-R ７ or a group of the general formula -C(Me) ２ -CH ２ -C(=O)-NH-R ７ or a group of the general formula -CH(R ６ )-CH ２ -C(=O)-NH-R ７ or a group of the general formula -CH(R ６ )-R ８ is a group of R ２ is an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group, or a heteroaralkyl group, all of which may be optionally substituted; R ３ is represented by the general formula -COR ３ａ or -CON(R ３ｂ ) ２ where R ３ａ is an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group, and R ３ｂ are independently selected from a hydrogen atom, an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group; R ４ is an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group; R ５ is an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group; R ６ is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl group, all of which may be optionally substituted; R ７ is an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group; R ８ is an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group; R １ａ is a hydrogen atom, or R １ is represented by the general formula -CH(R ６ )-C(=O)-NH-R ７ When R is a group １ａ and R ６ are taken together to form the formula -(CH ２ ) ３ - or - (CH ２ ) ４ - groups).

2. Use of a compound of general formula (Ia) or a pharmaceutically acceptable salt thereof for preparing a medicament for the treatment of bacterial infections: (In general formula (Ia), X is a group of formula -PO(OH) ２ , —SH, —C(═O)—NH—OH, an optionally substituted triazolyl group, —SR ３ , -PO(OH)(OR ４ ) or -PO(OR ４ ) (OR ５ ) group; R １ is an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group, or an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group; or a group of the general formula -CH(R ６ )-C(=O)-NH-R ７ or a group of the general formula -C(Me) ２ -CH ２ -C(=O)-NH-R ７ or a group of the general formula -CH(R ６ )-CH ２ -C(=O)-NH-R ７ or a group of the general formula -CH(R ６ )-R ８ is a group of R ２ is an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group, or a heteroaralkyl group, all of which may be optionally substituted; R ３ is represented by the general formula -COR ３ａ or -CON(R ３ｂ ) ２ where R ３ａ is an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group, and R ３ｂ are independently selected from a hydrogen atom, an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group; R ４ is an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group; R ５ is an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group; R ６ is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl group, all of which may be optionally substituted; R ７ is an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group; R ８ is an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group; R １ａ is a hydrogen atom, or R １ is represented by the general formula -CH(R ６ )-C(=O)-NH-R ７ When R is a group １ａ and R ６ are taken together to form the formula -(CH ２ ) ３ - or - (CH ２ ) ４ - groups).

3. A method of treating a subject suffering from or susceptible to a bacterial infection, comprising administering to the subject an effective amount of a compound of general formula (Ia) or a pharmaceutically acceptable salt thereof: (In general formula (Ia), X is a group of formula -PO(OH) ２ , —SH, —C(═O)—NH—OH, an optionally substituted triazolyl group, —SR ３ , -PO(OH)(OR ４ ) or -PO(OR ４ ) (OR ５ ) group; R １ is an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group, or an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group; or a group of the general formula -CH(R ６ )-C(=O)-NH-R ７ or a group of the general formula -C(Me) ２ -CH ２ -C(=O)-NH-R ７ or a group of the general formula -CH(R ６ )-CH ２ -C(=O)-NH-R ７ or a group of the general formula -CH(R ６ )-R ８ is a group of R ２ is an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group, or a heteroaralkyl group, all of which may be optionally substituted; R ３ is represented by the general formula -COR ３ａ or -CON(R ３ｂ ) ２ where R ３ａ is an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group, and R ３ｂ are independently selected from a hydrogen atom, an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group; R ４ is an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group; R ５ is an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group; R ６ is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl group, all of which may be optionally substituted; R ７ is an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group; R ８ is an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group; R １ａ is hydrogen or R １ is represented by the general formula -CH(R ６ )-C(=O)-NH-R ７ When R is a group １ａ and R ６ are taken together to form the formula -(CH ２ ) ３ - or - (CH ２ ) ４ - groups).

4. 4. The compound of claim 1, or the use of claim 2, or the method of claim 3, wherein the compound is a compound of general formula (I) or a pharmaceutically acceptable salt thereof: (where X, R １ and R ２ is as defined in claim 1, 2 or 3).

5. 10. The compound of claim 1, or the use of claim 2, or the method of claim 3, wherein the compound is a compound of general formula (II), (III), (IV), (V) or (VI) or a pharmaceutically acceptable salt thereof: (where R １ and R ２ is as defined in claim 1, 2 or 3).

6. R ２ is C １～６ alkyl groups; heteroalkyl groups containing 1 to 6 carbon atoms and 1, 2, 3 or 4 heteroatoms selected from O, S and N; C ４～１０ alkylcycloalkyl group; or C ７～１２ 6. A compound according to any one of claims 1, 4 or 5, or a use according to any one of claims 2, 4 or 5, or a method according to any one of claims 3, 4 or 5, wherein the compound is an aralkyl group; all of which are optionally substituted.

7. R ２ 6. A compound according to any one of claims 1, 4 or 5, or a use according to any one of claims 2, 4 or 5, or a method according to any one of claims 3, 4 or 5, wherein is an optionally substituted benzyl group.

8. R ２ is the formula -CH ２ CH (CH ３ ) ２ 6. A compound according to any one of claims 1, 4 or 5, or a use according to any one of claims 2, 4 or 5, or a method according to any one of claims 3, 4 or 5, wherein

9. R １ is an optionally substituted aryl group or an optionally substituted heteroaryl group.

10. R １ is an optionally substituted phenyl group, an optionally substituted naphthyl group, or an optionally substituted heteroaryl group containing 1 or 2 rings and 5 to 10 ring atoms selected from C, O, N and S; or a compound according to any one of claims 1 or 4 to 8, or a use according to any one of claims 2 or 4 to 8, or a method according to any one of claims 3 to 8,

11. R １ A compound according to any one of claims 1 or 4 to 8, or a use according to any one of claims 2 or 4 to 8, or a method according to any one of claims 3 to 8, wherein is an optionally substituted phenyl group.

12. R １ is represented by the general formula -Cy １ -L-Cy ２ In the general formula, Cy １ is an optionally substituted cycloalkylene group containing one or two rings and 3 to 7 carbon ring atoms, an optionally substituted heterocycloalkylene group containing one or two rings and 3 to 7 ring atoms selected from C, N, O and S, an optionally substituted phenylene group, or an optionally substituted heteroarylene group containing 5 or 6 ring atoms selected from C, N, O and S; Cy ２ is a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group, or a heteroaralkyl group, all of which may be optionally substituted; L is a bond, or —O—, —S—, —NH—, —CH ２ -, -CO-, -NHCO-, -CO-NH-, -CH ２ -CO-NH-, -NH-CO-CH ２ -, -CH ２ -O-CO-NH-, -NH-CO-O-CH ２ -, -O-CO-NH-, -NH-CO-O-, -NHSO ２ -, -SO ２ NH-, -CH ２ -SO ２ -NH-, -NH-SO ２ -CH ２ -, -S-CH ２ -, -CH ２ -S-, -NH-CH ２ -, -CH ２ -NH-, -O-CH ２ - or -CH ２ A compound according to any one of claims 1 or 4 to 8, or a use according to any one of claims 2 or 4 to 8, or a method according to any one of claims 3 to 8, wherein -O-.

13. Cy ２ is an optionally substituted phenyl group, an optionally substituted biphenyl group, an optionally substituted naphthyl group, an optionally substituted heteroaryl group containing one or two rings and 5, 6, 9 or 10 ring atoms selected from C, O, N and S, an optionally substituted cycloalkyl group containing 3 to 7 ring atoms, an optionally substituted heterocycloalkyl group containing 3 to 7 ring atoms selected from C, N, O and S, an optionally substituted heterocycloalkylaryl group containing 9 or 10 ring atoms selected from C, N, S and O, or a group of the formula -CH(CH ２ 13. The compound, or use, or method of claim 12, wherein Ph) is a group of Ph.

14. L is a bond, —NHCO—, —CO—NH—, or —CH ２ -CO-NH-, -NH-CO-CH ２ -, -NHSO ２ -or-SO ２ 14. The compound, or use, or method of claim 12 or 13, wherein said compound is NH-.

15. Cy １ A compound, or use, or method according to any one of claims 12 to 14, wherein is a 1,4-phenylene group.

16. R １ is represented by the general formula -CH(R ６ )-C(=O)-NH-R ７ or a group of the general formula -CH(R ６ )-R ８ A compound according to any one of claims 1 or 4 to 8, or a use according to any one of claims 2 or 4 to 8, or a method according to any one of claims 3 to 8, wherein

17. R ６ is a hydrogen atom or C １～６ Alkyl group, C ３～７ a cycloalkyl group, a heterocycloalkyl group containing 3 to 7 ring atoms selected from C, N, O and S, a phenyl group, or a heteroaryl group containing 5 or 6 ring atoms selected from C, N, S and O, or a group of the general formula -CH ２ -R ６ａ In the general formula, R ６ａ is C ３～７ 17. The compound, use, or method of claim 16, which is a cycloalkyl group, a heterocycloalkyl group containing 3 to 7 ring atoms selected from C, N, O, and S, a phenyl group, or a heteroaryl group containing 5 or 6 ring atoms selected from C, N, S, and O.

18. R ６ is of the formula -CH(CH ３ ) ２ 18. A compound, or a use or method according to claim 16 or 17, wherein

19. R ７ is an optionally substituted phenyl group or an optionally substituted C ３～７ 19. The compound, or use, or method according to any one of claims 16 to 18, which is a cycloalkyl group.

20. R ８ is an optionally substituted benzimidazole group, or an optionally substituted triazole group, or an optionally substituted imidazole group.

21. 21. A compound according to any one of claims 1 or 4 to 20, or a use according to any one of claims 2 or 4 to 20, or a method according to any one of claims 3 to 20, wherein the bacterial infection is caused by P. aeruginosa.

22. A compound of general formula (Ia) or a pharmaceutically acceptable salt thereof: (In general formula (Ia), X is a group of formula -PO(OH) ２ , —SH, —C(═O)—NH—OH, an optionally substituted triazolyl group, —SR ３ , -PO(OH)(OR ４ ) or -PO(OR ４ ) (OR ５ ) group; R １ is an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group, or an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group; or a group of the general formula -CH(R ６ )-C(=O)-NH-R ７ or a group of the general formula -C(Me) ２ -CH ２ -C(=O)-NH-R ７ or a group of the general formula -CH(R ６ )-CH ２ -C(=O)-NH-R ７ or a group of the general formula -CH(R ６ )-R ８ is a group of R ２ is an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group, or a heteroaralkyl group, all of which may be optionally substituted; R ３ is represented by the general formula -COR ３ａ or -CON(R ３ｂ ) ２ where R ３ａ is an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group, and R ３ｂ are independently selected from a hydrogen atom, an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group; R ４ is an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group; R ５ is an alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group; R ６ is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl group, all of which may be optionally substituted; R ７ is an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group; R ８ is an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group; R １ａ is a hydrogen atom, or R １ is represented by the general formula -CH(R ６ )-C(=O)-NH-R ７ When R is a group １ａ and R ６ are taken together to form the formula -(CH ２ ) ３ - or - (CH ２ ) ４ - groups).

23. 23. The compound of claim 22, wherein the compound is a compound of general formula (I) or a pharmaceutically acceptable salt thereof: (where X, R １ and R ２ is as defined in claim 22).

24. 23. The compound of claim 22, wherein the compound is a compound of general formula (II), (III), (IV), (V) or (VI) or a pharmaceutically acceptable salt thereof: (where R １ and R ２ is as defined in claim 22).

25. R ２ is C １～６ alkyl groups; heteroalkyl groups containing 1 to 6 carbon atoms and 1, 2, 3 or 4 heteroatoms selected from O, S and N; C ４～１０ alkylcycloalkyl group; or C ７～１２ aralkyl groups; all of which are optionally substituted.

26. R ２ The compound of any one of claims 22 to 24, wherein is an optionally substituted benzyl group.

27. R ２ is the formula -CH ２ CH (CH ３ ) ２ The compound according to any one of claims 22 to 24, wherein the compound is a group represented by the formula:

28. R １ The compound of any one of claims 22 to 27, wherein is an optionally substituted aryl group or an optionally substituted heteroaryl group.

29. R １ is an optionally substituted phenyl group, an optionally substituted naphthyl group, or an optionally substituted heteroaryl group containing 1 or 2 rings and 5 to 10 ring atoms selected from C, O, N, and S.

30. R １ The compound of any one of claims 22 to 27, wherein is an optionally substituted phenyl group.

31. R １ is represented by the general formula -Cy １ -L-Cy ２ In the general formula, Cy １ is an optionally substituted cycloalkylene group containing one or two rings and 3 to 7 carbon ring atoms, an optionally substituted heterocycloalkylene group containing one or two rings and 3 to 7 ring atoms selected from C, N, O and S, an optionally substituted phenylene group, or an optionally substituted heteroarylene group containing 5 or 6 ring atoms selected from C, N, O and S; Cy ２ is a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group, or a heteroaralkyl group, all of which may be optionally substituted; L is a bond, or —O—, —S—, —NH—, —CH ２ -, -CO-, -NHCO-, -CO-NH-, -CH ２ -CO-NH-, -NH-CO-CH ２ -, -CH ２ -O-CO-NH-, -NH-CO-O-CH ２ -, -O-CO-NH-, -NH-CO-O-, -NHSO ２ -, -SO ２ NH-, -CH ２ -SO ２ -NH-, -NH-SO ２ -CH ２ -, -S-CH ２ -, -CH ２ -S-, -NH-CH ２ -, -CH ２ -NH-, -O-CH ２ - or -CH ２ The compound according to any one of claims 22 to 27, wherein the group is -O-.

32. Cy ２ is an optionally substituted phenyl group, an optionally substituted biphenyl group, an optionally substituted naphthyl group, an optionally substituted heteroaryl group containing one or two rings and 5, 6, 9 or 10 ring atoms selected from C, O, N and S, an optionally substituted cycloalkyl group containing 3 to 7 ring atoms, an optionally substituted heterocycloalkyl group containing 3 to 7 ring atoms selected from C, N, O and S, an optionally substituted heterocycloalkylaryl group containing 9 or 10 ring atoms selected from C, N, S and O, or a group of the formula -CH(CH ２ 32. The compound of claim 31, wherein Ph is a group of Ph.

33. L is a bond, —NHCO—, —CO—NH—, or —CH ２ -CO-NH-, -NH-CO-CH ２ -, -NHSO ２ -or-SO ２ 33. The compound of claim 31 or 32, which is NH-.

34. Cy １ The compound according to any one of claims 31 to 33, wherein is a 1,4-phenylene group.

35. R １ is represented by the general formula -CH(R ６ )-C(=O)-NH-R ７ or a group of the general formula -CH(R ６ )-R ８ The compound according to any one of claims 22 to 27, wherein the compound is a group represented by the formula:

36. R ６ is a hydrogen atom or C １～６ Alkyl group, C ３～７ a cycloalkyl group, a heterocycloalkyl group containing 3 to 7 ring atoms selected from C, N, O and S, a phenyl group, or a heteroaryl group containing 5 or 6 ring atoms selected from C, N, S and O, or a group of the general formula -CH ２ -R ６ａ In the general formula, R ６ａ is C ３～７ The compound according to claim 35, which is a cycloalkyl group, a heterocycloalkyl group containing 3 to 7 ring atoms selected from C, N, O, and S, a phenyl group, or a heteroaryl group containing 5 or 6 ring atoms selected from C, N, S, and O.

37. R ６ is of the formula -CH(CH ３ ) ２ 37. The compound of claim 35 or 36, wherein the group is

38. R ７ is an optionally substituted phenyl group or an optionally substituted C ３～７ The compound according to any one of claims 35 to 37, which is a cycloalkyl group.

39. R ８ is an optionally substituted benzimidazole group, an optionally substituted triazole group, or an optionally substituted imidazole group.

40. A pharmaceutical composition comprising a compound according to any one of claims 22 to 39 and optionally one or more carrier substances and / or one or more adjuvants and / or one or more further antibacterial compounds.

41. A compound according to any one of claims 22 to 39 or a pharmaceutical composition according to claim 40 for use in the treatment of a bacterial infection.

42. A compound according to any one of claims 22 to 39 or a pharmaceutical composition according to claim 40 for use in the treatment of a bacterial infection caused by P. aeruginosa.

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