JP2007509082A - Benzimidazole derivatives and their use as peptide deformylase inhibitors - Google Patents

Abstract

【選択図】なしThe benzimidazole compounds of general formula (I) and their pharmaceutically acceptable salts or esters are useful for the treatment or prevention of infections and other diseases involving peptide deformylase, in particular bacterial and parasitic infections, such as Staphylococcus, Enterococcus, Streptococcus, Hemophilus, Moraxella, Escherichia, Mycobacterium, Mycoplasma, Pseudomonas, Chlamydia, Rickettsia, Klebsiella, Shigella, Salmonella, Bordetella, Clostridium, Helicobacter, Campylobacter, Legionella or completely Peptide deformylase inhibitors that are effective in the treatment of partially caused infections.

[Selection figure] None

Description

  The present invention relates to novel enzyme inhibitors, more specifically, peptide deformylases useful for the treatment / prevention of infections and other diseases involving peptide deformylase, particularly for the treatment of bacterial and parasitic infections. Relates to inhibitors. More specifically, the present invention relates to enzymes that catalyze the deformylation of formyl-L-methionyl peptides, benzimidazoles that can inhibit bacterial peptide deformylase, also known as PDF.

Background of the invention
Peptide deformylase (EC 3.4.1.88), also known as PDF, is an enzyme that catalyzes the deformylation of formyl-L-methionyl peptides. PDF removes the formyl group from the N-terminal Met of newly synthesized proteins, ie catalyzes the conversion of formyl-L-methionyl peptide to methionyl peptide (Adams and Capecchi, 1966; Adams, 1968). PDF is essential for bacteria, and bacterial peptide deformylase (PDF) is now widely recognized as an attractive target for antibacterial chemotherapy (Giglione et al., 2000; Giglione and Meinnel, 2001; Pei 2001; Yuan et al., 2001; Clements et al., 2002). Deformylation is a very important step in bacterial protein biosynthesis, PDF is an essential component of bacterial growth, and the gene encoding PDF is present in the genomes of all sequenced pathogenic bacteria. Exists.

  WO 02 / 41886A1 discloses hydroxamic acid or N-formylhydroxyamine derivatives as recent inhibitors of polypeptide deformylase.

  Due to the increased resistance exhibited by both gram negative and gram positive bacteria, as well as other microorganisms, new antibacterial compounds are urgently needed. Traditional antibiotics have targeted specific pathways for bacterial replication and maintenance. However, no new pathway has been targeted in such a way as to outweigh the increase in bacterial resistance. Therefore, there is a great need for new compounds and strategies that can be used to eradicate resistant bacteria.

［式中、R₁、R₂、R₃およびXは本明細書の詳細な説明で定義されているとおりである］
の化合物、またはそれらの医薬的に許容される塩もしくはエステルに関する。 SUMMARY OF THE INVENTION The present invention provides a compound of the general formula (I):

Wherein R ₁ , R ₂ , R ₃ and X are as defined in the detailed description herein.
Or a pharmaceutically acceptable salt or ester thereof.

  The compounds of the present invention are believed to be useful in the treatment of infections caused by bacteria or parasites. In particular, the compounds of the present invention are gram-positive or gram-negative bacteria such as Escherichia coli and Staphylococcus aureus, or Plasmodium falciparum, P. falciparum, It may be useful in the treatment of infections caused completely or partially by parasites such as protozoa.

An object of the present invention is to provide a novel compound having pharmacological activity as an inhibitor of PDF.
Further objects will become apparent from the description below.

Detailed Description of the Invention
DEFINITIONS The terms used herein are for the purpose of describing embodiments in particular and are not intended to be limiting, so the scope of the present invention is limited only by the appended claims.

  When values in a range are stated, each value intervening between the upper and lower limits of the range and any other stated or intervening value within that range is one tenth unless otherwise stated. It is understood that it is included in the scope of the present invention to the order of.

  The upper and lower limits of the narrow ranges that may be independently included in the narrow ranges are also included in the scope of the present invention unless they are any specific limits not included in the ranges described above.

  When the above-described ranges include either or both of the limits, ranges that do not include one or both of the included limits are also included in the invention.

  Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described.

  It should be noted that as used herein and in the appended claims, the singular forms “a”, “and” and “and” include plural references unless the context clearly dictates otherwise. .

  The term “peptide deformylase” or “PDF” as used herein is also known as PDF, which catalyzes the conversion of a newly synthesized protein N-terminal formyl-L-methionyl peptide to methionyl peptide. It is intended to mean the peptide deformylase (EC 3.4.1.88).

  The term “treatment” is defined as the management and care of a patient for the purpose of combating a disease, illness or disorder, and the prevention of the onset of symptoms or complications or the alleviation of symptoms or complications or the elimination of a disease, illness or disorder. For administration of the compounds of the present invention.

As used herein alone or in combination, the term “C _1-6 alkyl” means a straight or branched saturated hydrocarbon chain having 1 to 6 carbon atoms. C _1-6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-phenyl, iso-phenyl, 2- Including methylbutyl, 3-methylbutyl, n-hexyl, iso-hexyl, 4-methylphenyl, neopentyl, 2,2-dimethylpropyl and the like.

As used herein, alone or in combination, the term “C _2-6 alkenyl” refers to a straight or branched unsaturated hydrocarbon chain having 2 to 6 carbon atoms and at least one double bond. Means. C _2-6 alkenyl groups include, but are not limited to, vinyl, 1-propenyl, allyl, iso-propenyl, n-butenyl, n-pentenyl, n-hexenyl, and the like.

The term “C _1-6 alkoxy” in the context of the present specification denotes an —OC _1-6 alkyl group, wherein C _1-6 alkyl is as defined above, used alone or in combination. Examples of linear alkoxy groups are methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy. Examples of branched alkoxy are iso-propoxy, sec-butoxy, tert-butoxy, iso-pentoxy and iso-hexoxy. Examples of cyclic alkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.

The term “C _3-10 cycloalkyl” as used herein means one or more saturated mono-, bi-, tri-, or spirocyclic hydrocarbon groups having from 3 to 10 carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo [3.2.1] octyl, spiro [4.5] decyl, norpinyl, norbornyl, norcalyl, adamantyl and the like Including.

The term “C _3-10 cycloalkane” as used herein refers to a saturated cyclic hydrocarbon having from 3 to 10 carbon atoms. Examples include but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, adamantane and the like.

As used herein, the term “C _3-7 heterocycloalkyl” is fully saturated, such as a cyclic hydrocarbon that independently contains one or more heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Means a heterocyclic group which is Examples of heterocycles include, but are not limited to, pyrrolidine (1-pyrrolidine, 2-pyrrolidine, 3-pyrrolidine, 4-pyrrolidine, 5-pyrrolidine), pyrazolidine (1-pyrazolidine, 2-pyrazolidine, 3-pyrazolidine, 4-pyrazolidine) , 5-pyrazolidine),

Imidazolidine (1-imidazolidine, 2-imidazolidine, 3-imidazolidine, 4-imidazolidine, 5-imidazolidine), thiazolidine (2-thiazolidine, 3-thiazolidine, 4-thiazolidine, 5-thiazolidine), piperidine ( 1-piperidine, 2-piperidine, 3-piperidine, 4-piperidine, 5-piperidine, 6-piperidine), piperazine (1-piperazine, 2-piperazine, 3-piperazine, 4-piperazine, 5-piperazine, 6-piperazine) ), Morpholine (2-morpholine, 3-morpholine, 4-morpholine, 5-morpholine, 6-morpholine), thiomorpholine (2-thiomorpholine,

3-thiomorpholine, 4-thiomorpholine, 5-thiomorpholine, 6-thiomorpholine), 1,2-oxathiolane (3- (1,2-oxathiolane), 4- (1,2-oxathiolane), 5- ( 1,2-oxathiolane)), 1,3-dioxolane (2- (1,3-dioxolane), 3- (1,3-dioxolane), 4- (1,3-dioxolane)), tetrahydropyran (2- Tetrahydropyran, 3-tetrahydropyran, 4-tetrahydropyran, 5-tetrahydropyran, 6-tetrahydropyran), hexaihydropyrazidine, (1- (hexahydropyrazidine), 2- (hexahydropyrazidine) , 3- (hexahydropyrazidine), 4- (hexahydropyrazidine), 5- (hexahydropyrazidine), 6- (hexahydropyrazidine)).

The term “C _1-6 alkyl-C _3-10 cycloalkyl” as used herein has the indicated number of carbon atoms attached through an alkyl group as defined above. Refers to a cycloalkyl group as defined above.

The term “C _1-6 alkyl-C _3-7 heterocycloalkyl”, as used herein, has the indicated number of carbon atoms attached through an alkyl group as defined above. Refers to a heterocycloalkyl group as defined above.

  The term “aryl” as used herein is intended to include carbocyclic aromatic ring systems. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems listed below.

  The term “heteroaryl” as used herein includes heterocyclic unsaturated ring systems containing one or more heteroatoms selected between nitrogen, oxygen and sulfur, such as furyl, thienyl, pyrrolyl. It is intended to include the partially hydrogenated derivatives of the carbocyclic systems listed below.

  Examples of “aryl” and “heteroaryl” include, but are not limited to, phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxy Imidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), phenanthrenyl, fluorenyl, pentarenyl, azulenyl, biphenylenyl, thiophenyl (1-thienyl, 2-thienyl), furyl (1-furyl, 2-furyl), furanyl , Thiophenyl, isoxazolyl, isothiazolyl, 1,2,3-thiazolyl,

1,2,4-thiazolyl, pyranyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4- Thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl (thianaphthenyl),

Indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, benzisoxazolyl, purinyl, quinazolinyl, quinolidinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthylidinyl, pyrrolidinyl, azepinyl, azeridyl , Pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazole-2) -Yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl,

4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5 -Pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl) , 8-isoquinolyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl,

8-quinolyl), benzo [b] furanyl (2-benzo [b] furanyl, 3-benzo [b] furanyl, 4-benzo [b] furanyl, 5-benzo [b] furanyl, 6-benzo [b] furanyl 7-benzo [b] furanyl), 2,3-dihydro-benzo [b] furanyl (2- (2,3-dihydro-benzo [b] furanyl), 3- (2,3-dihydro-benzo [b ] Furanyl), 4- (2,3-dihydro-benzo [b] furanyl), 5- (2,3-dihydro-benzo [b] furanyl), 6- (2,3-dihydro-benzo [b] furanyl) ), 7- (2,3-dihydro-benzo [b] furanyl)), benzo [b] thiophenyl (2-benzo [b] thiophenyl, 3-benzo [b] thiophenyl, 4-benzo [b] thiophenyl, 5 -Benzo [b] thiophenyl, 6-benzo [b] thiophenyl, 7-benzo [b] thiophenyl), 2,3-dihydro-benzo [b] thiophenyl (2- (2,3-dihydro-benzo [b] thiophenyl) ), 3- (2,3-dihydro-benzo [b] thiophenyl), 4- (2,3-dihydro-benzo [b] thiophenyl) 5- (2,3-dihydro-benzo [b] thiophenyl), 6- (2,3-dihydro-benzo [b] thiophenyl), 7- (2,3-dihydro-benzo [b] thiophenyl)), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazolyl (1-indazolyl, 2-indazolyl,

3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl, (1-benzimidazolyl, 2-benzimidazolyl, 4-benzoimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8- Benzoimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), Including carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl).

  Non-limiting examples of partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like.

The term “C _1-6 alkylaryl” as used herein is attached through a C _1-6 alkyl group as defined above having 1, 2, 3, 4, 5 or 6 carbon atoms. Wherein the term is understood to include unsubstituted or substituted C _1-6 alkylaryl.

The term “C _1-6 alkylheteroaryl” as used herein is attached through a C _1-6 alkyl group as defined above having 1, 2, 3, 4, 5 or 6 carbon atoms. The term heteroaryl as defined above; the term is understood to include unsubstituted or substituted C _1-6 alkylheteroaryl.

As used herein, the term "thio C _1-6 - alkyl" group -SC _1-6 - alkyl (wherein, C _1-6 - alkyl is as defined above) means. Representative examples include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, n-phenylthio, isopentylthio, neopentylthio, tert- Including phenylthio, n-hexylthio, isohexylthio and the like.

As used herein, the term “C _1-6 alkylthio-C _1-6 alkyl” refers to the group —C _1-6 alkyl-SC _1-6 alkyl, where C _1-6 -alkyl is as defined above. Mean). Representative examples include, but are not limited to, methylthiomethyl, ethylthiomethyl _{(i.e., -CH 2 -SC 2 H 5)} , n- propyl thio methyl, isopropylthio methyl, butylthiomethyl, isobutyl thio methyl, sec -Butylthiomethyl, tert-butylthiomethyl, n-phenylthiomethyl, isopentylthiomethyl, neopentylthiomethyl, tert-phenylthiomethyl, methylthioethyl, methylthiopropyl, methylthioisopropyl, methylthiobutyl, methylthioisobutyl, methylthiopentyl Methylthioisopentyl, methylthiohexyl, methylthioisohexyl and the like.

The term “C _1-6 -alkyl mercapto” as used herein refers to the group —C _1-6 -alkyl-SH where C _1-6 -alkyl is as defined above. . Representative examples include, but are not limited to, mercaptomethyl (i.e., -CH ₂ -SH), mercaptoethyl, mercapto n- propyl, mercapto isopropyl, mercapto butyl, mercapto isobutyl, mercapto sec- butyl, mercapto tert- butyl , Mercapto n-phenyl, mercaptoisopentyl, mercaptoneopentyl, mercapto tert-phenyl, mercapto n-hexyl, mercaptoisohexyl and the like.

As used herein, the term “C _1-6 -alkylhydroxy” refers to the group —C _1-6 -alkyl-OH, where C _1-6 -alkyl is as defined above. . Representative examples include, but are not limited to, methyl hydroxy (i.e., -CH ₂ -OH), ethyl hydroxy, n- propyl hydroxy, isopropyl hydroxy, butyl hydroxy, isobutyl hydroxy, sec- butyl hydroxy, tert- butyl hydroxy, n -Phenylhydroxy, isopentylhydroxy, neopentylhydroxy, tert-phenylhydroxy, n-hexylhydroxy, isohexylhydroxy and the like.

The term “C _1-6 alkylcarboxy” as used herein refers to the group —C _1-6 -alkyl-COOH, wherein C _1-6 -alkyl is as defined above. Representative examples include, but are not limited to, carboxymethyl (ie, —CH ₂ —COOH), carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, carboxyhexyl, and the like.
The term “C _1-6 alkylamide” as used herein refers to the group —C _1-6 alkyl-CONH _2, where C _1-6 -alkyl is as defined above. Representative examples include, but are not limited to, carbamoylmethyl (ie, —CH ₂ —CONH ₂ ), carbamoylethyl, carbamoylpropyl, carbamoylbutyl, carbamoylpentyl, carbamoylhexyl, and the like.

The term “C _1-6 -alkylamino” as used herein refers to the group —C _1-6 -alkyl-NH _2, where C _1-6 -alkyl is as defined above. To do. Representative examples include, but are not limited to, methylamino (i.e., -CH ₂ -NH _2), ethylamino, n- propylamino, isopropylamino, butylamino, isobutylamino, sec- butylamino, tert- butylamino, n-phenylamino, isopentylamino, neopentylamino, tert-phenylamino, n-hexylamino, isohexylamino and the like.

As used herein, the term “alkylamino-C _1-6 -alkyl” refers to the group —C _1-6 -alkyl-NH—C _1-6 -alkyl where C _1-6 -alkyl is as defined above. As defined). Representative examples include, but are not limited to, methylaminomethyl, ethylaminomethyl _{(i.e., -CH 2 -NH-C 2 H} 5), n- propyl aminomethyl, isopropylamino methyl, butyl amino methyl, isobutyl aminomethyl, sec-Butylaminomethyl, tert-butylaminomethyl, n-phenylaminomethyl, isopentylaminomethyl, neopentylaminomethyl, tert-phenylaminomethyl, n-hexylaminomethyl, isohexylaminomethyl, methylaminoethyl, methyl Including aminopropyl, methylaminoisopropyl, methylaminobutyl, methylaminoisobutyl, methylaminopentyl, methylaminoisopentyl, methylaminohexyl, methylaminoisohexyl and the like.

As used herein, the term “dialkylamino-C _1-6 -alkyl” refers to the group (C _1-6 -alkyl) ₂ -NC _1-6 -alkyl where C _1-6 -alkyl is as defined above. As defined). Representative examples include, but are not limited to, dimethylaminomethyl, diethylaminomethyl _{(i.e., -CH 2 -N- (C 2 H} 5) 2), dipropyl aminomethyl, di - isopropylamino methyl, dibutyl aminomethyl, di -Isobutylaminomethyl, di-sec-butylaminomethyl, di-tert-butylaminomethyl, dipentylaminomethyl, di-isopentylaminomethyl, di-neopentylaminomethyl, di-tert-phenylaminomethyl, dihexylaminomethyl Diisohexylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, dimethylaminoisopropyl, dimethylaminobutyl, dimethylaminoisobutyl, dimethylaminopentyl, dimethylaminoisopentyl, dimethylaminohexyl, dimethylaminoisohexyl and the like.

The term “C _1-6 alkylamidine” as used herein refers to the group —C _1-6 -alkyl-C (═NH) NH _{2, where} C _1-6 -alkyl is as defined above. means. Representative examples include, but are not limited to, methylamidine, ethylamidine, propylamidine, butylamidine, pentylamidine, hexylamidine, and the like.

The term “C _1-6 alkylguanidine” as used herein refers to the group —C _1-6 -alkyl-NC (═NH) NH _2, where C _1-6 -alkyl is as defined above. Mean). Representative examples include, but are not limited to, 1-methylguanidine, 1-ethylguanidine, 1-propylguanidine, 1-butylguanidine, 1-phenylguanidine, 1-hexylguanidine, and the like.

  “Halogen” means an atom selected from the group consisting of F, Cl, Br and I.

The term “unsubstituted” or “substituted” as used herein refers to whether the group is optionally substituted or halogen, hydroxy, amino, mercapto, nitro, cyano, trifluoromethyl, trifluoromethylthio, Each other selected from fluoromethoxy, C _1-6 alkyl, C _1-6 alkoxy, thio C _1-6 alkyl, C _1-6 alkylamino, alkylamino-C _1-6 alkyl and dialkylamino C _1-6 alkyl It means substituted with 1, 2, or 3 independent substituents. When the group is substituted with more than one substituent, the substituents may be the same or different.

  As used herein, the terms "amino acid", "amino acid residue", "natural amino acid" and "natural amino acid residue" are all alanine (Ala), arginine (Arg), asparagine (Asn), asparagine. Acid (Asp), Cysteine (Cys), Glutamine (Gln), Glutamic acid (Glu), Glycine (Gly), Histidine (His), Isoleucine (Ile), Leucine (Leu), Lysine (Lys), Methionine (Met), D- or L-isomerism of more than 20 standard amino acid residues including phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr) and valine (Val) Refers to the body. Amino acids are monomers containing amino and carboxy groups that can be polymerized to form peptide and protein chains. Typically, peptide / protein forming amino acids have amino and carboxy groups attached to the same carbon atom (α carbon) and are referred to as α-amino acids. The term “α-amino acid side chain” means an α-carbon-like substituent. Variable substituents can produce different amino acids with different chemical properties. An amino acid residue is the portion of an amino acid that remains after being incorporated into a polypeptide chain. This residue contains the α-carbon and nitrogen / carbonyl moieties.

  Some of the terms defined above may appear more than once in a structural formula, but for such occurrences, each term should be defined independently of each other.

As used herein, the phrase “functional group capable of being converted to hydrogen in vivo” refers, for example, enzymatically or intragastrically when administering a compound of the invention to a patient in need thereof. It is intended to include any group that can be converted to hydrogen by the acidic environment of Non-limiting examples of such groups include C _1-6 alkylcarbonyl, aroyl, C _1-6 alkylcarbamoyl, di-C _1-6 alkyl-alkylcarbamoyl, C _1-6 alkoxycarbonyl and C _1-6 Acyl such as alkoxy-C _1-6 alkyl, carbamoyl, monoalkylated carbamoyl, dialkylated carbamoyl, alkoxycarbonyl, alkoxyalkyl groups and the like.

  As used herein, the phrase “diseases and disorders related to peptide deformylase” refers to any peptide deformylase, particularly an effect on bacterial peptide deformylase, preferably any beneficial inhibitory effect. It is intended to include a disease or disorder.

As used herein, the term “IC ₅₀ ” refers to the concentration required for 50% inhibition of PDF in a binding assay.

  Abbreviations and symbols commonly used in peptide and chemical arts are used herein to describe the compounds of the invention. In general, amino acid abbreviations follow IUPAC-IUB Joint Commission on Biochemical Nomenclature, as described in Eur. J. Biochem., 158, 9 (1984).

Certain groups of groups are abbreviated herein. t-Bu refers to tertiary butyl group, Boc refers to t-butyloxycarbonyl group, Fmoc refers to fluorenylmethoxycarbonyl group, Ph refers to phenyl group, Cbz refers to benzyloxycarbonyl group .
Compound The present invention provides a compound of the general formula (I)

[Where:
X is -CONHOH, -COOH, -OH or -SH;
R ₁ is C _1-6 alkyl, C _3-10 cycloalkyl, C _1-6 alkyl mercapto, C _1-6 alkylthio-C _1-6 alkyl, C _1-6 alkylhydroxy, C _1-6 alkylcarboxy, C _1-6 alkylamide, C _1-6 alkylamino, alkylamino-C _1-6 alkyl, dialkylamino-C _1-6 alkyl, C _1-6 alkylamidine, C _1-6 alkylguanidine, unsubstituted or substituted An aryl group, an unsubstituted or substituted heteroaryl group, an unsubstituted or substituted C _1-6 alkylaryl group, an unsubstituted or substituted C _1-6 alkylheteroaryl group and a side chain of a natural α-amino acid Selected from the group;
Provided that R ₁ cannot be hydrogen or tert-butyl;

R ₂ is C _1-6 alkyl, C _2-6 alkenyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _3-7 heterocycloalkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 alkyl mercapto, C _1-6 alkylhydroxy, thio C _1-6 alkyl, alkylamino-C _1-6 alkyl, dialkylamino-C _1-6 alkyl, unsubstituted or substituted Selected from the group consisting of a substituted aryl group, an unsubstituted or substituted heteroaryl group, an unsubstituted or substituted C _1-6 alkylaryl group, and an unsubstituted or substituted C _1-6 alkylheteroaryl group;
R ₃ is —NHCH (R ₄ ) COR ₅ , —NR ₆ R ₇ , —NHR ₇ or —OR ₇ ;
R ₄ is selected from the group consisting of hydrogen and the side chains of natural α-amino acids;
R ₅ is amino, hydroxy, C _1-6 alkoxy or —NH—C _1-6 alkyl;

R ₆ and R ₇ are the same or different and, independently of each other, a C _3-7 heterocycloalkyl, unsubstituted or substituted C _1-6 alkyl-C _3-7 heterocycloalkyl group, unsubstituted or substituted Selected from the group consisting of a substituted aryl group, an unsubstituted or substituted heteroaryl group, an unsubstituted or substituted C _1-6 alkylaryl group, and an unsubstituted or substituted C _1-6 alkylheteroaryl group;
Here, the substituted group is halogen, hydroxy, amino, mercapto, nitro, cyano, trifluoromethyl, C _1-6 alkyl, C _1-6 alkoxy, thio C _1-6 alkyl, C _1-6 alkylhydroxy, Substituted with 1, 2 or 3 substituents independently selected from C _1-6 alkylamino, alkylamino-C _1-6 alkyl and dialkylamino-C _1-6 alkyl]
Or a pharmaceutically acceptable salt or ester thereof.

  In preferred embodiments of the invention, X is —CONHOH or —COOH. However, in other useful compounds of the invention, X is —OH or —SH.

Preferably, R ₁ is natural such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine and valine. It is a side chain of α-amino acid, or R ₁ is C _1-6 alkyl, C _3-10 cycloalkyl, C _1-6 alkyl mercapto, C _1-6 alkylthio-C _1-6 alkyl, C _{1 -6} alkyl hydroxy, C _1-6 alkyl carboxy, C _1-6 alkyl amide, C _1-6 alkyl amino, alkylamino-C _1-6 alkyl, dialkylamino-C _1-6 alkyl, C _1-6 alkyl amidine , C _1-6 alkyl guanidine, unsubstituted or substituted aryl group, an unsubstituted or substituted heteroaryl group, an unsubstituted or substituted C _1-6 alkylaryl group, and is selected from the group consisting of unsubstituted or substituted C _1-6 alkylheteroaryl group. More preferably, R ₁ is ethyl, isobutyl, 2- (methylsulfanyl) ethyl, 4-aminobutyl, benzyl, 4-hydroxybenzyl, 2-phenylethyl and naphth-1-yl-methyl.

R ₂ is preferably C _1-6 alkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _1-6 alkylamino, C _1-6 alkylhydroxy, unsubstituted or Selected from the group consisting of a substituted C _1-6 alkylaryl group and an unsubstituted or substituted C _1-6 alkylheteroaryl group;

Wherein the substituted group is independently selected from halogen, hydroxy, amino, mercapto, nitro, cyano, trifluoromethyl, C _1-6 alkyl, C _1-6 alkoxy, and thio C _1-6 alkyl Substituted with 1, 2 or 3 substituents. More preferably, R ₂ is ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, cyclohexylethyl, aminoethyl, aminopropyl, aminobutyl, hydroxymethyl, hydroxy Selected from the group consisting of ethyl, hydroxypropyl, hydroxybutyl, phenyl, fluorine substituted phenyl, chloro substituted phenyl, benzyl, fluorine substituted benzyl, chloro substituted benzyl, thiophenylethyl and furanylmethyl.

In particular, R ₂ is butyl, cyclopropyl, cyclohexylmethyl, 2-aminoethyl, 2-hydroxyethyl, benzyl, 2-chlorobenzyl, 4-chlorobenzyl, 2,6-difluorobenzyl, 2-thiophen-2 It can be selected from -ylethyl or furan-2-ylmethyl.

In a preferred embodiment of the invention, R ₃ is -NHCH (R ₄ ) COR ₅ wherein R ₄ is hydrogen or alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine. Histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine or the side chain of a natural amino acid such as valine, preferably R ₄ is hydrogen; and R ₅ is C _1-6 alkoxy, preferably methoxy, ethoxy, propoxy or butoxy).

In another preferred embodiment of the invention, R ₃ is a group -NHR ₇ , a group -NR ₆ R ₇ or a group -OR ₇ (where R ₆ or R ₇ is a C _3-7 heterocycloalkyl or An unsubstituted or substituted C _1-6 alkyl-C _3-7 heterocycloalkyl group, or R ₆ or R ₇ is an unsubstituted or substituted aryl group, an unsubstituted or substituted heteroaryl group, an unsubstituted group; Or a substituted C _1-6 alkylaryl group or an unsubstituted or substituted C _1-6 alkylheteroaryl group).

Preferred compounds of the invention are:
([1-cyclopropyl-2- [1- (3-mercapto-propionylamino) -propyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([1- (4-Chloro-benzyl) -2- [1- (3-mercapto-propionylamino) -2-phenyl-ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
N- [1- [1-benzyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -3-methylsulfanyl-propyl] -succinamic acid,
N- [1- [1-butyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -2-phenyl-ethyl] -succinamic acid,

N- [1- [1-furan-2-ylmethyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzoimidazol-2-yl] -2-phenyl-ethyl] -succinamic acid,
N- [1- [1- (4-Chloro-benzyl) -5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -2-phenyl-ethyl] -succinamic acid,
N- [1- [1-cyclopropyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzoimidazol-2-yl] -3-phenyl-propyl] -succinamic acid,
N- [1- [1-cyclohexylmethyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -3-phenyl-propyl] -succinamic acid,
N- [1- [1- (2-chloro-benzyl) -5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -3-phenyl-propyl] -succinamic acid,

N- [1- [1-cyclopropyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -propyl] -succinamic acid,
N- [1- [1-furan-2-ylmethyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -propyl] -succinamic acid,
N- [1- [1-benzyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -propyl] -succinamic acid,
N- [1- [1-cyclopropyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzoimidazol-2-yl] -3-methyl-butyl] -succinamic acid,
N- [1- [1-butyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -3-methyl-butyl] -succinamic acid,

N- [1- [1-benzyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -3-methyl-butyl] -succinamic acid,
N- [1- [1-cyclopropyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -3-methylsulfanyl-propyl] -succinamic acid,
N- [1- [5- (methoxycarbonylmethyl-carbamoyl) -1- (2-thiophen-2-yl-ethyl) -1H-benzimidazol-2-yl] -2-naphthalen-1-yl-ethyl] -Succinamic acid,
N- [1- [1-butyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -2-naphthalen-1-yl-ethyl] -succinamic acid,
([2- [5-amino-1- (3-mercapto-propionylamino) -phenyl] -1-cyclohexylmethyl-1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,

([1-Cyclopropyl-2- [2- (4-hydroxy-phenyl) -1- (3-mercapto-propionylamino) -ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester ,
([1-Cyclohexylmethyl-2- [2- (4-hydroxy-phenyl) -1- (3-mercapto-propionylamino) -ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester ,
([1- (2-hydroxy-ethyl) -2- [1- (3-mercapto-propionylamino) -2-phenyl-ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
N- [5-amino-1- [1-cyclopropyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -phenyl] -succinamic acid,
N- [5-amino-1- [1-cyclohexylmethyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -phenyl] -succinamic acid,

N- [1- [1-cyclopropyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -2- (4-hydroxyphenyl) -ethyl] -succinamic acid,
N- [1- [1-cyclohexylmethyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -2- (4-hydroxyphenyl) -ethyl] -succinamic acid,
N- [1- [1- (2-hydroxy-ethyl) -5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -2-phenyl-ethyl] -succinamic acid,
N- [1- [1- (2-hydroxy-ethyl) -5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -3-methylbutyl] -succinamic acid,

([1-cyclopropyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -propyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
N- [1- [1-benzyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -2-naphthalen-1-yl-ethyl] -succinamic acid,
([1-furan-2-ylmethyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -propyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([1-benzyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -propyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([1-cyclopropyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -3-methyl-butyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,

([1-butyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -3-methyl-butyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([1-benzyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -3-methyl-butyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([1-cyclopropyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -3-methylsulfanyl-propyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([1-cyclohexylmethyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -3-methylsulfanyl-propyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,

([1-benzyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -3-methylsulfanyl-propyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([1-furan-2-ylmethyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -2-phenyl-ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([1- (4-Chloro-benzyl) -2- [1- (3-hydroxycarbamoyl-propionylamino) -2-phenyl-ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester ,
([1-cyclopropyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -3-phenyl-propyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,

([1-cyclohexylmethyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -3-phenyl-propyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([1- (2-Chloro-benzyl) -2- [1- (3-hydroxycarbamoyl-propionylamino) -2-phenyl-ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester ,
[[2- [1- (3-Hydroxycarbamoyl-propionylamino) -2-naphthalen-1-yl-ethyl] -1- (2-thiophen-2-yl-ethyl) -1H-benzimidazol-5-carbonyl ] -Amino] -acetic acid methyl ester,
([1-butyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -2-naphthalen-1-yl-ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,

([1-benzyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -2-naphthalen-1-yl-ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([1-butyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -2-phenyl-ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([2- [5-amino-1- (3-mercapto-propionylamino) -phenyl] -1-cyclopropyl-1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([2- [5-amino-1- (3-mercapto-propionylamino) -phenyl] -1-benzyl-1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([1- (2-amino-ethyl) -2- [1- (3-mercapto-propionylamino) -2-phenyl-ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
N- [5-amino-1- [1-benzyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -phenyl] -succinamic acid,

N- [1- [1- (2-amino-ethyl) -5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -2-phenyl-ethyl] -succinamic acid,
([2- [5-amino-1- (3-hydroxycarbamoyl-propionylamino) -phenyl] -1-cyclopropyl-1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([2- [5-amino-1- (3-hydroxycarbamoyl-propionylamino) -phenyl] -1-cyclohexylmethyl-1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([2- [5-amino-1- (3-hydroxycarbamoyl-propionylamino) -phenyl] -1-benzyl-1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,

([1- (2-Amino-ethyl) -2- [1- (3-hydroxycarbamoyl-propionylamino) -2-phenyl-ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester ,
([1-Cyclopropyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -2- (4-hydroxy-phenyl) -ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([1-cyclohexylmethyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -2- (4-hydroxy-phenyl) -ethyl] -1H-benzimidazol-5-carbonyl] -amino) -methyl acetate ester,
[[2- [1- (3-Hydroxycarbamoyl-propionylamino) -2-phenyl-ethyl] -1- (2-hydroxy-ethyl) -1H-benzimidazol-5-carbonyl] -amino] -acetic acid methyl ester ,
And their stereoisomers.

  The compounds of the present invention may exist as geometric isomers, optical isomers, stereoisomers or tautomers. Accordingly, the present invention includes tautomers including all geometric isomers and mixtures and racemic mixtures thereof and pharmaceutically acceptable salts thereof, particularly all R- and S-isomers.

  The present invention also includes pharmaceutically acceptable salts of the compounds of the present invention. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium salts and alkylated ammonium salts. Acid addition salts include salts of inorganic and organic acids. Representative examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid and the like. Representative examples of suitable organic acids are formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, lactic acid, maleic acid, malic acid, malonic acid, mandel Acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, bismethylenesalicylic acid, ethanedisulfonic acid, gluconic acid, citraconic acid, asparagine Including acid, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci., 1977, 66, 2, incorporated herein by reference. Including.

  Examples of metal salts include salts of lithium, sodium, potassium, magnesium and the like. Examples of ammonium salts and alkylated ammonium salts include salts of ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium and the like.

  Hydrate and solvent complexes that can be formed by the compounds of the present invention are also contemplated as pharmaceutically acceptable acid addition salts.

  Acid addition salts can be obtained as a direct product of compound synthesis. Alternatively, the free base can be dissolved in a suitable solvent containing the appropriate acid, and the salt is isolated by evaporating the solvent or by separating the salt and solvent.

  The compounds of the present invention may form solvates with standard low molecular weight solvents and solvates using methods well known to those skilled in the art. Such solvates are also considered to be within the scope of the present invention.

  The invention also encompasses prodrugs of the compounds of the invention that undergo chemical transformation upon administration by metabolic processes before becoming active drugs. In general, such prodrugs are functional derivatives of the compounds of the present invention that can be readily converted in vivo to the desired compound of formula I. Prodrugs are any covalently bonded compounds that release the active parent drug according to Formula I in vivo. If another form of chiral center or isomer center is present in the compounds of the invention, all forms of such isomers or isomers, including enantiomers and diastereoisomers, are included in the invention. Intended to be included. Compounds of the invention containing chiral centers can be used as racemic mixtures, enantiomerically enriched mixtures, which can be resolved using well-known methods and the individual enantiomers can be used alone. Can do. When a compound has an unsaturated carbon-carbon double bond, both the cis (Z) and trans (E) isomers are within the scope of the invention. Where a compound can exist in a tautomeric form, such as a keto-enol tautomer, each tautomeric form is considered to be included in the present invention even if equilibrium or one form predominates. . Conventional methods for the selection and production of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, edited by H. Bundgaard, Elsevier, (1985).

The present invention also encompasses active metabolites of the compounds of the present invention.
The present invention includes all complexes of the compounds of the invention.

The meaning of any substituent in any one present in Formula I or any of its subformulas, in any other presence, unless stated otherwise, its meaning, or any other Independent of the meaning of the substituent.
In a preferred embodiment of the invention, the compound of formula I is less than 500 μM, preferably less than 100 μM, more preferably less than 50 μM, even more preferably less than 1 μM, in particular less than 500 nM in a bacterial PDF assay (see below). In particular, IC ₅₀ values of 300 nM or less are shown.

Synthesis Method of Preparation The compounds of the present invention having the general formula I can be prepared by the methods shown in Scheme A and Scheme B of the “Materials and Methods” below.

Compounds where R ₃ is —NHCH (R ₄ ) COR ₅ can be synthesized as described in Scheme A. The aromatic nucleus is bound to the resin by standard techniques (step 1). Nucleophilic aromatic substitution with the corresponding amine gives the desired substituted aminonitrobenzoic acid attached to the resin (step 2). This reduction of the nitro functionality is accomplished by using SnCl ₂ in a suitable solvent such as DMF (step 3). Amino acid coupling to diaminobenzoic acid is achieved by standard techniques (HATU, HOAt) to give the desired material (step 4). Ring closure to produce benzimidazole is obtained by heating the resin in pure acetic acid (step 5). Amino acid residues are deprotected by standard methods, and each attachment of the terminal functionality (CONHOH, COOH, OH or SH) is achieved by standard attachment methods (TBTU, DIEA) (step 6). Finally, the target molecule is cleaved from the resin by treatment with a base (step 7).

Compounds where R ₃ is —NHR ₇ , —NR ₆ R ₇ or —OR ₇ can be synthesized as described in Scheme B. Nucleophilic aromatic substitution with the appropriate amine gives the desired substituted aminonitrobenzoate ester bound to the resin (step 1). This reduction of nitro functionality is achieved by using NaBH ₄ / Cu (acac) ₂ (step 2). Amino acid coupling to the diaminobenzoate ester is achieved by standard techniques (HATU, HOAt) to give the desired material (step 3). Ring closure to produce benzimidazole is obtained by heating in pure acetic acid (step 4). Amino acid residues are deprotected by standard methods, and each attachment of the terminal functionality (CONHOH, COOH, OH or SH) is achieved by standard attachment methods (TBTU, DIEA) (step 5). Corresponding primary amides are produced by aminolysis in NH ₃ / MeOH (step 6). Corresponding esters or amides are basic hydrolysis of methyl esters, followed by coupling of amines using standard techniques (TBTU, NEM) or alcohols using standard techniques (MSNT, methylimidazole). (Step 7).

Acid addition salts of the compounds of formula I can be obtained with the parent compound, such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid or methanesulfonic acid. From an excess of acid in an appropriate solvent by standard techniques. Certain compounds form internal salts or zwitterions that are acceptable. Cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent such as a hydroxide, carbonate or alkoxide containing the appropriate cation, or with a suitable organic amine. ^{Li +, Na +, K +} , Ca ++, Mg ++ and NH ₄ ⁺ cations, such as are specific examples of cations present in pharmaceutically acceptable salts. Halides, sulfates, phosphates, alkanoates (eg acetate and trifluoroacetate), benzoates and sulfonates (eg mesylate) are examples of anions present in pharmaceutically acceptable salts.

Pharmaceutical Compositions In one aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the invention as an active ingredient together with a pharmaceutically acceptable carrier or diluent. The compound can be in unit dosage form, for example from about 1 μg to about 1000 mg of a compound of the invention, such as from about 10 μg to about 500 mg, from about 0.05 to about 100 mg, or from about 0.1 to about 50 mg, or a pharmaceutical thereof May contain acceptable salts or esters. The compositions of the present invention can be used for oral, nasal, transdermal, pulmonary or parenteral administration. The pharmaceutical compositions of the invention are believed to be useful for the treatment of bacterial and / or parasitic infections.

  The compounds of the present invention can be administered either alone or in combination with a pharmaceutically acceptable carrier, diluent or excipient, either single or multiple doses. Thus, the compounds of formula I can be used in the manufacture of a medicament. The pharmaceutical composition according to the invention may be formulated with a pharmaceutically acceptable carrier or diluent and any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington ( The Science and Practice of Pharmacy, 19th supplement, edited by Gennaro, Mack Publishing Co., Easton, Pa., 1995).

  The pharmaceutical composition may be any suitable route, such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, intravaginal and parenteral (subcutaneous, muscle May be specifically formulated for administration by the intra, intrathecal, intravenous and intradermal routes, preferably the oral route. It will be appreciated that the preferred route will depend on the general condition and age of the patient to be treated, the nature of the condition to be treated and the active ingredient chosen.

  Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, troches, powders and granules. Where appropriate, the pharmaceutical composition can be manufactured with a coating, such as an enteric coating, or control of the active ingredient, such as sustained or sustained release, by methods well known in the art. It can be formulated to provide release.

  Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

  Pharmaceutical compositions for parenteral administration are sterile aqueous or non-aqueous injectable solutions, dispersions, suspensions or emulsions, and sterile powders that are returned to sterile injectable solutions or dispersions prior to use including. Injectable depot preparations are also considered to be within the scope of this invention.

  Other suitable administration forms include suppositories, sprays, ointments, creams, gels, inhalants, skin patches, implants and the like.

  A typical oral dosage is from about 0.001 to about 50 mg / kg body weight per day, preferably about 0.01 to about 30 mg / kg administered per day, such as one to three doses. Body weight, more preferably in the range of about 0.05 to about 20 mg / kg body weight. The exact dose depends on the frequency and mode of administration, the sex of the patient being treated, the age, weight and general condition of the patient to be treated, the condition being treated and the nature of any complications to be treated Depending on the severity and other factors apparent to those skilled in the art.

  The formulations can be conveniently provided in unit dosage forms by methods known to those skilled in the art. Typical unit dosage forms for oral administration one or more times per day, such as 1 to 3 times per day, are for example about 10 μg to about 500 mg, 0.05 to about 500 mg, preferably about 0.05 to about 100 mg. More preferably from about 1 μg to about 1000 mg, such as from about 0.1 to about 50 mg.

  For parenteral routes such as intravenous, intrathecal, intramuscular and similar administration, typical dosages are on the order of about half the dose used for oral administration.

  The compounds of the present invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof. One example is an acid addition salt of a compound having the utility of a free base. When the compound of formula (I) contains a free base, such salts can be used to convert solutions or suspensions of the free base of formula (I) into pharmaceutically acceptable acids, such as inorganic acids and organics. Manufactured in a conventional manner by treatment with chemical equivalents of acid. Representative examples are described above. Pharmaceutically acceptable salts of a compound having a hydroxy group include the anion of the compound in combination with a suitable cation such as sodium or ammonium ion.

  For parenteral administration, solutions of the novel compounds of formula (I) in sterile aqueous solution, aqueous propylene glycol or sesame oil or peanut oil may be used. Such an aqueous solution is appropriately treated with a buffer if necessary, and the liquid dilution is first made isotonic with sufficient saline or glucose. This aqueous solution is particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous medium used is readily available by standard methods known to those skilled in the art.

  Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, clay, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water. Similarly, the carrier or diluent may include any persistent material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with beeswax. Pharmaceutical compositions formed by combining a novel compound of formula (I) with a pharmaceutically acceptable carrier are then readily administered in a variety of dosage forms suitable for the disclosed route of administration. The formulations can be conveniently provided in unit dosage forms by methods known in the pharmaceutical arts.

  Formulations of the present invention suitable for oral administration can be presented as discrete units, such as capsules or tablets, each containing a predetermined amount of active ingredient and optionally containing suitable excipients. These formulations can be in the form of powders or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil emulsion.

  When a solid carrier is used for oral administration, the formulation can be tableted, placed in a gelatin hard capsule in the form of a powder or pellets, or in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g. When a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, gelatin soft capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

Typical tablets that can be manufactured by conventional tableting methods are:
core:
Active compound (free compound or salt) 5.0 mg
Lactosum European Pharmacy Law (Ph. Eur.) 67.8 mg
Microcrystalline cellulose (Avicel) 31.4 mg
Amberlite 1.0 mg
Magnesium stearate appropriate amount (qs)
coating:
Hydroxypropyl methylcellulose (approx.) 9 mg
Acylated monoglyceride (approx.) 0.9 mg
If desired, the pharmaceutical composition of the invention may comprise a compound of formula (I) in combination with further pharmacologically active substances such as those mentioned above.

The compounds of formula I according to the invention are useful as protease inhibitors, in particular as inhibitors of metalloproteases, more particularly as inhibitors of peptide deformylase, more particularly as inhibitors of bacterial peptide deformylase. The present invention provides useful compositions and formulations of the compounds, including pharmaceutical compositions and formulations of the compounds.

  The compounds of the present invention may be particularly effective in the treatment or prevention of diseases caused by various bacteria or prokaryotes. Examples are gram-positive and gram-negative aerobic and anaerobic bacteria such as Staphylococci, such as S. aureus and S. epidermidis; Enterococci, such as E. faecium and E. faecalis; (Streptococci), eg S. pneumoniae; Haemophilus, eg H. influenzae; Moraxella, eg M. catarrhalis; Escherichia, eg E. coli; Mycobacteria, eg M. tuberculosis and M. ranae; including Mycoplasma, such as M. pneumoniae; Pseudomonas, such as P. aeruginosa; intercellular microbes, such as Chlamydia and Rickettsiae.

  Other examples are Klebsiella pneumoniae, Shigella flexneri, Salmonella typhimurium, Bordetella pertussis, Clostridia perfringens (Helicobacter pylori), Campylobacter jejuni, Legionella pneumophila and Neisseria gonorrhoeae. It is further envisaged that the compounds of the present invention are effective in the treatment of parasitic infections such as those caused by Plasmodium falciparum.

  Accordingly, in one aspect of the invention, the invention relates to a method of treating a disease, the method comprising administering an effective amount of a compound or composition of the invention to a patient in need of treatment. An effective amount of a compound or composition of the invention is an active ingredient in the range of about 1 μg to about 1000 mg, ie active, for example about 10 μg to about 500 mg, about 0.05 to about 100 mg or about 0.1 to about 50 mg. It is contemplated that it corresponds to the amount of the compound or a pharmaceutically acceptable salt or ester thereof.

  In yet another aspect, the present invention relates to the use of a compound of the present invention for the manufacture of a medicament, preferably a gram positive or gram negative aerobic or anaerobic bacterium, or a medicament for the treatment of infection caused by infestation. Regarding use.

  In preferred embodiments of the invention, staphylococci, enterococci, streptococci, hemophilus, moraxella, escherichia, mycobacteria, mycoplasma, pseudomonas, chlamydia, rickettsia, klebsiella, shigella, salmonella, bordeterra, clostridium, helicobacter, campylobacter, legionella and Caused by Neisseria, preferably Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecium, Enterococcus faecalicus peptococcus faecalis peptococcus faecalis p , Haemophilus influenzae, Moraxella catarrhalis,

Escherichia coli, Mycobacterium tuberculosis, Mycobacterium ranae, Mycoplasma pneumoniae, Pseudomonas aeruginosa, Chlamydia, Chlamydia, Drugs for the treatment of infections caused by Klebsiella pneumoniae, Shigella flexinel, Salmonella typhimurium, Bordetella pertussis, Clostridia perfringens, Helicobacter pylori, Campylobacter jejuni, Legionella pneumophila and Neisseria gonorrheae are provided The

  The compounds of the present invention may also be useful in the treatment of parasitic infections such as those caused by Plasmodium falciparum.

  Intramuscular bone injection is also useful, but intravenous injection of this compound in 5% dextrose in water or normal saline, or similar formulations using appropriate excipients is most effective It is. Typically, parenteral dosages are about 0.01 to about 100 mg / kg; preferably 0.1 to 20 mg / kg, in a manner that maintains the concentration of drug in plasma at a concentration effective to inhibit PDF. between kg. The compound can be administered 1 to 4 times per day at a level to achieve a total daily dose of about 0.4 to about 400 mg / kg / day. The exact amount of a therapeutically effective compound of the present invention, and the route by which such compound is optimally administered, can be determined by comparing the blood level of the agent with the concentration required to have a therapeutic effect. Easily determined by the vendor.

  The compounds of the invention may be administered orally to a patient in such a manner that the concentration of the drug is sufficient to inhibit bone resorption or achieve any other therapeutic indication disclosed herein. You can also. Typically, pharmaceutical compositions containing the present compounds are administered at an oral dosage of between about 0.1 and about 50 mg / kg in a manner consistent with the patient's condition. Preferably, the oral dosage is from about 0.5 to about 20 mg / kg.

  Unacceptable toxic effects are not expected when administering the compounds of the invention according to the invention.

  The compounds of the present invention are useful for the treatment and / or prevention of a wide range of symptoms and disorders in which inhibition of PDF is fully or partially inhibited, and thus inhibition of PDF is beneficial.

  Accordingly, another aspect of the present invention is to provide any optical or geometric isomers or tautomers thereof, including compounds of general formula (I), or mixtures thereof, for use as pharmaceutical compositions It relates to a pharmaceutically acceptable salt.

  The present invention relates to any optical or geometric isomer or tautomer or pharmaceutically acceptable salt thereof comprising at least one compound of formula (I) as an active ingredient, or a mixture thereof. It also relates to a pharmaceutical composition comprising the above pharmaceutically acceptable carrier or diluent.

  In the following synthetic examples, all starting materials were obtained from commercial sources unless otherwise indicated. Without further explanation, using the foregoing description, it is believed that one skilled in the art will be able to make best use of the invention. These examples serve to illustrate the invention and are not intended to limit the scope thereof.

Materials and Methods The starting materials used herein are either commercially available or can be prepared according to methods previously described in the literature. Unless otherwise stated, commercially available starting materials were used without further purification. All solvents are HPLC grade. Anhydrous solvents were obtained by storage with 4 liters of active molecular sieves. Synthetic methods for making the compounds of the present invention must employ protecting groups to mask reactive functional groups or to minimize unwanted side reactions. Such protecting groups are generally described in Green et al. (1981).
Room temperature is about 20 ° C.
Mass spectra (ES-MS spectra) were obtained in positive mode on a Micromass Quattro micro® instrument unless otherwise stated.

Materials and abbreviations
AcOH acetic acid
BSA bovine serum albumin
DCM dichloromethane
DDQ 2,3-Dichloro-5,6-dicyano-p-benzoquinone
DIEA Diisopropylethylamine
Dhbt-OH 3-hydroxy-1,2,3-benzotriazine-4 (3H) -one
DMF N, N-dimethylformamide
DMSO Dimethyl sulfoxide

Fmoc 9-Fluorenylmethoxycarbonyl
HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (Aldrich; 97%)
HOAt 1-hydroxy-7-azabenzotriazole (Aldrich; 98%)
MOPS 4-morpholinepropanesulfonic acid hemisodium salt
NEM N-ethylmorpholine (Fluka; 98%)
POEPOP polyoxyethylene-polyoxypropylene copolymer
Pf pentafluorophenyl

RINK 4-[(2,4-Dimethoxyphenyl) -aminomethyl] phenoxyacetic acid
TBTU O-benzotriazol-1-yl-N, N, N´, N´-tetramethyluronium tetrafluoroborate (Fluka; 98%)
TFA trifluoroacetic acid
THF tetrahydrofuran
TIPS Triisopropylsilane
TMS trimethylsilyl
TNBS 2,4,6-trinitrobenzenesulfonic acid
Trt Trityl

Piperidine (98%) was obtained from Fluka; 3-fluoro-4-nitrobenzoic acid (98%) was obtained from Aldrich; SnCl ₂ (98%) was obtained from Fluka; succinic anhydride (97%) was Obtained from Aldrich; 3-mercaptopropionic acid (98%) was obtained from Aldrich; MaOMe (95%) was obtained from Aldrich.
All used amines (purity 95-98%) were obtained from Alrich.
All used amines (purity 95-99%) were obtained from Neosystem.

The following chemicals were used for biochemical assays: boric acid (Fluka, catalog number 15663); bovine serum albumin (Fluka, catalog number 5476); catalase (Fluka, catalog number 60640); f-Met-Ala (Bachem , Catalog number G-1855); methanol (Fluka, catalog number 65544); 4-morpholine-propanesulfonic acid hemi-sodium salt (Fluka, catalog number 69947); NaCl (Fluka, catalog number 71382); NaH ₂ PO ₄ (Fluka , Catalog number 71505); NaOH (Fluka, catalog number 71689); Na ₂ SO ₃ (Fluka, catalog number 71988); 2,4,6-trinitrobenzenesulfonic acid (Fluka, catalog number 92823); 4- (hydroxymercury) ) Sodium benzoate (Fluka, catalog number 55540).

Synthesis of the compounds of the present invention General synthetic methods for the compounds of the present invention are described in Scheme A (R ₃ = -NHCH (R ₄ ) COR ₅ ) and Scheme B (R ₃ = -NHR ₇ , -NR ₆ R ₇ Or -OR < ₇ >), and after each scheme, individual steps 1 to 7 are described in method A and method B, respectively.

Method A
Process 1:
Resin: In a typical example, 5.0 g of Fmoc protected glycine bound to POEPOP ₁₅₀₀ -resin (Renil et al. (1996)) (added ~ 1.0 mmol / g) was swollen with DMF. Fmoc deprotection was performed by treatment with 20% DMF solution of piperidine. A solution of 4-fluoro-3-nitrobenzoic acid (15.0 mmol, 2.8 g, 3 eq) is dissolved in DMF, TBTU (14.0 mmol, 4.50 g, 2.8 eq) and NEM (20.0 mmol, 2.30 g, 4 eq) Activated with. The acid was activated for 15 minutes prior to the addition of the swollen resin. The reaction was performed overnight at room temperature. The resin was then rinsed with DMF (10 times), DCM (10 times), and finally MeCN (10 times). The resin was lyophilized.

Process 2:
Dry resin (typically 800 mg, about 0.5 mmol) was placed in a plastic syringe and washed 5 times with DMF. To each resin was added 10% DMF solution of the appropriate amine. After about 3 hours, the resin was washed with DMF (10 times) and DMSO (3 times) and used directly in Step 3.

Process 3:
To each resin was added a 2M solution of SnCl ₂ in DMF. The resin mixture was allowed to stand overnight at room temperature before removing the liquid phase. The resin was washed with DMF (10 times) and used directly in Step 4.

Process 4:
HATU (0.95 mmol, 361 mg), HOAt (0.35 mmol, 50 mg), NEM (1.0 mmol, 126 μl) and the appropriate Fmoc-protected amino acid in DMF were added to the resin and allowed to react for 48 hours at room temperature. The resin was washed with DMF (10 times) and used directly in Step 5.

Process 5:
The resin was washed with AcOH (3 times) and finally AcOH was added to the resin and warmed to 80 ° C. for 48 hours. The resin was then washed with DMF (10 times) and used directly in the next step.

Process 6:
The resin was treated with 20% piperidine in DMF for 30 minutes at room temperature and then rinsed with DMF (8 times).

  (X = CONHOH): O-trityl succinamic acid (3.7 eq) was dissolved in DMF and activated with TBTU (3.0 eq) and NEM (3.7). This TBTU-activated succinamic acid was added to the resin and allowed to react overnight. The resin was then rinsed with DMF (10 times) and then treated with 95% TFA in DMF to remove the trityl protecting group.

  (X = COOH, OH): Succinic anhydride (10 eq) was dissolved in DMF and added to the resin. The reaction was allowed to proceed at room temperature for 60 minutes at room temperature. The resin was rinsed with DMF (8 times) and then treated with 95% TFA in water.

  (X = SH): S-trityl protected mercaptopropionic acid (4 eq) was dissolved in DMF (at a concentration of 0.1 M) and activated with TBTU (3.5 eq) and NEM (4 eq). Activated propionic acid was then added to the resin and allowed to react overnight. The resin was washed with DMF (10 times) and then treated with 95% TFA in DMF to cleave off the trityl protecting group.

Step 7:
The desired benzimidazoles were cleaved off from the resin by treatment with 0.1M NaOMe in MeOH. This material was collected and lyophilized. The material was analyzed by LC-MS (liquid chromatography-mass spectrum).

Method B:
Process 1:
Typically, 1 mmol of 4-fluoro-3-nitrobenzoic acid methyl ester was placed in a plastic tube and dissolved in THF (5 ml). To this solution was added 2 mmol of amine (1M solution in THF). To this solution was added triethylamine (2 ml). The solution was stirred at room temperature overnight. The solvent was removed in vacuo and the residue passed through a short silica plug.

Process 2:
The material from step 1 (typically 1 mmol) was dissolved in DCM / MeOH (50:50, typically 3 ml). In another MeOH solution (typically 20 ml), NaBH ₄ (10 eq) and Cu (acac) ₂ (0.6 eq) were dissolved. This borohydride / Cu (acac) ₂ solution was added to the material from Step 1. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed. Water was added and the aqueous solution was extracted with EtOAc. Drying and removal of the solvent gives the desired material that is used directly in the next step.

Process 3:
Typically, a DMF solution of HATU (0.95 mmol, 361 mg), HOAt (0.35 mmol, 50 mg), NEM (1.0 mmol, 126 μl) and the appropriate Fmoc-protected amino acid is added to the solution of the material from step 2. added. The reaction was performed overnight at room temperature. The solvent was removed in vacuo. Water was added and extracted with EtOAc. Drying and removal of the solvent gave material that was purified by column chromatography.

Process 4:
The material from step 3 was dissolved in AcOH and warmed to 60 ° C. overnight. The solvent was removed in vacuo and the material was used directly in the next reaction step.

Process 5:
The material from step 4 was treated with 20% piperidine in DMF for 30 minutes at room temperature. The solvent was removed in vacuo and then treated alternatively with:
(X = CONHOH): O-trityl succinamic acid (3.7 eq) was dissolved in DMF and activated with TBTU (3.0 eq) and NEM (3.7). TBTU-activated succinamic acid was added to the resin and allowed to react overnight. The solvent was removed in vacuo and then water was added. The aqueous phase was extracted with EtOAc. Drying and removal of the solvent followed by treatment with 95% TFA in DCM yielded a crude product in which the trityl protecting group was removed. The product was purified by preparative HPLC.

  (X = COOH, OH): Mono-tert-butyl succinate (10 eq) was dissolved in THF and added to the THF solution of the material from Step 4. The reaction was allowed to proceed for 60 minutes at room temperature. The solvent was removed in vacuo and then water was added. The aqueous phase was extracted with EtOAc. Drying and removal of the solvent yielded a crude product that was treated with 95% TFA in DCM to remove the tert-butyl group. This product was purified by preparative HPLC.

  (X = SH): S-trityl protected mercaptopropionic acid (4 eq) was dissolved in DMF (at a concentration of 0.1 M) and activated with TBTU (3.5 eq) and NEM (4 eq). The activated propionic acid was then added to the material from step 4 and allowed to proceed overnight. The solvent was removed in vacuo and then water was added. The aqueous phase was extracted with EtOAc. Drying and removal of the solvent then gave a combined product with 95% TFA in DCM to remove the trityl protecting group. This product was purified by preparative HPLC.

Process 6:
Each material from step 5 was dissolved in NH ₃ / MeOH (7M) and stirred at room temperature overnight. The solvent was removed in vacuo and the product was purified by preparative HPLC.

Step 7:
Each material from step 5 omitting the use of TFA and purification of the crude product was dissolved in MeOH and 1 equivalent of NaOH (1M MeOH solution) was added. The reaction was allowed to proceed overnight at room temperature. The solvent was then removed.

(R ₃ = NHR ₇ , NR ₆ R ₇ ) Hydrolyzed ester (1 eq) was dissolved in DMF and activated with TBTU (1 eq) and NEM (1 eq). Each amine (1.2 eq; NH ₂ R ₇ m or NHR ₆ R ₇ ) was dissolved in DMF and then added to the activated acid. The reaction was allowed to proceed overnight. The solvent was removed in vacuo and the crude product was dissolved in TFA and purified by preparative HPLC.

(R ₃ = OR ₇ ) Hydrolyzed ester (1 eq) was dissolved in DMF and activated with MSNT (1 eq) and methylimidazole (1 eq). Each alcohol (1.2 eq; R ₇ OH) was dissolved in DMF and then added to the activated sun. The reaction was allowed to proceed overnight. The solvent was removed in vacuo and the crude product was dissolved in TFA and purified by preparative HPLC.

Biological Assays Compounds of the invention can be tested in the following biological assays to determine the concentration of compound (IC ₅₀ ) required to exhibit the desired pharmacological effect.

In order to find inhibitors of peptide deformylase (PDF), a colorimetric cell-free assay for measuring the enzyme activity of PDF was adapted to a microtiter plate format (96 well). This assay includes three components, purified PDF, f-Met-Ala as a substrate and TNBS as a primary amino group detector. The resulting TNP-NH-Met-Ala sulfite complex can be detected at 420 nm. A PDF enzyme containing Fe ²⁺ as a natural metal is purified and stabilized by the addition of tris (2-carboxyethyl) phosphine (TCEP).

Bacterial Peptide Deformylase (PDF) Assay IC ₅₀ values of compounds of the invention as bacterial PDF inhibitors were determined using the following assay.

material:
Assay buffer: pH of 0.1 M MOPS containing 0.25 M NaCl, catalase 100 μg / mL and BSA 1 mg / mL was adjusted to 7.2 with NaOH.

Enzyme mix:
10 μl E. coli enzyme (2.5 mg / ml) + 290 μl assay buffer, 1 μl per ml enzyme mix.
S. aureus (15 mg / ml) 10 μl + assay buffer 990 μl, 0.3 μl per ml enzyme mix.

  Substrate mix: 10 mM f-Met-Ala was made from 200 mM f-Met-Ala in methanol and assay buffer.

  TNBS solution: 1 M TNBS stock solution freshly diluted 1:10 with water.

  Buffer C: 0.5 M borate buffer adjusted to pH 9.5 with NaOH.

Buffer D: 0.2 ml of freshly prepared 0.5 M Na ₂ SO ₃ was mixed with 9.8 mL of 0.5 M NaH ₂ PO ₄ .

  Inhibitor solution: 2 mM 4- (hydroxymercury) sodium benzoate in assay buffer.

  Compound mix: The compound of formula I was dissolved in a stock solution of DMSO 10 mg / mL. Further dilutions were made in DMSO at a concentration range of 0.05-100 mM.

Method (assay conditions):
The assay was performed in 96 microtiter plates containing test compounds. To each well containing the test compound mix, 75 μl of enzyme mix from E. coli was added followed by 25 μl of substrate mix. The resulting mixture was incubated for 30 minutes with shaking at room temperature. TNBS solution (50 μl / well) was added and the resulting mixture was incubated for 15 minutes with shaking. Buffer C (20 μl / well) was then added. After 15 minutes of incubation at room temperature with shaking, buffer D (50 μl / well) was added. IC ₅₀ values were then determined by measuring light diffraction at 420 nm.

  This assay was repeated using an enzyme mix from S. aureus.

  The compounds and methods of this invention are better understood in the context of the following examples, which are intended as an illustration of the invention and are not intended to limit the scope of the invention.

工程2でシクロプロピルアミン、工程4でα-アミノ酪酸および工程6でS-トリチル保護メルカプトプロピオン酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値(Mass found)：418.919.
IC₅₀ (μM)： 65.0 (E. coliからの酵素)
45.4 (S. aureusからの酵素) Example 1
([1-Cyclopropyl-2- [1- (3-mercapto-propionylamino) -propyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester

The title compound was prepared according to Method A using cyclopropylamine in Step 2, α-aminobutyric acid in Step 4 and S-trityl protected mercaptopropionic acid in Step 6.
Mass found: 418.919.
IC ₅₀ (μM): 65.0 (enzyme from E. coli)
45.4 (enzyme from S. aureus)

工程2で4-クロロベンジルアミン、工程4でフェニルアラニン酸および工程6でS-トリチル保護メルカプトプロピオン酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：564.774.
IC₅₀ (μM)：22.1 (E. coliからの酵素)
6.1 (S. aureusからの酵素) Example 2
([1- (4-Chloro-benzyl) -2- [1- (3-mercapto-propionylamino) -2-phenyl-ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester

The title compound was prepared according to Method A using 4-chlorobenzylamine in Step 2, phenylalanic acid in Step 4, and S-trityl protected mercaptopropionic acid in Step 6.
Mass measured value: 564.774.
IC ₅₀ (μM): 22.1 (enzyme from E. coli)
6.1 (Enzyme from S. aureus)

工程2でベンジルアミン、工程4でメチオニおよび工程6で無水コハク酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：526.863.
IC₅₀ (μM)： 80.0 (E. coliからの酵素)
31.4 (S. aureusからの酵素) Example 3
N- [1- [1-Benzyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -3-methylsulfanyl-propyl] -succinamic acid

The title compound was prepared according to Method A using benzylamine in Step 2, methioni in Step 4 and succinic anhydride in Step 6.
Mass measured value: 526.863.
IC ₅₀ (μM): 80.0 (enzyme from E. coli)
31.4 (Enzyme from S. aureus)

工程2でブチルアミン、工程4でフェニルアラニンおよび工程6で無水コハク酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：508.899.
IC₅₀ (μM)： 2.8 (E. coliからの酵素)
1.0 (S. aureusからの酵素) Example 4
N- [1- [1-Butyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -2-phenyl-ethyl] -succinamic acid

The title compound was prepared according to Method A using butylamine in Step 2, phenylalanine in Step 4, and succinic anhydride in Step 6.
Mass measured value: 508.899.
IC ₅₀ (μM): 2.8 (enzyme from E. coli)
1.0 (enzyme from S. aureus)

工程2でフリルメチルアミン、工程4でフェニルアラニンおよび工程6で無水コハク酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：532.875.
IC₅₀ (μM)：12.9 (E. coliからの酵素)
1.6 (S. aureusからの酵素) Example 5
N- [1- [1-Furan-2-ylmethyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -2-phenyl-ethyl] -succinamic acid

The title compound was prepared according to Method A using furylmethylamine in Step 2, phenylalanine in Step 4, and succinic anhydride in Step 6.
Mass measured value: 532.875.
IC ₅₀ (μM): 12.9 (enzyme from E. coli)
1.6 (enzyme from S. aureus)

工程2で4-クロロベンジルアミン、工程4でフェニルアラニンおよび工程6で無水コハク酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：576.825.
IC₅₀ (μM)： 1.3 (E. coliからの酵素)
0.093 (S. aureusからの酵素) Example 6
N- [1- [1- (4-Chloro-benzyl) -5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -2-phenyl-ethyl] -succinamic acid

The title compound was prepared according to Method A using 4-chlorobenzylamine in Step 2, phenylalanine in Step 4, and succinic anhydride in Step 6.
Mass measured value: 576.825.
IC ₅₀ (μM): 1.3 (enzyme from E. coli)
0.093 (enzyme from S. aureus)

工程2でシクロプロピルアミン、工程4でホモフェニルアラニンアラニンおよび工程6で無水コハク酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：506.884.
IC₅₀ (μM)：2.6 (E. coliからの酵素)
2.7 (S. aureusからの酵素) Example 7
N- [1- [1-Cyclopropyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -3-phenyl-propyl] -succinamic acid

The title compound was prepared according to Method A using cyclopropylamine in Step 2, homophenylalanine alanine in Step 4, and succinic anhydride in Step 6.
Mass measured value: 506.884.
IC ₅₀ (μM): 2.6 (enzyme from E. coli)
2.7 (Enzyme from S. aureus)

工程2でシクロヘキシルメチルアミン、工程4でホモフェニルアラニンおよび工程6で無水コハク酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：562.930.
IC₅₀ (μM)： 29.8 (E. coliからの酵素)
15.1 (S. aureusからの酵素) Example 8
N- [1- [1-cyclohexylmethyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -3-phenyl-propyl] -succinamic acid

The title compound was prepared according to Method A using cyclohexylmethylamine in Step 2, homophenylalanine in Step 4, and succinic anhydride in Step 6.
Mass measured value: 562.930.
IC ₅₀ (μM): 29.8 (enzyme from E. coli)
15.1 (Enzyme from S. aureus)

工程2で2-クロロベンジルアミン、工程4でホモフェニルアラニンおよび工程6で無水コハク酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：590.821.
IC₅₀ (μM)：27.8 (E. coliからの酵素)
18.0 (S. aureusからの酵素) Example 9
N- [1- [1- (2-Chloro-benzyl) -5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -3-phenyl-propyl] -succinamic acid

The title compound was prepared according to Method A using 2-chlorobenzylamine in Step 2, homophenylalanine in Step 4, and succinic anhydride in Step 6.
Mass measured value: 590.821.
IC ₅₀ (μM): 27.8 (enzyme from E. coli)
18.0 (enzyme from S. aureus)

工程2でシクロプロピルアミン、工程4でα-アミノ酪酸および工程6で無水コハク酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：430.926.
IC₅₀ (μM)：5.6 (E. coliからの酵素)
0.023 (S. aureusからの酵素) Example 10
N- [1- [1-Cyclopropyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -propyl] -succinamic acid

The title compound was prepared according to Method A using cyclopropylamine in Step 2, α-aminobutyric acid in Step 4 and succinic anhydride in Step 6.
Mass measured value: 430.926.
IC ₅₀ (μM): 5.6 (enzyme from E. coli)
0.023 (enzyme from S. aureus)

工程2でフリルメチルアミン、工程4でα-アミノ酪酸および工程6で無水コハク酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：470.877.
IC₅₀ (μM)：2.8 (E. coliからの酵素)
1.4 (S. aureusからの酵素) Example 11
N- [1- [1-Furan-2-ylmethyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -propyl] -succinamic acid

The title compound was prepared according to Method A using furylmethylamine in Step 2, α-aminobutyric acid in Step 4, and succinic anhydride in Step 6.
Mass measured value: 470.877.
IC ₅₀ (μM): 2.8 (enzyme from E. coli)
1.4 (Enzyme from S. aureus)

工程2でベンジルアミン、工程4でα-アミノ酪酸および工程6で無水コハク酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：480.906.
IC₅₀ (μM)：4.8 (E. coliからの酵素)
0.068 (S. aureusからの酵素) Example 12
N- [1- [1-Benzyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -propyl] -succinamic acid

The title compound was prepared according to Method A using benzylamine in Step 2, α-aminobutyric acid in Step 4 and succinic anhydride in Step 6.
Mass measured value: 480.906.
IC ₅₀ (μM): 4.8 (enzyme from E. coli)
0.068 (enzyme from S. aureus)

工程2でシクロプロピルアミン、工程4でロイシンおよび工程6で無水コハク酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：459.932.
IC₅₀ (μM)：4.0 (E. coliからの酵素)
0.119 (S. aureusからの酵素) Example 13
N- [1- [1-Cyclopropyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzoimidazol-2-yl] -3-methyl-butyl] -succinamic acid

The title compound was prepared according to Method A using cyclopropylamine in Step 2, leucine in Step 4, and succinic anhydride in Step 6.
Mass measured value: 459.932.
IC ₅₀ (μM): 4.0 (enzyme from E. coli)
0.119 (enzyme from S. aureus)

工程2でブチルアミン、工程4でロイシンおよび工程6で無水コハク酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：474.962.
IC₅₀ (μM)：7.3 (E. coliからの酵素)
2.6 (S. aureusからの酵素) Example 14
N- [1- [1-Butyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -3-methyl-butyl] -succinamic acid

The title compound was prepared according to Method A using butylamine in Step 2, leucine in Step 4, and succinic anhydride in Step 6.
Mass measured value: 474.962.
IC ₅₀ (μM): 7.3 (enzyme from E. coli)
2.6 (enzyme from S. aureus)

工程2でベンジルアミン、工程4でロイシンおよび工程6で無水コハク酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：508.910.
IC₅₀ (μM)：3.3 (E. coliからの酵素)
4.0 (S. aureusからの酵素) Example 15
N- [1- [1-Benzyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -3-methyl-butyl] -succinamic acid

The title compound was prepared according to Method A using benzylamine in Step 2, leucine in Step 4, and succinic anhydride in Step 6.
Mass measured value: 508.910.
IC ₅₀ (μM): 3.3 (enzyme from E. coli)
4.0 (enzyme from S. aureus)

工程2でシクロプロピルアミン、工程4でメチオニンおよび工程6で無水コハク酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：476.897.
IC₅₀ (μM)：47.2 (E. coliからの酵素)
17.6 (S. aureusからの酵素) Example 16
N- [1- [1-Cyclopropyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -3-methylsulfanyl-propyl] -succinamic acid

The title compound was prepared according to Method A using cyclopropylamine in Step 2, methionine in Step 4, and succinic anhydride in Step 6.
Mass measured value: 476.897.
IC ₅₀ (μM): 47.2 (enzyme from E. coli)
17.6 (enzyme from S. aureus)

工程2でチオフェネチルアミン、工程4で1-ナフチルアラニンおよび工程6で無水コハク酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：612.849.
IC₅₀ (μM)：0.071 (E. coliからの酵素)
0.099 (S. aureusからの酵素) Example 17
N- [1- [5- (methoxycarbonylmethyl-carbamoyl) -1- (2-thiophen-2-yl-ethyl) -1H-benzimidazol-2-yl] -2-naphthalen-1-yl-ethyl] -Succinamic acid

The title compound was prepared according to Method A using thiophenethylamine in Step 2, 1-naphthylalanine in Step 4, and succinic anhydride in Step 6.
Mass measured value: 612.849.
IC ₅₀ (μM): 0.071 (enzyme from E. coli)
0.099 (enzyme from S. aureus)

工程2でブチルアミン、工程4で1-ナフチルアラニンおよび工程6で無水コハク酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：558.894.
IC₅₀ (μM)：2.7 (E. coliからの酵素)
0.074 (S. aureusからの酵素) Example 18
N- [1- [1-Butyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -2-naphthalen-1-yl-ethyl] -succinamic acid

The title compound was prepared according to Method A using butylamine in Step 2, 1-naphthylalanine in Step 4, and succinic anhydride in Step 6.
Mass measured value: 558.894.
IC ₅₀ (μM): 2.7 (enzyme from E. coli)
0.074 (enzyme from S. aureus)

工程2でシクロヘキシルメチルアミン、工程4でBoc-リジンおよび工程6でS-トリチル保護メルカプトプロピオン酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：518.218.
IC₅₀ (μM)：38.1 (E. coliからの酵素)
27.1 (S. aureusからの酵素) Example 19
([2- [5-Amino-1- (3-mercapto-propionylamino) -phenyl] -1-cyclohexylmethyl-1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester

The title compound was prepared according to Method A using cyclohexylmethylamine in Step 2, Boc-lysine in Step 4, and S-trityl protected mercaptopropionic acid in Step 6.
Mass measured value: 518.218.
IC ₅₀ (μM): 38.1 (enzyme from E. coli)
27.1 (Enzyme from S. aureus)

工程2でシクロプロピルアミン、工程4でチロシンおよび工程6でS-トリチル保護メルカプトプロピオン酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：497.108.
IC₅₀ (μM)：> 200 (E. coliからの酵素)
> 200 (S. aureusからの酵素) Example 20
([1-Cyclopropyl-2- [2- (4-hydroxy-phenyl) -1- (3-mercapto-propionylamino) -ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester

The title compound was prepared according to Method A using cyclopropylamine in step 2, tyrosine in step 4 and S-trityl protected mercaptopropionic acid in step 6.
Mass measured value: 497.108.
IC ₅₀ (μM):> 200 (enzyme from E. coli)
> 200 (enzyme from S. aureus)

工程2でシクロヘキシルメチルアミン、チロシン 工程4で and 工程6でS-トリチル保護メルカプトプロピオン酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：553.146.
IC₅₀ (μM)：> 200 (E. coliからの酵素)
> 200 (S. aureusからの酵素) Example 21
([1-Cyclohexylmethyl-2- [2- (4-hydroxy-phenyl) -1- (3-mercapto-propionylamino) -ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester

The title compound was prepared according to Method A using cyclohexylmethylamine in step 2, tyrosine in step 4 and S-trityl protected mercaptopropionic acid in step 6.
Mass measured value: 553.146.
IC ₅₀ (μM):> 200 (enzyme from E. coli)
> 200 (enzyme from S. aureus)

工程2でアミノエタノール、工程4でフェニルアラニンおよび工程6でS-トリチル保護メルカプトプロピオン酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：485.133.
IC₅₀ (μM)：> 200 (E. coliからの酵素)
> 200 (S. aureusからの酵素) Example 22
([1- (2-Hydroxy-ethyl) -2- [1- (3-mercapto-propionylamino) -2-phenyl-ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester

The title compound was prepared according to Method A using aminoethanol in Step 2, phenylalanine in Step 4, and S-trityl protected mercaptopropionic acid in Step 6.
Mass measured value: 485.133.
IC ₅₀ (μM):> 200 (enzyme from E. coli)
> 200 (enzyme from S. aureus)

工程2でシクロプロピルアミン、工程4でBoc-リジンおよび工程6で無水コハク酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：474.204.
IC₅₀ (μM)：0.3 (E. coliからの酵素)
0.3 (S. aureusからの酵素) Example 23
N- [5-Amino-1- [1-cyclopropyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -phenyl] -succinamic acid

The title compound was prepared according to Method A using cyclopropylamine in step 2, Boc-lysine in step 4 and succinic anhydride in step 6.
Mass measured value: 474.204.
IC ₅₀ (μM): 0.3 (enzyme from E. coli)
0.3 (enzyme from S. aureus)

工程2でシクロヘキシルメチルアミン、工程4でBoc-リジンおよび工程6で無水コハク酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：530.225.
IC₅₀ (μM)：13.1 (E. coliからの酵素)
1.4 (S. aureusからの酵素) Example 24
N- [5-Amino-1- [1-cyclohexylmethyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -phenyl] -succinamic acid

The title compound was prepared according to Method A using cyclohexylmethylamine in step 2, Boc-lysine in step 4 and succinic anhydride in step 6.
Mass measured value: 530.225.
IC ₅₀ (μM): 13.1 (enzyme from E. coli)
1.4 (Enzyme from S. aureus)

工程2でシクロプロピルアミン、工程4でチロシンおよび工程6で無水コハク酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：509.143.
IC₅₀ (μM)：12.8 (E. coliからの酵素)
28.3 (S. aureusからの酵素) Example 25
N- [1- [1-Cyclopropyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -2- (4-hydroxyphenyl) -ethyl] -succinamic acid

The title compound was prepared according to Method A using cyclopropylamine in Step 2, tyrosine in Step 4 and succinic anhydride in Step 6.
Mass measured: 509.143.
IC ₅₀ (μM): 12.8 (enzyme from E. coli)
28.3 (Enzyme from S. aureus)

工程2でシクロヘキシルメチルアミン、工程4でチロシンおよび工程6で無水コハク酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：565.182.
IC₅₀ (μM)：35.2 (E. coliからの酵素)
25.0 (S. aureusからの酵素) Example 26
N- [1- [1-cyclohexylmethyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -2- (4-hydroxyphenyl) -ethyl] -succinamic acid

The title compound was prepared according to Method A using cyclohexylmethylamine in Step 2, tyrosine in Step 4 and succinic anhydride in Step 6.
Mass measured value: 565.182.
IC ₅₀ (μM): 35.2 (enzyme from E. coli)
25.0 (enzyme from S. aureus)

工程2でアミノエタノール、工程4でフェニルアラニンおよび工程6で無水コハク酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：497.155.
IC₅₀ (μM)：41.8 (E. coliからの酵素)
27.7 (S. aureusからの酵素) Example 27
N- [1- [1- (2-Hydroxy-ethyl) -5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -2-phenyl-ethyl] -succinamic acid

The title compound was prepared according to Method A using aminoethanol in Step 2, phenylalanine in Step 4, and succinic anhydride in Step 6.
Mass measured value: 497.155.
IC ₅₀ (μM): 41.8 (enzyme from E. coli)
27.7 (Enzyme from S. aureus)

工程2でアミノエタノール、工程4でロイシンおよび工程6で無水コハク酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：463.176.
IC₅₀ (μM)：> 200 (E. coliからの酵素)
34.4 (S. aureusからの酵素) Example 28
N- [1- [1- (2-Hydroxy-ethyl) -5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -3-methylbutyl] -succinamic acid

The title compound was prepared according to Method A using aminoethanol in step 2, leucine in step 4 and succinic anhydride in step 6.
Mass measured value: 463.176.
IC ₅₀ (μM):> 200 (enzyme from E. coli)
34.4 (Enzyme from S. aureus)

工程2でシクロプロピルアミン、工程4でα-アミノ酪酸および工程6でO-トリチルコハク酸 ヒドロキシアミドを用いて、方法Aに従って標記化合物を製造した。
マス実測値：446.115.
IC₅₀ (μM)：0.079 (E. coliからの酵素)
0.105 (S. aureusからの酵素) Example 29
([1-Cyclopropyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -propyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester

The title compound was prepared according to Method A using cyclopropylamine in Step 2, α-aminobutyric acid in Step 4 and O-trityl succinic acid hydroxyamide in Step 6.
Mass measured value: 446.115.
IC ₅₀ (μM): 0.079 (enzyme from E. coli)
0.105 (enzyme from S. aureus)

工程2でベンジルアミン、工程4で1-ナフチルアラニンおよび工程6で無水コハク酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：592.864.
IC₅₀ (μM)：7.0 (E. coliからの酵素)
0.3 (S. aureusからの酵素) Example 30
N- [1- [1-Benzyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -2-naphthalen-1-yl-ethyl] -succinamic acid

The title compound was prepared according to Method A using benzylamine in Step 2, 1-naphthylalanine in Step 4 and succinic anhydride in Step 6.
Mass measured value: 592.864.
IC ₅₀ (μM): 7.0 (enzyme from E. coli)
0.3 (enzyme from S. aureus)

工程2でフリルメチルアミン、工程4でα-アミノ酪酸および工程6でO-トリチルコハク酸 ヒドロキシアミドを用いて、方法Aに従って標記化合物を製造した。
マス実測値：486.090.
IC₅₀ (μM)：0.098 (E. coliからの酵素)
0.151 (S. aureusからの酵素) Example 31
([1-furan-2-ylmethyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -propyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester

The title compound was prepared according to Method A using furylmethylamine in Step 2, α-aminobutyric acid in Step 4 and O-trityl succinic acid hydroxyamide in Step 6.
Mass measured value: 486.090.
IC ₅₀ (μM): 0.098 (enzyme from E. coli)
0.151 (enzyme from S. aureus)

工程2でベンジルアミンアミン、工程4でα-アミノ酪酸および工程6でO-トリチルコハク酸 ヒドロキシアミドを用いて、方法Aに従って標記化合物を製造した。
マス実測値：496.112.
IC₅₀ (μM)：0.045 (E. coliからの酵素)
0.067 (S. aureusからの酵素) Example 32
([1-Benzyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -propyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester

The title compound was prepared according to Method A using benzylamine amine in Step 2, α-aminobutyric acid in Step 4 and O-trityl succinic acid hydroxyamide in Step 6.
Mass measured value: 496.112.
IC ₅₀ (μM): 0.045 (enzyme from E. coli)
0.067 (enzyme from S. aureus)

工程2でシクロプロピルアミンアミン、工程4でロイシンおよび工程6でO-トリチルコハク酸 ヒドロキシアミドを用いて、方法Aに従って標記化合物を製造した。
マス実測値：474.123.
IC₅₀ (μM)：0.3 (E. coliからの酵素)
0.496 (S. aureusからの酵素) Example 33
([1-Cyclopropyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -3-methyl-butyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester

The title compound was prepared according to Method A using cyclopropylamine amine in Step 2, leucine in Step 4, and O-trityl succinic acid hydroxyamide in Step 6.
Mass measured value: 474.123.
IC ₅₀ (μM): 0.3 (enzyme from E. coli)
0.496 (enzyme from S. aureus)

工程2でブチルアミンアミン、工程4でロイシンおよび工程6でO-トリチルコハク酸 ヒドロキシアミドを用いて、方法Aに従って標記化合物を製造した。
マス実測値：490.140.
IC₅₀ (μM)：0.3 (E. coliからの酵素)
2.266 (S. aureusからの酵素) Example 34
([1-Butyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -3-methyl-butyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester

The title compound was prepared according to Method A using butylamine amine in Step 2, leucine in Step 4, and O-trityl succinic acid hydroxyamide in Step 6.
Mass measured value: 490.140.
IC ₅₀ (μM): 0.3 (enzyme from E. coli)
2.266 (enzyme from S. aureus)

工程2でベンジルアミンアミン、工程4ロイシンでおよび工程6でO-トリチルコハク酸 ヒドロキシアミドを用いて、方法Aに従って標記化合物を製造した。
マス実測値：524.104.
IC₅₀ (μM)：0.3 (E. coliからの酵素)
0.804 (S. aureusからの酵素) Example 35
([1-Benzyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -3-methyl-butyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester

The title compound was prepared according to Method A using benzylamine amine in step 2, leucine in step 4 and O-trityl succinic acid hydroxyamide in step 6.
Mass measured value: 524.104.
IC ₅₀ (μM): 0.3 (enzyme from E. coli)
0.804 (enzyme from S. aureus)

工程2でシクロプロピルアミンアミン、工程4でメチオニンおよび工程6でO-トリチルコハク酸 ヒドロキシアミドを用いて、方法Aに従って標記化合物を製造した。
マス実測値：508.057 (スルホキシドのみが検出できた).
IC₅₀ (μM)：0.3 (E. coliからの酵素)
1.5 (S. aureusからの酵素) Example 36
([1-Cyclopropyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -3-methylsulfanyl-propyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester

The title compound was prepared according to Method A using cyclopropylamine amine in Step 2, methionine in Step 4, and O-trityl succinic acid hydroxyamide in Step 6.
Mass measured value: 508.057 (only sulfoxide could be detected).
IC ₅₀ (μM): 0.3 (enzyme from E. coli)
1.5 (enzyme from S. aureus)

工程2でシクロヘキシルメチルアミンアミン、工程4でメチオニンおよび工程6でO-トリチルコハク酸 ヒドロキシアミドを用いて、方法Aに従って標記化合物を製造した。
マス実測値：564.577 (スルホキシドのみが検出できた).
IC₅₀ (μM)：0.317 (E. coliからの酵素)
0.3 (S. aureusからの酵素) Example 37
([1-cyclohexylmethyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -3-methylsulfanyl-propyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester

The title compound was prepared according to Method A using cyclohexylmethylamine amine in Step 2, methionine in Step 4 and O-trityl succinic acid hydroxyamide in Step 6.
Mass measured value: 564.577 (only sulfoxide was detected).
IC ₅₀ (μM): 0.317 (enzyme from E. coli)
0.3 (enzyme from S. aureus)

工程2でベンジルアミン、工程4でメチオニンおよび工程6でO-トリチルコハク酸 ヒドロキシアミドを用いて、方法Aに従って標記化合物を製造した。
マス実測値：558.040 (スルホキシドのみが検出できた).
IC₅₀ (μM)：25.8 (E. coliからの酵素)
3.5 (S. aureusからの酵素) Example 38
([1-Benzyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -3-methylsulfanyl-propyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester

The title compound was prepared according to Method A using benzylamine in Step 2, methionine in Step 4, and O-trityl succinic acid hydroxyamide in Step 6.
Mass measured value: 558.040 (only sulfoxide was detected).
IC ₅₀ (μM): 25.8 (enzyme from E. coli)
3.5 (Enzyme from S. aureus)

工程2でフリルメチルアミン、工程4でフェニルアラニンおよび工程6でO-トリチルコハク酸 ヒドロキシアミドを用いて、方法Aに従って標記化合物を製造した。
マス実測値：548.059.
IC₅₀ (μM)：1.5 (E. coliからの酵素)
0.3 (S. aureusからの酵素) Example 39
([1-furan-2-ylmethyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -2-phenyl-ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester

The title compound was prepared according to Method A using furylmethylamine in Step 2, phenylalanine in Step 4, and O-trityl succinic acid hydroxyamide in Step 6.
Mass measured value: 548.059.
IC ₅₀ (μM): 1.5 (enzyme from E. coli)
0.3 (enzyme from S. aureus)

工程2で4-クロロベンジルアミン、工程4でフェニルアラニンおよび工程6でO-トリチルコハク酸 ヒドロキシアミドを用いて、方法Aに従って標記化合物を製造した。
マス実測値：592.044.
IC₅₀ (μM)：1.4 (E. coliからの酵素)
0.021 (S. aureusからの酵素) Example 40
([1- (4-Chloro-benzyl) -2- [1- (3-hydroxycarbamoyl-propionylamino) -2-phenyl-ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester

The title compound was prepared according to Method A using 4-chlorobenzylamine in Step 2, phenylalanine in Step 4, and O-trityl succinic acid hydroxyamide in Step 6.
Mass measured value: 592.044.
IC ₅₀ (μM): 1.4 (enzyme from E. coli)
0.021 (enzyme from S. aureus)

工程2でシクロプロピルアミン、工程4でホモフェニルアラニンおよび工程6でO-トリチルコハク酸 ヒドロキシアミドを用いて、方法Aに従って標記化合物を製造した。
マス実測値：522.095.
IC₅₀ (μM)：2.3 (E. coliからの酵素)
0.363 (S. aureusからの酵素) Example 41
([1-Cyclopropyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -3-phenyl-propyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester

The title compound was prepared according to Method A using cyclopropylamine in Step 2, homophenylalanine in Step 4, and O-trityl succinic acid hydroxyamide in Step 6.
Mass measured value: 522.095.
IC ₅₀ (μM): 2.3 (enzyme from E. coli)
0.363 (enzyme from S. aureus)

工程2でシクロヘキシルメチルアミン、工程4でホモフェニルアラニンおよび工程6でO-トリチルコハク酸 ヒドロキシアミドを用いて、方法Aに従って標記化合物を製造した。
マス実測値：578.138.
IC₅₀ (μM)：0.3 (E. coliからの酵素)
0.3 (S. aureusからの酵素) Example 42
([1-Cyclohexylmethyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -3-phenyl-propyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester

The title compound was prepared according to Method A using cyclohexylmethylamine in Step 2, homophenylalanine in Step 4, and O-trityl succinic acid hydroxyamide in Step 6.
Mass measured value: 578.138.
IC ₅₀ (μM): 0.3 (enzyme from E. coli)
0.3 (enzyme from S. aureus)

工程2で2-クロロベンジルアミン、工程4でフェニルアラニンおよび工程6でO-トリチルコハク酸 ヒドロキシアミドを用いて、方法Aに従って標記化合物を製造した。
マス実測値：606.054.
IC₅₀ (μM)：0.3 (E. coliからの酵素)
0.3 (S. aureusからの酵素) Example 43
([1- (2-Chloro-benzyl) -2- [1- (3-hydroxycarbamoyl-propionylamino) -2-phenyl-ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester

The title compound was prepared according to Method A using 2-chlorobenzylamine in Step 2, phenylalanine in Step 4, and O-trityl succinic acid hydroxyamide in Step 6.
Mass measured value: 606.054.
IC ₅₀ (μM): 0.3 (enzyme from E. coli)
0.3 (enzyme from S. aureus)

工程2でチオフェネチルアミン、工程4で1-ナフチルアラニンおよび工程6でO-トリチルコハク酸 ヒドロキシアミドを用いて、方法Aに従って標記化合物を製造した。
マス実測値：628.068.
IC₅₀ (μM)：3.1 (E. coliからの酵素)
0.3 (S. aureusからの酵素) Example 44
[[2- [1- (3-Hydroxycarbamoyl-propionylamino) -2-naphthalen-1-yl-ethyl] -1- (2-thiophen-2-yl-ethyl) -1H-benzimidazol-5-carbonyl ] -Amino] -acetic acid methyl ester

The title compound was prepared according to Method A using thiophenethylamine in Step 2, 1-naphthylalanine in Step 4, and O-trityl succinic acid hydroxyamide in Step 6.
Mass measured value: 628.068.
IC ₅₀ (μM): 3.1 (enzyme from E. coli)
0.3 (enzyme from S. aureus)

工程2でブチルアミン、工程4で1-ナフチルアラニンおよび工程6でO-トリチルコハク酸 ヒドロキシアミドを用いて、方法Aに従って標記化合物を製造した。
マス実測値：574.110.
IC₅₀ (μM)：5.8 (E. coliからの酵素)
0.3 (S. aureusからの酵素) Example 45
([1-Butyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -2-naphthalen-1-yl-ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester

The title compound was prepared according to Method A using butylamine in Step 2, 1-naphthylalanine in Step 4 and O-trityl succinic acid hydroxyamide in Step 6.
Mass measured value: 574.110.
IC ₅₀ (μM): 5.8 (enzyme from E. coli)
0.3 (enzyme from S. aureus)

工程2でベンジルアミン、工程4で1-ナフチルアラニンおよび工程6でO-トリチルコハク酸 ヒドロキシアミドを用いて、方法Aに従って標記化合物を製造した。
マス実測値：608.098.
IC₅₀ (μM)：6.5 (E. coliからの酵素)
0.9 (S. aureusからの酵素) Example 46
([1-Benzyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -2-naphthalen-1-yl-ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester

The title compound was prepared according to Method A using benzylamine in Step 2, 1-naphthylalanine in Step 4, and O-trityl succinic acid hydroxyamide in Step 6.
Mass measured value: 608.098.
IC ₅₀ (μM): 6.5 (enzyme from E. coli)
0.9 (enzyme from S. aureus)

工程2でベンジルアミン、工程4で1-ナフチルアラニンおよび工程6でO-トリチルコハク酸 ヒドロキシアミドを用いて、方法Aに従って標記化合物を製造した。
マス実測値：524.108.
IC₅₀ (μM)：5.3 (E. coliからの酵素)
0.019 (S. aureusからの酵素) Example 47
([1-Butyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -2-phenyl-ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester

The title compound was prepared according to Method A using benzylamine in Step 2, 1-naphthylalanine in Step 4, and O-trityl succinic acid hydroxyamide in Step 6.
Mass measured value: 524.108.
IC ₅₀ (μM): 5.3 (enzyme from E. coli)
0.019 (enzyme from S. aureus)

工程2でシクロプロピルアミン、工程4でBoc-リジンおよび工程6でS-トリチルプロピオン酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：462.087.
IC₅₀ (μM)：3.6 (E. coliからの酵素)
2.0 (S. aureusからの酵素) Example 48
([2- [5-Amino-1- (3-mercapto-propionylamino) -phenyl] -1-cyclopropyl-1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester

The title compound was prepared according to Method A using cyclopropylamine in step 2, Boc-lysine in step 4 and S-tritylpropionic acid in step 6.
Mass measured value: 462.087.
IC ₅₀ (μM): 3.6 (enzyme from E. coli)
2.0 (enzyme from S. aureus)

工程2でベンジルアミン、工程4でBoc-リジおよび工程6でS-トリチルプロピオン酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：512.084.
IC₅₀ (μM)：5.2 (E. coliからの酵素)
2.4 (S. aureusからの酵素) Example 49
([2- [5-Amino-1- (3-mercapto-propionylamino) -phenyl] -1-benzyl-1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester

The title compound was prepared according to Method A using benzylamine in Step 2, Boc-Ligi in Step 4, and S-tritylpropionic acid in Step 6.
Mass measured value: 512.084.
IC ₅₀ (μM): 5.2 (enzyme from E. coli)
2.4 (Enzyme from S. aureus)

工程2でエチレンジアミン、工程4でフェニルアラニンおよび工程6でS-トリチルプロピオン酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：484.068.
IC₅₀ (μM)：7.2 (E. coliからの酵素)
3.8 (S. aureusからの酵素) Example 50
([1- (2-Amino-ethyl) -2- [1- (3-mercapto-propionylamino) -2-phenyl-ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester

The title compound was prepared according to Method A using ethylenediamine in step 2, phenylalanine in step 4 and S-tritylpropionic acid in step 6.
Mass measured value: 484.068.
IC ₅₀ (μM): 7.2 (enzyme from E. coli)
3.8 (enzyme from S. aureus)

工程2でベンジルアミン、工程4でBoc-リジンおよび工程6で無水コハク酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：524.108.
IC₅₀ (μM)：0.3 (E. coliからの酵素)
0.3 (S. aureusからの酵素) Example 51
N- [5-Amino-1- [1-benzyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -phenyl] -succinamic acid

The title compound was prepared according to Method A using benzylamine in step 2, Boc-lysine in step 4 and succinic anhydride in step 6.
Mass measured value: 524.108.
IC ₅₀ (μM): 0.3 (enzyme from E. coli)
0.3 (enzyme from S. aureus)

工程2でエチレンジアミン、工程4でフェニルアラニンおよび工程6で無水コハク酸を用いて、方法Aに従って標記化合物を製造した。
マス実測値：496.085.
IC₅₀ (μM)：0.3 (E. coliからの酵素)
0.3 (S. aureusからの酵素) Example 52
N- [1- [1- (2-Amino-ethyl) -5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -2-phenyl-ethyl] -succinamic acid

The title compound was prepared according to Method A using ethylenediamine in step 2, phenylalanine in step 4 and succinic anhydride in step 6.
Mass measured value: 496.085.
IC ₅₀ (μM): 0.3 (enzyme from E. coli)
0.3 (enzyme from S. aureus)

工程2でシクロプロピルアミン、工程4でBoc-リジンおよび工程6でO-トリチルコハク酸 ヒドロキシアミドを用いて、方法Aに従って標記化合物を製造した。
マス実測値：489.159.
IC₅₀ (μM)：0.3 (E. coliからの酵素)
0.3 (S. aureusからの酵素) Example 53
([2- [5-Amino-1- (3-hydroxycarbamoyl-propionylamino) -phenyl] -1-cyclopropyl-1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester

The title compound was prepared according to Method A using cyclopropylamine in step 2, Boc-lysine in step 4 and O-trityl succinic acid hydroxyamide in step 6.
Mass measured value: 489.159.
IC ₅₀ (μM): 0.3 (enzyme from E. coli)
0.3 (enzyme from S. aureus)

工程2でシクロヘキシルメチルアミン、工程4でBoc-リジンおよび工程6でO-トリチルコハク酸 ヒドロキシアミドを用いて、方法Aに従って標記化合物を製造した。
マス実測値：545.136.
IC₅₀ (μM)：0.3 (E. coliからの酵素)
0.3 (S. aureusからの酵素) Example 54
([2- [5-Amino-1- (3-hydroxycarbamoyl-propionylamino) -phenyl] -1-cyclohexylmethyl-1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester

The title compound was prepared according to Method A using cyclohexylmethylamine in Step 2, Boc-lysine in Step 4, and O-trityl succinic acid hydroxyamide in Step 6.
Mass measured value: 545.136.
IC ₅₀ (μM): 0.3 (enzyme from E. coli)
0.3 (enzyme from S. aureus)

工程2でベンジルアミン、工程4でBoc-リジンおよび工程6でO-トリチルコハク酸 ヒドロキシアミドを用いて、方法Aに従って標記化合物を製造した。
マス実測値：539.080.
IC₅₀ (μM)：0.3 (E. coliからの酵素)
0.3 (S. aureusからの酵素) Example 55
([2- [5-Amino-1- (3-hydroxycarbamoyl-propionylamino) -phenyl] -1-benzyl-1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester

The title compound was prepared according to Method A using benzylamine in step 2, Boc-lysine in step 4 and O-trityl succinic acid hydroxyamide in step 6.
Mass measured value: 539.080.
IC ₅₀ (μM): 0.3 (enzyme from E. coli)
0.3 (enzyme from S. aureus)

工程2でエチレンジアミン、工程4でフェニルアラニンおよび工程6でO-トリチルコハク酸 ヒドロキシアミドを用いて、方法Aに従って標記化合物を製造した。
マス実測値：511.084.
IC₅₀ (μM)：2.0 (E. coliからの酵素)
1.6 (S. aureusからの酵素) Example 56
([1- (2-Amino-ethyl) -2- [1- (3-hydroxycarbamoyl-propionylamino) -2-phenyl-ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester

The title compound was prepared according to Method A using ethylenediamine in Step 2, phenylalanine in Step 4, and O-trityl succinic acid hydroxyamide in Step 6.
Mass measured value: 511.084.
IC ₅₀ (μM): 2.0 (enzyme from E. coli)
1.6 (enzyme from S. aureus)

工程2でシクロプロピルアミン、工程4でチロシンおよび工程6でO-トリチルコハク酸 ヒドロキシアミドを用いて、方法Aに従って標記化合物を製造した。
マス実測値：524.064.
IC₅₀ (μM)：0.3 (E. coliからの酵素)
0.3 (S. aureusからの酵素) Example 57
([1-Cyclopropyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -2- (4-hydroxy-phenyl) -ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester

The title compound was prepared according to Method A using cyclopropylamine in Step 2, tyrosine in Step 4 and O-trityl succinic acid hydroxyamide in Step 6.
Mass measured value: 524.064.
IC ₅₀ (μM): 0.3 (enzyme from E. coli)
0.3 (enzyme from S. aureus)

工程2でシクロヘキシルメチルアミン、工程4でチロシンおよび工程6でO-トリチルコハク酸 ヒドロキシアミドを用いて、方法Aに従って標記化合物を製造した。
マス実測値：580.101.
IC₅₀ (μM)：0.3 (E. coliからの酵素)
0.3 (S. aureusからの酵素) Example 58
([1-cyclohexylmethyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -2- (4-hydroxy-phenyl) -ethyl] -1H-benzimidazol-5-carbonyl] -amino) -methyl acetate ester

The title compound was prepared according to Method A using cyclohexylmethylamine in Step 2, tyrosine in Step 4 and O-trityl succinic acid hydroxyamide in Step 6.
Mass measured value: 580.101.
IC ₅₀ (μM): 0.3 (enzyme from E. coli)
0.3 (enzyme from S. aureus)

工程2でアミノエタノール、工程4でフェニルアラニンおよび工程6でO-トリチルコハク酸 ヒドロキシアミドを用いて、方法Aに従って標記化合物を製造した。
マス実測値：512.059.
IC₅₀ (μM)：0.3 (E. coliからの酵素)
0.3 (S. aureusからの酵素) Example 59
[[2- [1- (3-Hydroxycarbamoyl-propionylamino) -2-phenyl-ethyl] -1- (2-hydroxy-ethyl) -1H-benzimidazol-5-carbonyl] -amino] -acetic acid methyl ester

The title compound was prepared according to Method A using aminoethanol in Step 2, phenylalanine in Step 4, and O-trityl succinic acid hydroxyamide in Step 6.
Mass measured value: 512.059.
IC ₅₀ (μM): 0.3 (enzyme from E. coli)
0.3 (enzyme from S. aureus)

  The invention described and claimed in this specification should not be limited to the scope of the specific embodiments disclosed herein, which are intended as illustrations of various aspects of the invention. Has been. Any equivalent embodiments are intended to be within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description. Such variations are to be construed as falling within the scope of the appended claims. Various documents are cited herein, the disclosures of which are incorporated by reference in their entirety.

Literature list
Adams, JM; Capecchi, MR Proc. Natl. Acad. Sci., USA, 1966, 55, 147-155.
Adams, JMJ Mol. Biol. 1968, 33, 571-589.
Clements, JM; Ayscough, AP; Keavey, K .; East, SP Curr. Med. Chem. Anti-Infective Agents 2002, 1, 239-249.
Gennaro, AR; Gennaro AL Remington, The Science and Practice of Pharmacy, 19th Edition, Mack Publishing Co., Easton, Pa., 1995.
Giglione, C .; Pierre, M .; Meinnel, T. Mol. Microbiol. 2000, 36, 1197-1205.
Giglione, C .; Meinnel, T. Emerg. Ther. Targets 2001, 5, 41-57.
Green, TW; Wuts, PGM Protective Groups In Organic Synthesis, John Wiley & Sons, New York, 1999.
Pei, D. Emerg. Ther. Targets 2001, 5, 23-40.
Renil, M .; Meldal, M. Tetrahedron Lett. 1996, 37. 6185-6188.
Yuan, Z .; Trias, J .; White, RJ Drug Discov. Today 2001, 6, 954-961.
J. Pharm. Sci. 1977, 66, 2.

Claims (37)

Formula (I):

[Where:
X is -CONHOH, -COOH, -OH or -SH;
R ₁ is C _1-6 alkyl, C _3-10 cycloalkyl, C _1-6 alkyl mercapto, C _1-6 alkylthio-C _1-6 alkyl, C _1-6 alkylhydroxy, C _1-6 alkylcarboxy, C _1-6 alkylamide, C _1-6 alkylamino, alkylamino-C _1-6 alkyl, dialkylamino-C _1-6 alkyl, C _1-6 alkylamidine, C _1-6 alkylguanidine, unsubstituted or substituted An aryl group, an unsubstituted or substituted heteroaryl group, an unsubstituted or substituted C _1-6 alkylaryl group, an unsubstituted or substituted C _1-6 alkylheteroaryl group and a side chain of a natural α-amino acid Selected from the group;
Provided that R ₁ cannot be hydrogen or tert-butyl;
R ₂ is C _1-6 alkyl, C _2-6 alkenyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _3-7 heterocycloalkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 alkyl mercapto, C _1-6 alkylhydroxy, thio C _1-6 alkyl, alkylamino-C _1-6 alkyl, dialkylamino-C _1-6 alkyl, unsubstituted or substituted Selected from the group consisting of a substituted aryl group, an unsubstituted or substituted heteroaryl group, an unsubstituted or substituted C _1-6 alkylaryl group, and an unsubstituted or substituted C _1-6 alkylheteroaryl group;
R ₃ is —NHCH (R ₄ ) COR ₅ , —NR ₆ R ₇ , —NHR ₇ or —OR ₇ ;
R ₄ is selected from the group consisting of hydrogen and the side chains of natural α-amino acids;
R ₅ is amino, hydroxy, C _1-6 alkoxy or —NH—C _1-6 alkyl;
R ₆ and R ₇ are the same or different and, independently of each other, a C _3-7 heterocycloalkyl, unsubstituted or substituted C _1-6 alkyl-C _3-7 heterocycloalkyl group, unsubstituted or substituted Selected from the group consisting of a substituted aryl group, an unsubstituted or substituted heteroaryl group, an unsubstituted or substituted C _1-6 alkylaryl group, and an unsubstituted or substituted C _1-6 alkylheteroaryl group;
Here, the substituted group is halogen, hydroxy, amino, mercapto, nitro, cyano, trifluoromethyl, C _1-6 alkyl, C _1-6 alkoxy, thio C _1-6 alkyl, C _1-6 alkylhydroxy, Substituted with 1, 2 or 3 substituents independently selected from C _1-6 alkylamino, alkylamino-C _1-6 alkyl and dialkylamino-C _1-6 alkyl]
Or a pharmaceutically acceptable salt or ester thereof.   The compound according to claim 1, wherein X is -CONHOH.   The compound of claim 1, wherein X is -COOH.   The compound of claim 1, wherein X is selected from -OH and -SH. R ₁ is a natural α-amino acid such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine and valine The compound according to any one of claims 1 to 4, which is a side chain of R ₁ is C _1-6 alkyl, C _3-10 cycloalkyl, C _1-6 alkyl mercapto, C _1-6 alkylthio-C _1-6 alkyl, C _1-6 alkylhydroxy, C _1-6 alkylcarboxy, C _1-6 alkylamide, C _1-6 alkylamino, alkylamino-C _1-6 alkyl, dialkylamino-C _1-6 alkyl, C _1-6 alkylamidine, C _1-6 alkylguanidine, unsubstituted or substituted It is an aryl group, an unsubstituted or substituted heteroaryl group, an unsubstituted or substituted C _1-6 alkylaryl group, or an unsubstituted or substituted C _1-6 alkylheteroaryl group. Compounds described in 1. Any of claims 1-4, wherein R ₁ is ethyl, isobutyl, 2- (methylsulfanyl) ethyl, 4-aminobutyl, benzyl, 4-hydroxybenzyl, 2-phenylethyl and naphth-1-yl-methyl. A compound according to any one of the above. R ₂ is C _1-6 alkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _1-6 alkylamino, C _1-6 alkylhydroxy, unsubstituted or substituted C Selected from the group consisting of _1-6 alkylaryl groups, and unsubstituted or substituted C _1-6 alkylheteroaryl groups;
Wherein the substituted group is independently selected from halogen, hydroxy, amino, mercapto, nitro, cyano, trifluoromethyl, C _1-6 alkyl, C _1-6 alkoxy, and thio C _1-6 alkyl 8. A compound according to any one of claims 1 to 7 which is substituted with 1, 2 or 3 substituents. R ₂ is ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, cyclohexylethyl, aminoethyl, aminopropyl, aminobutyl, hydroxymethyl, hydroxyethyl, hydroxypropyl 8, selected from the group consisting of: hydroxybutyl, phenyl, fluorine substituted phenyl, chloro substituted phenyl, benzyl, fluorine substituted benzyl, chloro substituted benzyl, thiophenylethyl and furanylmethyl. Compound. R ₂ is butyl, cyclopropyl, cyclohexylmethyl, 2-aminoethyl, 2-hydroxyethyl, benzyl, 2-chlorobenzyl, 4-chlorobenzyl, 2,6-difluorobenzyl, 2-thiophen-2-ylethyl Or the compound of claim 9 which is furan-2-ylmethyl. R ₃ is -NHCH (R ₄₎ COR _5, A compound according to any one of claims 1 to 10. R ₃ is -NHR ₇ or -NR ₆ R _7, A compound according to any one of claims 1 to 10. R ₃ is -OR _7, A compound according to any one of claims 1 to 10. R ₄ is a natural α-amino acid such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine and valine. The compound according to claim 1, which is a side chain of R ₄ is hydrogen, A compound according to any one of claims 1 to 11 or 14. R ₅ is C _1-6 alkoxy, A compound according to any one of claims 1 to 11 or 14 to 15. R ₅ is methoxy, ethoxy, propoxy or butoxy, a compound according to any one of claims 1 to 11 or 14 to 16. R ₆ or R ₇ is, C _3-7 heterocycloalkyl or unsubstituted or substituted C _1-6 alkyl -C _3-7 heterocycloalkyl group, any one of claims 1 to 10 or 12 to 13 Compounds described in 1. R ₆ or R ₇ is an unsubstituted or substituted aryl group, an unsubstituted or substituted heteroaryl group, an unsubstituted or substituted C _1-6 alkylaryl group, or an unsubstituted or substituted C _1-6 alkylheteroaryl group The compound according to any one of claims 1 to 10 or 12 to 13. ([1-cyclopropyl-2- [1- (3-mercapto-propionylamino) -propyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([1- (4-Chloro-benzyl) -2- [1- (3-mercapto-propionylamino) -2-phenyl-ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
N- [1- [1-benzyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -3-methylsulfanyl-propyl] -succinamic acid,
N- [1- [1-butyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -2-phenyl-ethyl] -succinamic acid,
N- [1- [1-furan-2-ylmethyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzoimidazol-2-yl] -2-phenyl-ethyl] -succinamic acid,
N- [1- [1- (4-Chloro-benzyl) -5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -2-phenyl-ethyl] -succinamic acid,
N- [1- [1-cyclopropyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzoimidazol-2-yl] -3-phenyl-propyl] -succinamic acid,
N- [1- [1-cyclohexylmethyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -3-phenyl-propyl] -succinamic acid,
N- [1- [1- (2-chloro-benzyl) -5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -3-phenyl-propyl] -succinamic acid,
N- [1- [1-cyclopropyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -propyl] -succinamic acid,
N- [1- [1-furan-2-ylmethyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -propyl] -succinamic acid,
N- [1- [1-benzyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -propyl] -succinamic acid,
N- [1- [1-cyclopropyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzoimidazol-2-yl] -3-methyl-butyl] -succinamic acid,
N- [1- [1-butyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -3-methyl-butyl] -succinamic acid,
N- [1- [1-benzyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -3-methyl-butyl] -succinamic acid,
N- [1- [1-cyclopropyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -3-methylsulfanyl-propyl] -succinamic acid,
N- [1- [5- (methoxycarbonylmethyl-carbamoyl) -1- (2-thiophen-2-yl-ethyl) -1H-benzimidazol-2-yl] -2-naphthalen-1-yl-ethyl] -Succinamic acid,
N- [1- [1-butyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -2-naphthalen-1-yl-ethyl] -succinamic acid,
([2- [5-amino-1- (3-mercapto-propionylamino) -phenyl] -1-cyclohexylmethyl-1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([1-Cyclopropyl-2- [2- (4-hydroxy-phenyl) -1- (3-mercapto-propionylamino) -ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester ,
([1-Cyclohexylmethyl-2- [2- (4-hydroxy-phenyl) -1- (3-mercapto-propionylamino) -ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester ,
([1- (2-hydroxy-ethyl) -2- [1- (3-mercapto-propionylamino) -2-phenyl-ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
N- [5-amino-1- [1-cyclopropyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -phenyl] -succinamic acid,
N- [5-amino-1- [1-cyclohexylmethyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -phenyl] -succinamic acid,
N- [1- [1-cyclopropyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -2- (4-hydroxyphenyl) -ethyl] -succinamic acid,
N- [1- [1-cyclohexylmethyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -2- (4-hydroxyphenyl) -ethyl] -succinamic acid,
N- [1- [1- (2-hydroxy-ethyl) -5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -2-phenyl-ethyl] -succinamic acid,
N- [1- [1- (2-hydroxy-ethyl) -5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -3-methylbutyl] -succinamic acid,
([1-cyclopropyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -propyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
N- [1- [1-benzyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -2-naphthalen-1-yl-ethyl] -succinamic acid,
([1-furan-2-ylmethyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -propyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([1-benzyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -propyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([1-cyclopropyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -3-methyl-butyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([1-butyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -3-methyl-butyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([1-benzyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -3-methyl-butyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([1-cyclopropyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -3-methylsulfanyl-propyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([1-cyclohexylmethyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -3-methylsulfanyl-propyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([1-benzyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -3-methylsulfanyl-propyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([1-furan-2-ylmethyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -2-phenyl-ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([1- (4-Chloro-benzyl) -2- [1- (3-hydroxycarbamoyl-propionylamino) -2-phenyl-ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester ,
([1-cyclopropyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -3-phenyl-propyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([1-cyclohexylmethyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -3-phenyl-propyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([1- (2-Chloro-benzyl) -2- [1- (3-hydroxycarbamoyl-propionylamino) -2-phenyl-ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester ,
[[2- [1- (3-Hydroxycarbamoyl-propionylamino) -2-naphthalen-1-yl-ethyl] -1- (2-thiophen-2-yl-ethyl) -1H-benzimidazol-5-carbonyl ] -Amino] -acetic acid methyl ester,
([1-butyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -2-naphthalen-1-yl-ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([1-benzyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -2-naphthalen-1-yl-ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([1-butyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -2-phenyl-ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([2- [5-amino-1- (3-mercapto-propionylamino) -phenyl] -1-cyclopropyl-1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([2- [5-amino-1- (3-mercapto-propionylamino) -phenyl] -1-benzyl-1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([1- (2-amino-ethyl) -2- [1- (3-mercapto-propionylamino) -2-phenyl-ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
N- [5-amino-1- [1-benzyl-5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -phenyl] -succinamic acid,
N- [1- [1- (2-amino-ethyl) -5- (methoxycarbonylmethyl-carbamoyl) -1H-benzimidazol-2-yl] -2-phenyl-ethyl] -succinamic acid,
([2- [5-amino-1- (3-hydroxycarbamoyl-propionylamino) -phenyl] -1-cyclopropyl-1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([2- [5-amino-1- (3-hydroxycarbamoyl-propionylamino) -phenyl] -1-cyclohexylmethyl-1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([2- [5-amino-1- (3-hydroxycarbamoyl-propionylamino) -phenyl] -1-benzyl-1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([1- (2-Amino-ethyl) -2- [1- (3-hydroxycarbamoyl-propionylamino) -2-phenyl-ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester ,
([1-Cyclopropyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -2- (4-hydroxy-phenyl) -ethyl] -1H-benzimidazol-5-carbonyl] -amino) -acetic acid methyl ester,
([1-cyclohexylmethyl-2- [1- (3-hydroxycarbamoyl-propionylamino) -2- (4-hydroxy-phenyl) -ethyl] -1H-benzimidazol-5-carbonyl] -amino) -methyl acetate ester,
[[2- [1- (3-Hydroxycarbamoyl-propionylamino) -2-phenyl-ethyl] -1- (2-hydroxy-ethyl) -1H-benzimidazol-5-carbonyl] -amino] -acetic acid methyl ester ,
The compound of claim 1 selected from the group consisting of and stereoisomers thereof. In PDF assay, of less than 500 [mu] M, any one of claims 1 to 20, preferably less than 100 [mu] M, more preferably less than 50 [mu] M, more preferably showing less than 1 [mu] M, especially less than 500 nM, especially 300 nM or lower an IC ₅₀ value Compound described in 1.   22. A compound according to any one of claims 1 to 21 for use in medicine.   23. A compound according to any one of claims 1 to 22 for use as a protease inhibitor.   24. A compound according to claim 23 for use as a peptide deformylase inhibitor.   Staphylococcus, Enterococcus, Streptococcus, Hemophilus, Moraxella, Escherichia, Mycobacterium, Mycoplasma, Pseudomonas, Chlamydia, Rickettsia, Klebsiella, Shigella, Salmonella, Bordetella, Clostridium, Helicobacter, Campylobacter, Legionella genus 25. A compound according to any one of claims 1 to 24 for use in the treatment, prevention and / or diagnosis of a bacterial infection caused completely or partly by a microorganism.   A pharmaceutical composition comprising, as an active ingredient, the compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.   27. A pharmaceutical composition according to claim 26 comprising a second active substance having antibacterial activity.   The composition comprises from about 1 μg to about 1000 mg of the active ingredient or a pharmaceutically acceptable salt or ester thereof, for example from about 10 μg to about 500 mg, from about 0.05 to about 100 mg, or from about 0.1 to about 50 mg. 28. A pharmaceutical composition according to claim 26 or 27 in unit dosage form.   Treatment of infection, wherein the composition comprises as an active ingredient a compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent. 29. A pharmaceutical composition according to any one of claims 26 to 28.   Staphylococcus, Enterococcus, Streptococcus, Hemophilus, Moraxella, Escherichia, Mycobacteria, Mycoplasma, Pseudomonas, Chlamydia, Rickettsia, Klebsiella, Shigella, Salmonella, Bordetella, Clostridium, Helicobacter, Campylobacter, Legionella genus 30. A pharmaceutical composition according to claim 29 for the treatment of a bacterial infection caused completely or partly by.   31. A pharmaceutical composition according to any one of claims 26 to 30 for oral, nasal, transdermal, pulmonary or parenteral administration. 36. The method of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, or any one of claims 26-31, wherein the method comprises administration to a patient in need of treatment. A method of treating a disease comprising administering an effective amount of the described composition.   An effective amount of a compound according to any one of claims 1 to 25 or a salt or ester thereof is, for example, from about 10 μg to about 500 mg, from about 0.05 to about 100 mg, or from about 0.1 to about 50 mg per day. 33. The method of claim 32, wherein the method is in the range of about 1 [mu] g to about 1000 mg.   Use of a compound as defined in any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament.   Use of a compound as defined in any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of bacterial infections.   Staphylococcus, Enterococcus, Streptococcus, Hemophilus, Moraxella, Escherichia, Mycobacteria, Mycoplasma, Pseudomonas, Chlamydia, Rickettsia, Klebsiella, Shigella, Salmonella, Bordetella, Clostridium, Helicobacter, Campylobacter, Legionella genus 26. Use of a compound as defined in any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of an infection caused completely or partly by.   Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecium, Enterococcus faecalis, Streptococcus pneumoniae, Hemophilus influenza, Moraxella catarralis, Escherichia coli, Mycobacterium tuberculosis, Mycobacterium lanae, Mycoplasma pneumoniae, Pseudomonas aeruginosa, Chlamydia, Rickettsia, Klebsiella pneumoniae, Shigella flexinel, Salmonella typhimurium, Bordetella pertussis, Clostridia perfringens, Helicobacter pylori, Campylobacter jejuni and Regionella Completely by microorganisms belonging to the group consisting of Or partially compound according to any one of claims 1 to 25 for the manufacture of a medicament for the treatment of infections caused or use of a pharmaceutically acceptable salt thereof.