Cyclic peptide antibiotics

Abstract

Provided herein is an antibacterial peptide compound that is active against gram-negative bacteria.In various embodiments, the compound acts by inhibiting BAM A membrane protein.Also provided are pharmaceutical compositions and methods for treatment using the compounds described herein.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 196,374, filed June 3, 2021, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] background Most Gram-negative bacteria are more intrinsically resistant to antibacterial agents than Gram-positive bacteria, which currently poses a problem in anti-infective therapy. Initially, this "intrinsic resistance" was attributed to the outer membrane (OM) permeability barrier. However, OM permeability alone cannot fully explain it, since most drug molecules can equilibrate the rather impermeable OM of P. aeruginosa in less than a minute (H. Nikado, Antimicrob. Agent Chemother. 1989 33(11):1831). It has been shown that the intrinsic drug resistance of Gram-negative bacteria results from cooperation between the OM barrier and the expression of broad-specificity multidrug efflux pumps (HIZgurskaya and H. Nikado, Proc. Nat. Acad. Sci. 1999 96(13):7190). Gram-negative bacteria also possess drug-specific efflux pumps that mediate resistance to certain classes of antibacterial agents (X.-Z. Li and H. Nikaido, Drugs 2004 64:159-204). Summary of the Invention

[0003] Disclosure Summary Described herein are novel cyclic peptides useful for treating microbial infections.In various embodiments, the disclosure provides macrocyclic peptides for treating bacterial infections.In various embodiments, the disclosure provides classes and subclasses of compounds for treating gram-negative infections.The macrocyclic compounds act by inhibiting the folding and insertion of nascent proteins into OM mediated by OPM BAM complex.

[0004] In some embodiments of the present invention, the compound of formula (I) TIFF2024522985000002.tif60170R 1 But, C 1-6 Alkyl, Hydroxyl-C 1-6 alkyl, or optionally substituted benzyl; R 1a is hydrogen or C 1-6 is alkyl; R 2 is hydrogen, C 1-6 alkyl, or optionally substituted (imidazol-4-yl)methyl; R 3 is a bicyclic aryl, a bicyclic heteroaryl, C 1-6 Alkyl or Hydroxyl-C 1-6 alkyl, and bicyclic aryl and bicyclic heteroaryl are C 1-6 may be substituted once or twice with alkyl, hydroxyl or halo; R 3a is hydrogen or C 1-6 is alkyl; R 4 is C 1-6 alkyl or optionally substituted (imidazol-4-yl)methyl; R 5 is hydrogen, C 1-6 Alkyl, Hydroxyl-C 1-6 alkyl, optionally substituted (imidazol-4-yl)methyl, or optionally substituted guanidino-C 2-4 is alkyl; R 6 is hydroxyl-C 1-6 Alkyl or Amino-C 1-6 is alkyl; R 7 is C 1-6 Alkyl, Hydroxyl-C 1-6 Alkyl or optionally substituted guanidino-C 2-4 is alkyl; R 8 is optionally substituted benzyl; R8a is hydrogen or C 1-6 is alkyl; R 9 is optionally substituted benzyl or optionally substituted 1H-imidazol-5-ylmethyl; R 10 is C 1-6 Alkyl, Amino-C 1-6 Alkyl, optionally substituted 1H-imidazol-5-ylmethyl, optionally substituted guanidino-C 2-4 Alkyl or optionally substituted C 1-2 It is an alkyl-carboxamide; R 11 is an optionally substituted 1-C 1-6 alkyl-1H-imidazol-5-yl)methylbenzyl, or R b is hydrogen or C 1-6 is alkyl; R 12 is an optionally substituted N-(3-amino-3-oxo-(CH2) 2-3 ) carboxamide; R 15a , R 15b , R 15c , R 15d , R 15f , R 15g , R 15h , R 15i , R 15j , R 15k , R 16a , R 16b , R 16c and R 16d is independently at each occurrence hydrogen or C 1-6 (It is alkyl) or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof is provided.

[0005] In another embodiment of the present invention, TIFF2024522985000003.tif71170 (in the formula, R 1 is C 1-6Alkyl, Hydroxyl-C 1-6 alkyl, or optionally substituted benzyl; R 1a is hydrogen or C 1-6 is alkyl; R 2 is hydrogen, C 1-6 alkyl, or optionally substituted (imidazol-4-yl)methyl; R 3 is a bicyclic aryl, a bicyclic heteroaryl, C 1-6 Alkyl or Hydroxyl-C 1-6 alkyl, and bicyclic aryl and bicyclic heteroaryl are C 1-6 may be substituted once or twice with alkyl, hydroxyl or halo; R 3a is hydrogen or C 1-6 is alkyl; R 4 is C 1-6 alkyl, or optionally substituted (imidazol-4-yl)methyl; R 5 is hydrogen, C 1-6 Alkyl, Hydroxyl-C 1-6 alkyl, optionally substituted (imidazol-4-yl)methyl, or optionally substituted guanidino-C 2-4 is alkyl; R 6 is hydroxyl-C 1-6 Alkyl or Amino-C 1-6 is alkyl; R 7 is C 1-6 Alkyl, Hydroxyl-C 1-6 Alkyl or optionally substituted guanidino-C 2-4 is alkyl; R 8 is optionally substituted benzyl; R 8a is hydrogen or C 1-6 is alkyl; R 9is optionally substituted benzyl or optionally substituted (imidazol-4-yl)methyl; R 10 is C 1-6 Alkyl, Amino-C 1-6 Alkyl, optionally substituted (imidazol-4-yl)methyl, optionally substituted guanidino-C 2-4 Alkyl or optionally substituted C 1-2 It is an alkyl-carboxamide; R 11 is optionally substituted benzyl; R 12 is 1H-indolyl-3-methyl or optionally substituted benzyl; R 13 is optionally substituted benzyl; R 14 is an optionally substituted N-(3-amino-3-oxo-(CH2) 2-3 ) carboxamide; R b , R c , R d , R e , R f , R 15a , R 15b , R 15c , R 15d , R 15e , R 15f , R 15g , R 15h , R 15i , R 15j , R 15k , R 15l , R 15m , R 15n , R 16a , R 16b , R 16c and R 16d is independently in each occurrence hydrogen or C 1-6 is alkyl; R a is hydrogen, C 1-6 is alkyl, hydroxyl, or halo; n is 0 to 2; q is 0 or 1; r is 1 or 2) or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. [Brief description of the drawings]

[0006] [Figure 1] FIG. 1a and FIG. 1b - Program used for the preparation of Example 1 and Example 2 on the automated peptide synthesizer. [Diagram 2] Figures 2a and 2b - Program used for the preparation of Examples 3 and 4 on the automated peptide synthesizer. [Diagram 3] Figures 3a and 3b - Program used for the preparation of Examples 5 and 6 on the automated peptide synthesizer. Detailed Description of the Invention

[0007] Detailed Description of the Disclosure Antibiotic resistance is a serious and growing phenomenon in modern medicine, emerging in the 21st century as a major public health concern and a significant obstacle to treatment. Many Gram-negative (GN) bacteria are intrinsically more resistant to antibacterial agents than Gram-positive bacteria. This enhanced resistance is due in part to the cell wall. Gram-positive bacteria have a cell wall made of a thick layer of peptidoglycan that surrounds a cytoplasmic lipid membrane. In contrast, the cell wall of Gram-negative bacteria contains only a thin layer of peptidoglycan, but also an outer membrane (OM) that is absent in Gram-positive bacteria. The outer membrane of Gram-negative bacteria confers rigidity to the cell and acts as a permeability barrier to cytotoxic molecules, including antibiotics. In addition, the OM contains integral outer membrane proteins (OMPs), porins, which have a characteristic β-barrel structure and perform essential functions, including the efflux of harmful molecules from the cell. Thus, the presence of BamA in the outer membrane represents a potential target for small molecule inhibitors that inhibit the formation of antibiotic efflux pumps. (KM Lehman and M. Grabowicz, Antibiotics 2019 8:163)

[0008] Library cyclic peptides were prepared using mRNA display. (Roberts, RW and Szostak, Proc. Nat. Acad. Sci. USA 1997 94:12297; Sohrabi, C. et al., Nature Rev. Chem. 2020 4:90; Josephson, K. et al., Drug Discov. Today, 2014 19(4):388). A thioether-macrocyclic peptide library was constructed by using N-chloroacetyl-D-phenylalanine (ClAc-F) as an initiator in a genetically reprogrammed in vitro translation system (Kashiwagi, K. and Reid, P., WO 2011 / 049157). The resulting library of macrocyclic peptides was screened to identify peptides targeting Bam A1 and Bam A2. TIFF2024522985000004.tif76170

[0009] definition As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or cells) known to those of skill in the art, and equivalents thereof. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or numerical range means that the referenced number or numerical range is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range will vary in some instances between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude certain other embodiments, such as embodiments of any compositions of matter, compositions, methods, or processes described herein that "consist of" or "consist essentially of" the recited features.

[0010] As used in this specification and the appended claims, unless specified to the contrary, the following terms have the meanings indicated below.

[0011] "Alkyl" refers to an optionally substituted straight chain or optionally substituted branched chain saturated hydrocarbon monoradical having from 1 to about 10 carbon atoms, or from 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, and the like. Whenever a numerical range appears herein, such as "C1-C6 alkyl," it means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, however, this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is any of the C1-C6 alkyl groups. 10 Alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, or C1 alkyl. Unless otherwise specifically indicated herein, alkyl groups may be substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc., as described below. In some embodiments, alkyl may be substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkyl may be substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, alkyl may be substituted with halogen.

[0012] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise specifically indicated in the specification, the alkylene group may be substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc., as described below. In some embodiments, the alkylene may be substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene may be substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkylene may be substituted with halogen.

[0013] "Alkoxy" is R a is an alkyl radical as defined herein; a Unless otherwise specifically indicated in the specification, the alkoxy group may be substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkoxy may be substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy may be substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkoxy may be substituted with halogen.

[0014] "Aryl" refers to a group derived from a hydrocarbon ring system containing hydrogen, 6 to 30 carbon atoms, and at least one aromatic ring. Aryl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems and can include fused ring systems (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6-membered aryl. In some embodiments, the aryl is a 6-membered aryl. Aryl radicals include, but are not limited to, aryl radicals derived from anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene hydrocarbon ring systems. In some embodiments, the aryl is phenyl. Unless otherwise specifically indicated herein, aryl may be substituted as described below, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, aryl may be substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, aryl may be substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, aryl may be substituted with halogen or methyl. In some embodiments, aryl may be substituted with halogen.

[0015] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the halogen is fluoro.

[0016] "Haloalkyl" refers to an alkyl radical, as defined above, substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. "Aminoalkyl" refers to an alkyl radical as defined above substituted by one or more -NH2, e.g., -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH(NH2)CH3, -CH2CH(NH2)CH3, -CH(NH2)CH2CH3, and the like.

[0017] "Hydroxyalkyl" refers to an alkyl radical as defined above substituted by one or more -OH, e.g., -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH(OH)CH3, -CH2CH(OH)CH3, -CH(OH)CH2CH3, and the like.

[0018] "Heteroaryl" refers to a 5-14 membered ring system radical containing a hydrogen atom, 1-13 carbon atoms, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur, and at least one aromatic ring. Heteroaryl groups can be monocyclic, bicyclic, tricyclic or tetracyclic ring systems, can include fused (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems, and the nitrogen, carbon or sulfur atoms in the heteroaryl group can be optionally oxidized and the nitrogen atom can be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl.Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, Examples include, but are not limited to, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclinidyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless specifically stated otherwise in the specification, heteroaryl may be substituted as described below, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroaryl may be substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroaryl may be substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.In some embodiments, the heteroaryl is optionally substituted with halogen or methyl. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0019] The following nomenclature is used herein:

[0020] Optionally substituted benzyl is C 1-6 Alkyl, Hydroxyl, C 1-3 Alkoxy, Halo, C 1-6 Haloalkyl or C 1-6 It refers to benzyl which may be substituted with haloalkyloxy.

[0021] 1H-imidazol-5-ylmethyl is R b is hydrogen; and optionally substituted (imidazol-4-yl)methyl refers to (ii) where R b is hydrogen or C 1-6 (ii) refers to (3-methylimidazol-4-yl)methyl and (1-methyl-1H-imidazol-5-yl)methyl, both of which are R b is methyl (iib). TIFF2024522985000005.tif15170

[0022] Guanidino-C 2-4 Alkyl is the moiety -(CH2) 2-4 -NH(C=NH)NH2; optionally substituted guanidino-C 2-4 Alkyl is the moiety -(CH2) p -NR c (C=NR c )N(R c )2(iii) and R c is independently in each occurrence hydrogen, or C 1-6 alkyl, p is 0 to 2, preferably R c is hydrogen or methyl, and p is 1. TIFF2024522985000006.tif16170

[0023] Optionally substituted C 1-2 Alkyl-carboxamide (iv) is 3-amino-3-oxo-propyl (-(CH2)2C(=O)N(R d )2) and 2-amino-2-oxo-ethyl refers to CH2C(=O)N(R d ) 2), and R d is each independently, at each occurrence, hydrogen or C 1-6 alkyl, preferably R d is hydrogen or methyl, and q is 0 or 1. TIFF2024522985000007.tif18170

[0024] N-(3-amino-3-oxo-(CH2) 2-3 ) Carboxamide, r is 1 or 2, R e N-(3-amino-3-oxo-propyl)carboxamide is C(=O)NR e (CH2)2C(=O)N(R e )2, and N-(2-amino-2-oxo-ethyl)carboxamide refers to C(=O)NR e CH2C(=O)N(R e )2, R e is hydrogen. When these moieties are optionally substituted, R e is independently C 1-6 It is alkyl or hydrogen. TIFF2024522985000008.tif16170

[0025] 1H-indolyl-3-methyl is R f is hydrogen; and optionally substituted 1H-indolyl-3-methyl refers to (vi) where R f is hydrogen or C 1-6 (vi) is alkyl. TIFF2024522985000009.tif24170

[0026] The term aromatic amino acid refers to amino acids of the formula H2NCH(CH2R a )CO2H, Ra is benzyl, phenyl, 2-phenethyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, and the aromatic ring is C 1-6 Alkyl, halogen, C 1-6 -Haloalkyl, Hydroxyl, C 1-6 -Alkoxy, C 1-6 -Haloalkoxy, C 1-6 -thioalkyl, C 1-6 N-methyl-aromatic amino acids are represented by the formula MeHNCH(CHR a )CO2H.

[0027] The term aliphatic amino acid refers to amino acids of the formula H2NCH(CH2R a )CO2H (where R a is hydrogen or C 1-6 Linear or branched alkyl, C 1-4 Alkoxy-C 1-2 It refers to compounds in which the aryl group is an alkyl or methionine.

[0028] The term basic amino acid refers to amino acids of the formula H2NCH(CH2R a )CO2H, R a is C 1-6 -Aminoalkyl, guanidino-C 2-4 Alkyl or optionally substituted C 2-4 alkyl-(guanidine), R c are independently hydrogen or C 1-3 alkyl, pyrrolidin-3-yl.

[0029] The term heteroaryl amino acid refers to histidine, tryptophan, N-alkyl-histidine or N-alkyltryptophan, where the alkyl group is 1 to 3 carbons.

[0030] The term polar amino acid refers to serine, threonine, cysteine, asparagine, or glutamine.

[0031] Abbreviations used herein include: 4-ClPh (4-chlorophenyl); F4C (4-chloro-L-phenylalanine); 4-HO-Ph (4-hydroxyphenyl); Boc (t-butoxycarbonyl; Pbf (2,2,4,6,7 pentamethyldihydrobenzofuran-5-sulfonyl); Trt (trityl); Abu ((S)-2-aminobutyric acid); H3Me (3-methyl-L-histidine); MeY (N-methyl-L-tyrosine); MeF (N-methyl-L-phenylalanine); TFA (trifluoroacetic acid); MeCN (acetonitrile); TEA (triethylamine); DCM (dichloromethane); DMF (N,N-dimethylformamide).

[0032] The terms "treat", "prevent", "ameliorate" and "inhibit" as used herein, and words derived therefrom, do not necessarily mean 100% or complete treatment, prevention, amelioration or inhibition. Rather, there are various degrees of treatment, prevention, amelioration and inhibition that one of skill in the art would recognize as having potential benefit or therapeutic effect. In this regard, the disclosed methods may provide any amount of treatment, prevention, amelioration or inhibition of any level of a disorder in a mammal. For example, a disorder, including its symptoms or symptoms, may be reduced, for example, by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%. Furthermore, the treatment, prevention, amelioration or inhibition provided by the methods disclosed herein may include treatment, prevention, amelioration or inhibition of one or more symptoms or symptoms of a disorder, such as cancer or inflammatory disease. Also, as used herein, "treatment", "prevention", "amelioration" or "inhibition" encompasses delaying the onset of a disorder, or its symptoms or symptoms.

[0033] The term "effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of a compound disclosed herein being administered that relieves to some extent one or more of the symptoms of the disease or condition being treated, such as cancer or inflammatory disease. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound disclosed herein that is required to cause a clinically significant reduction in a disease symptom. In some embodiments, the appropriate "effective" amount in any individual case is determined using techniques such as a dose escalation study.

[0034] The terms defined herein above refer to the broadest definition described in the Summary of the Invention or the larger embodiment to which it refers.

[0035] As used herein, "prodrug" refers to a compound having one or more moieties that can be metabolized in vivo to generate an active drug. For example, there are prodrugs that are metabolized in vivo to active drugs by esterases or other mechanisms. Examples of prodrugs and their uses are well known in the art (see, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19). Prodrugs can be prepared during the final isolation and purification of the compound or in situ by separately reacting the purified compound in its free acid form or at the hydroxyl with a suitable esterifying agent. Hydroxyl groups can be converted to esters via treatment with carboxylic acids. Examples of prodrug moieties include substituted and unsubstituted, branched or unbranched lower alkyl ester moieties (e.g., propionate esters), lower alkenyl esters, di-lower alkylamino lower alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g., acetyloxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl esters), aryl lower alkyl esters (e.g., benzyl esters), substituted aryl and aryl lower alkyl esters (e.g., with methyl, halo or methoxy substituents), amides, lower alkyl amides, di-lower alkyl amides and hydroxyamides.

[0036] The term "substantially" as used herein means completely or nearly completely, e.g., a composition that is "substantially free" of a component is either free of the component or contains such minor amounts that any relevant functional properties of the composition are not affected by the presence of such minor amounts, or a compound is "substantially pure" in that only negligible amounts of impurities are present.

[0037] In some embodiments, the compounds described herein are present as their pharmaceutically acceptable salts.In some embodiments, the methods disclosed herein include methods of treating disease by administering such pharmaceutically acceptable salts.In some embodiments, the methods disclosed herein include methods of treating disease by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0038] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with a number of inorganic or organic bases, and both inorganic and organic acids, to produce pharma- ceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting the purified compound in its free form with the appropriate acid or base and isolating the salt thus formed.

[0039] Examples of pharma- ceutically acceptable salts include salts prepared by reacting the compounds described herein with a mineral, organic acid, or inorganic base, such as acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, Hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methyl benzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate undeconate, and xylenesulfonate.

[0040] In some embodiments, the compounds described herein exist as solvates. The present disclosure provides a method of treating a disease by administering such a solvate. The present disclosure further provides a method of treating a disease by administering such a solvate as a pharmaceutical composition.

[0041] Solvates contain stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments are formed during the process of crystallization with pharma- ceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the process described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from an aqueous / organic solvent mixture using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methanol. Furthermore, the compounds provided herein can exist in unsolvated and solvated forms. In general, solvated forms are considered equivalent to unsolvated forms in the compounds and methods provided herein.

[0042] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that can be interconverted by the migration of a hydrogen atom accompanied by the exchange of a single bond with an adjacent double bond. In bond configurations that allow tautomerization, chemical equilibrium of tautomers exists. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent and pH.

[0043] In another embodiment, the compound is a hydrate or metabolite of any of the preceding compounds.

[0044] In another aspect is a pharmaceutical composition comprising any of the aforementioned compounds together with a pharma- ceutically acceptable excipient.

[0045] compound In one embodiment of the present invention, there is provided a cyclic dodecapeptide of formula (I) as disclosed in the Summary of the Disclosure above, or a pharma- ceutically acceptable salt, solvate or stereoisomer thereof. TIFF2024522985000010.tif51170

[0046] In one embodiment of the compound of formula (I), R 12 is N-(2-amino-2-oxo-ethyl)carboxamide, R 1a , R 3a and R 8a is hydrogen, and R 4 and R 9 is 1H-imidazol-5-ylmethyl, R 2 is C 1-6 In one embodiment of the compound of formula (I), R 2 is ethyl, isopropyl or sec-butyl.

[0047] In some embodiments of the compounds of Formula (I), R 1 is optionally substituted benzyl. In some embodiments of the compounds of Formula (I), R 1 is unsubstituted benzyl, hydroxybenzyl, or chlorobenzyl. In some embodiments of the compounds of Formula (I), R 1 is 4-hydroxybenzyl or 4-chlorobenzyl. In some embodiments of the compound of Formula (I), R 1 is C 1-6 In some embodiments of the compounds of formula (I), R 1 is butyl. In some embodiments of the compounds of Formula (I), R 1 is C 1-6 It is hydroxyalkyl or hydroxymethyl.

[0048] In some embodiments of the compounds of Formula (I), R 1 is hydroxymethyl.

[0049] In some embodiments of the compounds of Formula (I), R 3 is a bicyclic aryl, a bicyclic heteroaryl, C 1-6 Alkyl or Hydroxyl-C 1-6 alkyl, and bicyclic aryl and bicyclic heteroaryl are C 1-6 It may be substituted once or twice with alkyl, hydroxyl, or halo. In some embodiments, R3 is 1-naphthylmethyl substituted with any one to three halogens; or unsubstituted 1-naphthylmethyl. In some embodiments, R 3 is 2-naphthmethyl substituted with any one to three halogens; or unsubstituted 2-naphthmethyl. In some embodiments, R 3 is optionally substituted 3-indolylmethyl; R f is hydrogen or C 1-6 In some embodiments, R 3 is 3-indolylmethyl. In some embodiments, R 3 is N-substituted-3-indolylmethyl, R f is methyl. In some embodiments, R 3 is optionally substituted benzyl. In some embodiments, R 3 is 4-phenylphenyl)methyl.

[0050] In some embodiments of the compounds of Formula (I), R 4 is C 1-6 In some embodiments of the compounds of formula (I), R 4 is C 1-6 In some embodiments of the compound of formula (I), R is 4-(imidazolyl)methyl, optionally substituted with alkyl. 4 is 4-(imidazolyl)methyl. In some embodiments of the compound of Formula (I), R 4 is 4-(imidazolyl)methyl with an N-substituted methyl. In some embodiments of the compound of Formula (I), R 4 is C 1-6 In some embodiments of the compounds of formula (I), R 4 is methyl.

[0051] In some embodiments of the compounds of Formula (I), R 5 is hydrogen. In some embodiments of the compounds of Formula (I), R 5is hydroxy-C 1-6 In some embodiments of the compounds of formula (I), R 5 is hydroxymethyl. In some embodiments of the compounds of Formula (I), R 5 is C 1-6 In some embodiments of the compounds of formula (I), R 5 is methyl. In some embodiments of the compounds of Formula (I), R 5 Optionally substituted 3-guanide-C 2-4 is alkyl, R c are independently hydrogen or C 1-6 In some embodiments of the compounds of Formula (I), R 5 is 3-guanidopropyl.

[0052] In some embodiments of the compounds of Formula (I), R 6 is hydroxyl-C 1-6 In some embodiments of the compounds of formula (I), R 6 is hydroxymethyl or hydroxyethyl. In some embodiments of the compound of Formula (I), R 6 is 1-hydroxy-ethyl. In some embodiments of the compound of Formula (I), R 6 is amino-C 1-6 In some embodiments of the compounds of formula (I), R 6 is 4-aminobutyl. In some embodiments of the compound of Formula (I), R 6 is an optionally substituted guanidino-C 2-4 is alkyl, R c are independently hydrogen or C 1-6 In some embodiments of the compounds of formula (I), R is 3-guanido-propyl, which may be substituted or alkyl. 5 is 3-guanidopropyl.

[0053] In some embodiments of the compounds of Formula (I), R 7 is an optionally substituted 3-guanide-C 2-4is alkyl, R c are independently hydrogen or C 1-6 In some embodiments of the compounds of formula (I), R 5 is 3-guanidopropyl. In some embodiments of the compound of Formula (I), R 7 is C 1-6 In some embodiments of the compounds of formula (I), R 7 is methyl or ethyl. In some embodiments of the compounds of Formula (I), R 7 is methyl. In some embodiments of the compounds of Formula (I), R 7 is ethyl. In some embodiments of the compound of Formula (I), R 7 is hydroxyl C 1-6 In some embodiments of the compounds of formula (I), R 7 is 1-hydroxyethyl.

[0054] In some embodiments of the compounds of Formula (I), R 8 is optionally substituted benzyl. In some embodiments of the compounds of Formula (I), R 8 is hydroxybenzyl. In some embodiments of the compounds of Formula (I), R 8 is 4-hydroxybenzyl. In some embodiments of the compounds of Formula (I), R 8 is halo-substituted benzyl. In some embodiments of the compounds of formula (I), R 8 is benzyl substituted with one or two halogens. In some embodiments of the compound of Formula (I), R 8 is benzyl substituted with one or two chlorines. In some embodiments of the compounds of Formula (I), R 8 is 4-chlorobenzyl.

[0055] In some embodiments of the compounds of Formula (I), R 9 is optionally substituted (imidazol-4-yl)methyl. In some embodiments of the compound of Formula (I), R 9 is C 1-6In some embodiments of the compound of formula (I), R is 4-(imidazolyl)methyl, optionally substituted with alkyl. 4 is 4-(imidazolyl)methyl. In some embodiments of the compound of Formula (I), R 4 is 4-(imidazolyl)methyl with an N-substituted methyl. In some embodiments of the compound of Formula (I), R 9 is C 1-6 In some embodiments of the compounds of formula (I), R 9 is methyl.

[0056] In some embodiments of the compounds of Formula (I), R 10 is an optionally substituted 3-guanide-C 1-6 is alkyl, R c are independently hydrogen or C 1-6 In some embodiments of the compounds of formula (I), R 5 is 3-guanidopropyl. In some embodiments of the compounds of Formula (I), R 10 -CH2(CH2) q C(=O)NH2 and q is 0 or 1. In some embodiments of the compound of formula (I), 3-oxo-3-aminopropyl. In some embodiments of the compound of formula (I), R 10 is amino-C 1-6 In some embodiments of the compounds of formula (I), R 10 is aminomethyl, 2-aminoethyl, or 4-aminobutyl. In some embodiments, R 10 is 3-(methylimidazol-4-yl)methyl (iib, where R b In some embodiments of the compound of Formula (I), R 10 is C 1-6 In some embodiments of the compounds of formula (I), R 10 is ethyl.

[0057] In some embodiments of the compounds of Formula (I), R 11 is C 1-6In some embodiments of the compound of formula (I), R is 4-(imidazolyl)methyl, optionally substituted with alkyl. 11 is C 1-6 In some embodiments of the compounds of formula (I), R 11 is 4-(imidazolyl)methyl with an N-substituted methyl. In some embodiments of the compound of Formula (I), R 110 is 3-(methylimidazol-4-yl)methyl (iib, where R b In some embodiments of the compound of Formula (I), R 11 is 4-(imidazolyl)methyl.

[0058] In some embodiments of the compounds of Formula (I), R b , R c , R d , R e , R f , R 1a , R 3a , R 8a , R 15a , R 15b , R 15c , R 15d , R 15e , R 15f , R 15g , R 15i , R 15j , R 15k , R 16a , R 16b , R 16c and R 16d is hydrogen, or C 1-6 alkyl; in some embodiments, R b , R c , R d , R e , R f , R 1a , R 3a , R 8a , R 15a , R 15b , R 15c , R 15d , R 15e , R 15f , R 15g , R 15i , R 15j , R 15k, R 16a , R 16b , R 16c and R 16d is hydrogen or methyl. In some embodiments of the compounds of Formula (I), R a is hydrogen, C 1-6 alkyl, hydroxyl, or halo; in some embodiments, R a In some embodiments of the compounds of Formula (I), R f is hydrogen, C 1-6 In some embodiments of the compounds of formula (I), R f is hydrogen. In some embodiments of the compounds of Formula (I), R f is methyl. In some embodiments of the compound of Formula (I), n and p are independently 0-2. In some embodiments of the compound of Formula (I), n and p are 1 or 0. In some embodiments of the compound of Formula (I), n is 1. In some embodiments of the compound of Formula (I), n is 0. In some embodiments of the compound of Formula (I), q is independently 0 or 1. In some embodiments of the compound of Formula (I), q is 1. In some embodiments of the compound of Formula (I), r is independently 1 or 2. In some embodiments of the compound of Formula (I), r is 1.

[0059] In some embodiments, a compound of Formula (I) is present and is selected from Table 1. [Table 1] TIFF2024522985000012.tif247170TIFF2024522985000013.tif247170TIFF2024522985000014.tif247170TIFF2024522985000015.tif247170 TIFF2024522985000016.tif247170TIFF2024522985000017.tif248170TIFF2024522985000018.tif247170TIFF2024522985000019.tif248170 TIFF2024522985000020.tif248170TIFF2024522985000021.tif248170TIFF2024522985000022.tif247170TIFF2024522985000023.tif248170 TIFF2024522985000024.tif247170TIFF2024522985000025.tif247170TIFF2024522985000026.tif248170TIFF2024522985000027.tif166170

[0060] In another embodiment of the present invention there is a cyclic dodecapeptide of formula (Ia), or a pharma- ceutically acceptable salt, solvate or stereoisomer thereof. TIFF2024522985000028.tif53170

[0061] In some embodiments, a compound of Formula (Ia) is present, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 is as stated above.

[0062] In one embodiment of the invention, a compound of formula (Ib) is present: TIFF2024522985000029.tif34170 formula, AA 1 is an aromatic amino acid or an N-methyl-aromatic amino acid, the aromatic amino acid being phenylalanine, in which either phenyl ring is 1-6 Alkyl, halogen, C 1-6 -Haloalkyl, Hydroxyl, C 1-6 -Alkoxy, C 1-6 -Haloalkoxy, C 1-6 -thioalkyl, C 1-6 -optionally substituted with alkylsulfonyl or cyano; AA 2 is the formula H2NCHR a CO2H is an aliphatic amino acid, R a is C 1-6 Alkyl or C 1-3 Alkoxy-C 1-3 is alkyl; AA 3 is the formula H2NCHR a Aromatic amino acids of CO2H, R a is 1-naphthylmethyl, 2-naphthylmethyl or 4-phenylbenzyl; R a 1 to 3 C 1-6 Alkyl, halogen, C 1-6 -Haloalkyl, Hydroxyl, C 1-6 -Alkoxy, C 1-6 -Haloalkoxy, C 1-6 -thioalkyl, C 1-6 -alkylsulfonyl or cyano substituted or heteroaryl amino acid; R a is 3-indolemethyl, optionally C1-3N-alkyl-3-indolemethyl; AA 4 is histidine; AA 5 is an aliphatic amino acid, and the aliphatic amino acid is a is hydrogen, methyl or hydroxymethyl; a COH compounds, preferably AA 5 is glycine; AA 6is arginine, formula H2NCHR a CO2H is an amino acid, R a is C 1-6 Hydroxyalkyl, preferably AA 7 is serine; AA 7 is the formula H2NCHR a CO2H is a basic amino acid, and R a is guanidino-C 1-4 -alkyl, preferably AA 8 is arginine; AA 8 is an aromatic amino acid or an N-methyl-aromatic amino acid, and an aromatic amino acid is one having one to three C 1-6 Alkyl, halogen, C 1-6 -Haloalkyl, C 1-6 -Alkoxy, C 1-6 -Haloalkoxy, C 1-6 -phenylalanine optionally substituted with thioalkyl; preferably AA 9 is phenylalanine; AA 9 is a heteroaryl amino acid, said heteroaryl amino acid being R a is 1H-imidazol-5-ylmethyl, 3-methylimidazol-4-yl-methyl; a COH compounds, preferably AA 10 is histidine; AA 10 is a basic amino acid, and the basic amino acid is a C 1-6 Aminoalkyl, guanidino-C 1-4 -Alkyl, (CH2) 1-3 CONH2, or C 1-6 Alkyl group of the formula H2NCHR a It is a compound of CO2H; AA 11a is a heteroaryl amino acid, said heteroaryl amino acid being R a is 1H-imidazol-5-ylmethyl, 3-methylimidazol-4-yl-methyl, preferably R ais 3-methylimidazol-4-yl-methyl; a It is a compound of CO2H.

[0063] In another embodiment, a compound of formula (Ib) is obtained: AA 1 is phenylalanine; AA 2 is R a is ethyl, isopropyl or sec-butyl; a CO2H is an aliphatic amino acid; AA 3 is 2-amino-3-(naphthalen-1-yl)propanoic acid or tryptophan; AA 4 is histidine; AA 5 is glycine; AA 6 is R a is hydroxymethyl or -CH(OH)Me a CO2H is an aliphatic amino acid; AA 7 is arginine; AA 8 is phenylalanine optionally substituted with hydroxyl or halo; AA 9 is histidine; AA 10 is arginine, aminomethyl, aminoethyl or aminobutyl; AA 11 is R a is (3-methylimidazol-4-yl)methyl a It is a basic amino acid with CO2H.

[0064] In another embodiment of the present invention, a cyclic tetradecapeptide of formula (II) or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof as disclosed above in the Summary of the Disclosure.

[0065] In one embodiment of the compound of formula (II), R 1a is methyl or hydrogen. In one embodiment of the compound of formula (II), R 1a is hydrogen. In another embodiment of the compound of formula (II), R 1a is methyl. TIFF2024522985000030.tif51170

[0066] In some embodiments of the compound of Formula (II), R 1 is optionally substituted benzyl. In some embodiments of the compound of formula (II), R 1 is unsubstituted benzyl.

[0067] In some embodiments of the compound of Formula (II), R 2 is C 1-6 In some embodiments of the compound of formula (II), R is 4-(imidazolyl)methyl, optionally substituted with alkyl. 2 In some embodiments of the compound of formula (II), (iib R b In some embodiments of the compound of formula (II), R 2 is 4-(imidazolyl)methyl.

[0068] In some embodiments of the compound of Formula (II), R 3 is C 1-6 In some embodiments of the compound of formula (II), R 3 is (1S)-methylpropyl. In some embodiments of the compound of formula (II), R 3 is methyl. In some embodiments of the compound of Formula (II), R 3 is C 1-6 In some embodiments of the compound of formula (II), R 3 is (1R)-1-hydroxyethyl.

[0069] In some embodiments of the compound of Formula (II), R 4 is C 1-6 alkyl; in some embodiments, R 4 is (1S)-methylpropyl; in some embodiments, R 4 is methyl.

[0070] In some embodiments of the compound of Formula (II), R 5 is C 1-6 In some embodiments of the compound of formula (II), R is 4-(imidazolyl)methyl, optionally substituted with alkyl. 5 is 4-(imidazolyl)methyl with an N-substituted methyl. In some embodiments of the compound of formula (II), R 5 is 3-(methylimidazol-4-yl)methyl (iib(R b In some embodiments of the compound of formula (II), R 5 is 4-(imidazolyl)methyl. In some embodiments of the compound of Formula (II), R 5 is an optionally substituted 3-guanidino-C 2-4 In some embodiments of the compound of formula (II), R 5 is 3-guanidinopropyl.

[0071] In some embodiments of the compound of Formula (II), R 6 is an optionally substituted 3-guanide-C 2-4 In some embodiments of the compound of formula (II), R 6 is 3-guanidopropyl. In some embodiments of the compound of formula (II), R 6 is amino-C 1-6 In some embodiments of the compound of formula (II), R 6 is 4-aminobutyl.

[0072] In some embodiments of the compound of Formula (II), R 7 is hydroxy-C 1-6 In some embodiments of the compound of formula (II), R 7 is (1R)-1-hydroxyethyl. In some embodiments of the compound of formula (II), R 7 3-guanide-C 2-4 In some embodiments of the compound of formula (II), R 6is 3-guanidopropyl.

[0073] In some embodiments of the compound of Formula (II), R 8 is optionally substituted benzyl. In some embodiments of the compound of formula (II), R 8 is hydroxybenzyl. In some embodiments of the compound of Formula (II), R 8 is halo-substituted benzyl. In some embodiments of the compound of formula (II), R 8 is benzyl substituted with one or two halogens. In some embodiments of the compound of Formula (II), R 8 is benzyl substituted with one or two chlorines. In some embodiments of the compound of formula (II), R 8 is 4-chlorobenzyl.

[0074] In some embodiments of the compound of Formula (II), R 9 is optionally substituted benzyl. In some embodiments of the compound of formula (II), R 9 is hydroxybenzyl. In some embodiments of the compound of Formula (II), R 9 is 4-hydroxybenzyl. In some embodiments of the compound of formula (II), R 9 is halo-substituted benzyl. In some embodiments of the compound of Formula (II), R 9 is benzyl substituted with one or two halogens. In some embodiments of the compounds of formula (II), R 9 is benzyl substituted with one or two chlorines. In some embodiments of the compound of formula (II), R 9 is 4-chlorobenzyl. In some embodiments of the compound of Formula (II), R 9 is unsubstituted benzyl.

[0075] In some embodiments of the compound of Formula (II), R 10 is an optionally substituted 3-guanide-C 1-6In some embodiments of the compound of formula (II), R 10 is 3-guanidopropyl. In some embodiments of the compound of formula (II), R 10 is amino-C 1-6 In some embodiments of the compound of formula (II), R 10 is 4-aminobutyl. In some embodiments of the compound of Formula (II), R 10 is C 1-6 In some embodiments of the compound of formula (II), R is 4(imidazolyl)methyl, optionally substituted with alkyl. 10 is 4-(imidazolyl)methyl with an N-substituted methyl. In some embodiments of the compound of formula (II), R 10 is 3-(methylimidazol-4-yl)methyl (iib, where R b In some embodiments of the compound of formula (II), R 10 is 4-(imidazolyl)methyl.

[0076] In some embodiments of the compound of Formula (II), R 11 is optionally substituted benzyl. In some embodiments of the compound of formula (II), R 11 is hydroxybenzyl. In some embodiments of the compound of Formula (II), R 11 is 4-hydroxybenzyl. In some embodiments of the compound of formula (II), R 11 is halo-substituted benzyl. In some embodiments of the compound of formula (II), R 11 is benzyl substituted with one or two halogens. In some embodiments of the compounds of formula (II), R 11 In some embodiments of the compound of Formula (II), R is benzyl substituted with one or two chlorines. 11 is 4-chlorobenzyl. In some embodiments of the compound of Formula (II), R 11 is unsubstituted benzyl.

[0077] In some embodiments of the compound of Formula (II), R 12 is optionally substituted benzyl. In some embodiments of the compound of formula (II), R 12 is hydroxybenzyl. In some embodiments of the compound of Formula (II), R 12 is 4-hydroxybenzyl. In some embodiments of the compound of formula (II), R 12 is halo-substituted benzyl. In some embodiments of the compound of formula (II), R 12 is benzyl substituted with one or two halogens. In some embodiments of the compound of Formula (II), R 12 is benzyl substituted with one or two chlorines. In some embodiments of the compound of formula (II), R 12 is 4-chlorobenzyl. In some embodiments of the compound of Formula (II), R 12 is N-substituted-3-indolylmethyl, R f is hydrogen or C 1-6 In some embodiments, R 12 is N-substituted-3-indolylmethyl, R f is hydrogen. In some embodiments, R f is methyl. In some embodiments of the compound of Formula (II), R 12 is indolyl-3-methyl (vi [wherein R f In some embodiments of the compound of formula (II), R 12 is optionally substituted benzyl. In some embodiments of the compound of formula (II), R 12 is hydroxybenzyl. In some embodiments of the compound of Formula (II), R 12 is 4-hydroxybenzyl. In some embodiments of the compound of formula (II), R 12 is halo-substituted benzyl. In some embodiments of the compound of formula (II), R 12 is benzyl substituted with one or two halogens. In some embodiments of the compound of Formula (II), R 12is benzyl substituted with one or two chlorines. In some embodiments of the compound of formula (II), R 12 is 4-chlorobenzyl. In some embodiments of the compound of Formula (II), R 12 is unsubstituted benzyl.

[0078] In some embodiments of the compound of Formula (II), R 13 is optionally substituted benzyl. In some embodiments of the compound of formula (II), R 13 is hydroxybenzyl. In some embodiments of the compound of Formula (II), R 13 is 4-hydroxybenzyl. In some embodiments of the compound of formula (II), R 13 is halo-substituted benzyl. In some embodiments of the compound of formula (II), R 13 is benzyl substituted with one or two halogens. In some embodiments of the compound of Formula (II), R 13 is benzyl substituted with one or two chlorines. In some embodiments of the compound of formula (II), R 13 is 4-chlorobenzyl. In some embodiments of the compound of Formula (II), R 13 is unsubstituted benzyl.

[0079] In some embodiments of the compound of Formula (II), R 14 is N-(2-amino-2-oxo-ethyl)carboxamide.

[0080] In some embodiments of the compound of Formula (II), R b , R c , R d , R e , R f , R 1a , R 3a , R 8a , R 15a , R 15b , R 15c , R 15d , R 15e , R 15f , R 15g , R15i , R 15j , R 15k , R 16a , R 16b , R 16c , and R 16d is hydrogen or C 1-6 alkyl; in some embodiments, R b , R c , R d , R e , R f , R 1a , R 3a , R 8a , R 15a , R 15b , R 15c , R 15d , R 15e , R 15f , R 15g , R 15i , R 15j , R 15k , R 16a , R 16b , R 16c , and R 16d is hydrogen or methyl. In some embodiments of the compound of formula (II), R a is hydrogen, C 1-6 In some embodiments of the compound of formula (II), R a is chloro. In some embodiments of the compound of Formula (II), R f is hydrogen or C 1-6 In some embodiments of the compound of formula (II), R f is hydrogen. In some embodiments of the compound of Formula (II), R fis methyl. In some embodiments of the compound of formula (II), n and p are independently 0-2. In some embodiments of the compound of formula (II), n and p are 1 or 0. In some embodiments of the compound of formula (II), n is 1. In some embodiments of the compound of formula (II), n is 0. In some embodiments of the compound of formula (II), q is independently 0 or 1. In some embodiments of the compound of formula (II), q is 1. In some embodiments of the compound of formula (II), r is independently 1 or 2. In some embodiments of the compound of formula (II), r is 1.

[0081] In another embodiment of the present invention, R 1 But, C 1-6 Alkyl, Hydroxyl-C 1-6 alkyl or benzyl; R 1a is hydrogen or C 1-6 R is alkyl; 2 C 1-6 R is alkyl; 3 is 1-naphthylmethyl, 2-naphthylmethyl, (4-phenylphenyl)methyl or indolyl-3-methyl; R 3a is hydrogen; R 4 is (iic); R 5 is hydrogen or 3-guanidopropyl; R 6 is hydroxymethyl, (1R)-1-hydroxyethyl or 4-aminobutyl; R 7 But, C 1-6 Alkyl, optionally substituted guanidino-C 2-4 R is alkyl; 8 is (i); R 8a is hydrogen; R 9 is (iic); R 10 But, C 1-6 Alkyl, Amino-C 1-6 Alkyl, optionally substituted guanidino-C 2-43 alkyl or (iv); R 11 is (iib) or (iic); R 12 is (v); R 1a , R3a , R 8a , R 15a , R 15b , R 15c , R 15d , R 15e , R 15f , R 15g , R 15i , R 15j , R 15k , R 16a , R 16b , R 16c and R 16d is hydrogen; R 15h is methyl.

[0082] In a subembodiment, R 3 is 1H-indol-3-ylmethyl; R 4 and R 9 is (1H-imidazol-4-yl)methyl; R 5 is hydrogen; R 6 is hydroxymethyl, R 7 and R 10 is 3-guanidinyl-propyl; R 11 is (3-methylimidazol-4-yl)methyl; R 12 is N-(2-amino-2-oxo-ethyl)-carboxamide, the remaining non-limiting substituents being as described hereinabove.

[0083] In a subembodiment, R 3 is 1-naphthylmethyl; R 4 and R 9 is (1H-imidazol-4-yl)methyl; R 5 is hydrogen; R 6 is hydroxymethyl, R 7 and R 10 is 3-guanidinyl-propyl; R 11 is (3-methylimidazol-4-yl)methyl; R 12 is N-(2-amino-2-oxo-ethyl)-carboxamide, the remaining non-limiting substituents being as described hereinabove.

[0084] In some embodiments, a compound of formula (II) is present and is selected from Table 2. [Table 2] TIFF2024522985000032.tif251170TIFF2024522985000033.tif248170TIFF2024522985000034.tif169170TIFF2024522985000035.tif172170

[0085] In some embodiments of the present invention, a cyclic tetradecapeptide of formula (IIa), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. TIFF2024522985000036.tif68170

[0086] In one embodiment of the compound of Formula (IIa), R 14 is N-(2-amino-2-oxo-ethyl)carboxamide (v,r=1,R e =H); R 4 is (1S)-1-methylpropyl, and R 2 is 1-methyl-1H-imidazol-5-yl)methyl, R 9 is benzyl optionally substituted with halo or hydroxyl. In one embodiment of the compound of formula (II), R 9 is unsubstituted benzyl.

[0087] In one embodiment of the invention, a compound of formula (IIb) is present: TIFF2024522985000037.tif22170 formula, AA 1 is an aromatic amino acid, which is a group of amino acids that have one to three C 1-6 Alkyl, halogen, C 1-6 -Haloalkyl, Hydroxyl, C 1-6 -Alkoxy, C 1-6 -Haloalkoxy, C 1-6 -thioalkyl, C1-6 -phenylalanine optionally substituted by alkylsulfonyl or cyano; AA 2 is a heteroaryl amino acid, said heteroaryl amino acid being R a is 1H-imidazol-5-ylmethyl, 3-methylimidazol-4-yl-methyl, preferably R a is 3-methylimidazol-4-yl-methyl; a Heteroaryl amino acids, which are compounds of the formula COH, or AA 2 is glycine; AA 3 is R a C 1-6 Alkyl or C 1-5 -hydroxyalkyl, of the formula HNCHR a COH aliphatic amino acids or R a and R b But independently, C 1-6 alkyl, preferably α-aminoisobutyric acid (Aib), of the formula HNCR a R b CO2H is an aliphatic amino acid; AA 4 is R a C 1-6 The formula HNCHR is an alkyl a aliphatic amino acids of COH, preferably AA 4 is isoleucine; AA 5 is R a H-imidazol-5-ylmethyl or guanidino-C 1-4 -alkyl, of the formula HNCHR a COH basic amino acid, preferably arginine; AA 6 is R a C 1-6 -aminoalkyl or guanidino-C 1-4 -alkyl, preferably aminobutyl, of the formula HNCHR a CO2H is a basic amino acid; AA7 is R a C 1-6 -Hydroxyalkyl or guanidino-C 1-4 -alkyl, preferably aminobutyl, of the formula HNCHR a It is a basic amino acid with CO2H; AA 8 is R a C 1-6 is alkyl, R b is hydrogen or C 1-6 is an alkyl group, the formula HNCR a R b It is an aliphatic amino acid of COH; preferably α-aminoisobutyric acid (Aib); AA 9 is an aromatic amino acid, wherein any phenyl ring of the aromatic amino acid is selected from the group consisting of 1 to 3 C 1-6 Alkyl, halogen, C 1-6 -Haloalkyl, Hydroxyl, C 1-6 -Alkoxy, C 1-6 -Haloalkoxy, C 1-6 Phenylalanine optionally substituted with thioalkyl; preferably phenylalanine; AA 10 is R a But, C 1-6 -Aminoalkyl, guanidino-C 1-4 -alkyl, 3-methylimidazol-4-yl-methyl, a It is a basic amino acid with CO2H; AA 11 is an aromatic amino acid, wherein any phenyl ring of the aromatic amino acid is selected from the group consisting of 1 to 3 C 1-6 Alkyl, halogen, C 1-6 -Haloalkyl, Hydroxyl, C 1-6 -Alkoxy, C 1-6 -Haloalkoxy, C 1-6 Phenylalanine optionally substituted with thioalkyl; preferably phenylalanine; AA 12 is the formula H2NCHR a COH heteroaryl amino acid, R ais 3-indole methyl or an aromatic amino acid, and R a But 1 to 3 C 1-6 Alkyl, halogen, C 1-6 -Haloalkyl, Hydroxyl, C 1-6 -Alkoxy, C 1-6 -Haloalkoxy, C 1-6 - is a phenyl ring optionally substituted with thioalkyl; preferably tryptophan; AA 13 is a C group with 1 to 3 phenyl rings. 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 -Alkoxy, C 1-6 -Haloalkoxy, C 1-6 -thioalkyl, C 1-6 -phenylalanine optionally substituted by alkylsulfonyl or cyano.

[0088] In another embodiment, a compound of formula (IIb) is present, wherein AA 1 is phenylalanine; AA 2 is N α -methylhistidine; AA 3 is serine or alanine; AA 4 is isoleucine; AA 5 is arginine or histidine; AA 6 is lysine or arginine; AA 7 is arginine or serine; AA 8 is α-aminoisobutyric acid; AA 9 is phenylalanine; AA 10 is arginine, N α -Methylhistidine or H2NCHR a CO2H, Ra is aminomethyl, aminoethyl or aminobutyl; AA 11 is 4-hydroxy-phenylalanine; AA 12 is tryptophan; AA 13 is a phenylalanine optionally substituted with hydroxyl or halo.

[0089] Dosage and Administration The present invention provides pharmaceutical compositions or medicaments containing the compounds of the present invention and at least one therapeutically inert carrier, diluent or excipient, as well as methods for preparing such compositions and medicaments using the compounds of the present invention. In one example, the compounds of formula I having a desired degree of purity can be formulated by mixing with a physiologically acceptable carrier, i.e., a carrier that is non-toxic to the recipient at the dosage and concentration used in the dosage form at ambient temperature and appropriate pH. The pH of the formulation will depend primarily on the specific use and concentration of the compound, but typically ranges from about 3 to about 8. In one example, the compounds of formula I are formulated in acetate buffer at pH 5. In another embodiment, the compounds of formula I are sterile. The compounds can be stored, for example, as solid or amorphous compositions, as lyophilized formulations, or as aqueous solutions.

[0090] The composition is formulated, dosed, and administered in a manner consistent with good medical practice.Factors to be considered in this context include the specific disease to be treated, the severity of the disease, the specific patient to be treated, the clinical condition of the individual patient, the cause of the disease, the delivery site of the agent, the method of administration, the administration schedule, and other factors known to physicians.The "effective amount" of the compound to be administered is determined by such considerations and is the minimum amount necessary to provide antibacterial activity.Typically, such amount may be below the amount that is toxic to normal cells or to the patient as a whole.

[0091] The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending on the method used to administer the drug. Generally, the article for distribution includes a container having the pharmaceutical formulation disposed therein in a suitable form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-evident assembly to prevent unintentional access to the contents of the package. In addition, the container has a label disposed thereon that describes the contents of the container. The label may also include appropriate warnings.

[0092] Sustained release preparations can also be prepared.Suitable examples of sustained release formulations include semipermeable matrices of solid hydrophobic polymers containing the compound of formula I, which matrices are in the form of shaped articles such as films or microcapsules.Examples of sustained release matrices include polyesters, hydrogels (e.g. poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactides, copolymers of L-glutamic acid and γ-L-ethyl glutamate, non-degradable ethylene vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT (injectable microspheres composed of lactic acid-glycolic acid copolymers and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.

[0093] Doses for treating human patients can range from about 0.1 mg to about 1000 mg of a compound of formula I or II. A typical dose can be from about 1 mg to about 300 mg of a compound. Doses can be administered once daily (QD), twice daily (BID), or more frequently depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism, and excretion, of the particular compound. In addition, toxicity factors can affect the dose and administration regimen.

[0094] The compounds of the present invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural and intranasal, and, if desired for localized treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0095] The compounds of the present invention may be administered in any convenient dosage form, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional components of pharmaceuticals, such as diluents, carriers, pH adjusters, sweeteners, fillers, and further active agents.

[0096] Typical preparation is prepared by mixing the compound of the present invention and carrier or additive.Suitable carrier and additive are well known to those skilled in the art and are described in detail in, for example, Ansel, HC, et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia: Lippincott, Williams&Wilkins,2004;Gennaro, Alfonso R., et al., Remington: The Science and Practice of Pharmacy.Philadelphia: Lippincott, Williams&Wilkins,2000;and Rowe, RC, Handbook of Pharmaceutical Excipients, Chicago, Pharmaceutical Press,2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, fragrances, flavorings, diluents, and other known additives to provide an aesthetic appearance of the drug product (i.e., a compound of the present invention or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (i.e., a medicament).

[0097] In another aspect is a method of treating a mammal in need of such treatment comprising administering to said mammal an antibacterial effective amount of any of the above compounds at a frequency and for a duration sufficient to provide a beneficial effect to said mammal, hi one embodiment, the causative bacterial species of the bacterial infection is an infection involving gram-negative bacteria. In such embodiments, the gram-negative bacteria may be, for example, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumanii, Neisseria gonorrhoeae, Neisseria meningitidis, Chlamydia trachomatis, Moraxella catarrhalis, Haemophilus influenzae, Proteus mirabilis, Enterobacter cloacae, Serratia marcescens, Helicobacter pylori, pylori, Salmonella enteritidis, Salmonella typhi, Legionella pneumophila, Haemophilus influenzae, Vibrio cholerae, Pseudomonas stutzeri, Ralstonia solanacearum, or Xylella fastidiosa.

[0098] In another embodiment, the bacterial infection is an infection involving a gram-negative bacterium and the bacterium is E. coli.

[0099] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, are optionally formulated using suitable dispersing or wetting agents and suspending agents according to known techniques. Sterile injectable preparations are optionally sterile injectable solutions, suspensions or emulsions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be optionally used are water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile non-volatile oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating non-volatile oils can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0100] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0101] According to the methods of treatment described herein, bacterial infections are treated or prevented in a patient, such as a human or lower mammal, by administering to the patient a therapeutically effective amount of a compound described herein in an amount and for a time necessary to achieve the desired result. A "therapeutically effective amount" of a compound described herein means an amount of the compound sufficient to treat bacterial infections at a reasonable benefit / risk ratio applicable to any medical treatment. However, it will be understood that the total daily usage of the compounds and compositions described herein will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient may depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the age, weight, general health, sex and diet of the patient; the time of administration, route of administration and excretion rate of the specific compound used; the duration of treatment; drugs used in combination or simultaneously with the specific compound used, and similar factors known in the medical arts.

[0102] The total daily dose of the compounds described herein (i.e., compounds disclosed herein) administered to a human or other mammal in single or divided doses can be, for example, in amounts of 0.01 to 50 mg / kg body weight or, more usually, 0.1 to 25 mg / kg body weight. Single dose compositions can contain such amounts or multiples thereof to make up the daily dose. In general, the treatment regimes described herein include administration to a patient in need of such treatment of about 10 mg to about 2000 mg of the compounds described herein per day, in single or multiple doses. EXAMPLES

[0103] Experimental procedure All starting materials, components, reagents, acids, bases, solid phase resins, and solvents used in the following examples were generally commercially available products without further purification. When purification was required, standard techniques were used. Unless otherwise specified, commercially available protected amino acids were used without further purification.

[0104] The structures of the cyclic peptides were confirmed by mass spectrometry analysis using ESI-MS(+), which shows that in electrospray ionization mass spectrometry performed in positive ion mode on cyclic peptides with molecular weights above about 1000, they were frequently detected as doubly or triply charged ions.

[0105] Peptide synthesis performed by standard solid-phase synthesis methods using Sieber Amide resin or Fmoc-NH-SAL-PEG resin and Fmoc-protected amino acids. Coupling steps were typically performed using 5.2 equivalents of Fmoc-amino acid, 5 equivalents of HATU and 10 equivalents of DIEA as coupling reagents with an automated Liberty Blue automated peptide synthesizer (CEM Inc.) or 3.2 equivalents of Fmoc-amino acid, 3 equivalents of HATU and 6 equivalents of DIEA as coupling reagents with a Syro I automated parallel peptide synthesizer (Biotage) for peptide elongation. Deprotection was performed with either 20% piperidine in DMF or 5% piperazine in DMF with 0.1 M HOBt.

[0106] Cyclic peptides were purified by reversed-phase high performance liquid chromatography (HPLC) using a Waters AutoPurification System or a Shimadzu prep-HPLC system. The peptides were identified from mass spectra obtained in ESI-positive scan mode, and the mass spectra including multiply charged ions calculated from the molecular formulas of the compounds were consistent within the error range of the mass spectrometer used.

[0107] Analytical LCMS conditions: Column: Kinetex EVO C18 100 Å 2.6 μm, 2.1 mm i.d. x 150 mm column was eluted with 0.025% TFA in water (mobile phase A) and 0.025% TFA in MeCN (mobile phase B) with a 5-45% gradient of B over 20 min and a flow rate of 0.25 mL / min. The eluent was monitored with a UV 225 nm detector.

[0108] Representative Examples Example 1: Compound 16 The Fmoc amino acids used in the synthesis included Fmoc-Gly-OH; Fmoc-Cys(Trt)-OH; Fmoc-H3Me-OH; Fmoc-Arg(Pbf)-OH; Fmoc-His(Boc)-OH; Fmoc-MeTyr(tBu)-OH; Fmoc-Ser(Trt)-OH; Fmoc-Nal1-OH; Fmoc-Abu-OH; Fmoc-Phe-OH.

[0109] The automated synthesizer program is shown in FIG. 1a.

[0110] 5. The synthesis was carried out on Sieber Amide resin using 2 equivalents of Fmoc-amino acid, 5 equivalents of HATU and 10 equivalents of DIEA as coupling reagents, 20% piperidine in DMF for Fmoc deprotection on a, and Liberty Blue on the peptide synthesizer. Double couplings were used at positions 6, 7, and 10 from the N-terminal amino acid.

[0111] After deprotection of the N-terminal amino acid, the resin was washed with DMF, then 5 equivalents of 2-chloroacetic acid, 5 equivalents of HATU, and 10 equivalents of DIEA in DMF were added, and the resulting mixture was stirred for 30 min. The resin was washed successively with DMF and DCM, then dried under high vacuum. Global deprotection was carried out by adding a mixture of TFA / water / TIS / DODT (92.5:2.5:2.5:2.5, v / v / v / v) and stirring the resulting mixture at room temperature for 1.5 h. The resulting solution was filtered through a disposable filter column and diluted with diisopropyl ether-hexane (1:1, v / v). The precipitated solid was centrifuged, and the supernatant solution was decanted. The remaining solid was washed three times with Et2O and dried under high vacuum.

[0112] The crude peptide was dissolved in DMSO to a final concentration of 5 mM, and 10 equivalents of TEA were added. The mixture was stirred at room temperature for 18 hours.

[0113] The crude material was purified by reverse-phase HPLC using an XSelect C18 5 μm 19 mm×150 mm column. The product was eluted with 0.1% TFA in water (mobile phase A) and 0.1% TFA in MeCN (mobile phase B) with a programmed gradient of 5-17% B over 3 min, 17-22% B over 8 min, then 22-60% B over 1 min. The flow rate was 17 mL / min and the column temperature was 40°C. ° C. Retention time was 9.06 min. Fractions containing the desired product were combined and dried by lyophilization. MS (ESI+m / z 853.93 [M+2H] 2+

[0114] Example 2 Compound 50 The Fmoc amino acids used in the synthesis included Fmoc-Gly-OH; Fmoc-Cys(Trt)-OH; Fmoc-Phe-OH; Fmoc-Trp(Boc)-OH; Fmoc-Tyr(tBu)-OH; Fmoc-Arg(Pbf)-OH; Fmoc-Lys(Boc)-OH; Fmoc-His(Trt)-OH; Fmoc-Ile-OH; Fmoc-Thr(tBu)-OH.

[0115] The automated synthesizer program is shown in Figure 1b.

[0116] The synthesis was carried out on Sieber Amide resin utilizing 3.2 equivalents of Fmoc-amino acid, 3 equivalents of HATU and 6 equivalents of DIEA as coupling reagents; 5% piperazine in DMF with 0.1 M HOBt for Fmoc deprotection with Syro I for the automated peptide synthesizer. Double coupling was used at all positions.

[0117] After deprotection of the N-terminal Fmoc-Phe-OH, the resin was washed with DMF, then 3.2 equivalents of 2-chloroacetic acid, 3 equivalents of HCTU and 6 equivalents of DIEA in DMF were added, and the resulting mixture was stirred for 20 min. The resin was washed successively with DMF and DCM, then dried under high vacuum. A TFA-water-TIS-DODT mixture (92.5:2.5:2.5:2.5, v / v / v / v) was added, and the resulting mixture was stirred at room temperature for 2 h. The solution was filtered through a disposable filter column and diluted with Et2O-Hexane (1:1, v / v). The precipitated solid was centrifuged, the supernatant solution was decanted, and the resulting solid was washed three times with Et2O and dried under high vacuum.

[0118] The crude peptide was dissolved in DMSO-50% IPA (10:1, v / v) to a final concentration of 5 mM, and 5 equivalents of TEA were added. The mixture was stirred at room temperature for 18 h.

[0119] The crude material was purified by reversed-phase HPLC using an XBridge C18 5 μm 50 mm x 150 mm column. The product was eluted with 0.1% TFA in water (mobile phase A) and 0.1% TFA in MeCN (mobile phase B) using a programmed gradient of 5-26% B over 3 min, 26-31% B over 8 min, then 31-60% B over 1 min. The flow rate was 120 mL / min. The retention time was 13.83 min and the column temperature was 40 ° C. The fractions containing the desired product were combined and dried by lyophilization. MS(ESI+) m / z 1007.54[M+2H] 2+

[0120] Example 3 - Compound 1 The Fmoc amino acids used in the synthesis included Fmoc-Gly-OH; Fmoc-Cys(Trt)-OH; Fmoc-His(Trt)-OH; Fmoc-Arg(Pbf)-OH; Fmoc-MePhe-OH; Fmoc-Ser(tBu)-OH; Fmoc-Trp(Boc)-OH; Fmoc-Val-OH; Fmoc-Phe-OH.

[0121] The automated synthesizer program is shown in Figure 2a.

[0122] The crude material was purified by reversed-phase HPLC using a Kinetex EVO C18 21.2 mm x 150 mm column and eluted with 0.1% TFA in water (mobile phase A) and 0.1% TFA in MeCN (mobile phase B) with a programmed gradient of 5-15% B over 3 min, 15-20% B over 8 min, then 20-60% B over 1 min. The flow rate was 21 mL / min. The retention time was 13.83 min and the column temperature was 40 ° C. The fractions containing the desired product were combined and lyophilized. MS(ESI+) m / z 840.31 [M+2H] 2++

[0123] Example 4 - Compound 55 These included Fmoc-Gly-OH; Fmoc-Cys(Trt)-OH; Fmoc-Tyr(tBu)-OH; Fmoc-Trp(Boc)-OH; Fmoc-Lys(Boc)-OH; Fmoc-Phe-OH; Fmoc-Aib-OH; Fmoc-Arg(Pbf)-OH; Fmoc-Ile-OH; Fmoc-Thr(tBu)-OH; and Fmoc-H3Me-OH.

[0124] The automated synthesizer program is shown in Figure 2ba.

[0125] The crude material was purified by reversed-phase HPLC using an XBridge C18 5 μm 30 mm x 150 mm column and eluted with 0.1% TFA in water (mobile phase A) and 0.1% TFA in MeCN (mobile phase B) with a programmed gradient of 5-21% B over 3 min, 21-26% B over 8 min, then 26-60% B over 1 min. The flow rate was 45 mL / min. Fractions containing the desired product were combined and dried by lyophilization. MS (ESI+) m / z 1022.57 [M+2H] 2+

[0126] Example 5 - Compound 61 The Fmoc amino acids used in the synthesis included Fmoc-Gly-OH; Fmoc-Cys(Trt)-OH; Fmoc-Tyr(tBu)-OH; Fmoc-Trp(Boc)-OH; Fmoc-Lys(Boc)-OH; Fmoc-Phe-OH; Fmoc-Aib-OH; Fmoc-Ser(tBu)-OH; Fmoc-Arg(Pbf)-OH; Fmoc-Ile-OH; Fmoc-Thr(tBu)-OH; Fmoc-H3Me-OH.

[0127] The automated synthesizer program is shown in Figure 3a.

[0128] The crude material was purified by reversed-phase HPLC using an XBridge C18 5 μm 19 mm x 150 mm column and eluted with 0.1% TFA in water (mobile phase A) and 0.1% TFA in MeCN (mobile phase B) with a programmed gradient of 5-21% B over 3 min, 21-26% B over 8 min, then 26-60% B over 1 min. The flow rate was 45 mL / min. Fractions containing the desired product were combined and lyophilized. MS(ESI+) m / z 988.07[M+2H] 2+

[0129] Example 6 - Compound 58 The Fmoc amino acids used in the synthesis included Fmoc-Gly-OH; Fmoc-Cys(Trt)-OH; Fmoc-Tyr(tBu)-OH; Fmoc-F4C-OH; Fmoc-Lys(Boc)-OH; Fmoc-Phe-OH; Fmoc-Aib-OH; Fmoc-Arg(Pbf)-OH; Fmoc-Ile-OH; Fmoc-Thr(tBu)-OH; Fmoc-H3Me-OH.

[0130] The automated synthesizer program is shown in Figure 3b.

[0131] The crude material was purified by reversed-phase HPLC using an XBridge C18 5 μm 30 mm x 150 mm column and eluted with 0.1% TFA in water (mobile phase A) and 0.1% TFA in MeCN (mobile phase B) with a programmed gradient of 5-24% B over 3 min, 24-29% B over 8 min, then 29-60% B over 1 min. The flow rate was 45 mL / min. Fractions containing the desired product were combined and lyophilized. MS(ESI+) m / z 1034.23 [M+2H] 2+

[0132] Biological assays Measurement of minimum inhibitory concentration (MIC) MICs were determined by two-fold serial dilutions of peptides in LB broth to a final volume of 0.1 ml in round-bottom 96-well assay plates (Corning Life Sciences No3788). Peptides were first resuspended to 10 mM in 100% DMSO and subsequently diluted to the appropriate concentration in LB medium. 5 × 10 5 CFU / ml of screening stain was inoculated and incubated without agitation for 18 hours at 37° C. Plates were scored visually and the lowest compound concentration that prevented visible growth was determined as the MIC. [Table 3] TIFF2024522985000039.tif18170

[0133] While preferred embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It will be understood that various alternatives to the embodiments described herein may be used in carrying out the invention. It is intended that the following claims define the scope of the invention, and that methods and structures within the scope of the claims and their equivalents are covered.

[0134] The patents, published applications, and scientific literature referred to in this specification establish the knowledge of those skilled in the art and are hereby incorporated by reference in their entireties to the same extent as if each was specifically and individually indicated.

Claims

1. Formula I wherein R １ is C １－６ alkyl, hydroxyl-C １－６ alkyl, or benzyl which may be substituted with halogen or hydroxy; R １ａ is hydrogen; R ２ is hydrogen, C １－６ alkyl, or optionally substituted (imidazol-4-yl)methyl; R ３ is a bicyclic aryl, bicyclic heteroaryl, C １－６ alkyl, or hydroxyl-C １－６ alkyl, wherein the bicyclic aryl and the bicyclic heteroaryl may be substituted one or two times with C １－６ alkyl, hydroxyl or halo; R ３ａ is hydrogen or C １－６ alkyl; R ４ is C １－６ alkyl, or optionally substituted (imidazol-4-yl)methyl; R ５ is hydrogen; C １－６ alkyl, hydroxyl-C １－６ alkyl, optionally substituted (imidazol-4-yl)methyl, or optionally substituted guanidino-C ２－４ alkyl; R ６ is a hydroxyl-C １－６ alkyl or amino-C １－６ alkyl; R ７ is C １－６ alkyl, hydroxyl-C １－６ alkyl or optionally substituted guanidino-C ２－４ alkyl; R ８ is an optionally substituted benzyl; R ８ａ is hydrogen or C １－６ alkyl; R ９ is optionally substituted benzyl or optionally substituted 1H-imidazol-5-ylmethyl; R １０ is C １－６ alkyl, amino-C １－６ alkyl, optionally substituted 1H-imidazol-5-ylmethyl, optionally substituted guanidino-C ２－４ alkyl, or optionally substituted C １－２ alkyl-carboxamide; R １１ is optionally substituted benzyl or optionally substituted (imidazol-4-yl)methyl; R １２ is either N-(3-amino-3-oxo-propyl)carboxamide or N-(2-amino-2-oxo-ethyl)carboxamide, both of which may be substituted; R ｂ , R ｃ , R ｄ , R ｅ , R ｆ , R １５ａ , R １５ｂ , R １５ｃ , R １５ｄ , R １５ｆ , R １５ｇ , R １５ｈ , R １５ｉ , R １５ｊ , R １５ｋ , R １６ａ , R １６ｂ , R １６ｃ , and R １６ｄ are each independently hydrogen or C １－６ is alkyl; R １５ｅ is hydrogen, C １－６ alkyl, amino-C １－６ alkyl, or optionally substituted C １－２ alkyl-carboxamide; R ａ is hydrogen, C １－６ alkyl, hydroxyl or halo; n and p are independently 0 to 2; q is 0 or 1; r is 1 or 2) a compound, or a stereoisomer or pharmaceutically acceptable salt thereof.

2. R １２ is N-(2-amino-2-oxo-ethyl)carboxamide, R ４ and R ９ is 1H-imidazol-5-ylmethyl, R ２ is C １－６ alkyl, the compound according to claim 1.

3. R １ is C １－６ alkyl, hydroxyl-C １－６ alkyl, or optionally substituted benzyl; R ３ is 1-naphthylmethyl, 2-naphthylmethyl, (4-phenylphenyl)methyl, or optionally substituted 1H-indolyl-3-methyl; R ５ is hydrogen or 3-guanidinopropyl; R ６ is hydroxyl-C １－６ alkyl or 4-aminobutyl; R ７ is 3-guanidinopropyl; R １０ is 3-guanidino-propyl, methyl, ethyl, aminomethyl, aminoethyl, 4-aminobutyl, (3-methylimidazol-4-yl)methyl, or 3-amino-3-oxo-propyl; R １１ is 1H-imidazol-5-ylmethyl or (3-methylimidazol-4-yl)methyl; R ｂ 、 R ｃ 、 R ｅ 、 R １ａ 、 R ３ａ 、 R ８ａ 、 R １５ｂ 、 R １５ｃ 、 R １５ｄ 、 R １５ｆ 、 R １５ｇ 、 R １５ｉ 、 R １５ｋ 、 R １６ａ 、 R １６ｂ 、 R １６ｃ and R １６ｄ are hydrogen; R １５ａ 、 R １５ｅ 、 R １５ｈ and R １５ｊ are each independently hydrogen or methyl; R ｂ and R ｆ are each independently hydrogen or methyl; R １５ｈ The compound according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R is methyl.

4. R １ is benzyl which may be substituted with halogen or hydroxy; R ２ is hydrogen, ethyl, isopropyl, or (1S)-1-methylpropyl; R ３ is 1-naphthylmethyl or 1H-indol-3-ylmethyl; R ４ is 1H-imidazol-5-ylmethyl; R ５ is hydrogen; R ６ is hydroxymethyl or (1R)-1-hydroxyethyl; R ７ is 3-guanidinopropyl; R ８ is benzyl or 4-hydroxybenzyl; R ９ is 1H-imidazol-5-ylmethyl; R １０ is 3-guanidinopropyl, methyl or ethyl; R １１ is 1H-imidazol-5-ylmethyl, (3-methylimidazol-4-yl)methyl; R １２ is -C(=O)NHCH ２ C(=O)NH ２ The compound according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof.

5. R １ is benzyl; R ２ is ethyl or isopropyl; R ３ is 1-naphthylmethyl; R ４ is 1H-imidazol-5-ylmethyl; R ５ is hydrogen; R ６ is hydroxymethyl; R ７ is 3-guanidinopropyl; R ８ is 4-hydroxylbenzyl or 4-chlorobenzyl; R ９ is 1-methyl-1H-imidazole-5-methylene; R １０ is 3-guanidinopropyl; R １１ is (3-methylimidazol-4-yl)methyl; R １２ is N-(2-amino-2-oxo-ethyl)carboxamide; R ｂ and R ｆ which, in each occurrence, is independently hydrogen or methyl, of the compound according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, which is a compound of formula Ia or a stereoisomer or pharmaceutically acceptable salt thereof.

7. The compound according to claim 1, which is selected from Table 1.

8. Formula (II) wherein R １ is benzyl which may be substituted; R １ａ is hydrogen or C １－６ alkyl; R ２ is hydrogen or (imidazol-4-yl)methyl which may be substituted; R ３ is C １－６ alkyl or hydroxyl-C １－６ alkyl; R ３ａ is hydrogen or C １－６ alkyl; R ４ is C １－６ alkyl, or optionally substituted (imidazol-4-yl)methyl; R ５ is optionally substituted guanidino-C ２－４ alkyl, or optionally substituted (imidazol-4-yl)methyl; R ６ is amino-C １－６ alkyl, or optionally substituted guanidino-C ２－４ alkyl; R ７ is hydroxyl-C １－６ alkyl, or optionally substituted guanidino-C ２－４ alkyl; R ８ is methyl or 3-propylguanidine; R ８ａ is hydrogen or methyl; R ９ is an optionally substituted benzyl; R １０ is amino-C １－６ alkyl, optionally substituted (imidazol-4-yl)methyl, or optionally substituted guanidino-C ２－４ alkyl; R １１ is an optionally substituted benzyl; R １２ is indril-3-methyl or optionally substituted benzyl; R １３ is benzyl which may be substituted; R １４ is either N-(3-amino-3-oxo-propyl)carboxamide or N-(2-amino-2-oxo-ethyl)carboxamide, both of which may be substituted; R ｂ , R ｃ , R ｄ , R ｅ , R ｆ , R １５ａ , R １５ｂ , R １５ｃ , R １５ｄ , R １５ｅ , R １５ｆ , R １５ｇ , R １５ｈ , R １５ｉ , R １５ｊ , R １５ｋ , R １５ｌ , R １５ｍ , R １５ｎ , R １６ａ , R １６ｂ , R １６ｃ and R １６ｄ is independently in each occurrence hydrogen or C １－６ is alkyl; R ａ is hydrogen, C １－６ alkyl, hydroxyl, or halo; n and p are each independently 0 to 2; q is 0 or 1) a compound, or a stereoisomer or pharmaceutically acceptable salt thereof.

9. R １ is benzyl which may be substituted; R １ａ is hydrogen or C １－６ alkyl; R ２ is (3-methylimidazol-4-yl)methyl; R ３ is C １－６ alkyl or hydroxyl-C １－６ alkyl; R ３ａ is hydrogen or C １－６ alkyl; R ４ is C １－６ alkyl; R ５ is 3-guanidino-propyl; R ６ is 3-guanidino-propyl or amino-C １－６ alkyl; R ７ is 3 - guanidino - propyl or hydroxyl - C １－６ alkyl; R ８ is benzyl which may be substituted; R ８ａ is methyl; R ９ is benzyl which may be substituted; R １０ is optionally substituted guanidino-C ２－４ alkyl, (3-methylimidazol-4-yl)methyl, or amino-C １－６ alkyl; R １１ is 4-hydroxybenzyl or 4-chlorobenzyl; R １２ is 1H-indol-3-ylmethyl or 4-chlorobenzyl; R １３ is benzyl which may be substituted; R １４ is -C(=O)NHCH ２ C(=O)NH ２ ; R １５ａ 、R １５ｂ 、R １５ｃ 、R １５ｄ 、R １５ｅ 、R １５ｆ 、R １５ｇ 、R １５ｈ 、R １５ｉ 、R １５ｊ 、R １５ｋ 、R １５ｌ 、R １５ｍ 、R １５ｎ 、R １６ａ 、R １６ｂ 、R １６ｃ and R １６ｄ is hydrogen, the compound according to claim 8, or a stereoisomer or pharmaceutically acceptable salt thereof.

10. R １ is benzyl; R １ａ is hydrogen; R ２ is (3-methylimidazol-4-yl)methyl; R ３ is methyl or (1R)-1-hydroxyethyl; R ３ａ is hydrogen or methyl; R ４ is (1S)-1-methylpropyl; R ５ is 3-guanidinopropyl; R ６ is 4-amino-butyl; R ７ is 3-guanidinopropyl or -(1R)-1-hydroxyethyl; R ８ and R ８ａ is methyl; R ９ is benzyl; R １０ is guanidino-propyl, (3-methylimidazol-4-yl)methyl, or amino-C １－６ alkyl; R １１ is 4-hydroxybenzyl; R １２ is 1H-indole-3-methyl; R １３ is 4-hydroxybenzyl; R １４ is -C(=O)NHCH ２ C(=O)NH ２ and; R １５ａ 、R １５ｂ 、R １５ｃ 、R １５ｄ 、R １５ｅ 、R １５ｆ 、R １５ｇ 、R １５ｈ 、R １５ｉ 、R １５ｊ 、R １５ｋ 、R １５ｌ 、R １５ｍ 、R １５ｎ 、R １６ａ 、R １６ｂ 、R １６ｃ and R １６ｄ is hydrogen, the compound according to claim 8, or a stereoisomer or pharmaceutically acceptable salt thereof.

11. R １ is benzyl; R １ａ is hydrogen; R ２ is (3-methylimidazol-4-yl)methyl; R ３ is methyl or (1R)-1-hydroxyethyl; R ４ is (1S)-1-methylpropyl; R ５ is 3-guanidino-propyl; R ６ is 4-aminobutyl; R ７ is rac-(1R)-1-hydroxyethyl; R ８ and R ８ａ is methyl; R ９ is benzyl; R １０ is 3-guanidinopropyl, (3-methylimidazol-4-yl)methyl, aminomethyl, 2-amino-ethyl, 3-aminopropyl or 4-aminobutyl; R １１ is 4-hydroxybenzyl; R １２ is 1H-indole-3-methyl; R １３ is 4-hydroxybenzyl; R １４ is -C(=O)NHCH ２ C(=O)NH, the compound according to claim 8.

12. R １ is benzyl; R １ａ is hydrogen; R ２ is (3-methylimidazol-4-yl)methyl; R ３ is methyl or (1R)-1-hydroxyethyl; R ４ is (1S)-1-methylpropyl; R ５ is 3-guanidino-propyl; R ６ is 4-aminobutyl; R ７ is rac-(1R)-1-hydroxyethyl; R ８ and R ８ａ is methyl; R ９ is benzyl; R １０ is 3-guanidinopropyl; R １１ is 4-hydroxybenzyl; R １２ is 1H-indole-3-methyl; R １３ is 4-hydroxybenzyl; R １４ is -C(=O)NHCH ２ C(=O)NH, the compound according to claim 8, or a stereoisomer or pharmaceutically acceptable salt thereof.

13. R １ is benzyl; R １ａ is hydrogen; R ２ is (3-methylimidazol-4-yl)methyl; R ３ is methyl or (1R)-1-hydroxyethyl; R ４ is (1S)-1-methylpropyl; R ５ is 3-guanidinopropyl; R ６ is 4-aminobutyl; R ７ is rac-(1R)-1-hydroxyethyl; R ８ and R ８ａ is methyl; R ９ is benzyl; R １０ is (3-methylimidazol-4-yl)methyl; R １１ is 4-hydroxybenzyl; R １２ is 1H-indole-3-methyl; R １３ is 4-hydroxybenzyl; R １４ is -C(=O)NHCH ２ C(=O)NH, the compound according to claim 8, or a stereoisomer or pharmaceutically acceptable salt thereof.

14. R １ is benzyl; R １ａ is hydrogen; R ２ is (3-methylimidazol-4-yl)methyl; R ３ is methyl or (1R)-1-hydroxyethyl; R ４ is (1S)-1-methylpropyl; R ５ is 3-guanidino-propyl; R ６ is 4-aminobutyl; R ７ is rac-(1R)-1-hydroxyethyl; R ８ and R ８ａ is methyl; R ９ is benzyl; R １０ is 3-aminopropyl or 4-aminobutyl; R １１ is 4-hydroxybenzyl; R １２ is 1H-indole-3-methyl; R １３ is 4-hydroxybenzyl; R １４ is -C(=O)NHCH ２ C(=O)NH, the compound according to claim 8, or a stereoisomer or pharmaceutically acceptable salt thereof.

15. The compound according to claim 8, which is a compound of formula IIa

16. The compound according to claim 8, which is selected from Table 2.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a pharmaceutically acceptable additive.

18. Use of a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof in the preparation of a medicament for the treatment of bacterial infections in a patient.

19. A medicament for treating bacterial infections in a mammal, comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein an effective amount of the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is administered to the mammal at a frequency and for a period sufficient to provide a beneficial effect to the mammal.

20. A medicament for treating Gram-negative bacteria-mediated infectious diseases in a mammal, comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein an effective amount of the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is administered to the mammal at a frequency and for a period sufficient to provide a beneficial effect to the mammal.

21. The medicament according to claim 19, wherein the bacterial infection is an infection involving Escherichia coli. ​

22. The medicament according to claim 19, wherein the treatment further comprises administering a second therapeutic agent.

23.

22. The medicament according to claim 22, wherein the second therapeutic agent is an aminoglycoside antibiotic, a fluoroquinolone antibiotic, a β-lactam antibiotic, a macrolide antibiotic, a glycopeptide antibiotic, rifampicin, chloramphenicol, florfenicol, colistin, mupirocin, bacitracin, daptomycin or linezolid.

24. The medicament according to claim 20, wherein the Gram-negative bacteria-mediated infectious disease is an infectious disease involving Escherichia coli.

25. The medicament according to claim 20, wherein the treatment further comprises administering a second therapeutic agent.

26. The medicament according to claim 25, wherein the second therapeutic agent is an aminoglycoside antibiotic, a fluoroquinolone antibiotic, a β-lactam antibiotic, a macrolide antibiotic, a glycopeptide antibiotic, rifampicin, chloramphenicol, florfenicol, colistin, mupirocin, bacitracin, daptomycin or linezolid.

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