BR112014020375A2 - LIPOPEPTIDIC COMPOUNDS, THEIR PHARMACEUTICAL COMPOSITION AND THEIR USE - Google Patents

Abstract

lipopeptide compounds, their pharmaceutical composition and their use. provided here, are antibacterial compounds, in which the compounds, in some embodiments, have a broad spectrum of bioactivity. the compounds provided herein can, in other embodiments, overcome the resistance conferred by single amino acid mutations at defined positions of bacterial signal peptidases (spases) and, in other embodiments, to provide a broad spectrum of antibiotic bioactivity . pharmaceutical compositions and methods for treatment using the compounds described herein are also provided.

Description

LIPOPEPTIDIC COMPOUNDS, ITS PHARMACEUTICAL COMPOSITION AND ITS USE QUOTE

[001] This application claims the benefit of the US provisional application of Serial No. 61/730928, filed on November 28, 2012 and the US provisional application of Serial No. 61/599851, filed on February 16, 2012; both of which are incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

[002] Since the appearance of the first antibiotic-resistant bacterial strains in the 1940s, at least thirteen strains that are impervious to many antibiotics have been discovered. According to the Infectious Disease Society of America, bacteria that are resistant to one or more medications are responsible for about 100,000 deaths in hospitals in the United States each year, and cost the health care system more than $ 34 billion. The discovery of new antibiotics, especially those that act by inhibiting a new target, is an urgent need.

SUMMARY OF THE INVENTION

[003] Linear peptides are described herein for the treatment of microbial infections, such as for the treatment of bacterial infections. In various embodiments, the present disclosure provides lipopeptide compounds for the treatment of bacterial infections. In various embodiments, the compounds act by lipopeptide inhibition of bacterial signal peptidase (SpsB) type 1, an essential protein in bacteria.

[004] In one aspect, compounds of

Formula (I): Formula (I); where: R1 is selected from: A) R7 'R8 l N 1 v10 .1R12 Jl. /

N, "" \ f] to

O B) R1ª R11 R19 R13 C) ~ ~ y {R7.R8Y ~ Y '~~ N R18 r2 i o R1o R19 R13) q D) RZ E) F) G), and

H) R ~~ Jl, 1; tt-RlO, Ri2, and are each independently -H, CH2C (O) NH2, -CH2CH2C (O) NH2, -CH2CH2C (O) N (H) C (H ) (CH3) C02H, 21 22 21 22 CH2CH2C (O) N (H) C (H) (C02H) CH2C02H, -CH2NR R, - (CH 2) 2NR R, (CH2) 4N (H) C (O) (2,3-dihydroxybenzene), optionally substituted alkyl, optionally substituted C1 -C 8 heteroalkyl, optionally substituted C3 -C 8 cycloalkyl, - optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, ~~ OH ? e_ ~ ~ OH, - N ~ r, NH ou! {_ õ ~ ~ #

NH R3 is methyl, ethyl, isopropyl, or cyclopropyl;

R 5 is H, methyl, ethyl, or -CH 20H; or R 5 and R 24 together with the boron atom form a 5- or 6-membered ring containing boron; 6 R is -C (= O) H, -CH2C (= O) H, -C (= O) NHCH2C (= O) H, -e 1 ~ 01e1 ~ 01 N IR14),, -B IOR23 1 (OR 24 1 'or y • -o? ~; ~ P, or R5 and R6 together with the carbon atom forms the N, R26:

Rx is optionally substituted H, C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted cycloalkyl; together with the nitrogen atom form an optionally substituted nitrogen-containing ring; RY is H or methyl; or RY and R 5 together with the nitrogen atom form an optionally substituted nitrogen-containing ring;

R 2 is -NR 15 R 16, -CH2 -NR 15 R 16, or - (CH2) rNR 15 R 16; is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, or a linear or branched alkyl chain of about 1-22 carbon atoms, optionally comprising within the alkyl chain or at an end of the alkyl chain an optionally aryl substituted, an optionally substituted heteroaryl, an optionally substituted heterocycloalkyl 2 or an optionally substituted 0 '0, where Z is a bond, O, S, NH, CH 2, NHCH2, or C = C; R8 is a bond, -0, or -N (R 17) -, optionally substituted aryl or optionally substituted heteroaryl; ~ {'Q 1 - [_ õ - ::::::

NH OH, or ~, f R 14 1 Ris, and R16 - are, ca d to one, independently H, or C1 -C4 alkyl; R17 is H, methyl, ethyl, isopropyl, or cyclopropyl;

R1s 1 R19 1 and R2ü are, - each, independently, H, or methyl; each R21 is, independently, H or C1-C4 alkyl; each is, independently, H, alkyl, C (= NH) (NH2), or -CH (= NH); R23 and R24 are each independently H, or C1-C 4 alkyl; or R23 and R24 together with the boron atom form a 5- or 6-membered ring containing optionally substituted boron; each R25, independently, is C1-C 6 alkyl; R26 is H, C1-C4 alkyl, C1-C4 alkoxy, -CH2C (O) OR 25, or OCH2C (O) OR2s; n is o or 1; p is o or 1; and q is o or 1; or a pharmaceutically acceptable salt, solvent, or prodrug thereof.

[005] In one embodiment is a compound of Formula (I) in which R1 is

[006] In another embodiment is a compound of Formula (I) in which R8 is a bond. In another embodiment is a compound of Formula (I) in which R2, R4, R1º, R11, R12, and R13 are each, independently, -H, - CH3, -CH (CH3) 2, - C ( CH3) 3, -CH (CH3) (CH2CH3), -CH2CH (CH3) 2, CH20H, -CH (OH) (CH3), -CH2CF3, -CH2C (O) OH, -CH2CH2C (O) OH,

[007] In another embodiment is a compound of Formula (I) in which R2, R10 'Rn, Ri2 1 and R13 are each independently H, \.' 'Q

OH

[008] In another embodiment there is a compound of Formula (I) in which n is 1 and p is O.

[009] In another embodiment there is a compound of Formula (I) having the structure of Formula (Ib): HHO R2 H ~ R4 H RYN ~ N0 ~~ NY'N ~ NyR6 OOR ~ HO = HO = Formula Ib ; where R 2, and R12 are each independently -

[010] In another embodiment there is a compound of Formula (I) in which R1 is: O R12 O R7, RªJlN _Á. H ... \ 'ffr1Jl., /

I R13

[011] In another embodiment is a compound of Formula (I) in which R2, Ri2 and R13 are each, 'independently, -H. In yet another embodiment is a compound of Formula (I) in that Ri2 and are each, '

independently, -H, In another embodiment is a compound of Formula (I) in which n is O. In yet another embodiment, it is a compound of Formula (I) in which RB is a bond.

[012] In another embodiment there is a compound of Formula (I) having the structure of Formula (Ic): H O R2 H O R4 H RYN0 ~~ N0N ~ NyR6 O R12 H O: H O: Formula (Ic); where R2, R4, and R12 are each, independently,

[013] In another embodiment there is a compound of Formula (I) in which R1 is: R: z

[014] In another embodiment is a compound of Formula (I) in which R2 and R4 are each, independently, -H,, or! {Ô - .. ::::: ~ ~

NH

[015] In another embodiment is a compound of Formula (I) where q is 1; and R8 is a bond.

[016] In one.other embodiment is a compound of Formula (I) having the structure of Formula (Id): Formula (Id); where is and and are each, independently, -CH2CH (CH 3) 2, -CH (OH) (CH 3), CH 2C (O) NH2, CH2CH2C (O) NH2, -CH2NH2, - (CH2) 2NH2, - (CH2) 3NH2, or - (CH2) 4NH2.

[017] In another aspect, it is a hydrate or metabolite of a compound of Formula (I).

[018] In another aspect it is a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable excipient.

[019] In another aspect is the use of a compound of Formula (I) or a pharmaceutically acceptable salt, pharmaceutically acceptable or pharmaceutically acceptable prodrug for the preparation of a medicament for the treatment of an infection bacterial infection in a patient.

[020] In one aspect it is a method for treating a bacterial infection in a mammal, comprising administering to the mammal a compound of Formula (I) or a pharmaceutically acceptable salt or prodrug at a frequency and for a period enough to provide a beneficial effect to the mammal. In another embodiment, the bacterial infection is an infection involving Pseudomonas aeruginosa, Pseudomonas fluorescens,

Pseudomonas acidovorans, Pseudomonas alkaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella para typhi, Salmonella tyigi, Salmonella aerogenes, Klebsiella pneumoniae, Klebsiella oxitoca, Serratia marcescens, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Acinetobactery, tincensis, acinetobactery pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteur steurella haemolytica, Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoella, Gardensis, Morais, Gardneria Bacteroides distasonis, Bacteroides homologous group 3452A, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium

Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecal, Staocylococcus, Staphylococcus, Staphylococcus, Staphyloccus hyicus, Staphylococcus haemolyticus, Staphylococcus hominis or Staphylococcus saccharolyticus.

[021] In another embodiment, the bacterial infection is an infection involving a Gram-negative bacterium. In another embodiment, it comprises topical administration.

[022] In another embodiment are methods of treating a mammal in need of such treatment comprising administering to the mammal a second therapeutic agent. In another embodiment, the second therapeutic agent is not an SpsB inhibitor. In another embodiment, the second therapeutic agent is an aminoglycoside antibiotic, fluoroquinolone antibiotic, β-lactam antibiotic, macrolide antibiotic, glycopeptide antibiotic, rif ampicin, chloramphenicol, fluoramphenicol, colistin, mupirocin, bacitracin, line or daptomycin. In another embodiment, the second therapeutic agent is a ~ - lactam antibiotic. In another embodiment, the β-lactam antibiotic is selected from penicillins, cephalosporins, monobactams and carbapenenes. Another embodiment comprises the administration of a β-lactamase inhibitor.

INCORPORATION BY REFERENCE

[023] All publications, patents and patent applications mentioned in this specification are hereby incorporated by reference to the same extent as if each individual FOSSE publication, patent or patent application is specifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION Definitions

[024] As used in the specification and in the appended claims, the singular forms "one", "one" and "o" include plural referents unless the context clearly indicates otherwise.

[025] The term "about", as used herein, when referring to a numerical value or range, allows for a degree of variability in the value or range, for example, within 10%, or within 5% of a declared value or an established range limit. [02 6] All percent compositions are given as percentages by weight, unless otherwise stated. [027] All average molecular weights of polymers are average molecular weights, unless otherwise specified.

[028] As used herein, "individual" (as in the field of treatment) means mammals and non-mammals. Mammals include, for example, humans; non-human primates, for example, apes and monkeys; and not primates, for example, dogs, cats, cattle, horses, sheep and goats. Non-mammals include, for example, fish and birds.

[029] The term "disease" or "disorder" or "condition" is used interchangeably, and is used to refer to diseases or conditions in which a bacterial SPase plays a role in the biochemical mechanisms involved in the disease or condition such that a Therapeutically beneficial effect can be achieved by acting on the enzyme. "Acting on" Spase can include binding to Spase and / or inhibiting the bioactivity of a Spase.

[030] The term "effective amount", when used to describe therapy for an individual suffering from a disorder, refers to the amount of a compound described herein that is effective to inhibit or otherwise act on SPase in the tissues of individuals, where the SPase involved in the disorder is active, where such inhibition or other action occurs to an extent sufficient to produce a beneficial therapeutic effect. [031] The term "substantially" as used herein, means completely or almost completely; for example, a composition that is "substantially free" of a component or has no component or contains a trace amount such that any relevant functional property of the composition is not affected by the presence of the trace amount, or a compound being "substantially pure" is, there are only negligible traces of impurities present. [032] "Treat" or "treatment" as defined herein refers to a relief of the symptoms associated with a disorder or disease, or the inhibition of progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder, or cure disease or disorder. Likewise, as used herein, an "effective amount" or an

"therapeutically effective amount" of a compound refers to an amount of the compound that alleviates, in whole or in part, the symptoms associated with the disorder or condition, or stops or further slows the progression or worsening of those symptoms, or prevents or provides prophylaxis for the disorder or condition. In particular, a "therapeutically effective amount" refers to an amount effective, in dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount is also one in which any toxic or harmful effects of compounds described herein are outweighed by the therapeutically beneficial effects.

[033] By "chemically viable" means a bonding arrangement or a compound where the generally understood rules of organic structure are not violated; for example, a structure within a definition of a claim that it would contain, in certain situations, a pentavalent carbon atom that does not exist in nature would be understood except within the vindication king. The structures disclosed here, in all their embodiments, are intended to include only "chemically viable" structures, and all recited structures that are not chemically possible, for example, in a structure shown with variable atoms or groups, they are not intended to be disclosed, or claimed herein. [034] When a substituent is indicated to be an atom or atoms of specific identity, "or a bond", a configuration is referred to, when the substituent is "a bond", that the groups that are immediately adjacent to the specified substituent are directly connected to each other in a chemically viable connection configuration.

[035] All chiral, diastereoisomeric, racemic forms of a structure are intended, unless a specific stereochemistry or isomeric form is specifically indicated. The compounds described in this document can include enriched or resolved optical isomers in any or all asymmetric atoms, as is evident from the descriptions, in any degree of enrichment. Both the racemic and diastereoisomeric mixtures, as well as the individual optical isomers, can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereoisomeric partners, and these are all within the scope of the invention.

[036] The inclusion of an isotopic form of one or more atoms of a molecule, which is different from the naturally occurring isotopic distribution of the atom in nature, is referred to as an "isotopically marked form" of the molecule. All isotopic forms of atoms are included as optional in the composition of any molecule, unless an isotopic form of an atom is indicated. For example, any hydrogen atom, or a set of these in a molecule, can be any of the isotopic forms of hydrogen, that is, protium (1H), deuterium (2H) or tritium (3H) in any combination. Likewise, any carbon atom, or a set of these, in a molecule can be any of the isotopic forms of carbon, such as nc, 12c, 13c or 14c, or any nitrogen atom, or a set of these, in a molecule can be any of the isotopic forms of nitrogen, such as or N.

A molecule can include any combination of isotopic forms in the component atoms that make up the molecule, the isotopic form of all the atoms that make up the molecule being selected independently.

In a multi-molecular sample of a compound, each of the individual molecules does not necessarily have the same isotopic composition.

For example, a sample of a compound can include molecules that contain a variety of different isotopes.

The compositions, as in a radiolabeled sample of tritium 14 or C, where only a few fractions of the set of molecules constitute the macroscopic sample, contain a radioactive atom.

It is also understood that many elements that are not artificially enriched isotopically are mixtures of naturally occurring isotopic forms such as N and N, S and S, and so on.

A molecule as recited here is defined as including isotopic forms of all its constituent elements, at each position in the molecule.

As is well known in the art, isotopically labeled compounds can be prepared by the usual methods of chemical synthesis, but replacing an isotopically precursor molecule.

Radioactive, or stable, isotopes can be obtained by any method known in the art, such as the generation of neutron absorption from a precursor isotope in a nuclear reactor, through cyclotron reactions, or by isotopic separation such as by mass spectrometry. .

Isotopic forms are incorporated into the precursors as needed for use in any particular synthesis pathway.

For example, C and H, can be prepared using neutrons generated in a nuclear reactor.

After the nuclear transformation, C and H are incorporated into the precursor molecules, followed by further elaboration as needed. [037] The term 11 amine protection group 11 or 11 N-

protected11, as used herein, refers to groups designed to protect an amino group against undesirable reactions during synthesis procedures and which can later be removed to reveal the amine.

Commonly used amine protecting groups are described in Protective Groups in Organic Synthesis, Greene, T.W .; Wuts, P.G.M., John Wiley & Sons, New York, NY, (3rd Edition, 1999). Amine protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, triclaroacetyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzool, 4-bromobenzoyl, 4-nitrobenzoyl and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; alkoxy or aryloxycarbonyl groups (which form urethanes with the protected amine), such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3, 4 , 5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxy-benzyloxycarbonyl, l- (p-biphenylyl) -1-methylethoxycarbonyl, a, a -dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl (Boc), diisopropylmethoxy-

carbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethyloxycarbonyl (Teoc), phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl (Fmoc) , adamantyl-oxycarbonyl, cyclohexyloxycarbonyl, phenyl thio-carbonyl and the like; aralkyl groups, such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like.

Amine protecting groups also include cyclic amine protecting groups such as phthaloyl and dithiosuccinimidyl, which incorporate the nitrogen of the amino in the heterocycle.

Typically, amino protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, Alloc, Teoc, benzyl, Fmoc, Boc and Cbz.

It is well within the skill of the person skilled in the art to select and use the appropriate amine protection group for the synthetic task at hand. [038] The term 11 hydroxyl protection group 11 or 11 0-

Protected 11 as used herein refers to groups designed to protect an OH group against undesirable reactions during synthesis procedures and which can later be removed to reveal the amine.

Hydroxyl protecting groups commonly used are described in Protective Groups in Organic Synthesis, Greene, T.W .; Wuts, PGM, John Wiley & Sons, New York, NY, (3 ~ Edition, 1999) Hydroxyl protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl , trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, O '.- chlorobutyryl,

benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitro trobenzoyl and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; acyloxy groups (which form urethanes with the protected amine), such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyl, 3,4-dimethoxybenzyl , 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxy-carbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1- (p-biphenylyl) -1- methylethoxycarbonyl, a, a-dimethyl-3 , 5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyoxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilyl fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; aralkyl groups, such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like.

It is well within the skill of the person skilled in the art to select and use the appropriate hydroxyl protection group for the synthetic task at hand. [039] In general, substituted 11 refers to an organic group, as defined herein, in which one or more bonds to a hydrogen atom contained therein are replaced by one or more bonds to a non-hydrogen atom such as, but not limited to, a halogen atom (i.e., F, Cl, Br, and I); an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkylxy groups, oxo (carbonyl) groups, carboxyl groups, including carboxylic acids, carboxylates and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxylamines, nitriles, nitro groups, N-oxides, hydrazides, azides and enamines; and other heteroatoms in several other groups. Non-limiting examples of substituents that can be attached to a substituted (or other) carbon atom include F, Cl, Br, I, OR ', OC (O) N (R') 2, CN, NO, N02, ON02 , azide, CF3, OCF3, R ', O (oxo), S (thiono), C (O), S (O), methylenedioxy, ethylenedioxy, N (R') 2, SR ', SOR', S02R ', S02N (R ') 2, S03R', C (O) R ', C (O) C (O) R', and (o) CH2C (o) R 1, and (s) R 1, C (O) OR ', OC (O) R', C (O) N (R'h, OC (O) N (R ') 2, C (S) N (R') 2, (CH2) o-2N (R 1) and (o) R 1, (CH2) o-2N (R ') N (R') 2, N (R ') N (R') C (O) R ', N (R') N ( R ') C (O) OR', N (R) N (R ') CON (R') 2, N (R ') S02R', N (R ') S02N (R') 2, N (R ' ) C (O) OR ', N (R') C (O) R ', N (R') C (S) R ', N (R') C (O) N (R ') 2, N ( R ') C (S) N (R'h, N (COR') COR ', N (OR') R ', C (= NH) N (R') 2, C (O) N (OR ') R 'or C (= NOR') R 'where R' can be hydrogen or the carbon-based radical, and where the carbon-based portion itself can be further substituted.

[040] When a substituent is monovalent, such as, for example, F or Cl, it is attached to the atom it is replacing with a single bond. When a substituent is more than monovalent, such as O, which is divalent, it can be attached to the atom it is replacing with more than one bond, that is, a divalent substituent attached by a double bond; for example, one and replaced with O forms a carbonyl group, C = O, which can also be written as 11 C0 11, 11 C (O) 11, or 11 C (= 0) 11, where C and O are doubly linked. When a carbon atom is replaced with a double bonded oxygen group (= O), the oxygen substituent is called an 11 oxo group 11 • When a divalent substituent, such as NR is doubly attached to a carbon atom, the group The resulting C (= NR) is called an imino group 11 • When a valiant substitute, such as S is doubly bound to a carbon atom, the resulting C (= S) group is called a 11 thiocarbonyl group 11 •

[041] Alternatively, a divalent substituent, such as O, S, C (O), S (O), or S (0) 2 can be linked by two simple bonds to two different carbon atoms. For example, O, a divalent substituent, may be attached to each of the two adjacent carbon atoms, to provide an epoxide group, or O may form a bridge ether group, a group called 11 oxy 11, between the atoms adjacent or non-adjacent carbon, for example, bridged with the 1,4 carbons of a cyclohexyl group to form a [2.2.1] -oxybicycle system. In addition, any substitute can be attached to another carbon atom or via a linker, such as (CH 2) n or (CR '2) n where n is 1, 2, 3, or more, and each R 'is selected independently.

[042] Groups C (O) and S (0) 2 can be attached to one or two heteroatoms, such as nitrogen, instead of to a carbon atom. For example, when a C (O) group is attached to a carbon atom and a nitrogen atom, the resulting group is called an 11 amide 11 or 11 carboxamide 11 • When the C (S) group is attached to two carbon atoms nitrogen, the functional group is called a urea. When an S (0) 2 group is attached to a carbon atom and a nitrogen atom, the resulting unit is called an 11 sulfonamide 11 • When an S (0) 2 group is attached to two nitrogen atoms, the resulting unit is called an 11 sulfamate 11 •

[043] Substituted alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl, as well as other substituted groups, also include groups in which one or more bonds to a hydrogen atom are replaced by one or more bonds, including double or triple bonds, with a carbon atom, or a heteroatom such as, but not limited to, oxygen in carbonyl (oxo), carboxyl, ester, amide, imide, urethane and urea groups; and nitrogen in imines, hydroxyimines, oximes, hydrazones, amidines, guanidines and nitriles.

[044] Substituted ring groups, such as cycloalkyl, aryl, heterocyclic and substituted heteroaryl include rings and fused ring systems in which a bond to a hydrogen atom is replaced by a bond to a carbon atom. Therefore, the cycloalkyl, aryl, heterocyclic and substituted heteroaryl groups can also be substituted with alkyl, alkenyl and alkynyl groups, as defined herein.

[045] By a "ring system", as the term is used here, it means a radical comprising one, two, three or more rings, which can be replaced with non-ring groups or with other ring systems, or of both, which can be fully saturated, partially unsaturated, totally unsaturated, or aromatic, and when the ring system includes more than a single ring, the rings can be fused, bridged or spirocyclic. By "spirocyclic" is meant the class of structures in which two rings are fused into a single tetrahedral carbon atom, as is well known in the art.

[046] As for any of the groups described here, which contain one or more substituents, it is understood, obviously, that these groups do not contain any substitution or substitution patterns that are sterically impractical and / or synthetically non-viable. In addition, the compounds of this disclosed object include all stereochemical isomers resulting from the substitution of these compounds.

[047] The substituents selected within the compounds described herein are present in a recursive degree. In this context, "recursive substituent" means that a substituent can recite another example of himself or another substituent that is recited the first substituent. Due to the recursive nature of such substituents, theoretically, a large number can be present in any given claim. One of ordinary skill in the art of medicinal chemistry and organic chemistry understands that the total number of such substituents is reasonably limited by the desired properties of the intended compound. Such properties include, for example and are not limited to, physical properties, such as molecular weight, solubility or P log, application properties, such as activity against the intended target and practical properties, such as ease of synthesis.

[048] Recursive substituents are an intended aspect of the revealed matter. A common expert in the art of medicinal and organic chemistry understands the versatility of these substituents. To the extent that recursive substituents are present in a claim on the revealed object, the total number should be determined as described above.

[049] Time 11 alkyl 11 refers to a radical group of straight or branched hydrocarbon chain consisting only of carbon and hydrogen atoms of 1 to about 20 carbon atoms, and typically 1 to 12 atoms of carbon or, in some embodiments, from 1 to 8 carbon atoms. Examples of straight-chain alkyl groups include those with 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl and 2,2-dimethylpropyl groups. As used herein, the term 11 alkyl 11 encompasses n-alkyl, isoalkyl, and anteisoalkyl groups, as well as other branched chain forms of an alkyl group. Representative substituted alkyl groups can be substituted one or more times, with any of the groups mentioned above, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The description here that an alkyl group is a chain "optionally comprising within the alkyl chain or to an alkyl chain terminal 11, means that a portion may be arranged between two subunits of the alkyl chain, or may be arranged at the end of the chain substituted, or can be arranged between the chain and the point of attachment of the chain, for example, to a carbonyl, NR or S group. For example, an alkylbenzoyl group is an alkyl chain with a phenyl group arranged between the alkyl group and a carbonyl group, fitting the description above, an N-alkylphenylcarboxamido is an alkyl chain with a phenyl group arranged between the alkyl group and the amino carbonyl, fitting within the description above.

[050] The term 11 alkylene 11 means a linear saturated bivalent hydrocarbon radical of one to six carbon atoms or a divalent branched saturated hydrocarbon of one to six carbon atoms, unless otherwise indicated, such as methylene, ethylene , propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.

[051] The term "carbonyl" means C = O. [052] The terms 11 carboxy 11 and 11 hydroxycarbonyl "mean COOH.

[053] Cycloalkyl groups are cyclic alkyl groups, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohepty, and cyclooctyl groups. In some embodiments, the cycloalkyl group may have 3 to about 8-12 members in the ring, while in other embodiments the number of carbon atoms in the ring varies from 3 to 4, 5, 6 or 7. Cycloalkyl groups still include polycyclic cycloalkyl groups, such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl and carenyl groups, and fused rings, such as, but not limited to, decalinyl and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above. Representative substituted cycloalkyl groups can be mono-substituted or substituted once more, such as, but not limited to, cyclohexyl, 2,2-, 2,3-, 2,4-, 2,5- or 2,6- groups di-substituted or monborne, di or tri-substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy and halogen groups. The term 11 cycloalkenyl 11 alone or in combination means a cyclic alkenyl group.

[054] The terms 11 carbocyclic, "11 carbocyclyl" and "carbocycle" mean a ring structure, in which the ring atoms are carbon, such as a cycloalkyl group or an aryl group. In some embodiments, the carbocycle has 3 to 8 ring members, while in other embodiments the number of ring carbon atoms is 4, 5, 6 or 7. Unless specifically stated otherwise, the carbocyclic ring can be substituted with up to N-1 substituents where N is the size of the carbocyclic ring with groups, for example, alkyl, alkenyl, alkynyl, amino, aryl, hydroxy, cyano, carboxy, heteroaryl, heterocyclyl, nitro, uncle, alkoxy and halogen, or other groups as listed above. A carbocyclyl ring can be a cycloalkyl ring, a cycloalkenyl ring or an aryl ring. A carbocyclyl can be monocyclic or polycyclic, and each polycyclic ring can be, independently, a cycloalkyl ring, a cycloalkenyl ring or an aryl ring.

[055] (Cycloalkyl) alkyl groups, also denoted cycloalkylalkyl, are alkyl groups as defined above in which a bond to the hydrogen or carbon of the alkyl group is replaced by a bond to a cycloalkyl group as defined above.

[056] Alkenyl groups include straight and branched chain cyclic alkyl groups and, as defined above, except that there is at least one double bond between two carbon atoms. Thus, alkenyl groups have from 2 to about 20 carbon atoms, and usually from 2 to 12 carbon atoms or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to vinyl, -CH = CH (CH 3), -CH = C (CH 3) 2, -C (CH 3) = CH 2, C (CH 3) = CH (CH 3) , -C (CH 2 CH 3) = CH 2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl and hexadienyl among others.

[057] Cycloalkenyl groups include cycloalkyl groups having at least a double bond between two carbon atoms. Thus, for example, cycloalkenyl groups include, but are not limited to, cyclohexenyl, cyclopentenyl and cyclohexadienyl groups. Cycloalkenyl groups can have 3 to about 8-12 members in the ring, while in other embodiments the number of carbon atoms in the ring varies from 3 to 5, 6, or 7. Cycloalkyl groups still include cycloalkyl groups polycyclic such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl and carenyl groups and fused rings, such as, but not limited to, decalinyl and the like, provided that they contain at least one double bond in a ring. Cycloalkenyl groups include rings that are substituted with straight or branched chain alkyl groups as defined above.

[058] Alkyl (cycloalkenyl) groups are alkyl groups as defined above in which a bond to the hydrogen or carbon of the alkyl group is replaced by a bond to a cycloalkenyl group, as defined above.

[059] Alkynyl groups include straight and branched chain alkyl groups, except that there is at least one triple bond between two carbon atoms. Thus, alkynyl groups have from 2 to about 20 carbon atoms, and usually from 2 to 12 carbon atoms or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to, C = CH, C = C (CH3), -C = C (CH2CH3), -CH2C = CH, -CH20C (CH3) and CH2 = C (CH2CH3) among others.

[060] The term "heteroalkyl" alone or in combination with another term means, unless otherwise indicated, a stable straight or branched chain group, consisting of an alkyl chain of the indicated number of carbon atoms and one or two hetero atoms selected from the group consisting of O, N, and S, and in which the nitrogen and sulfur atoms can be optionally oxidized and the nitrogen hetero atom can be optionally quaternized. The heteroatom (s) can be placed in any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distant carbon atom in the heteroalkyl group. Examples include: -O-CH2-CH2 -CH3, -CHrCH2CH20H, -CH2-CHrNH-CH 3, CH2-S-CHrCH3, -CH2CH2S (= O) -CH3 and -CH2CHrCH-02CHr0-CH 3. Up to two heteroatoms can be consecutive, such as, for example, -CH 2-NH-OCH 3 or -CH 2-CH 2-CH-SS =.

[061] A "cycloheteroalkyl" ring or a "heterocycloalkyl" ring represents a cycloalkyl ring that contains at least one heteroatom. A cycloheteroalkyl ring can also be called a "heterocyclic", described below. [o 62] the term "heteroalkenyl" alone or in combination with another term means, unless otherwise stated, a stable, monounsaturated or di-unsaturated straight or branched hydrocarbon group consisting of the established number of atoms. carbon and one or two hetero atoms selected from the group consisting of O, N and S, and in which the nitrogen and sulfur atoms can optionally be oxidized and the nitrogen hetero atom can optionally be quaternized. Up to two heteroatoms can be placed consecutively. Examples include -CH = CH-0-CH 3, -CH = CH-CH 20H, -CH 2-CH = N-OCH 3, -CH = CH- N (CH3) -CH3, -CH2-CH = CH- CH2-SH and -CH = CH-O-CH2CH2-CH-03.

[063] Aryl groups are cyclic aromatic hydrocarbons that do not contain ring heteroatoms. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphtacenyl, chrysenyl, biphenylenyl, anthracenyl and naphthyl. In some embodiments, the aryl groups contain from about 6 to about 14 carbon atoms in the ring portions of the groups. Aryl groups can be unsubstituted or substituted, as defined above. Representative substituted aryl groups may be mono-substituted or substituted more than once, such as, but not limited to, 2-, 3-

4-, 5-, or 6- substituted phenyl or 2-8 substituted naphthyl groups, which can be substituted with carbon or non-carbon groups, such as those listed above. [064] Aralkyl groups are alkyl groups as defined above in which a bond to the hydrogen or carbon of an alkyl group is replaced by a bond to an aryl group as defined above. Representative aralkyl groups include benzyl and phenylethyl and fused (cycloalkylaryl) alkyl groups, such as 4-ethyl-indanyl. Aralkenyl groups are alkenyl groups, as defined above, in which a bond to the hydrogen or carbon of an alkyl group is replaced by a bond to an aryl group, as defined above.

[065] Heterocyclyl groups or the term "heterocyclic" include aromatic and non-aromatic ring compounds containing 3 or more ring members, of which one or more is a hetero atom such as, but not limited to, N, O , and S. Thus, a heterocyclic may be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof. In some embodiments, heterocyclic groups include 3 to about 20 ring members, while other groups have 3 to about 15 ring members. A heterocyclic group designated as a C2-heterocyclic can be a 5-membered ring with two carbon atoms and three heteroatoms, a 6-membered ring with two carbon atoms and four heteroatoms and so on. Likewise, a C4-heterocyclic can be a 5-membered ring with a heteroatom, a 6-membered ring with two heteroatoms, and so on. The number of carbon atoms, plus the number of hetero atoms are summarized to be equal to the total number of atoms in the ring.

A heterocyclic ring can also include one or more double bonds.

A heteroaryl ring is an embodiment of a heterocyclic group.

The phrase "heterocyclic group" includes fused ring species including those comprising fused aromatic and non-aromatic groups.

For example, a dioxolanil ring and a benzdioxolanil ring system (methylenedioxyphenyl ring system) are both heterocyclic groups within the meaning here.

The phrase also includes polycyclic ring systems that contain a hetero atom, such as, but not limited to, quinuclidyl.

Heterocyclic groups can be unsubstituted or can be substituted as discussed above.

Heterocyclic groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophilyl, dihydrophenyl, dihydrol, , indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolium, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, tianaftalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, quinolinyl, quinolinyl, quinolinyl, quinolinyl, quinolinyl, quinolinyl, quinolinyl, quinolinyl

Representative substituted heterocyclic groups can be mono- substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl, which are groups of 2, 3, 4, 5, or 6- substituted or di- replaced with groups such as those listed above. [066] Heteroaryl groups are aromatic ring compounds containing five or more ring members, of which, one or more is a hetero atom such as, but not limited to, N, O, and S; for example, heteroaryl rings can have 5 to about 8-12 members in the ring.

A heteroaryl group is a variety of a heterocyclic group that has an aromatic electronic structure.

A heteroaryl group designated as C2-heteroaryl can be a member ring with two carbon atoms and three hetero atoms, a 6 member ring with two carbon atoms and four hetero atoms and so on.

Likewise, a C4 - heteroaryl can be a 5-membered ring with one heteroatom, a 6-membered ring with two heteroatoms, and so on.

The number of carbon atoms, plus the number of hetero atoms are summarized to be equal to the total number of atoms in the ring.

Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranil, indolyl, azaindolyl, benzazolyl, benzazolyl, benzazol, benzazol, benzazol , benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl and quinazolinyl.

Heteroaryl groups can be unsubstituted or can be substituted by groups as discussed above.

Representative substituted heteroaryl groups can be substituted one or more times with groups, such as those listed above. [067] Additional examples of aryl and heteroaryl groups include, but are not limited to, phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytrazrazyl, N-hydroxythriazolyl, N-hydroxyimidazolyl, anthracenyl (1- anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furil (2-furyl, 3-furyl), indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acrid , thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-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), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl , 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), 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 [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), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazol, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz [b, f] azepin (5H-dibenz [b, f] azepin-1-yl, 5H- dibenz [b, f] azepine-2-yl, 5H-dibenzo [b, f] azepin-3-yl, 5H-dibenzo [b, f] azepin-4-yl, 5H-dibenzo [b, f] azepin- 5-yl), 10,11-dihydro-5H-dibenzo [b, f] azepine (10,11-dihydro-5H-dibenzo [b, f] azepin-l-yl, 10,11-di -hydro- 5H-dibenzo [b, f] a zepin-2-yl, 10,11-dihydro-5H-dibenzo [b, f] azepin-3-yl, 10,11-dihydro-5H-dibenzo [b, f] azepine-4-yl, 10,11-dihydro-5H-dibenzo [b, f] azepin-5-yl), and the like. [068] Heterocyclylalkyl groups are alkyl groups as defined above in which a bond to the hydrogen or carbon of an alkyl group, as defined above, is replaced by a bond to a heterocyclic group as defined above. Representative heterocyclic alkyl groups include, but are not limited to, furan-2-yl-methyl, furan-3-yl-methyl, pyridine-3-yl-methyl, tetrahydrofuran-2-yl-ethyl and indol-2- useful propyl.

[069] Heteroarylalkyl groups are alkyl groups as defined above in which a bond to the hydrogen or carbon of an alkyl group is replaced by a bond to a heteroaryl group as defined above.

[070] The term "alkoxy" refers to an oxygen atom attached to an alkyl group, including a cycloalkyl group, as defined above. Examples of linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and the like. Examples of branched alkoxy include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy and the like. Examples of cyclic alkoxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like. An alkoxy group can include one up to about 12-20 carbon atoms attached to the oxygen atom, and can include more double or triple bonds, and can also include hetero atoms. For example, an allyloxy group is an alkoxy group within the meaning here. A methoxyethoxy group is also an alkoxy group within the meaning here, like a methylenedioxy group, in a context where two adjacent atoms of a structure are replaced with them.

[071] The term "thioalkoxy" refers to a previously defined alkyl group attached to the parent molecular moiety through a sulfur atom.

[072] The term "glycosyloxyoxy" refers to a glycoside attached to the parent molecular moiety through an oxygen atom. [07 3] The term "alkoxycarbonyl" represents as an ester group; that is, an alkoxy group, attached to the parent molecular moiety through a carbonyl group such as methoxycarbonyl, ethoxycarbonyl and the like. [07 4] The terms "halo" or "halogen" or "halide" by itself or as part of another substituent means, unless otherwise specified, a fluorine, chlorine, bromine, or iodine atom, preferably fluorine, chlorine, or bromine. [07 5] A "haloalkyl" group includes monohaloalkyl groups, polyhaloalkyl groups, where all halogen atoms can be the same or different, and perhaloalkyl groups, where all hydrogen atoms are replaced by halogen atoms, such as fluorine. Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, perfluorobutyl and the like. [07 6] A "haloalkoxy" group includes monoalkoxy alkoxy groups, polyhalo alkoxy groups, where all halogen atoms can be the same or different, and by alkoxyhalo groups, where all hydrogen atoms are replaced by halogen atoms, such as fluorine. Examples of haloalkoxy include trifluoromethoxy, 1, 1-dichloroethoxy, 1,2-dichloroethoxy, 1,3-dibromo-3,3-difluoropropoxy, perfluorobutoxy and the like. [07 7] The term 11 (Cx-Cy) perfluoroalkyl 11, where x <y, means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, where all hydrogen atoms are replaced by fluorine atoms. Preferred is - (C 1 -C 6) perfluoroalkyl, more preferred is - (C 1 -C 3) perfluoroalkyl, the most preferred is -CF3.

[078] The term 11 (Cx-Cy) perfluoroalkylene 11, where x <y, means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, where all hydrogen atoms are replaced by fluorine atoms. Preferred is - (C 1 -C 6) perfluoroalkylene, more preferred is - (C 1 -C 3) perfluoroalkylene, most preferred is -CFr.

[07 9] The terms 11 aryloxy 11 and 11 arylalkoxy 11 refer, respectively, to an aryl group attached to an oxygen atom and an aralkyl group attached to the oxygen atom in the alkyl portion. Examples include, but are not limited to, phenoxy, naphthyloxy and benzyloxy.

[080] An acyl 11 group, as the term is used herein, refers to a group containing a carbonyl radical, in which the group is attached via the carbonyl carbon atom. The carbonyl carbon atom is also attached to another carbon atom, which may be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl or the like group. In the special case where the carbonyl carbon atom is attached to a hydrogen atom, the group is a formyl group 11, an acyl group, as the term is defined herein. An acyl group can include from 0 to about 12-20 additional carbon atoms attached to the carbonyl group. An acyl group can include double or triple bonds within the meaning here. An acryloyl group is an example of an acyl group. An acyl group can also include heteroatoms, as defined here. A nicotinoyl group (3-pyridylcarbonyl) is an example of an acyl group, as defined herein. Other examples include acetyl, benzoyl, phenylacetyl,

pyridylacetyl, cinnamoyl and acryloyl and the like. When the group containing the carbon atom is attached to the carbon atom of the carbonyl that contains a halogen, the group is a group called "haloacil". An example is a trifluoro acetyl group.

[081] the term "amine 11 includes primary, secondary and tertiary amines having, for example, the formula N (group) 3 wherein each group can be independently H or non-H, such as alkyl, aryl and the like Amines include, but are not limited to, R-NH 2, for example, alkylamines, arylamines, alkylarylamines; R2 NH, where each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R3 N where each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines and the like The term 11 amine 11 also includes ammonium ions, as used herein.

[082] An 11 amino 11 group is a substituent of the form -NH 2, NHR, -NR 2, -NR 3 +, where each R is independently selected, and the protonated forms of each, with the exception of -NR 3 +, which cannot be protonated. Consequently, any compound substituted with an amino group can be seen as an amine. An 11 alkylamino 11 group as defined herein may be a primary, secondary, tertiary or quaternary amino group. An 11 alkylamino group 11 includes a monoalkylamino, dialkylamino and trialkylamino group.

[083] An "ammonium" ion includes the unsubstituted ammonium ion NH 4 +, but unless otherwise specified, it also includes any protonated or quaternized forms of amines. Thus, trimethylammonium hydrochloride and tetramethylammonium chloride are both ammonium ions, and amines, as defined here.

[084] the term "amide" (or "starch") includes e- and N-amide groups, that is, -C (O) NR 2 and NRC (O) R groups, respectively. Therefore, amide groups include, but are not limited to, primary carboxamide groups (- C (O) NH2) and formamide groups (NHC (O) H). A "carboxamido" or "aminocarbonyl" group represents a group of formula C (O) R 2, where R can be H, alkyl, aryl, etc. [085] The term "azide" refers to an N3 group • An "azide" can be an organic azide or it can be an anion salt of azide (N 3 -). The term "nitro" refers to a NO 2 group attached to an organic radical. The term "nitrous" refers to an NO group attached to an organic radical. The term nitrate refers to an ON0 2 group attached to an organic group or a nitrate anion salt (N0 3 -).

[086] the term "polyurethane" ("carbamoyl" or "carbamyl") includes N and 0-urethane groups, that is, NRC (O) OR and -OC (O) NR 2 groups, respectively.

[087] The term "sulfonamide" (or "sulfonamido") includes S- and N-sulfonamide groups, that is, groups -S0 2NR 2 and NRS0 2R, respectively. Therefore, sulfonamide groups include, but are not limited to sulfamoyl groups, organosulfuric structure represented by the formula -S (O) (NR) -, is understood to be a sulfoximine, in which both oxygen and nitrogen atoms are linked to the sulfur atom, which is also attached to two carbon atoms.

[088] The term "amidine" or "amidino" includes groups of the formula -e (NR) NR 2. Typically, it is an amidino C (NH) NH2 group.

[089] The term "guanidine" or "guanidine" includes groups of the formula NRC (NR) NR 2. Typically, a guanidino group is - NHC (NH) NH2. [O 90] A "salt" as is well known in the art includes an organic compound, such as a carboxylic acid, a sulfonic acid, or an amine, in ionic form, in combination with a counterion. For example, acids in their anionic form can form salts with cations, such as metal cations, for example, sodium, potassium, and the like; with ammonium salts, such as NH 4 + or cations of various amines, including tetra-ammonium salts, such as tetramethylammonium, or other cations such as trimethylsulfonium, and the like. A "pharmaceutically acceptable" or "pharmacologically acceptable" salt is a salt formed from an ion that has been approved for human consumption and is generally non-toxic such as a chloride salt or a sodium salt. A "zwitterion" is an internal salt, as it can be formed in a molecule that has at least two ionizable groups, one forming an anion and the other a cation, which serve to balance the other. For example, amino acids, such as glycine, can exist in a zwitterionic form. A "zwitterion" is a salt within the meaning here. The compounds described herein can be in the form of salts. The term "salts" includes addition salts of free acids or free bases, which are the compounds described herein. The salts can be "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salt" refers to salts that have toxicity profiles within a range that provides utility in pharmaceutical applications. Unacceptable salts can, however, have properties such as high crystallinity, which are useful in the practice of the present description, as for example, useful in the process of synthesis, purification or formulation of compounds of the present disclosure.

[091] Suitable pharmaceutically acceptable acid addition salts can be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Suitable organic acids can be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric acid, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamhoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, phanethenyl toluenesulfonic, sulfanilic, cyclohexylamino-sulfonic, stearic, alginic, ~ - hydroxybutyric, salicylic, galactarian and galacturonic. Examples of pharmaceutically unacceptable acid addition salts include, for example, perchlorates and tetrafluoroborates.

[092] Suitable pharmaceutically acceptable base addition salts of the compounds of the present description include, for example, metal salts, including alkali metals, alkaline earth metals and transition metal salts, such as, for example, calcium salts , magnesium, potassium, sodium and zinc. Pharmaceutically acceptable base addition salts also include organic salts made from base amines, such as, for example, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Examples of pharmaceutically acceptable base addition salts include lithium salts and cyanate salts. Although pharmaceutically unacceptable salts are generally not useful as medicaments, such salts can be useful, for example, as intermediates in the synthesis of the compounds of formula (I), for example, in their purification by recrystallization. All of these salts can be prepared by conventional means from the corresponding compound according to Formula (I) by reacting, for example, the appropriate acid or base with the compound according to Formula (I) The term "pharmaceutically salts" acceptable "refers to non-toxic organic or inorganic acid and / or base addition salts, see, for example, Lit et al., Salt t Selection for basic Drugs (198 6), Int J.

Pharm., 33, 201-217, incorporated herein by reference.

[093] A "hydrate" is a compound that exists in a composition with water molecules. The composition can include water in stoichiometric amounts, such as a monohydrate or dihydrate, or it can include water in random amounts. As the term is used herein, a "hydrate" refers to a solid form, that is, a compound in aqueous solution, whereas they can be hydrated, it is not a hydrate as the term is used here.

[094] A "solvate" is a similar composition except that another solvent that water replaces water. For example, methanol or ethanol can form an "alcoholate", which can again be stoichiometric or non-stoichiometric. As the term is used herein, a "solvate" refers to a solid form, that is, a compound in solution in a solvent, although it may be solvated, it is not a solvate as the term is used herein.

[095] A "prodrug," as it is well known in the art, is a substance that can be administered to a patient, where the substance is converted in vivo by the action of biological chemicals within the patient's body, such as enzymes, to the active pharmaceutical ingredient. Examples of prodrugs include esters of groups of carboxylic acids, which can be hydrolyzed by endogenous esterases as found in the bloodstream of humans and other mammals. Conventional procedures for the selection and preparation of appropriate prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

[096] In addition, where the characteristics or aspects of the present disclosure are described in terms of Markush groups, those skilled in the art will recognize that the compounds presently described are also so described in terms of any individual member or subgroup of members of the Markush group. For example, if X is described as selected from the group consisting of bromine, chlorine and iodine, the claims for X being bromine and claims for X being bromine and chlorine are fully described. In addition, where the characteristics or aspects of the present disclosure are described in terms of Markush groups, those skilled in the art will recognize that the present disclosure is also described in terms of any combination of any member or subgroup of members of the Markush group. Thus, for example, if X is described as selected from the group consisting of bromine, chlorine, and iodine, and Y is described as selected from the group consisting of methyl, ethyl and propyl, claims for X being bromine and Y being methyl are completely described.

[097] If a value of a variable that necessarily represents an integer, for example, the number of carbon atoms in an alkyl group or the number of substituents in a ring, is described as a range, for example, 0-4 , what is understood is that the value can be any integer between 0 and 4, inclusive, that is, O, 1, 2 '3' or 4.

[098] In various embodiments, the compound or set of compounds, as used in the methods of the invention, can be any of any of the combinations and / or sub-combinations of the above-listed embodiments.

[099] In various embodiments, a compound, as shown in any of the Examples, or among the exemplary compounds, is provided. Disclaimers can be applied to any of the disclosed categories or forms of realization in which one or more of the other embodiments disclosed above or species can be excluded from such categories or embodiments.

[100] This specification also covers compounds isolated according to Formula (I). The term "isolated compound" refers to a preparation of a compound of Formula (I), or a mixture of compounds according to Formula (I), in which the isolated compound has been separated from the reagents used, and / or by-products formed, in the synthesis of the compound or compounds. "Isolated" does not mean that the preparation is technically pure (homogeneous), but it is sufficiently pure for the compound in a form that can be used therapeutically. Preferably, an "isolated compound" refers to a preparation of a compound of Formula (I) or a mixture of compounds according to Formula (I), which contain the mentioned compound or mixture of compounds according to Formula (I) in an amount of at least 10 weight percent of the total weight. Preferably, the preparation contains the mentioned compound or mixture of compounds in an amount of at least 50 weight percent of the total weight; more preferably, at least 80 weight percent of the total weight; and more preferably, at least 90 percent, at least 95 percent, or at least 98 percent, by weight, of the total weight of the preparation.

[101] The compounds described herein and intermediates can be isolated from their reaction mixtures and purified by conventional techniques, such as filtration, liquid-liquid extraction, solid phase extraction, distillation, recrystallization or chromatography, including flash column chromatography or CLAE. Isomerism and Tautomerism in Compounds Described Here

Ta utomer ism

[102] Within the present disclosure, it is to be understood that a compound of Formula (I) or a salt thereof can exhibit the tautomerism phenomenon where two chemical compounds are capable of easy interconversion by exchanging a hydrogen atom between two atoms, for each of which a covalent bond is formed. Since the tautomeric compounds exist in mobile equilibrium with each other, they can be considered as different isomeric forms of the same compound. It is to be understood that the formula designs in this specification can represent only one of the possible tautomeric forms. However, it is also to be understood that the present disclosure encompasses any tautomeric form, and is not to be limited to just any of the tautomeric forms used in formula designs. The designs of the formulas in this specification can represent only one of the possible tautomeric forms and it is to be understood that the specification covers all possible tautomeric forms of the compounds designed and not just those forms that have been convenient to show graphically in this document. For example, tautomerism can be displayed by a linked pyrazolyl group as indicated by the wavy line. Although both substituents are called a 4-pyrazolyl group, it is evident that a different nitrogen atom carries the hydrogen atom in each structure.

"" '-

[103] Such tautomerism can also occur with substituted pyrazoles such as 3-methyl, 5-methyl or 3,5-dimethylpyrazoles, and the like. Another example of. tautomerism is starch-lactide tautomerism (lactam-lactime when cyclic), as seen in heterocyclic compounds containing a ring oxygen atom adjacent to a ring nitrogen atom. For example, the balance:

OH HN ~ N ~ ANÀJ ~ N ~ is an example of tautomerism. Therefore, a structure described herein as a tautomer is intended to include the other tautomer as well. Optical isomerism

[104] It should be understood that when the compounds of the present disclosure contain one or more chiral centers, the compounds can exist in, and can be isolated in, pure enantiomeric form or diastereoisomeric weapons or as racemic mixtures. Accordingly, the present disclosure includes possible enantiomers, diastereomers, racemates or mixtures of the compounds described herein.

[105] Isomers resulting from the presence of a chiral center comprise a pair of non-overlapping isomers that are called "enantiomers". Individual enantiomers of a pure compound are optically active, that is, they are able to rotate the plane of plane polarized light. Individual enantiomers are designated according to the Cahn-Ingold-Prelog system. The priority of the substituents is classified based on atomic weights, a higher atomic weight, as determined by the systematic procedure, having a higher order of priority. Once the order of priority of the four groups is determined, the molecule is oriented so that the lowest ranking group is pointed away from the viewer. Then, if the descending sort order of the other groups proceeds clockwise, the molecule is designated (R), and if the decreasing degree of other groups proceeds counterclockwise, the molecule is designated (S). In the example in Scheme 14, the Cahn-Ingold-Prelog ranking is A> B> C> D. The smallest ranking atom, D, is oriented away from the viewer. i ..110 C./"'ÇB (R) configuration (S) configuration [1o6] This specification is intended to cover diastereomers as well as their racemic and resolved forms, and diastereomerically and enantiomerically pure salt forms thereof. be separated by known separation techniques, including normal and reverse phase chromatography, and crystallization.

[107] "Isolated optical isomer" means a compound that has been substantially purified from the corresponding optical isomer (s) of the same formula. Preferably, the isolated isomer is at least about 80%, more preferably, at least 90% pure, even more preferably, at least 98% pure, more preferably, at least about 99% pure, by weight.

[108] Isolated optical isomers can be purified from racemic mixtures by known chiral separation techniques. According to such a method, a racemic mixture of a compound described herein, or a chiral intermediate thereof, is separated by 99% by weight of pure optical isomers by HPLC using a suitable chiral column, such as a member of the series DAICEL® family of CHIPvALPAK® columns (Daicel Chemical Industries, Ltd., Tokyo, Japan). The column is operated according to the manufacturer's instructions. Rotational Isomerism

[109] It is understood that due to its chemical properties (for example, resonance lending some character from the double bond to the CN bond) of restricted rotation of the amide bonding molecule (as illustrated below), it is possible to observe separate rotamer species and furthermore, under some circumstances, isolate such species (see below) It is further understood that certain structural elements, including steric volume or substituents in amide nitrogen, can improve the stability of a rotamer, as a compound can be isolated in the form, and exist indefinitely, as a single stable rotamer. Accordingly, the present disclosure includes any possible stable rotamers of Formula (I), which are biologically active in the treatment of cancer or other proliferative disease states. O The impeded rotation »~ B Regioisomerismo

[110] In some embodiments, the compounds described herein have a particular spatial arrangement of substituents on the aromatic rings, which is related to the structure-activity relationship shown by the class of compounds. Such a replacement arrangement is often indicated by a numbering system; however, numbering systems are often not compatible between different ring systems. In six-membered aromatic systems, spatial arrangements are specified by the common nomenclature "for" for substitution 1,4, "goal" for substitution 1, 3 and "ortho" for substitution 1,2, as shown below: p Mill'M íll • y • º ~ º • "para- ''" meta- "" ortho- "

[111] In various embodiments, the compound or set of compounds, such as being among the compounds of the invention, or used in the methods of the invention, can be any of any of the combinations and / or sub-combinations of the forms of achievement listed above.

Compounds [112] In one aspect described herein, there are compounds of Formula (I): Formula (I); where: R1 is selected from:

A) R7 Jl v10 R12 O 'R8.

N N. 1TfpJlI., /. . .l_ B) R1a R11 R19 R13 C) r2 ~ çl R7.R8Y ~ Y '~~ N Rts f1o R1o R19 R13) q D) RZ E) F) G)' and H) Rl..R '. fty; Rio, Ri2 and are each, 'independently, -H, CH (CH3) (CH2CH3), -CH2CH (CH3) 2, -CH20H, -CH (OH) (CH3), -CH2CF3, 25 -CH2C (O) OH, -CH2C (O) OR, -CH2CH2C (O) OH, -CH2CH2C (O) OR 25,

(CH2) 4N (H) C (O) (2,3-dihydroxybenzene), optionally substituted alkyl, optionally substituted C1-C 8, optionally substituted C3 -C 8 cycloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, aryl optionally replaced,

\ ~ OH ~ OH, 7c..Y "N ~ NH 'ou! {_ Õ ~ # ~ NH

R3 is a methyl, ethyl, isopropyl or cyclopropyl group; R5 is H, methyl, ethyl or -CH 20H; or R5 and R 24 together with the boron atom form a 5- or 6-membered ring containing boron; is -C (= O) H, -CH2C (= O) H, -C (= O) NHCH2C (= O) H,

? ~ 24 C (= O) C (= O) N (R 14) 2, -B (OR 23) (OR), or '<{ª o;

5 6 or R and R together with the carbon atom they form

Rx is H, optionally substituted C1-C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, or 2 optionally substituted cycloalkyl; or Rx and R together with the nitrogen atom form an optionally substituted nitrogen-containing ring; RY is H or methyl; or RY and R5 together with the nitrogen atom form an optionally substituted nitrogen-containing ring;

is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, or a linear or branched alkyl chain of about 1-22 carbon atoms, optionally comprising within the alkyl chain or at an end of the alkyl chain a radical optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or optionally substituted ~ z'Q where Z is a bond, O, S, NH, CH 2, NHCH 2,

R8 is a bond, -0 or -N (R) -, optionally substituted aryl or optionally substituted heteroaryl;

~ "and" '- "O"' -U, OH, or NH

R14, R15, and R16 are each, independently, H, or C1-

C4 alkyl;

R17 is H, methyl, ethyl, isopropyl or cyclopropyl;

R is, R19, and R2o - are, ca d to one, independently, H or methyl; each R21 is, independently, H or C 1 -C 4 alkyl;

each is, independently, H, alkyl,

C (= NH) (NH2) or -CH (= NH);

R23 and R24 are each, independently, H or C1 -C4 alkyl, or R23 and R24 together with the boron atom form a 5- or 6-membered ring containing optionally substituted boron; each R25, independently, is C1 -C6 alkyl;

R26 is H, C 1-C 4 alkyl, C1-C 4 alkoxy, -CH 2C (O) OR 25 or

OCH2C (O) OR2s; n is o or 1; p is o or 1; and q is o or 1; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[113] In one embodiment, there is a compound of Formula (I) having the structure of Formula (I '): R2 ~ R4 RY R \ ~ Jy ~ yA ~ Jy ~ yR6 Rx O R3 O R5 Formula (I' ); where: R1 is selected from: R18? i R1o O R12 o R7.RY ~ Y '~ v ~~ 1 A) o R9 R19 R11 R2o R13, R7 l' R8 N v10 R12 NÁ Jl ~ /

O 1. ~ 1rfp / B) R1s R11 R19 R13 C) R7.R8tt ~ Y '~~ N

O R18 R1o ff rz R19 R13 ~ ci-) q f D) RZ E) F)

R12 O 7th ~~ º ~ R, 8.s, ../ R f; -1 n / G) R1s R13 'and H) R ~ ... .lly. 'Rio, R11, R12, and are each, independently, -H, CH2C (0) NH2, -CH2CH2C (O) NH2, -CH2CH2C (O) N (H) C (H) (CH3) C02H, CH2CH2C ( O) N (H) C (H) (C02H) CH2C02H, -CH2NR 21 R 22, - (CH2) 2NR 21 R 22, (CH2) 4N (H) C (O) (2,3-dihydroxybenzene) , optionally substituted alkyl, optionally substituted C1 -C 8 heteroalkyl, optionally substituted C3 -C 8 cycloalkyl, - optionally substituted cycloalkyl CHrCrCs, optionally substituted heterocycloalkyl, 7 {0 optionally substituted, optionally substituted heteroaryl, '<i _ "' Q Y ' Q '<i_U): oH ~~ ~ NH, OH, OH N ~ NH' or ~ # R3 is a methyl, ethyl, isopropyl or cyclopropyl;

R 5 is H, methyl, ethyl or -CH 20H; or R 5 and R 24 together with the boron atom form a 5- or 6-membered ring containing boron; -C (= O) H, -CH2C (= O) H, C (= O) H, C (= O) C (= O) N (R 14) 2, -B (OR 23) (OR 24) , or; or R5 and R6 together with the carbon atom they form;

O} J, R26; Rx is optionally substituted H, C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted cycloalkyl; together with the nitrogen atom form an optionally substituted nitrogen-containing ring; RY is H or methyl; or RY and R5 together with the nitrogen atom form an optionally substituted nitrogen-containing ring; is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, or a linear or branched alkyl chain of about 1-22 carbon atoms, optionally comprising within the alkyl chain or at an end of the alkyl chain a radical optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl or V-: z ~ I r (YI V-:. optionally substituted, where Z is a bond, O, S, NH, CH 2, NHCH 2, or C = C; 8 R is a bond, -0, or -N (R 17) -, optionally substituted aryl or optionally substituted heteroaryl; R14, R15 and R16 are each, independently, H, or C1- C4 alkyl; R17 is H, methyl, ethyl, isopropyl or cyclopropyl; R18, R19 and R2 º are each independently H or methyl; each R 21 is independently H or C 1 -C 4 alkyl; each is independently, H, alkyl, C (= NH) (NH2), or -CH (= NH); 23 24 R and R are each, independently, H or C1 -C4 alkyl; or R 23 and R 24 together with the boron atom form a 5- or 6-membered ring containing optionally substituted boron; each R 25 is, independently, C1 -C 6 alkyl; R26 25 is H, C1 -C4 alkyl, C1-C4 alkoxy, -CH2C (O) OR or OCH2C (O) OR2s; n is o or 1; p is o or 1; and q is o or 1; or a pharmaceutically acceptable salt, solvent, or prodrug thereof.

[114] In one embodiment there is a compound of Formula (I) or Formula (I ') where R1 is O R10 O f2 ft R7 .Ry ~ 0NvN ~ / O R9 H R11 H R13 In another embodiment , R8 is a link. In 2 4 10 11 12 13 another embodiment, R, R, R, R, R, and R are each, independently, -H, -CH 3, -CH (CH 3) 2, -C (CH3) 3, - '? {_ Õ - = ::::

NH, or ~ # In a 2 4 10 11 12 13 other embodiment, R, R, R, R, R, and R are each, independently, -H, ~ "'() ~~, OH, ~ "'C (° H OH,! E_ ~ - r N ~ / ~, NH' or? {Ô \ \\ ~

A u

NH in yet another embodiment, R10, R12, and R13 are each, independently, -H, -CH 3, C (O) OH, "- ~; ::, ..... / NH. another embodiment of N ~ or of the aforementioned embodiments is a compound of Formula (I) or Formula (I ') wherein n is O and p is O. In another embodiment, n is O and p is 1. In yet another embodiment, n is 1 and p is O.

[115] In another embodiment is a compound Formula (Ia).

[116] In another embodiment is a compound of Formula (Ia) in which R2 is - CH (OH) (CH 3), -CH 2CH 2C (O) OH, or - (CH2) 4NH 2 • In some embodiments, R2 is CH (OH) (CH 3). In some embodiments, R2 is CH 2CH 2C (O) OH. In some embodiments, R2 is (CH 2) 4NH 2 • In another embodiment there is a compound of Formula (Ia) in which R4 or CH 2C (O) NH 2. In some embodiments, R4 is a CH 2CH (CH 3) 2 group. In some embodiments, R4 is CH 2C (O) NH 2. In yet another embodiment is a compound of Formula (Ia) in which R5 is H or CH 3. In some embodiments, R4 is H. In some embodiments, R4 is -CH 3 •

[117] In another embodiment there is a compound of Formula (I) or Formula (I ') in which R1 is fº ~ r ~ JlN ~ N ~ / 2 7 R'R 8 H R11 H R13 In another form realization, R8 is a bond. In another embodiment, R2, R4, R10, R11, R12, and R13 are each, independently, -H, -CH 3, -CH (CH 3) 2, -C (CH 3) 3, - 'or '! í ~ b ~ ~ - = :::

NH In another embodiment, R2, R4, R1º, R11, R12, and R13 are each, independently, -H, in yet another embodiment, R2, R4, R 10 R11, R12, and R13 are each, independently, -H, -CH3,

\ _ ~ OH "In another embodiment of the above embodiments is a compound of Formula (I) or Formula (I ') where n is O and p is O. In another embodiment, n is O ep is 1. In yet another embodiment, n is 1 and p is O.

[118] In another embodiment is a compound Formula (Ib); where R2, R4, and R12 are each independently -

[119] In another embodiment is a compound of formula (Ib) in which R2, R4, and R12 are each - (CH 2) 4NH 2.

In another embodiment there is a compound of formula (Ib) in which R2, R4, and R12 are each - (CH 2) JNH 2 • In another embodiment there is a compound of formula (Ib) in which R4 is -CH2CH (CH3) 2, R2 is - (CH2) 3NH2 and R12 is (CH 2) 4NH 2 • In another embodiment there is a compound of formula (Ib) where R4 is -CH 2CH (CH 3) 2, R2 is - (CH 2) 4NH 2 and 12 R is - (CH2) 4NH2.

[120] In another embodiment there is a compound of Formula (I ') having the structure of Formula (Ibb): o' (OH rNH2 Ry ~~~ 0 ~~~ 0NJy ~ yRG oo \ º '"o • 'NH 2

Formula (Ibb); where R5 is -H or -CH 3 •

[121] In another embodiment there is a compound of Formula (I ') having the structure of Formula (Ibbb):

Â. : 'N ~ H O ~ HH N._Â O l; O 2: H N ........,. R6

R 7 N ~ ~: N 1 H O H O :: H O R5 Formula (Ibbb); where R5 is -H or -CH3.

[122] In another embodiment is a compound 12

The R O of Formula (I) or Formula (I ') where R1 is R7,

R sJl N'.1_ \ PnJl /../. H R13 In another embodiment, R8 is a bond. In 2 12 13 another embodiment, R, R and R are each, independently, -H,. In another embodiment, R2, R4, R12 and R13 are each, independently, -H, In yet another embodiment, R2, R4, R12 and R13 are each, independently, -H, -CH 3 , -CH 2CH (CH3) 2, -CH20H, ~ ('O "- ~ - r' NH or N ~. In another embodiment

The OH of the above embodiments is a compound of Formula (I) or Formula (I ') where n is O. In yet another embodiment, n is 1.

[123] In another embodiment there is a compound of Formula (I ') having the structure of Formula (Ic): H O R2 H O R4 H RYN0 ~ JyN0NJyNyR6 O R12 H O :: H O :: Formula (Ic); where R2, and R12 'are each independently -CH (OH) (CH3),

[124] In another embodiment there is a compound of formula (Ic) in which R4 is - (CH 2) 4 NH 2, R2 is -CH (OH) (CH 3) and R12 is - (CH 2) 2NH 2 • In another embodiment there is a compound of formula (Ic) in which R4 is - (CH 2) 4NH 2, R2 is CH (OH) (CH3), and R12 is -CH 2NH 2. In another embodiment there is a compound of formula (Ic) in which R4 is - CH2C (O) NH 2, R2 is -CH (OH) (CH 3) and R12 is - (CH 2) 4NH 2. In another embodiment there is a compound of formula (Ic) in which R4 is - (CH2) 4NH2, R2 is - (CH2) 4NH2 and R12 is -CH 2NH2. In another embodiment there is a compound of formula (Ic) in which R4 is -CH 2C (O) NH 2, R2 is - (CH 2) 4NH 2 and R12 is -CH 2NH 2 • In another embodiment is a compound of formula (Ic) in which R4 is -CH2CH (CH3) 2, R2 is - (CH 2) 2NH2, and R12 is - (CH 2) 2NH 2.

[125] In another embodiment there is a compound of Formula (I ') having the structure of Formula (Ice): Formula (Ice); where R5 is -H or -CH 3.

[126] In another embodiment of Formula (I) or Formula (I ') where R is 1 is: ~ x ~ compound R''R'Jl. \ __ z), RZ. 2 In another embodiment, R and R are each, independently, -H, ~~ In OH another embodiment, q is 1 and R8 is a bond.

[127] In another embodiment is a compound of Formula (I ') having the structure of Formula (Id): Formula (Id); where is and and are each, independently, -CH2CH (CH3) 2, -CH (OH) (CH 3), - CH 2C (O) NH 2, -CH2CH2C (O) NH2, -CH2NH2, - (CH2) 2NH2, - (CH2) 3NH2 or - (CH2) 4NH2.

[128] In another embodiment is a compound 4 of formula (Id) where R2 is -CH (OH) (CH 3) and R is -CH 2C (O) NH 2. In another embodiment there is a compound of formula (Id) in which R2 is -CH (OH) (CH 3) and R4 is - (CH 2) 2NH 2. In another embodiment there is a compound of formula (Id) in which R2 is -CH (OH) (CH 3) and R 4 is - (CH 2) 3NH 2. In another embodiment there is a compound of formula (Id) in which R2 is -CH (OH) (CH 3) and R4 is - (CH 2) 4NH 2. In another embodiment there is a compound of formula (Id) where R2 is - 4 (CH2) 4NH 2 and R is -CH 2CH (CH 3) 2. In another embodiment there is a compound of formula (Id) in which R2 is - (CH2) 4NH 2 and R4 is -CH 2C (O) NH2. In another embodiment there is a compound of formula (Id) in which R2 is - 4 (CH2) 4NH2 and R is - (CH2) 4NH2.

[129] In another embodiment is a compound 1 of Formula (I) or Formula (I ') where R is In another form of

RZ realization, R 8 is a bond. In another embodiment, R2, R4, R1º, R12, and R13 are each, independently, -H, - CH3, -CH (CH3) 2, -C (CH3) 3, -CH (CH3) (CH2CH3) , -CH2CH (CH3) 2, CH20H, -CH (OH) (CH3}, -CH2CF3, -CH2C (O) OH, -CH2CH2C (O) OH, In another embodiment, Rlü Ri2, 13 and R are each independently, -H, -CH3, -CH (CH3) 2, CH (CH3} (CH2CH3),

-CH (OH) (CH3), In yet another embodiment, R10 'R12 and R13 are' each, independently, -H, -CH 3, -CH2CH (CH 3) 2, -CH20H, 1-i ~ - r 'NH or N :::::::: / • In another embodiment of the above embodiments is a compound of Formula (I) or Formula (I') in which n is O. In yet another embodiment, n is 1.

[130] In another embodiment there is a compound of Formula (I ') having the structure of Formula (Idd): Formula (Idd); where R5 is -H or -CH3.

[131] In another embodiment is a compound of Formula (Idd) in which R10 is -CH 20H and R12 is -CH 3. In another embodiment is a compound of Formula (Idd) in which R1 is -CH 2CH (CH 3) 2 and R12 is -CH (OH) (CH 3). In another embodiment of the compounds of Formula mentioned above (Id) is a compound in which R4 is -CH 2C (O) NH 2. In yet another embodiment of the compounds of Formula mentioned above (Idd) is a compound in which R4 is

\ _ ~

OH

[132] In another embodiment there is a compound of Formula (I) or Formula (I ') in which R1 is R1 ..) l)'. ~} -N ~ O / - H R13 In another form of Rs achievement is

RZ a connection. In another embodiment, R2, R 4, R12 and R13 are each, independently, -H, -CH3, -CH (CH3) 2, -CH2C (O) OH, -CH2CH2C (O) OH, -CH2C (O) NH2, CH2CH2C (O) NH2, -CH2NH2, - (CH2) 2NH2, - (CH2) 3NH2, - (CH2) 4NH2, \ _ ~ \ _ ~ ~~ ~ NH N ~ o ~ -... . :::::, #

NH OH, or In another embodiment, R2, R4, R12 and R13 are each, CH2CH (CH3) 2, -CH20H, -CH (OH) (CH3), -CH2CH2C (O) OH, -CH2C ( O) NH2, -CH2CH2C (O) NH2, -CH2NH2, - (CH2) 2NH2, \ _ ~ OH In yet another embodiment, R2, R 4, R12, and R13 are each, independently, -H, -CH20H, CH2CH2C (O) OH, -CH2C (O) NH2, \ _ ~ ~~ ~ r 'NH In another form of OH or N ~ embodiment of the above embodiments is a compound of Formula (I) or Formula (I ') where n is O. In yet another embodiment, n is 1.

[133] In another embodiment there is a compound of Formula (I) or Formula (I ') in which R 1 is R! .. R8 ~. In another embodiment, R8 is a bond. In another embodiment, R2 and R4 are each, independently, -H, \. '"' Q! -R_õ -.... :::::: ~ #

NH. In an OH 'or other embodiment, R e are each independently H, CH2CH (CH3) 2, CH20H, CH (OH) (CH3), CH2CH2C (O) OH, CH2C (O) NH2, CH2CH2C (O ) NH2, - (CH2) 2NH2, - (CH2) 3NH2, - (CH2) 4NH2,! E .. ~ - r, NH N ~! -R_õ -.... :::::: ~ #

NH Still in 'or another embodiment, R2 and R4 are each, independently, -H, CH (OH) (CH3),

[134] In another embodiment is a compound of Formula (I) or Formula (I ') in which Rx and R2 together with the nitrogen atom form an optionally substituted nitrogen-containing ring. In another embodiment there is a compound of Formula (I ') having the structure of Formula (Ie):

Formula (Ie); where R5 is -H or -CH3.

[135] In another embodiment there is a compound of formula (Ie), in which and are each,

[136] In another embodiment of any of the above formula (I) or Formula (I ') embodiments is a compound in which R6 is -C (= O) H.

[137] In another aspect described here, the compounds of Formula (II): Formula (II) where: R2, R4, and R12 are each, independently, -H, -CH3, CH (OH) (CH3) , -CH2CF3, -CH2C (O) OH, -CH2CH2C (O) OH, -CH2C (O) NH2, -CH2CH2C (O) NH2, -CH2NR 21 R22, - (CH2) 2NR 21 R22, - (CH2) 3NR 21 R22, (CH 2) 4 NR 21 R22, C1-C 8 optionally substituted alkyl, C1-C 8 optionally substituted heteroalkyl, optionally substituted C3-C 8 cycloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally heteroaryl substituted,

~~ ~~ ~ / NH N ~ f {_õ "" '-. ::::: ~ #

NH; OH, 'or R3 is methyl, ethyl, isopropyl, or cyclopropyl; R5 is H, methyl, ethyl, or -CH 20H; or R 5 and R 24 together with the boron atom form a 5- or 6-membered ring containing boron 6 14 R is -CH2C (= O) H, -C (= O) NHCH2 C (= O) H, - C (= O) C (= O) N (R) 2, B (OR 23) (OR 24), or Rx is optionally substituted H, C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl or C3 - C 8 optionally substituted cycloalkyl; or Rx and R2 together with the nitrogen atom form an optionally substituted nitrogen-containing ring; RY is H or methyl; or RY and R 5 together with the nitrogen atom form an optionally substituted nitrogen-containing ring; is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, or a linear or branched alkyl chain of about 1-22 carbon atoms, which optionally comprises a radical within the alkyl chain or at one end of the alkyl chain optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or optionally substituted ~ I ~ ~ z ~ I ~ ~, where Z is a bond, O, S, NH, CH 2, NHCH 2, or C = Ç; R8 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycloalkyl; R14 is each, independently, H or C1-C4 alkyl; each R21 is, independently, H or C1-C 4 alkyl; each is, independently, H, alkyl, C (= NH) (NH2) or -CH (= NH); R23 and R24 are each, independently, H or C1 -C4 alkyl, or R23 and R24 together with the boron atom form a 5- or 6-membered ring containing optionally substituted boron, and m is 0-4; or a pharmaceutically acceptable salt, solvent, or prodrug thereof.

[138] In another embodiment there is a compound of Formula (II) with the structure of Formula (II '): Formula (II') where: R2, R4, and R12 are each, independently, -H, -CH 3, -CH (OH) (CH3), -CH2CF3, -CH2C (O) OH, CH2CH2C (O) OH, -CH2C (O) NH2, -CH2CH2C (O) NH2, -CH2NR 21 R22, - ( CH2) 2NR 21 R22, - (CH2) 3NR 21 R22, (CH 2) 4NR 21 R22, optionally substituted C1-C 8 alkyl, optionally substituted heteroalkyl C1 -Cs, optionally substituted C3-C 8 cycloalkyl, optionally substituted cycloalkyl, heterocycloalkyl optionally substituted, optionally substituted aryl, heteroaryl! {. is optionally substituted,

NH ~ ~ # 'or R3 is methyl, ethyl, isopropyl or cyclopropyl; R5 is H, methyl, ethyl or -CH 20H; or R5 and R24 together with the boron atom form a 5- or 6-membered ring containing boron; 14 R6 is -CH2 C (= O) H, -C (= O) NHCH2C (= O) H, -C (= O) C (= O) N (R) 2, Rx is H, C 1 -C 6 optionally substituted alkyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted cycloalkyl; together with the nitrogen atom form an optionally substituted nitrogen-containing ring; RY is H or methyl; or RY and R5 together with the nitrogen atom form an optionally substituted nitrogen-containing ring; is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, or a linear or branched alkyl chain of about 1-22 carbon atoms, which optionally comprises a radical within the alkyl chain or at one end of the alkyl chain optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or optionally substituted, where Z is a bond, O, S, NH, CH 2, NHCH 2, or C = C; R is a bond, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycloalkyl; R14 is each, independently, H or C1-C 4 alkyl; each R21 is, independently, H or C1-C 4 alkyl; each is, independently, H, alkyl, C (= NH) (NH2), or -CH (= NH);

R 23 and R24 are each, independently, H or C1-C4 alkyl; or R 23 and R 24 together with the boron atom form a 5- or 6-membered ring containing optionally substituted boron; and m is 0-4; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[139] In another embodiment is a compound 8 of Formula (II) or formula (II ') in which it is a bond. In another embodiment of formula (II) or formula (II '), R2 and R4 are each, independently, -H, -CH3, -CH (CH3) 2, -C (CH3) 3, -CH (CH3) (CH2CH3), -CH2CH (CH3) 2 1 CH20H, -CH (OH) (CH3), -CH2CF3, -CH2C (O) OH, -CH2CH2C (O) OH, CH2C (O) NH2, -CH2CH2C (O) NH2, - (CH2) 2NH2, - (CH2) 3NH2, - (CH2) 4NH2, In another embodiment, they are each, independently H,

! {_ õ ~ # ~

NH Still in 'or another embodiment, R2 and R4 are each, independently, -H, Í-i. ~ - r' NH or N ::::::: / '

[140] In another aspect, the compounds of Formula (III) are described here: R2 R18O RY O R4 R1 · R8y ~~~ Jy ~ 0NJy ~ yR6 o R13 R12 RX o Rl H o R5 Formula (III); where: 2 R and R4 are each, independently, -H, -CH3, 21 22 21 22 21 22 NH2, -CH2CH2C (O) NH2, -CH2NR R, - (CH2) 2NR R, - (CH 2) 3NR R, - (CH 2) 4 NR 21 R 22, C 1 -C 8 alkyl optionally substituted, C 1 -C 8 optionally substituted heteroalkyl, C3 -C 8 optionally substituted cycloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl , optionally substituted heteroaryl,! {_ õ ~ # ~

NH, or 12 21 22 R and R 13 are each, independently, -H, -NR R,

CH3, -CH (CH3) z, -C (CH3) 3, -CH (CH3) (CH2CH3), -CH2CH (CH3) z,

CH20H, -CH (OH) (CH3), -CH2CF3, -CH2C (O) OH, -CH2CH2C (O) OH,

CH2C (O) NH2, -CH2CH2C (O) NH2,

(CH2) 3NR21R22 '- (CH2) 4NR21R22' optionally substituted alkyl or optionally substituted heteroalkyl 12 13; or R and R together with the carbon atoms to which they are attached form a heterocycloalkyl ring; R3 is a methyl, ethyl, isopropyl or cyclopropyl; R5 is H, methyl, ethyl, or -CH 20H; or R 5 and R 24 together with the boron atom form a 5- or 6-membered ring containing boron; R6 is -CH2 C (= O) H, -C (= O) C (= O) N (R 14) 2,

B (OR 23) (OR 24),

optionally substituted heteroalkyl or optionally substituted C3 -C8 cycloalkyl; or Rx and R2 together with the nitrogen atom form an optionally substituted nitrogen-containing ring; RY is H or methyl; or RY and R 5 together with the nitrogen atom form an optionally substituted nitrogen-containing ring; is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, or a linear or branched alkyl chain of about 1-22 carbon atoms, optionally comprising within the alkyl chain or at an end of the alkyl chain a radical optionally substituted aryl, optionally substituted heteroaryl, heterocycloalkyl 0 (optionally substituted z ~, or optionally substituted VV, where Z is a bond, O, S, NH, CH 2, NHCH 2, R8 is a bond, aryl optionally substituted, optionally substituted heteroaryl or optionally substituted heterocycloalkyl, R14 is each, independently, H or C1-C 4 alkyl;

R 18 is H or methyl; or R 18 and R 12 together with the atoms to which they are attached form a heterocycloalkyl ring; each R21 is, independently, H or C1-C 4 alkyl; each is, independently, H, alkyl, C (= NH) (NH2), or -CH (= NH); R23 and R24 are each, independently, H or C1-C4 alkyl, or R23 and R24 together with the boron atom form a 5- or 6-membered ring containing optionally substituted boron, and m is 0-4; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[141] In another embodiment there is a compound of Formula (III) that has the structure of Formula (III '): R18 O R2 ?. R4 RY R1 · RY ~~~~~ Y '~~~ yR6 O R13 R12 Rx O R3 O Rs Formula (III'); where: R2 and R4 are each, independently, -H, -CH 3, CH (CH3) 2 1 -C (CH3) 3, -CH (CH3) (CH2CH3), - CH2CH (CH3) 2 1 -CH20H , CH (OH) (CH3), -CH2CF3, -CH2C (O) OH, -CH2CH2C (O) OH, - CH2 C (O)

NH2, -CH2CH2C (O) NH2, -CH2NR R, - (CH2) 2NR R, - (CH 2) 3NR R, 21 22 - (CH 2) 4NR R, C 1 -C 8 optionally substituted alkyl, Ci-Cs optionally substituted heteroalkyl, optionally substituted C3 -C8 cycloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, 7-t.

NH 'or 12 13 21 22 R and R are each, independently, -H, -NR R, CH3, -CH (CH3) 2, -C (CH3) 3, - CH (CH3) (CH2CH3), -CH2CH (CH3) 2, CH20H, -CH (OH) (CH3), -CH2CF3, -CH2C (O) OH, - CH2CH2C (O) OH, CH2C (O) NH2, -CH2CH2C (O) NH2, 21 22 (CH2 ) 3NR21R22 '- (CH2) 4NR R, optionally substituted alkyl or optionally substituted heteroalkyl 12 13; or R and R together with the carbon atoms to which they are attached form a heterocycloalkyl ring; R3 is methyl, ethyl, isopropyl or cyclopropyl; 5 5 24 R is H, methyl, ethyl or -CH 20H; or R and R together with the boron atom form a 5- or 6-membered ring containing boron;

R 6 is -CH2 and (= O) H, -e (= O) NHCH2 and (= O) H, -e (= O) and (= O) N (R 14) 2r B (OR 23) (OR 24), or ys-o? ~ 'Rx is optionally substituted H, C 1-C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl or optionally substituted C 3 -C 8 cycloalkyl 2; or Rx and R together with the nitrogen atom form an optionally substituted nitrogen-containing ring; RY is H or methyl; or RY and R 5 together with the nitrogen atom form an optionally substituted nitrogen-containing ring; is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, or a linear or branched alkyl chain of about 1-22 carbon atoms, which optionally comprises a radical within the alkyl chain or at one end of the alkyl chain optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl or V ~ z ~ I r (YI V ~ optionally substituted, where Z is a bond, O, S, NH, CH 2, NHCH2, R8 is a bond , optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycloalkyl: 14 R is each, independently, H or C 1 -C 4 alkyl;

R 18 is H or methyl; or R 18 and R 12 together with the atoms to which they are attached form a heterocycloalkyl ring; each R 21 is, independently, H or C 1 -C 4 alkyl; each is, independently, H, alkyl, C (= NH) (NH2) or -CH (= NH); R23 and R24 are each, independently, H or C1 -C4 alkyl, or R23 and R24 together with the boron atom form a 5- or 6-membered ring containing optionally substituted boron, and m is 0-4; or a pharmaceutically acceptable salt, solvent, or prodrug thereof.

[142] In some embodiments, there is a compound of Formula (III) or Formula (III ') in which R8 is a bond. In another embodiment is a compound 24 of Formula (III) or Formula (III ') in which R and R are each, independently, -H, -CH 3, -CH (CH 3) 2, - C (CH 3) 3, - CH (CH3) (CH2CH3), -CH2CH (CH3) 21 -CH20H, -CH (OH) (CH3), -CH2CF3, -CH2C (O) OH, -CH2CH2C (O) OH , -CH2C (O) NH2, -CH2CH2C (O) NH2, 22 21 22 21 22 21 22 CH2NR 21 R, - (CH2) 2NR R, - (CH2) 3NR R or - (CH2) 4NR R. In yet another embodiment is a compound of Formula 4 (III) or Formula (III ') in which R and R are each, independently, -CH (CH 3) 2, CH (CH 3) (CH2CH 3), CH2CH (CH3) 2 1 -CH20H, -CH (OH) (CH3), CH2C (O) OH, -CH2CH2C (O) OH, 21 22 21 22 -CH2C (O) NH2, -CH2CH2C (O) NH2, -CH2NR R, - (CH2) 2NR R, 21 22 21 22 (CH2) 3NR R or - (CH2) 4NR R.

[143] In another embodiment is a compound 12 of Formula (III) or Formula (III ') in which R and R, together with the carbon atoms to which they are attached, form a heterocycloalkyl ring. In another embodiment there is a compound of Formula (III) or Formula 12 (III ') in which R and R 13, together with the carbon atoms to which they are attached, form a pyrrolidine ring. In yet another embodiment is a compound of Formula (III) or Formula (III ') in which R2 and R4 are each, independently, -CH (CH 3) 2, CH (CH3) (CH2CH3), - CH2CH (CH3) 2, -CH20H, -CH (OH) (CH3), 21 22 21 22 CH2C (O) NH2, -CH2CH2C (O) NH2, -CH2NR R, - (CH 2) 2NR R,

[144] In another embodiment is a compound of Formula (III) or Formula (III ') in which R 18 and R 12, together with the atoms to which they are attached, form a heterocycloalkyl ring. In another embodiment there is a compound of Formula (III) or Formula (III ') in 18 that R and R 12, together with the atoms to which they are attached, form a piperidine ring. In yet another embodiment is a compound of Formula (III) or Formula (III ') in which R 13 is H and R2 and R 4 are each, independently, -CH (CH3) 2, CH (CH3) ( CH2CH3), -CH2CH (CH3) 2, - CH20H, -CH (OH) (CH3), CH2C (O) NH2, -CH2CH2C (O) NH2, -CH2NR 21 R 22, - (CH2) 2NR 21 R 22, - (CH2) 3NR 21 R 22 or - (CH2) 4NR 21 R 22.

[145] In another embodiment of the above-mentioned embodiments of formula (I), (II) or (III) is a compound in which R7 is a straight or branched alkyl chain of about 1-22 carbon atoms . In another embodiment of the embodiments of the general formula (I), (II) or (III) mentioned above is a compound in which R7 is ~. In another embodiment of the above-mentioned embodiments of general formula 7 (I), (II) or (III) is a compound in which R is ~. In another embodiment of the aforementioned embodiments (II) or (III) is a compound in which R 7 is In another embodiment of the aforementioned embodiments of formula (I), (II) or (III) is a compound in which R5 is H. In another embodiment of the aforementioned embodiments and general formula (I), (II) or (III) is a compound in which R5 is methyl. In another embodiment of the above-mentioned embodiments of formula (I), (II) or (III) is a compound in which R5 is -CH 20H. In another embodiment of the above-mentioned embodiments of formula (I), (II) 6 or (III) is a compound in which R is -B (OH) 2. In another embodiment of the above-mentioned embodiments of general formula (I), (II) or (III) is a -B (OR23) (0R24), 23 24 composition in which R 6, and in which R and R together with the boron atom form a 5- or 6-membered ring containing optionally substituted boron. In another embodiment of the aforementioned embodiments of general formula (I), (II) or (III) is a compound in which R6 is

[146] In another embodiment of the above-mentioned embodiments of formula (I) is a compound in which R5 is methyl, R6 is R8 is a bond; and In another embodiment of the above-mentioned embodiments of formula (I) 5 6 8 is a compound in which R is methyl, R is -B (OH) 2, R is a bond; and . In another embodiment of the aforementioned embodiments of Formula (I)

there is a compound in which R5 is methyl, R6 is

R8 is a bond,. In another embodiment of the aforementioned embodiments of Formula (I) is a compound in which R5 is methyl, R6 is

B (OH) 2i

R8 is a bond and R 7 is In another embodiment of the aforementioned embodiments of Formula (I) is a compound in which R5 is methyl, R6 is

, R8 is a bond, In another embodiment of embodiments (I) is a compound in which R5

, RS is heteroalryl and R7 is

In another embodiment of the aforementioned embodiments of Formula (I) there is an asosto where R5 is methyl, R6 is -B (OH) 2, R8 is heteroaryl, and

~ \ [14 7] In another embodiment of the previously mentioned embodiments of Formula (I '), (II') or (III ') is a compound in which R7 is a straight or branched alkyl chain of about 1-22 carbon atoms.

In another embodiment of the aforementioned embodiments of Formula (I '), (II') or (III ') is a compound in which R7 is ~ \ In other embodiments of Formula (I') '( II ') or (III') mentioned above is a compound in which R7 is

~ ~ I -:> z.

In another embodiment of the aforementioned embodiments of Formula (I ')' (II ') or (III') is a compound in which R7 is:

~ \ A ~

In another embodiment of the aforementioned embodiments of Formula (I '), (II') or (III ') is a compound in which R5 is H.

In another embodiment of the aforementioned embodiments of Formula (I '), (II') or

(III ') is a compound in which R5 is methyl.

In another embodiment of the aforementioned embodiments of Formula (I '), (II') or (III ') is a compound in which R5 is CH 2 OH.

In another embodiment of the aforementioned embodiments of Formula (I '), (II') or (III ') is a compound in which R 6 is

-B (OH) 2 • In another embodiment of the aforementioned embodiments of Formula (I '), (II') or (III ') is a compound in which R6 is -B (OR 23) (OR 24), wherein R23 and R24 together with the boron atom form an optionally substituted or 6-membered ring containing boron.

In another embodiment of the aforementioned embodiments of Formula (I '), (II') or (III ') is a compound in which R6 is

[148] In another embodiment of the aforementioned embodiments of formula (I ') is a compound in which R5 is methyl, R 6 is, R8 is a bond, and R7 is In another embodiment of the forms above-mentioned embodiments of Formula (I ') is a compound in which Rs is methyl, R6 is -B (OH) 2, Rª is a bond, and R7 is ~ \, -,:; ::: ,, .. In another embodiment of the aforementioned embodiments of Formula (I ') is a compound in which R5 is methyl, R6 is º ,, ~~ 1 • ys-o, ~ Ú \

R 8 is a bond and R 7 is Cio "" "In another embodiment of the aforementioned embodiments of Formula (I ') is a compound in which R5 is ~ methyl, R6 is -B (OH) 2, R8 is a bond, and R 7 is Em

CI is another embodiment of the above mentioned embodiments and Formula (I ') is a compound in which R5 is methyl, R 6 is R8 is a bond, and R7 is ~. In another embodiment of the aforementioned embodiments of Formula (I ') is a compound in which R5 is methyl, R6 is -B (OH) 2, R8 is a bond, and R7 is ~.

In another embodiment of the aforementioned embodiments of Formula (I ') is a compound in which R5 is methyl, R6 is. In another embodiment of the aforementioned embodiments of 6, formula (I ') is a compound in which R5 \ ~ methyl, R and - B (OH) 2, R8 is heteroaryl, and R7 is ~ \

[149] In another aspect, compounds of Formula (IV) are described herein: R2 O R4 RY R1, ~ Rx 0 ~ Jy ~ yR6 Rx O R3 O R5 Formula (IV); where: R1 is selected from:

E) R ~ R8JlN º • R, ª v: J; - n R13) Rz q 'R',) 'ç (/) q F) Rz R12 O 1º ~~~ R'Rs · S, f'; I ny G) R18 R13, and H) Rl..R'.l ;; R1O 'Ri1, and are each, independently, -H, CH2C (O) NH2, -CH2CH2C (O) NH2, -CH2CH2C (O) N (H) C (H) (CH3) C02H, 21 22 21 22 CH2CH2C (O) N (H) C (H) (C02H) CH2C02H, -CH2NR R, - (CH2) 2NR R, (CH2) 4N (H) C (O) (2,3-dihydroxybenzene), alkyl optionally substituted, optionally substituted C1 -C 8 heteroalkyl, optionally substituted C3 -C 8 cycloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally heteroaryl ~~ - r, NH N :::: d, or! {_ õ ~ ~ #

NH R 6 is -C (= O) OH; Rx is optionally substituted H, C 1-C 6 alkyl, optionally substituted C 1-C 6 heteroalkyl, or optionally substituted cycloalkyl; together with the nitrogen atom form an optionally substituted nitrogen-containing ring; RY is H or methyl; or RY and R5 together with the nitrogen atom form an optionally substituted nitrogen-containing ring;

is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, or a linear or branched alkyl chain of about 1-22 carbon atoms, which optionally comprises a radical within the alkyl chain or at one end of the alkyl chain optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl ~ z, or optionally substituted V, where Z is a bond, O, S, NH, CH 2, NHCH 2,

R8 is a bond, -0, or -N (R17) -, optionally substituted aryl or optionally substituted heteroaryl;

~~ y-0 9 R is -CH20H, CH2CH (CH3) 2, • OH. or

R15 and R16 are each, independently, H or C 1 -C4 alkyl; R17 is H, methyl, ethyl, isopropyl or cyclopropyl; R18, R19 and R2 º are each, independently, H or methyl; each R21 is, independently, H or C 1 -C 4 alkyl; each is, independently, H, alkyl, C (= NH) (NH2) or -CH (= NH); each R25 1 independently, is C1-C6 alkyl; n is o or 1; p is o or 1; and q is o or 1; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[150] In another embodiment there is a compound of Formula (IV) which has the structure of Formula (IV): R2 O R4 RY R1, ~~~ 0 ~~~ yR6 Rx O R3 O R5 Formula (IV) where: R1 is selected from:

Rt.R) lef./) q F) Rz

R12 O 70 ~, p ~ R, a · S, R f ';' n y G) R18 R13, and

H)

R10 R11, R12 and are each, '' independently, -H, CH (CH3) (CH2CH3), -CH2CH (CH3) 2, -CH20H, -CH (OH) (CH3), -CH2CF3, 25 -CH2C ( O) OH, -CH2C (O) OR, -CH2CH2C (O) OH, -CH2CH2C (O) OR 25,

CH2C (O) NH2, -CH2CH2C (O) NH2, -CH2CH2C (O) N (H) C (H) (CH3) C02H, 21 22 21 22 CH2CH2C (O) N (H) C (H) (C02H) CH2C02H, -CH2NR R, - (CH 2) 2NR R,

(CH2) 4N (H) C (O) (2,3-dihydroxybenzene), optionally substituted alkyl, optionally substituted C1 -C 8 heteroalkyl, optionally substituted C3 -C 8 cycloalkyl, - optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, \ _ ~ OH ~ OH,

R3 is a methyl, ethyl, isopropyl or cyclopropyl;

R5 sub H, methyl, ethyl, or -CH 2 0H; R6 represents -C (= O) OH; Rx is optionally substituted H, C1 -C 6 alkyl, optionally substituted C1 -C 6 heteroalkyl or optionally substituted C3 -C 8 cycloalkyl; or Rx and R2 together with the nitrogen atom form an optionally substituted nitrogen-containing ring; RY is H or methyl; or RY and R5 together with the nitrogen atom form an optionally substituted nitrogen-containing ring; is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, or a linear or branched alkyl chain of about 1-22 carbon atoms, which optionally comprises a radical within the alkyl chain or at one end of the alkyl chain optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl ~ z, or optionally substituted VV 1, where Z is a bond, O, S, NH, CH 2, NHCH 2 R8 is a bond, -0, or -N (R17) -, optionally substituted aryl or optionally substituted heteroaryl; '! {_ º or ~ ~ #

NH R15 and R16 are each, independently, H or C1-C4 alkyl; R17 is H, methyl, ethyl, isopropyl or cyclopropyl;

R18 I R19 I and R2 º are each, independently, H or methyl; each R 21 is, independently, H or C1-C4 alkyl; each is, independently, H, alkyl, C (= NH) (NH2) or -CH (= NH); each R25 I independently is C1-C6 alkyl; n is o or 1; p is o or 1; and q is o or 1; or a pharmaceutically acceptable salt, solvate, or prodrug.

[151] In another aspect is a compound selected from: Me Me ~: and N "" Jr ~ and ~ Jq_

N o OHH o o Hº ~ H2 Me HN O o NYO H, Me ~ Jx; O {°: rH o) - ~ o Mo o HN ~ Nu ~ H2 O _.- ~

MÕ H O o NYO H,

Me Me Mo 0Me: çOH ~ O Me Mo ~ N0N

H N i = OH O '! ~ O Mo

The HN

O N! ° i} · --1 (; f '~ ~ b OH Me HN

NH O O Mo /-}.- Ntt O Mo,

Me 0 Mo: çOH ° - <Me

H N ~ f1 N JOH O Mo o ~ • Me o HN ~~ Jf '~ bO •• · ~ ~ OH Me' HN O Nfi-H

Me NH \ O Me, Me H O Me H OMe: çOH. O, çNH ~ O N0 ~ JyN0 ~ ~ 0 ~ ~ ....) lH O l_OH _ O Me O Me O Me H0 O ~ Me: çOH ~ ~ Me Jl Mo i H H H ~

O ~ H O N l __ ~ gN ~ e ~ e ~ Nl lfO N O N'Me OH,

Me

Me or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[153] In another embodiment there is a compound selected from: Mo ~ NH 2 Mo: çMo ~ 0 ~: ~ J ~ o ~ J ~ ._. J,

OH N N. N OH H 1: H O O Mo O Mo O

OH Mo ~ 0 N ~ ~ e ~ Jo: çOH ~ J N • N H li 1: H O OH O Me O Mo o Me Mo Mo

~ ri Me ,, .- MeYOIBu '> - I ~) LN "l (~ Y \ lVi __ (t_J: OH O = H O Me H O BocHN: r Me Me ~ {N ~~ ~ Je: çOH

N ~ J. N H 1: H O O Me O Me O Me

OH Me 9 ° 'NH ~ {~ º ~ f? 4N- ~ N ~~ N 0N ll ~ N "B r Y'oH H li 1:. H:. O O Mo O Mo O Mo

OH

O Mo w: ç ~~ ~ "'YN' -" 'N = o

H Me 1 Me

OH o: -

THE N

H, <; NH2. ~ ............ ~ H: e,

OH Me O Me Me o ~ _; _ ~.; ~ J: • M • l ~ -., Jl ~ NH ~ ~~ Mo, "J (. N N ..._... BV o OH Mo O : Me HO -: Me O

H Mo

The H! N

H: ~ and H 11 N ~ N ......., .- .. li

O ~ OH O Mo

Me

H '{º ~ o N .............. H li o ~ 0ºMe: çOH' N H? I H Nz 2 • ..., ......,. : N H M ~ ºMe O -._ I ... o N ......., and Me O - Me H O! -M and

OH Me Me Me H 0Me: çOHH w ~ O N ~~ .__) l._ j> H o = ~ ~

N 11 N ......, ........: H B, O H O,: Me o N- {OHMe NH2 H2N

O N ~~ y "N H ftle: çOH

O ~ J ~: ~ ~ 'H

THE , - N

H N-} 'OH Me O Me NH 2

Me HiN ~~ ~ ~ J: ç ~ J 1; ~ - J3'o '1111 Me OH O?

H ~ • N • I have not read "1: H

THE :. Me

H is Me ~ NH 2 Me Mex; J; HiNOf> H ~ ~ li ~ J .; • N

H ~ J •:.

N

H ~ -! Jª '•:. o O 'l O Me O ~ NH2, and Me ~ l (~~~ J: ç ~ J

O O • • \ Me

N

H l ...._., NH2

OH

O • - Me

N H \ O

The ~ -tª'oo • - Me f> "or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[154] In another embodiment is a compound selected from: ...

~ o ") = o, __ ~ Me o \ nY0n ~ \ ... o

K.tN a

~ "W) t

... .º ~ º H ~ º ~ i ...... o ......;

~~ nW <> H o ...

.. -. !, -1 1

1 _J 'r - ~ --- = ·

...

"'~' i-o;) uv *" 'º! .j nWaY:; o ~ ----- 1 - · ~~~ 1 ~ - "'" - · 1 ~ JHH! ~ t \ N - ·

...

~, ~~ ---- - 11 1

'

-,1

~ 1171

Ili

~ O ~ Ollt OUt

""

· ~ Uf!. (I) rv'l "~ º'- ~ â o ... ..., o .. o ..

it · ~ Wlll ~ o ~ ... o .. o • - ~ ÍM ?! lllr ~ l »lil º \ º" 011 lllt

~~ o "111i o .. o Ili · ~. ~ º" 011 011! Ili is either a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[155] In another aspect, they are hydrates, or metabolites that comprise any of the compounds mentioned above.

[156] In another aspect, it is pharmaceutical compositions that comprise any of the compounds mentioned above together with a pharmaceutically acceptable excipient. [157] In another aspect, the use of a compound described herein for the manufacture of a medicament for the treatment of a bacterial infection in a patient is described herein.

[158] In another aspect are methods of treating a mammal in need of such treatment comprising administering to the mammal an effective antibacterial amount of any of the aforementioned compounds with a frequency and of sufficient duration to provide a beneficial effect to the mammal.

In another embodiment, the bacterial species causing the bacterial infection is an infection involving Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, Escherichia, Escherichia, Escherichia typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumonia and, Klebsiella oxi play, Serratia marcescens, Proteellaella, Morganella tularisis, Proteella, Francisella alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia en terocoli tica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetellaper, para ronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Helicobacter pylori, Vibrobacteri, Campylobi bacteryl, bacterylacteri Lister ia monocytogenes, Neisser ia gonorrhoeae, Neisseria meningi tidis, Kingella, Moraxella,

Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Mycobacterium, bacterium, bacterium, bacterium, bacterium, bacterium , Ulcerans Corynebacterium, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus staprocticusus, Staphylococcus intermedia, Staphylococcus, hyicus, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus saccharolyticus. In another embodiment, the bacterial infection is an infection involving a Gram-negative bacterium. In another embodiment, the bacterial infection is an infection involving gram-positive bacteria. In another embodiment, the mammal has a bacterial-related infection that is resistant to treatment with arylomycin A2.

[159] In another aspect, they are methods of treating a mammal in need of such treatment comprising administering to the mammal arylomycin A and / or arylomycin B and / or any of the compounds mentioned above, wherein the infection involves a bacterial species which expresses a signal peptidase without a proline residue within 10 N-terminal amino acids for the signal peptidase catalytic serine. In another embodiment, bacterial species encode or express an enzyme

SPase without a proline residue at 5-7 N-terminal amino acids for the catalytic serine SPase. In another embodiment, the bacterial infection is an infection involving Corynebacterium diphtheriae, Corynebacterium glutamicum, Campylobacter jejuni, Chlamydia trachomatis, Chlamydophila pneumonia and, Francisella tularensis, Helicobacter pylori, Lactococcus lactis subsp. cremoris, Lactococcus lactis subsp. lactis, Propionibacterium acnes, Rhodococcus equi, Staphylococcus carnosus, Staphylococcus cohnii, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus hominis subsp. hominis, Staphylococcus hominis subsp. novobiosepticus, Staphylococcus lugdunensis, Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus mi tis, Streptococcus oral is, Streptococcus pyogenes and / or Streptococcus pnemoniae. In another embodiment, the bacterial infection is an infection involving a gram-negative bacterium. In another embodiment, the administration comprises topical administration.

[160] In another aspect, they are methods of treating a mammal in need of such treatment comprising administering to the mammal any or any combination of the aforementioned compounds, wherein the infection involves a bacterial species that expresses a signal peptidase, without a proline residue within 10 N-terminal amino acids, for the signal peptidase catalytic serine. In another embodiment, bacterial species encode or express an SPase enzyme without a proline residue in 5-7 N-terminal amino acids for the catalytic serine SPase. In another embodiment, the bacterial infection is an infection involving Staphylococcus capitis, Staphylococcus caprae and / or Yersinia pestis.

[161] In another embodiment, methods of treating a mammal in need of such treatment comprising administering to the mammal a second therapeutic agent for any of the above-mentioned treatment methods. In another embodiment, the second therapeutic agent is a non-arylomycin antibiotic. In another embodiment, the non-arylomycin antibiotic is an aminoglycoside antibiotic, fluoroquinolone antibiotic, penicillin antibiotic, cephalosporin antibiotic, macrolide antibiotic, glycopeptide antibiotic, rifampicin, chloramphenicol, fluoramine, colistin, colistin, colistin, colistin, colistin, colistin, linezolid.

[162] In one embodiment, it is a compound described herein that exhibits antibiotic activity useful in the treatment of bacterial infections, such as, by way of example only, various strains of S. aureus, S. pneumoniae, E. faecalis, E faecium, B. subtilis and E. coli, including species that are resistant to several antibiotics known as methicillin-resistant S. aureus (MRSA), Enterococcus sp. (VRE) resistant to vancomycin, E. faecium multi-resistant, S. aureus and S. epidermidis resistant to macrolides, and s. aureus and E. faecium resistant to linezolid. Methicillin-resistant Staphylococcus aureus

[163] Staphylococcus aureus (S. aureus), a spherical bacterium, is the most common cause of staph infections. S. aureus has been known to cause a range of diseases from minor skin infections, such as pimples, boils, impetigo, cellulite, folliculitis, boils, carbuncles, scalded skin syndrome, abscesses, to fatal diseases such as pneumonia, meningitis, osteomyelitis endocarditis, toxic shock syndrome and septicemia. In addition, S. aureus is one of the most common causes of nosocomial infections, often causing post-surgical wound infections.

[164] Methicillin was introduced in the late 1950s to treat infections caused by penicillin-resistant S. aureus. It was previously reported that S. aureus had acquired resistance to methicillin (S.

methicillin-resistant aureus, MRSA) The methicillin-resistant gene (mecA) encodes a methicillin-resistant penicillin-binding protein that is not present in sensitive strains. MecA is transported in a mobile genetic element, the staphylococcal cassette mec chromosome (SCCmec), of which four forms have been described that differ in size and genetic composition. The methicillin-resistant penicillin-binding protein allows resistance to ~ -lactam and prevents its clinical use during MRSA infections.

[165] In one aspect, there is a method for treating an individual with a resistant bacterium, comprising administering to the individual a compound of Formula (I), (I '), (II), (II'), (III) or (III ') or a sa 1 thereof, is to have, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or its pharmaceutically acceptable prodrug. In one embodiment, the bacterium is a Gram-positive bacterium.

In another embodiment, the gram-positive bacterium is S. aureus.

In another embodiment, S. aureus is resistant or refractory to a beta-lactam antibiotic.

In yet another embodiment, the beta-lactam antibiotic belongs to the penicillin class.

In another embodiment, the beta-lactam antibiotic is methicillin.

In yet another embodiment, the individual has methicillin-resistant S. aureus bacteria.

In one embodiment, the beta-lactam antibiotic is flucloxacillin.

In another embodiment, there is a method for treating an individual with a dicloxacillin-resistant bacterium, comprising administering to the individual a compound of Formula (I), (I '), (II), (II'), ( III) or (III ') or a salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or pharmaceutically acceptable prodrug thereof, in which the individual is refractory to dicloxacillin.

Also described herein is a method for treating an individual with methicillin-resistant bacteria comprising administering a compound of Formula (I), (I '), (II),

(II '), (III) or (III') or a salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or its pharmaceutically acceptable prodrug, in which the individual has been determined to have a bacteria resistant to methicillin.

In one embodiment, the individual is screened for methicillin-resistant bacteria.

In another embodiment, the examination and the individual is performed through a nasal culture.

In another embodiment, methicillin-resistant bacteria are detected by scraping the individual's nostril (s) and isolating the bacteria. In another embodiment, real-time PCR and / or quantitative PCR is used to determine whether the individual has methicillin-resistant bacteria.

[166] In one embodiment, there is a method for treating an individual with a first-generation cephalosporin-resistant bacteria that comprises administering a compound of Formula (I) or (I), (I '), (Ia) , (Ib), (Ibb), (Ic), (Id), (Ie), (II), or (II ') or a salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prof pharmaceutically acceptable drug thereof, in which the individual is refractory to a first generation cephalosporin. In one embodiment, the bacteria are resistant to a first-generation cephalosporin. In another embodiment, the bacteria are resistant to Cefacetril. In another embodiment, the bacteria are resistant to cefadroxil. In yet another embodiment, the bacteria are resistant to cephalexin. In one embodiment, the bacteria are resistant to cephaloglycine. In another embodiment, the bacteria are resistant to cephalonium. In another embodiment, the bacteria are resistant to cephaloridin. In yet another embodiment, the bacteria are resistant to cephalothin. In another embodiment, the bacteria are resistant to cefapyrine. In yet another embodiment, the bacteria are resistant to cephatrizine. In one embodiment, the bacteria are resistant to cefazaflur. In another embodiment, the bacteria are resistant to cefazedone. In yet another embodiment, the bacteria are resistant to cephazoline. In another embodiment, the bacteria are resistant to cefradine. In yet another embodiment, the bacteria are resistant to cefroxadine. In one embodiment, the bacteria are resistant to ceftezole.

[167] In one embodiment, there is a method for treating an individual with second-generation cephalosporin-resistant bacteria, which comprises administering a compound of Formula (I) or (I) '(I'), (Ia), (Ib), (Ibb), (Ic), (Id), (Ie), (II), or (II ') or a salt thereof, you are to have, solvato, alkylated quaternary ammonium salt, stereoisomer, tautomer or pharmaceutically acceptable prodrug thereof, in which the individual is refractory to a second generation cephalosporin. In another embodiment, the bacteria are resistant to a second generation cephalosporin. In another embodiment, the bacteria are resistant to cefaclor. In another embodiment, the bacteria are resistant to cefonicide. In yet another embodiment, the bacteria are resistant to cefprozil. In one embodiment, the bacteria are resistant to cefuroxime. In another embodiment, the bacteria are resistant to cefuzonam. In another embodiment, the bacteria are resistant to cefmetazole. In yet another embodiment, the bacteria are resistant to cefotethane. In another embodiment, the bacteria are resistant to cefoxitin.

[168] In one embodiment, there is a method for treating an individual with a third-generation cephalosporin-resistant bacteria that comprises administering a compound of Formula (I), (I '), (II), (II' ) '(III) or (III') or a salt thereof 'is to have' sol V at 'a1 of alkylated quaternary ammonium, stereoisomer, tautomer or pharmaceutically acceptable prodrug thereof, in which the individual is refractory to a cephalosporin of third generation.

In another embodiment, the bacterium is resistant to a third generation cephalosporin.

In another embodiment, the bacterium is resistant to cefcapene.

In another embodiment, the bacterium is resistant to cefdaloximo.

In yet another embodiment, the bacterium is resistant to cefdinir.

In one embodiment, the bacterium is resistant to pivoxil.

In another embodiment, the bacterium is resistant to cefixime.

In another embodiment the bacterium is resistant to cefmenoxime.

In yet another embodiment, the bacterium is resistant to cefodizime.

In another embodiment, the bacterium is resistant to cefotaxime.

In yet another embodiment, the bacterium is resistant to cefpimizole.

In one embodiment, the bacterium is resistant to cefpodoxime.

In another embodiment, the bacteria is resistant to cefteram.

In yet another embodiment, the bacterium is resistant to ceftibuten.

In another embodiment, the bacterium is resistant to ceftiofur.

In yet another embodiment, the bacterium is resistant to ceftiolene.

In one embodiment, the bacterium is resistant to ceftizoxime.

In another embodiment, the bacteria is resistant to ceftriaxone.

In yet another embodiment, the bacteria is resistant to cefoperazone.

In yet another embodiment, the bacterium is resistant to ceftazidime.

[169] In one embodiment, there is a method for treating an individual with fourth generation cephalosporin-resistant bacteria that comprises administering a compound of Formula (I), (I '), (II), (II '), (III), or (III') or a salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or pharmaceutically acceptable prodrug thereof, in which the individual is refractory to a fourth generation cephalosporin. In another embodiment, the bacterium is resistant to a fourth generation cephalosporin. In another embodiment, the bacterium is resistant to cefclidine. In another embodiment, the bacterium is resistant to cefepime. In yet another embodiment, the bacterium is resistant to cefluprenam. In one embodiment, the bacterium is resistant to cefoselis. In another embodiment, the bacterium is resistant to cefozopran. In another embodiment, the bacterium is resistant to cefpyroma. In yet another embodiment, the bacterium is refractory to cefquinome.

[170] In one embodiment, there is a method for treating an individual with a carbapenem-resistant bacterium that comprises administering a compound of Formula (I), (I '), (II), (II'), ( III) or (III ') or a salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or pharmaceutically acceptable prodrug thereof, in which the individual is refractory to a carbapenem. In another embodiment, the bacterium is resistant to a carbapenem. In another embodiment, the bacterium is resistant to imipenem. In another embodiment, the bacterium is resistant to meropenem. In yet another embodiment, the bacterium is resistant to ertapenem. In one embodiment, the bacterium is resistant to faropenem. In another embodiment, the bacterium is resistant to doripenem. In another embodiment, the bacterium is resistant to panipenem. In yet another embodiment, the bacterium is resistant to biapenem. Staphylococcus aureus of intermediate resistance to vancomycin and resistant to vancomycin

[171] Vancomycin-resistant staphylococcus aureus and vancomycin-resistant staphylococcus aureus are specific types of antimicrobial-resistant staphylococcal bacteria that are refractory to vancomycin treatment. S. aureus isolates for which vancomycin MICs are 4-8 µg / mL are classified as intermediate vancomycin resistance and isolates for which vancomycin MICs are> 16 µg / mL are classified as vancomycin resistant (Institute of Standards clinical and laboratory / NCCLS Performance Standards for Assessing Antimicrobial Susceptibility Information Supplement XVI. M100-Sl6. Wayne, PA: CLSI, 2006).

[172] As used herein, the term "minimum inhibitory concentration" (MIC) refers to the lowest concentration of the antibiotic that is needed to inhibit the growth of a bacterial isolate in vitro. A common method for determining the MIC of an antibiotic is to prepare several tubes containing serial dilutions of antibiotic,

which are then inoculated with the bacterial isolate of interest. The MIC of an antibiotic is determined from the tube with the lowest concentration that shows no turbidity (no growth).

[173] In one aspect, there is a method of treating an individual who has a bacterial infection which comprises administering to the individual a compound of Formula (I), (I '), (II), (II'), ( III) or (III ') or a sa 1 thereof, esters, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or pharmaceutically acceptable prodrug thereof, wherein the bacterial infection comprises a Staphylococcus aureus bacterium of intermediate resistance to vancomycin. In one embodiment, the vancomycin intermediate-resistant Staphylococcus aureus bacterium has a MIC of between about 4 to about 8 µg / mL. In another embodiment, the vancomycin intermediate resistant Staphylococcus aureus bacteria has an MIC of about 4 µg / mL. In yet another embodiment, the vancomycin intermediate resistant Staphylococcus aureus bacteria has an MIC of about 5 µg / mL. In another embodiment, the vancomycin intermediate resistant Staphylococcus aureus bacteria has an MIC of about 6 µg / mL. In yet another embodiment, the vancomycin intermediate resistant Staphylococcus aureus bacteria has an MIC of about 7 ng / ml. In one embodiment, the vancomycin intermediate resistant Staphylococcus aureus bacteria has a MIC of about 8 µg / mL.

[174] In another aspect, there is a method of treating an individual who has a bacterial infection which comprises administering to the individual a compound of Formula (I), (I '), (II), (II'), ( III) or (III ') or a salt, ester thereof. solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or pharmaceutically acceptable prodrug thereof, wherein the bacterial infection comprises a vancomycin resistant Staphylococcus aureus bacterium. In one embodiment, the vancomycin-resistant Staphylococcus aureus bacteria has a MIC of between about 16 µg / mL. In another embodiment, the vancomycin-resistant Staphylococcus aureus bacteria has a MIC of about> 16 µg / mL. In yet another embodiment, the vancomycin resistant Staphylococcus aureus bacteria has a MIC of about 20 µg / mL. In another embodiment, the vancomycin-resistant Staphylococcus aureus bacterium has a MIC of about 25 µg / mL.

[175] In one embodiment, treatment conditions by the compounds described herein include, but are not limited to, endocarditis, osteomyelitis, meningitis, infections of the skin and skin structure, genito-urinary tract infections, abscesses and infections necrotizing. In another embodiment, the compounds disclosed herein are used to treat conditions such as, but not limited to, diabetic foot infections, decubitus ulcers, burn infections, animal or human bite wound infections, necrotizing synergistic gangrene ! necrotizing fascilitis, intra-abdominal infection associated with bowel barrier, pelvic infection associated with bowel barrier, aspiration pneumonia and post-surgical wound infections. In another embodiment, the conditions listed here are caused by, contain, or result from the presence of VISA and / or VRSA. Vancomycin Resistant Enterococci

[176] Enterococci are bacteria that are normally present in human intestines and the female genital tract and are often found in the environment. These bacteria sometimes cause infections. In some cases, enterococci have become resistant to vancomycin (also known as vancomycin-resistant enterococci or VRE). The most common forms of resistance to vancomycin occur in strains of enterococci that involve the acquisition of a set of proteins that encode genes that direct peptidoglycan precursors to incorporate D -Ala-D-Lac instead of D-Ala- D-Ala. The six different types of vancomycin resistance shown by enterococci are: Van-A, Van-B, Van-e, Van-D, Van-E and Van-F. In some cases, Van-A VRE is resistant to both vancomycin and teicoplanin, while in other cases, Van-B VRE is resistant to vancomycin, but sensitive to teicoplanin; in other cases, Van-e is partly resistant to vancomycin and sensitive to teicoplanin.

[177] In one aspect, there is a method of treating an individual having vancomycin-resistant enterococci which comprises administering to the individual a compound of Formula (I), (I '), (II), (II'), (III) or (III ') or a salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or pharmaceutically acceptable prodrug thereof, in which the enterococci developed resistance to vancomycin. In one embodiment, the individual was previously treated with vancomycin for a sustained period of time. In another embodiment, the individual was hospitalized. In yet another embodiment, the individual has a weakened immune system, such as patients in Intensive Care Units or in cancer or transplant wards. In another embodiment, the individual has undergone surgical procedures such as, for example, abdominal or thoracic surgery. In yet another embodiment, the individual was colonized with VRE. In one embodiment, the individual has a medical device, such that he has developed an infection. In another embodiment, the medical device is a urinary catheter or central intravenous (IV) catheter

[178] In another embodiment, there is a method of treating an individual having a vancomycin resistant enterococcus which comprises administering to the individual a compound of Formula (I), (I '), (II), (II '), (III) or (III') or a salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or pharmaceutically acceptable prodrug thereof, in which the enterococcus has Van-A resistance.

[179] In another embodiment, there is a method of treating an individual having a vancomycin resistant enterococcus which comprises administering to the individual a compound of Formula (I), (I '), (II), (II '), (III) or (III') or a salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or pharmaceutically acceptable prodrug thereof, in which the enterococcus has Van-B resistance.

[180] In another embodiment, there is a method of treating an individual having a vancomycin resistant enterococcus which comprises administering to the individual a compound of Formula (I), (I '), (II), (II '), (III) or (III') or a sa1 thereof, is to have, only 1 v, alkylated quaternary ammonium sa1, stereoisomer, tautomer or pharmaceutically acceptable prodrug thereof, in which the enterococcus has Van-e resistance.

Pharmaceutical Administration and Composition [181] The pharmaceutical compositions described herein comprise a therapeutically effective amount of a compound described herein (i.e., a compound of any of the formulas (I), (I '), (II), (II' ), (III), or (III ')) formulated together with one or more pharmaceutically acceptable carriers.

As used herein, the term "pharmaceutically acceptable carrier" means a non-toxic, inert, semi-solid or liquid filler, diluent, encapsulating material or formulation aid of any kind.

Some examples of materials that can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; baby powder; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soy oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline solution; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other compatible non-toxic lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweeteners, flavorings and perfumers, preservatives and antioxidants also be present in the composition, according to the formulator's judgment. The pharmaceutical compositions described herein can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (such as through powders, ointments, or drops), orally, or as an oral or nasal spray, or an aerosol liquid or dry powder for inhalation formulation.

[182] Liquid dosage forms for oral administration include emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms optionally contain inert diluents commonly used in the art such as, for example, water or other solvents, agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate , benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, peanuts, corn, germ, olive, castor and sesame), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and és esters of sorbitan fatty acids, and mixtures thereof. In addition to inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavorings, and perfuming agents.

[183] Injectable preparations, for example, sterile injectable aqueous or oilseed suspensions, are optionally formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation is optionally a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent, or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can optionally be used are water, Ringer's solution, U. S. P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any mild fixed oil can be employed, including synthetic mono- or diglycerides. In addition, fatty acids, such as oleic acid, are used in the preparation of injectables.

[184] Injectable formulations can be sterilized, for example, by filtration through a bacteria retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium , before using.

[185] In order to prolong the effect of a drug, it is often desirable to delay drug absorption from subcutaneous or intramuscular injection. This is optionally accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends on its rate of dissolution which, in turn, may depend on the size of the crystal and the crystalline shape. Alternatively, delayed absorption of a parenterally administered drug form is optionally accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsulation matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Injectable depot formulations are optionally prepared by trapping the drug in liposomes or microemulsions that are compatible with body tissues.

[186] Compositions for rectal or vaginal administration are preferably suppositories that can be prepared by mixing the compound described herein (i.e., a compound of any of the formula (I), (I '), (II), (II' ), (III) or (III ')) with suitable non-irritants, excipients or vehicles such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at room temperature but liquid at body temperature and therefore melt in rectum or vaginal cavity and release the active compound. [187] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one pharmaceutically acceptable excipient or inert carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or diluents such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose and acacia, c) wetting agents such as glycerol, d) disintegrating agents such as agar, calcium carbonate, starch potato or tapioca, alginic acid, certain silicates and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, alcohol acetyl and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, e) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, lauryl s sodium ulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form optionally comprises buffering agents.

[188] Solid compositions of a similar type can optionally be employed as fillers in hard and soft gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[189] Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other coatings known in the pharmaceutical formulation art. They optionally contain opacifying agents and may also be of a composition that they release only the active ingredient (s), or preferably, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of infiltration compositions that can be used include polymeric substances and waxes.

[190] Solid compositions of a similar type can optionally be employed as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[191] The active compounds can also be in micro encapsulated form with one or more excipients, as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release control coatings and other coatings known in the pharmaceutical formulation art. In such solid dosage forms the active compound is optionally mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms optionally comprise, as is normal practice, additional substances other than inert diluents, for example, press lubricants and other press aids, such as magnesium stearate and micro crystalline cellulose. In the case of capsules, tablets and pills, the dosage forms optionally comprise buffering agents. They optionally contain opacifying agents and can also be of a composition that they release only the active ingredient (s), or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of infiltration compositions that can be used include polymeric substances and waxes.

[192] Dosage forms for topical or transdermal administration of a compound described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or adhesives. The active component is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers as optionally required. Ophthalmic formulations, ear drops, and the like, are also contemplated. [193] Ointments, pastes, creams and gels may contain, in addition to an active compound described here, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, benthos, silicic acid, talc and zinc oxide, or mixtures thereof.

[194] The compositions described herein are optionally formulated for delivery as a liquid aerosol or inhalable dry powder. Liquid aerosol formulations are optionally nebulized, predominantly, in particle sizes that can be delivered to terminal and respiratory bronchioles where the bacteria reside in patients with bronchial infections, such as chronic bronchitis and pneumonia. Pathogenic bacteria are commonly present throughout the airway to the bronchi, bronchioles and appear in the lung,

particularly in terminal and respiratory bronchioles. During the exacerbation of the infection, bacteria may also be present in the alveoli. Liquid aerosol and inhalable dry powder formulations are preferably supplied along the endobronchial tree to terminal bronchioles and, eventually, to the tissue of the parenchyma. [195] The aerosol formulations described here are optionally delivered using an aerosol-forming device, such as a jet, porous vibrating plate or ultrasound nebulizer, preferably selected to allow the formation of an aerosol with particles with an average diameter of mass medium predominantly between 1 to 5 µ. In addition, the formulation has balanced ionic strength of osmolarity and chloride concentration, and the smaller aerosolizable volume capable of delivering the effective dose of the compounds described here, the compound described here (that is, a compound of either formula (I ), (I '), II), (II'), (III), or (III ')) to the infection site. In addition, the aerosol formulation preferably does not negatively affect the functionality of the airways and does not cause undesirable side effects.

[196] Aerosol dispersion devices suitable for the administration of aerosol formulations described herein include, for example, jet, vibrating porous plate, ultrasonic nebulizers and energized dry powder inhalers, which are capable of nebulizing the aerosol formulation of particle size predominantly in the size range of 1 -5 µm. Predominantly in this application it means that at least 70%, but preferably more than 90%, of all generated aerosol particles are within the range of 1-5 µm. A jet nebulizer operated by air pressure to break a liquid solution into aerosol drops. Vibrating porous plate nebulizers work using a sonic vacuum produced by a fast vibrating porous plate to extrude a drop of solvent through a porous plate. An ultrasonic nebulizer works by a piezoelectric crystal that cuts a liquid into small aerosol drops. A variety of suitable devices are available, including, for example, AeroNebTM and AeroDoseTM porous plate nebulizers (AeroGen, Inc., Sunnyvale, California), Sidestream® nebulizers (Medic-Aid Ltd., West Sussex, England), nebulizers Pari LC® and Pari LC Star® jet (Pari Respiratory Equipment, Inc., Richmond, Virginia), and AerosonicTM ultrasonic nebulizers (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and Ul traAire® (Omron Healthcare, Inc. , Vernon Hills, Illinois)

[197] In some embodiments, the compounds described herein, the compound described herein (i.e., a compound of any of the formulas (I), (I,), (II), (II '), (III) or (III ')) are formulated for use in the form of topical powders and sprays that contain, in addition to the compounds described herein, excipients, such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays optionally contain the usual propellants such as chlorofluorohydrocarbons.

[198] Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be prepared by dissolving or dispensing the compound in the appropriate medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. The rate can be controlled either by providing a rate-controlling membrane or by dispersing the compound in a polymer or gel matrix.

[199] According to the treatment methods described herein, bacterial infections are treated or prevented in a patient such as a human or a lower mammal by administering to the patient a therapeutically effective amount of a compound described herein, in such amounts and for the time as needed to achieve the desired result. By a "therapeutically effective amount" of a compound described herein is meant a sufficient amount of the compound to treat bacterial infections, with a reasonable benefit / risk ratio applicable to any medical treatment. It will be understood, however, that the total daily use of the compounds and compositions described herein will be decided by the attending physician within the scope of the judgment of the medical opinion. The specific therapeutically effective dose level for any particular patient will depend on a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the patient's age, body weight, general health, sex and diet; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of treatment; drugs used in combination or coincident with the specific compound employed; and similar factors known in the medical arts.

[200] The total daily dose of the compounds described herein, the compound described herein (i.e., a compound of any of the formulas (I), (I '), (II), (II'), (III) or ( III ')), administered to a human or other mammal in single or divided doses may be in amounts, for example, from 0.01 to 50 mg / kg of body weight or more usually from 0.1 to 25 mg / kg body weight. Single dose compositions can contain such amounts or their sub-multiples to make up the daily dose. In general, the treatment regimens described herein include administration to a patient, in need of such treatment, from about 10 mg to about 2000 mg of the compound (s) described herein, per day, in single or multiple doses.

EXAMPLES Example 1

[201] General Method 1: The preparation of fully protected peptide fragments. The fully protected peptide fragments of 4-6 amino acids in length terminated by a tail of lipophilic carboxylic acid are synthesized in solid phase using chlorotritil functionalized polystyrene resin (Trt-Cl) and a Fmoc / tBu / Trt protection group strategy / t-Boc and is shown in Scheme I. Cleavage of the fully protected peptide is carried out by repeated treatment of the resin with 1% TFA in CH 2 Cl 2 and treatment in aqueous medium of the combined filtrates. A representative example of General Method 1 is shown in Scheme IA to give peptide 1A. Diagram I ~ 1 O 73 O R5 FmocHN "'j (OH FmocHN-yÂOH Fmo \ ~ oH FmocHN0oH FmocHN ~ OH G) -c1 _ _ _A_1_0_ _ _A2._R_ = 2_ _. _Al_RA__o _... ___M_ _R' __ AS Trt.CI o R7 FmocHN0oH OH ~. QRS JL., L. ~ º \ O ~ li ~ li A6 R8 .. A7) "1% TFNDCM R7 [(jo 'N' R6 H 1 ('(" (N R4 V'N

OH R "o R2 H o 1 Scheme lA o FmocHN li y-" OH Trt.CI "" o "fª ('t") FmocHN - ..} l.OH V ~ OH: Bu-Oj Ó 1% TFM> CM

[202] General Method 2: The synthesis of aldehydes. General Method 1 peptides are used in the next steps without further purification, as shown in Scheme II. Peptide 1 is dissolved in an N, N-dimethylformamide, and hydroxybenzotriazole (HOBt), dimethyl acetal aminoacetaldehyde (R = H) or acetal dimethyl 2-aminopropionaldehyde (R = Me) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC). The reaction is then sealed and heated to 50 ° C for 3 hours. The reaction is then cooled to room temperature and diluted with water, 10% citric acid and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic layers are washed with a solution of sodium bicarbonate, water and brine, then dried over sodium sulfate and concentrated. The crude material is then treated with a 95: 2.5: 2.5 mixture of trifluoroacetic acid: dichloromethane: water for approximately 5 minutes. The volatile solvents are then evaporated, the crude material is taken up in dichloromethane and evaporated again. The crude material is purified by HPLC on a Hypersil Gold column (10 mm x 250 mm, particle size - 5 µm), to obtain the desired compound. Scheme II HOBt

EDC Me ~ 'CN ~.

O ~~ N1 Me 9 OM: çOH .. ~ 0N J; O

O ~~ H NH 2

T-li.: H O M & O Mt O · OH · 101 [203] Compound 101: This compound was prepared according to General Method 1 and 2, to provide the title compound. MS (ESI) for (C35H54N8011): m / z 763.1 (M + H). Example 2 ~ ~ '{NJ ....... ~~ Ny- · ~ yAM ~~ H O Me OMe OH O O H li 1 "rr - H O Me O Mo O OH 102

[204] Compound 102: This compound was prepared according to General Method 1 and 2, to provide the title compound. MS (ESI) for (C3 7H59 N70 10): m / z 762.1 (M + H). Example 3 H OMe, OH \ \ .OMe Me o N0 ~~ N-L {HNi = OH. - o ~ Mo .. NH O NHz Me O) --- {~ Me 'HN O 103 O Nyo

H

[205] Compound 103: This compound was prepared according to General Method 1 and 2, to provide the title compound. MS (ESI) for (C4 2 H74 N8 0 11): m / z 8 67, 3 (M + Na). Example 4 Me Mo OH i; M Me ~ -co N ............._. ~ and ~ J N: ç ~ J. N I ~~ H H li 1: H O O Me O Me O

OH 104

[206] Compound 104: This compound was prepared according to General Method 1 and 2, to provide the title compound. MS (ESI) for (C3 8 H69 N701 0): m / z 784.3 (M + H). Example 5 Me

H

NJ, - ·· \ '\ Me OH _OMe N ~ N - .. L. {_) - oH o) - ~ ..e HN -} - NH o ~ Me O} - f ~ IÍ OH Me' HN \\ 105 NH O o '- {

H

[207] Compound 105: This compound was prepared according to General Method 1 and 2, to provide the title compound. MS (ESI) for (C47 H77 N70n): m / z 938.5 (M + Na). Example 6 Me ~ {e

N O_ ~ e. H ~ q_ N ...........-... ~ lr N

O OH O NH O NH º Me ~ KHN __; - {o 2 106 J - NiJ (

H

[208] Compound 106: This compound was prepared according to General Method 1 and 2, to provide the title compound. MS (ESI) for (C 3 7H64Ns0 10): m / z 767.3 (M + H) ·. Example 7 O (OH O Me ~ 0 ~ 1 (~~ (\ _o Me o - "-Me o - 'oH ~ -.L. {HN) - .. / NH O

M H HN ~ 107 ') = o) -H HzN O

[209] Compound 107: This compound was prepared according to General Method 1 and 2, to provide the title compound. MS (ESI) for (C40H70NsOn): m / z 839.4 (M + H). Example 8 Me -....._ ,, /

[210] Compound 108: This compound was prepared according to General Method 1 and 2, to provide the title compound. MS (ESI) for (C43H16Ns011): m / z 881.6 (M + H). Example 9

[211] Compound 109: This compound was prepared according to General Method 1 and 2, to provide the title compound. MS (ESI) for (C 44 H71 N7 0 11): m / z 874.5 (M + H). Example 10 H O tt. and H O Me y- · OHH O, çMe Me

H O H Me N._JlNAyN .._) l ~~ N0N N, A _.... N ..._ O l __, OHH O 110 Me O Me H O T ~

[212] Compound 110: The synthesis of Compound 110 is described in Scheme III. Peptide 1-110 is prepared according to General Method 1. A solution of 1-110 (40 mg, 0.047 mmol) in anhydrous DMF (1 mL) was treated with EDCI (54 mg, 0.28 mmol) and HOBt (31.7 mg, 0.235 mmol) followed by DI EA (18, 2 mg, O, 14 1 mmo 1) and K4 (6, 2 mg, O, O4 7 mmo 1). The mixture was stirred at room temperature overnight. After ELSD showed that the reaction was complete, the mixture was purified by preparative HPLC to obtain 3-110 (17 mg, 37.4% yield). To a solution of 3-110 (17 mg, 0.018 mmol) in anhydrous dichloromethane (1 mL) was added Dess-Martin periodinane (22.9 mg, 0.054 mmol) in one portion at 0 ° C. The reaction mixture was allowed to stir at room temperature overnight. After HPLC showed that the reaction was complete, the mixture was filtered and the filtrate was concentrated in vacuo at room temperature to give 4-110 (16 mg) as a white solid. A solution of 4-110 (16 mg, 0.016 mmol) in 1 ml of trifluoroacetic acid containing 5% water and 5% dichloromethane was stirred at room temperature for 15 minutes. After ELSD showed that the reaction was complete, the solvent was removed. The residue was purified by preparative HPLC (Luna C8 5 µm 150 x 21, 2 mm) to obtain compound 110 (1.6 mg, 13.7% yield) as a mixture of diastereomers. MS (ESI) for (C 41 H74 N8 0 11): m / z 855.5 (M + H) Scheme III Mo OH H H2NnN ..._ Me

THE

H N__jl

The l_. ~

M _e ~ N __) l ~

THE H OMe: çOt · BU Me

H

O N0 ~ O Me, <; Mo

THE

OH the KA EOCllHOBVOIENOMF Ot.au 1-110 Mo Mo

Scheme IV

[213] The K4 preparation is shown in Scheme IV.

) yo __, - _m_ · tr_o_et_an_o _, _ A_mb_er_li_st_A _-_ 12 ...,

DCE r21 ~ "'1 ~ 0 the OH K1 K2

[214] A mixture of nitroethane (3.6 g, 0.5 mol) and r21 ~.) Lyo ...., ..- 1 -0 _n1-ºtr_o_et_a_no _, _ A_mb_er_li_st_A _-_ 12 .., Ni / H2 NH2 The DCE ,,, - - - 1 ....... ~ o ~ o OH EtOH OH K1 K2 K3 CH3NH2 EtOH. Amberlyst A-12 (20 g) in 1,2-dichloroethane (30 ml) was cooled to 0 ° C. Kl (5 g, 50% toluene solution) was added. The resulting mixture was stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated in vacuo to give K2 (4.2 g, 97% ield), as an oil.

~ ° "" OH K2 [215] A mixture of K2 (0.2 g, 1.1 mmol) and Raney nickel (0.2 g) in ethanol (5 mL) was subjected to hydrogen gas at 30 psi hydrogen at room temperature for 10 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give K3. The residue was used in the next step without further purification. NH2 O NH2 O ~ º ~ AAN / OH 6H H K3 K4

[216] To a 30% solution of methylamine in absolute ethanol (20 mL), K3 was added (160 mg, 1 mmol). The solution was refluxed for 2 hours. After evaporation of the solvent, the residue was recrystallized from dichloromethane / ethyl acetate to give K4 (100 mg, 70% yield), as a yellow solid. Example 11 ~ MeyOH j \ _OMe H Me ~ N ~ ~ N-L .- <_- t: H O.: ~ O HN) - {~~ Me NH O -) 8 - 111 o OH M ~ HN

NH O O Me> i-N, H O Me

[217] Compound 111: The synthesis of Compound 111 is shown in Scheme V. Peptide 1-111 is prepared according to General Method 1. A solution of 1-111 (100 mg, 0.1 mmol) in anhydrous DMF (1 mL) was treated with EDCI (115.2 mg, 0.6 mmol) and HOBt (67.5 mg, 0.5 mmol) followed by DIEA (38.7 mg, 0.3 mmol) and K4 (13 , 2 mg, 0.1 mmol). The mixture was stirred at room temperature overnight. After ELSD showed that the reaction was complete, the mixture was purified by preparative HPLC (Luna CB, 5 µm, 150 x 21.2 mm) to give 45 mg (40.5%) of 3-111 as a mixture of diastereomers . To a solution of 3-111 in 1 ml of anhydrous dichloromethane was added Dess-Martin periodinane (3 eq) in a portion at OºC. The reaction mixture was allowed to stir at room temperature overnight. After ELSD showed that the reaction was complete, the mixture was filtered and the filtrate was concentrated in vacuo at room temperature to provide 45 mg (100%) of 4-111 as a mixture of diastereomers. A solution of 4-111 in 1 ml of trifluoroacetic acid containing 5% water and 5% dichloromethane was stirred at room temperature for 15 minutes. After ELSD showed that the reaction was complete, the solvent was removed under reduced pressure. The residue was purified by preparative HPLC (Luna C8, 5 µm, 150 x 21.2 mm) to obtain 2.6 mg (6.8%) of Compound 111 as a mixture of diastereomers. MS (ESI) for Scheme V 0 Me Ot · h <Me ~~ 0Ny- · N-L.i (_O-ÇMeOt-Bu li O: · H ~

MO

HN H NO - "') - e 1-111 0) ---- {~ # Ot-Bu Má Mlt HN EDCl / HOBVDIEA / DMF Me Ot · D OH HO, - · OMe O Me ~ NYlN ~ NL { ~, -Bu O ~ HO HN '-.Me M, - 3-111 o NH) ---- {o ~ ~ / 1 /. Ot-Bu Dess-Martin and Mlt HN \\ DCM

NH OH

H Me ~, -. Ot- ~ OMe O) - {Mi} -NH Me ~ N ~ N ~ N i: • Bu o Me O _ H O HN) -Me o ~ Me 4-111 O Mà '

NH) ---- {

HN ~ # Ot · Bu TFA / DCM / u-o '' 2

NH O O Me> -} - N, H O Me Me H ~ y- · OH j ° \ .OMe Me ~ N'I ~ gN4N _ / - oH '-t-Me Md 111 rNHH º _, - Q- o ~. MEi HN · '-' # OH ~ -NH O O M ~, f-N, H O Me

Example 12 Mo OH Me O ~ 0 ~ X (~.:> - OH) -Me '~ NH o ~ Me 112 O} - {~ li OH M ~ HN

NH O O Me> i-N {i o Me

[218] The synthesis of Compound 112 is described in Scheme VI. Peptide 1-112 is prepared according to General Method 1. A solution of 1-112 (100 mg, 0.096 mmol) in anhydrous DMF (1 mL) was treated with EDCI (96 mg, 0.5 mmol) and HOBt (67.5 mg, 0.5 mmol) followed by DIEA (64.5 mg, 0.5 mmol) and K4 (13.2 mg, 0.1 mmol). The mixture was stirred at room temperature overnight. After ELSD showed that the reaction was complete, the mixture was purified by preparative HPLC (Luna C8, 5 µm, 150 x 21.2 mm) to give 32 mg (29%) of 3-112 as a mixture of diastereomers. To a solution of 3-112 in 1 ml of anhydrous dichloromethane was added Dess-Martin periodinane (3 equv.) In one portion at OºC. The reaction mixture was allowed to stir at room temperature overnight. After ELSD showed that the reaction was complete, the mixture was filtered and the filtrate was concentrated in vacuo at room temperature to give 31 mg (100%) of 4-112 as a mixture of diastereomers. A solution of 4-112 in 1 ml of trifluoroacetic acid containing 5% water and 5% dichloromethane was stirred at room temperature for 15 minutes. After ELSD showed that the reaction was complete, the solvent was removed under reduced pressure. The residue was purified by preparative HPLC (Luna C8, 5 µm,

150 x 21.2 mm) to give 5.1 mg (19%) of Compound 112 as a mixture of diastereomers. MS (ESI) for (C50 Hs2N 8 012): m / z 987.5 (M + H). Scheme VI Me OtBu Me ~ 0 ~~~) -otsu O) -Me O -} - NH O ~ Me 1-1 12 O Me

H HN ~ A OtSu EDCl / HOSt / DIEAIOMF H ~ Me ~ OIB ~ uOMe O

OH Me N ......, ........ N _> - otSu: i- ~ and NHO ~ Ó • N} - O 3.:12 HN O OtBu Dess-Martln Me HN DCM

NH OH 0Me ~ OtB ~ uo) - {Me ~ li N 0-tMeOtSu M! Í o,? - N [iMe y "'~ O ~ Me O HN N ~ 11º, o- TFNHi () / OCM Me 4 -112 O11.1 / ~ N ~ N;: OtBu 15 mln Me

O ~;: x; °!: ÇH O 31- · ~,: i-Me112 o

MÕ ~ Hº ~, HN \\ "

OH

NH O O Me> -} - Ntt O Me Example 13 H2N ~ o ~ 'CO N ~~ .JlN y- · ~ vlN ~~ 1 - ~' Me Me Me OH

O OH H Oli 13 Me1 "'n

O: H O jMe 'lfO Me 1

[219] Compound 113: The synthesis of Compound 113 is shown in Scheme VII. The lA peptide (Example 1) was prepared according to General Method 1. A solution of lA (100 mg, 0.096 mmol) in anhydrous DMF (1 mL) was treated with EDCI (96 mg, 0.5 mmol) and HOBt (67.5 mg, 0.5 mmol) followed by DIEA (64.5 mg, 0.5 mmol) and K4 (13.2 mg, 0.1 mmol). The mixture was stirred at room temperature overnight.

After ELSD showed that the reaction was complete, the mixture was purified by preparative HPLC (Luna C8, 5 µm, 150 x 21.2 mm) to give 3-113 (40 mg, 38.1% yield). To a solution of 3-113 in 1 mL of anhydrous dichloromethane was added Dess Martin periodinane (3 eq) in one portion, at 0 ° C. The reaction mixture was allowed to stir at room temperature overnight. After ELSD showed that the reaction was complete, the mixture was filtered and the filtrate was concentrated in vacuo at room temperature to give 4-113 (40 mg, 100% yield). A solution of 4-113 (40 mg, 0.034 mmol) in 1 ml of trifluoroacetic acid containing 5% water and 5% dichloromethane was stirred at room temperature for 15 minutes. After ELSD showed that the reaction was complete, the solvent was removed under reduced pressure. The residue was purified by preparative HPLC (Luna C8, 5 µm, 150 x 21.2 mm) to give 6 mg (20%) of Compound 113, as a mixture of diastereomers. MS (ESI) for (C 38 H59 N9 0 1 2): 834.4 m / z (M + H). Scheme VII

OH H H, NhN · 1.10 K4 M & o EDCUHOBl / DIEAIDMF ...

M ~~ J ~; _ ~ J ~ x; ~ -1 ~ -9h ~ - 1 a- ;; ' O .. O 3.113 Ma O Mo O o ~~; ~;, ~ J ~ x; ~ -1 / 5 / r ~, TFAfH ~ 0 o lotsu o 4.1 13 Me O Me oo M ~~ J ~,; ~ J ~ x; ~ -1 ~~~ h ~ • Mo lOH OO 113 Me O Ma O Ma O Example 14 H {~ e HR HR, Çr> kH ~ H

N

N "YN ~ N

H Mex; OH 1 N ~ • N .: H N N, Me O OH O 114 Me O Me O Me O

[220] Compound 114: The synthesis of Compound 114 is shown in Scheme VIII. Peptide 1-114 was prepared according to General Method 1. A solution of 1- 114 (100 mg, 0.12 mmol) in anhydrous DMF (1 mL) was treated with EDCI (115, 2 mg, O, 6 mmol) and HOBt (81 mg, 0.6 mmol) followed by DIEA (77.4 mg, 0.6 mmol) and K4 (15.8 mg, 0.12 mmol). The mixture was stirred at room temperature overnight. After ELSD showed that the reaction was complete, the mixture was purified by preparative HPLC (Luna C8, 5 µm, 150 x 21.2 mm) to give 43 mg (47%) of 3- 114 as a mixture of diastereomers. To a solution of 3- 114 in 1 ml of anhydrous dichloromethane was added Dess Martin periodinane (3 eq.) In one portion, at OºC. The reaction mixture was allowed to stir at room temperature overnight. After ELSD showed that the reaction was complete, the mixture was filtered and the filtrate was concentrated in vacuo at room temperature to obtain 62 mg (100%) of 4-114 as a mixture of diastereomers. A solution of 4-114 in 1 ml of trifluoroacetic acid containing 5% anisole and 5% thioanisole was stirred at room temperature for 15 minutes. After ELSD showed that the reaction was complete, the solvent was removed. The residue was purified by preparative HPLC (Luna CS, 5 µm, 150 x 21, 2 mm) to obtain compound 114 as a mixture of diastereomers. MS (ESI) for 833.4 m / z (M + H). Scheme VIII

OH Me 1 J .... lf- ~ - Me Mo ~ Ht'- o Mo ºMe: çOt · BU o, çMo Mo o :::, ... j ~ 'CNHJ, ~ J._Jl.NI li ~ ._Jl. = · _

NH OH K4 EDClfHOBUDIEA / OMF OO, Me O Mo O Ot · BU 1 "11 • Me Me ~ o We ºMe: ço: -Bu o, çMe OH :::, ... 1 ~ 'CN ~~ ._Jl. N ~ 0N ~ - Á_ - ~ "'Me Dess-Martln O Ot-Bu H li O 3-114 Me 1

O :: Mo

H

The 1Mo lf

THE

DCM Me ~ H'Cº ~ º N

H N ~ N ......, ........ N ~ Me: çoi-: u ~ N '= "" "N, çMe

N o H N "'Mo ~ nº TFA / anisoUtioanisol H li 1 :: H 15mln O Ot · Bu O 4-114 Me O Me O Me The Example 15

[221] General Method 3: The addition of a (bis (trimethylsilyl) amino) methylboronic acid ester to a peptidyl carboxylic acid (Scheme IX). A mixture of a peptidyl carboxylic acid (consisting of 4-7 residues) (1 eq) 'HATU (1, 5 2.0 eq)' [Bis (trimethylsilyl) amino] pinacol esters of methylboronic acid (Bl) (2 , 5 eq) is cooled to O, after dichloromethane (O, 1 M) and DMF (O, 1 M) are added.

Sufficient DMF is added, where most of the starting material is dissolved. Then, diisopropylethylamine (DIEA, 3 eq), followed by the addition of water (6 eq). The mixture is allowed to warm up to room temperature. After 2 to 8 hours, the mixture is partitioned between dichloromethane and water. The aqueous layer is extracted twice with dichloromethane. The combined organic layers are washed with diluted (0.05 M) HCl solution, then diluted (0.2 M) NaHC0 3 • The organic layers are dried over Na 2 S0 4, with a small amount of methanol added if necessary , then filtered, and concentrated. The resulting oil was precipitated with either a cold ether wash or a 1: 1 ether: hexane wash to obtain the corresponding amidoboronic acid (5-115), which was used without further purification.

[222] General Method 4: 0-t-butyl acid-catalyzed deprotection and / or trityl residues using thioanisole and anisole as a trap (Scheme IX). To a mixture of amidoboronic acid (1 eq), anisol (2 eq) and thioanisol (2 eq), is added dichloromethane (0.02 M), then TFA (0.02 M) at OºC in a ratio of 1: 1. The reaction is allowed to warm up to room temperature. The reaction is monitored by LC-MS until the starting material has been consumed. The solvents were evaporated, and the product was precipitated with either cold ether, or cold ether: hexane (1: 1). The crude product was purified by preparative HPLC (Hypersil column, x 250 mm, 5 µm), to obtain the desired boronic acid product.

Scheme IX TrtHN?) 1 :: ,, .. .H

The N t '' N ~. Me H ll N ~ N 0Me: ç0l · Bu, H 11 N .._ A O!; '·, OH --0 1 H "'" '((H'! ~ 'O Ot · Bu O 1-115 O tte O s1 TMS p.-V · o>: (º 6 TrtHN TMS'Nv HATU O Me OMe: ç0: -3u O OH H: H i! H 1 DIEA N {w ·· "- ,, J_Jl.NN ° Y "" N N... A DCMIDM; <Hli H: H! OH HP O 01-Si O 5 · 115 O Mo O Anisol Thioanisol

TFNOCM

[223] Compound 115: Compound 1-115 was prepared according to General Method 1. Compound 1-115 was subjected to General Method 3 and general process 4, to obtain Compound 115. MS (ESI) for ( C 3 7H 53 BN 6 012): m / z 835.2 (M + Na).

NHTrt

O, .... OtBu ~ H ~

M B O ofOt u O f 1

O ~~ NY: N ~ N ~~~ N ~ OH O Me HO Me HO and 1-116 o, ..... oH o Me OH, çNH2 1: ~ - Jl o, - · oo ~~ y; N ~ N ~~ ._,) lN General Methods 3 e4 o Mo and H o Mo H o NH .._ B (OH) 2 116 Example 16

[224] Compound 116: Compound 1-116 was prepared according to General Method 1. Compound 1-116 was subjected to General Method 3 and general process 4, to obtain Compound 116. MS (ESI) for ( C 40 H57 BN 8 0 12): m / z 875.3 (M + Na).

Example 17 Me

[225] Compound 117: Compound 117 was prepared according to general methods 1, 3 and 4. Example 18

[226] Compound 118: Compound 118 was prepared according to General Methods 1, 3 and 4. Example 19

OH HN Me 2

The ~ -e ~: N ~ ~~ ~~ '- "is'

THE OH N

H Me

THE

H 119

THE

N 1Z Me O Me. :

THE N H THE The OH OH

[227] Compound 119: Compound 119 was prepared according to General Methods 1, 3 and 4. Example 20 Me

[228] Compound 120: Compound 120 was prepared according to general methods 1, 3 and 4. Example 21 [22 9] Compound 121: Compound 121 was prepared according to General Methods 1, 3 and 4. Example 22 Scheme X Me HATUIOIEA / DMF / OCM O ~ OMe! ROl · Bu O ÇMe Me 'O-; ~ HTFA / H20 Me NH (NHrr: NH __) 1 N NH.,) 1. NH .., / 8:. 1 NH • •. • '___ .. Me Me H l · Bu 5-122 Me O Ma OMe, OH O; -Me OH NH. ,, JlNH ~ NH. ,, Jl ~' ° 'r (NH ~ N ~ NH ... .-yeah, 0 HO l OH ... 8 122 Me O Me O

[230] Compound 122: Compound 122 was prepared as described in Scheme X. Compound 1-122 was prepared according to General Method 1. Compound 1-122 (100 mg, 0.117 mmol), HATU (89 mg , 0.234 mmol), then B2 (57.3 mg, 0.234 mmol) were placed in an ice bath. To this mixture, 2.4 ml of DCM and 0.8 ml of DMF were added. To the mixture, DIEA (45.4 mg, 0.351 mmol) was added. After 15-30 minutes, the reaction was allowed to warm to room temperature and stirred at room temperature for 30 minutes.

After ELSD showed that the reaction was complete, the mixture was extracted with DCM (10 ml) and water (5 ml) The resulting mixture was extracted with DCM (5 ml x 2). The combined organic layers were washed sequentially with diluted HCl (<0.1 M), NaHC0 3 solution and brine.

The solvents were evaporated, and the residue was extracted with EA (30-50 ml): water (10-15 ml). The organic layers were washed sequentially with water (10 ml), and brine, dried over Na 2 SO 4, and filtered.

The filtrate was concentrated.

The residue was crystallized from acetonitrile to give 5-122 (100 mg, 86%). A solution of 5-122 (70 mg, 0.067 mmol) in 95% TFA / H 2 O (1 ml) was stirred at room temperature for 2 hours.

The TFA was then evaporated with a stream of N 2 • The crude residue was dissolved in MeOH and purified by means of prep-HPLC (Luna C8 5 µmL 150 x 21.2 mm) to give 12 mg (22%) Compound 122. MS (ESI) to (C 37 H70 BN 70n): m / z 822.5 (M + Na). Example 23 Scheme XI

Me o: -eu (;. H ~ 'v (~ _) l ~~ O ~ and OO HCI: O B3 Me NH: NH NH OH - 1, .ÂNH "j (yJlNH HATU / DIPEAIDMF / OCM O lOt · Bu O 1 • 122 Mo O Mo o

Me

[231] Compound 123: Compound 123 was prepared according to Scheme XI.

Compound 1-122 (Example 22) was prepared according to General Method 1. Compound 1-123 (100 mg, 0.117 mmol), HATU (89 mg, 0.234 mmol), then B3 (60, 7 mg , 0.234 mmol) were combined in a flask and cooled in an ice bath.

To this mixture, 2.4 ml of DCM and 0.8 ml of DMF were added.

DIEA (45.4 mg, 0.351 mmol) was added to the mixture, and after 15-30 minutes, the reaction was allowed to warm to room temperature and stirred at room temperature for 30 minutes.

After ELSD showed that the reaction was complete, the mixture was treated with DCM (10 ml) and water (5 ml). The aqueous layer was extracted with DCM (10 ml). The combined organic layers were washed with dilute hydrochloric acid (<0.1 M), then NaHCO 3, solution, then with brine, and the solvent was evaporated under reduced pressure.

The residue was extracted with EA (30-50 ml): water (10-15 ml), and the EA layer was washed with water (10 ml), then with brine, dried over Na 2 SO 4, filtered and concentrated.

The residue was crystallized from acetonitrile to obtain 5-123 (80 mg, 64%). A solution of 5-123 (25 mg, 0.024 mmol in 95% TFA / H 2 O (1 ml) was stirred at room temperature for 20 minutes.

Then TFA was evaporated with a flow of N2 and ELSD showed that the reaction was completed.

The residue was crystallized from acetonitrile to give the crude product.

Then the crude residue was purified by preparative HPLC (Luna C8 5 µm 150 x 21.2 mm) to give Compound 123 (5 mg, yield: 54%). MS (ESI) for (C4sHs6BN7011): m / z 948.5 (M + H).

Example 24 Scheme XII Me OtBu ÇNHTrt NH.) L.NH ~ NH.) L. ~ X; NH ~ NH Me O Me O O O

OH O l_ ,. OtBu

O 1A Me O Me O HATU / OIEAJOMF / DCM Me O! Bu ÇNHTrt NH.) L.NH ~ NH.) L_ ~ x; NH ~ NH NH "r ~ / Me O Me O O O O H O l___ Ot8u

O 5 · 124 Me O Me O H ~. TFNH20 2 hrs

H

[232] Compound 124: Compound 124 was prepared according to Scheme XII. Compound 1a (Example 1) was prepared according to General Method 1. In a round-bottomed flask, Compound 1-124 (100 mg, 0.093 mmol), HATU (70 mg, O, 186 mmol), then , B2 (39 mg, O, 186 mmol was placed in an ice bath. To this mixture 2.4 ml of DCM and 0.8 ml of DMF were added. DIEA (24 mg, 0.186 mmol) was added, and then After 15-30 minutes, the reaction was allowed to warm to room temperature and stirred at room temperature for 30 minutes After ELSD showed that the reaction was complete, the mixture was treated with DCM (10 ml) and water (5 ml). The mixture was extracted with DCM (5 mL x 2). The combined organic layers were washed sequentially with diluted HCl (<0.1 M), NaHC0 3 solution, and brine. The solvent was evaporated, and the residue was extracted. with EA (30-50 mL) and water (10-15 mL). The organic layers were washed with water (10 mL), brine, and dried with Na 2 SO 4, filtered and concentrated. The residue was crystallized from act nitrile to give 5-124 (100 mg, yield: 85.5%).

A solution of 5-124 (100 mg; 0.079 mmol) in 95% TFA / H 2 O (1 ml) was stirred at room temperature for 2 hours.

Then TFA was evaporated and ELSD showed that the reaction was completed. The crude residue was purified by means of prep-HPLC (Luna C8 5 µm 150 x 21.2 mm) to give Compound 124 (16 mg, 26%). MS (ESI) for (C3 4 H55 BNs0 12): m / z 801.3 (M + Na). Example 25 Scheme XIII HATU / DIENDMF / DCM Me Ot · Bu ÇMe M NH.) LN / yNH.) L ~: çN0NH Me O Me O O and O l._. Ot · BU O · 5-125 Mo O Me O NHJ «-O .- • '' H H '' '. TFAJH20 Me OH ÇMeM H NH.) LNH ~ NH.) L ~: çNH; t-NH Ma O Me OO and OH • NH ._ .., \ 'oH O l._., O Me O Me O OH 125 [233] Compound 125: Compound 125 was prepared according to Scheme XIII. Compound 1-125 was prepared according to General Method 1. Compound 1-125 (100 mg,

0.12 mmol), HATU (91.2 mg, 0.24 mmol), and 82 (50 mg, 0.24 mmol) were added to a small round bottom flask and cooled in an ice bath.

To this mixture, 2.4 ml of DCM and 0.8 ml of DMF were added.

DIEA (31 mg,

0.24 mmol) was added, and after 15-30 minutes, the reaction was allowed to warm to room temperature and stirred at room temperature for 30 minutes.

After ELSD showed that the reaction was complete, the mixture was extracted with DCM (10 ml) and water (5 ml). The mixture was extracted with DCM (5 ml x 2). The combined layers were washed sequentially with diluted HCl (<0.1 M), NaHC0 3 solution, and brine.

The solvent was evaporated, and the residue was extracted with EA (30-50 ml): water (10-15 ml). The organic layer was washed, sequentially, with water (10 ml) and brine, dried Na 2 SO 4, filtered and concentrated.

The residue was crystallized from acetonitrile to give 5-125 (100 mg, 80.3%). MS (ESI) for (C 36 H60 BN 7 0 11): m / z

800.3 (M + Na). A solution of 5-125 (40 mg, 0.039 mmol) in 95% TFA / H 2 O (1 ml) was stirred at room temperature for 2 hours.

Then, TFA was evaporated and ELSD showed that the reaction was completed.

Then, the crude residue was purified by preparative HPLC to give Compound 125

(2.4 mg, 7.9%). MS (ESI) for (C 36 H60 BN 7 0 11): m / z 800.3 (M + Na). Example 26

[234] Compound 126: This compound was prepared in a similar manner to Compound 122 (Example 22) from general methods 1, 3, and 4, to obtain the title compound. Example 27

[235] Compound 127: Compound 126 (EXAMPLE 26) (9 mg) was dissolved in MeOH and diluted with water and acetic acid to a final mixture of 80% MeOH: 19% water: 1% acetic acid to a final concentration of 5 mg / mL. The solution was heated and sonicated as needed to facilitate dissolution. The reaction was monitored by LC-MS, which indicated a 1: 1 mixture from starting material: product. Preparative HPLC gave 1 mg of Compound

127.

[236] Compound 128: Compound 1-128 was treated in a similar manner to Compound 124 (Example 24) to produce the title compound. Examples 29-130

Scheme XIV R2a FmocHN * OH R: z. R'ª 20% R '' H2N ~ O ~ FmocHN ~~ + O ~ piperidine ... ~ f g 3A2 3B HCTU, HOBT

DIPEA R2n: 2n g: pg 381 R "FmocHN_,. Film -OH R" R2 • R1 • 3c 'lf T FmocHNn ~~~ nº ~ 3 1 HCTU, HOBT RO R2 ORO OIPEA 3C1 .. R'ª R3 • R'ª R3 • R : z. R1 • 20% FmocHN + ~ + ~~~ + O ~ piperidine:, ng ~, ng R2 o ~, n A 301 R '' H2Nn ~ n ~~~ nº ~ Rla R2 • R1 • r R5 OH 3E2 R4 O R3 O R2 O R1 O HCTU, HOBT 302 OIPEA 1% TFA

DCM.

[237] Fully protected peptide fragments of up to six amino acids in length terminated by a lipophilic carboxylic acid tail are synthesized in solid phase using chlorotrityl functionalized polystyrene resin (Trt-Cl) and a Fmoc / protection group strategy tBu / Trt / t-Boc. the representative scheme of a fragment of four amino acids terminated with a lipophilic carboxylic acid is shown in Scheme XIV. Cleavage of the fully protected 3F peptide is performed by repeated treatment of the resin with 1% TFA in CH 2 Cl 2 and treatment in aqueous medium of the combined filtrates.

[238] General Method 5: The attachment of an Fmoc-protected amino acid to a 2-chlorotrityl resin is described in Scheme XV. Scheme XV R1 'Fmoc :: HN_ ••! Ll.m -OH R1' 20% c1-Q + Ynn1

DIPEA .. Fmoc :: HN ~ O'Q ~~ _Pi_pe_n_ · d_in .... ~, "

R O 3A OCM chloride resin A trityl chlorine 3A1 n, m = Oor 1

[239] Step 1: A mixture of 2-chlorotrityl resin (500 mg, 0.5 mmol), diisopropylethylamine (DIPEA) (0.26 g, 2 mmol) in dry DCM (10 mL) was added to a solution of an amino acid protected with Fmoc 3A (1.5 mmol) in dry DCM (10 mL) at 0 ° C. Then, the mixture was stirred for 5 hours at room temperature. The mixture was filtered and the cake was washed with DCM (30 ml x 3), DMF (30 ml x 3) and MeOH (30 ml x 3) to obtain compound 3Al. [2 4 O] Step 2: About 20% of. piperidine / DMF (70 mL) to remove the Fmoc group. The mixture was stirred for 10 min, and the cycle was repeated three times. The mixture was washed with DCM (2 x 30 ml) and DMF (3 x 30 ml) to give Compound 3A2.

[241] General Method 6: Coupling of solid phase peptides of different lengths and Fmoc cleavage of the peptide. The coupling of fragments of peptides and / or amides of amino acids in length, followed by removal of Fmoc, is described in Scheme XVI.

Scheme XVI R2 • R1 'FmocHN- ..Lllm -OH "" tJ1; ((R2.a R1' H2Nn0 ~ 3B R2 O FmocHN ~~~ 0'0 R1 O HCTU, HOBT R2 O ~ p 381 g 3A2 DIPEA 20 % piperidine ~

[242] Step 1: A mixture of 3B amino acid (1.5 eq), HCTU (1.5 eq), HOBT (1.5 eq) and DIPEA (1.5 eq) in dry DMF (6-8 mL / eq) was stirred at 20 ° C for 30 min. Then, the above mixture was added to Compound 3A2 (1 eq) and stirred at 20 ° C for 1.5 hours. After LCMS showed that the reaction was complete, the mixture was filtered and the residue was washed with DMF (3 x 10 ml / mmol) and DCM (3 x 10 ml / mmol) to give Compound 3Bl. A portion of the analytical resin 3Bl was treated and mixed in 1% TFA / DCM to cleave the peptide from the resin, and the desired product was detected by MS with confirmation that no starting material remains. In cases where peptide coupling is slow or not complete, HCTU can be replaced with EDCI.

[243] Step 2: To the 3Bl, 20% piperidine / DMF (70 mL) was added to remove the Fmoc group. The mixture was stirred for 10 min and the cycle was repeated three times. The mixture was washed with DCM (2 x 30 ml) and DMF (3 x ml) to give Compound 3B2. In cases where more than one protected amine is present, a protection group other than Fmoc, for example, t-Boc or CBz, is used so that only one reactive amine is present after deprotection of Fmoc.

[244] Step 3 and Step 4: The process from Step 1 and Step 2 can be repeated in 3B2 as described in Scheme I.

[245] General Method 7: The coupling of an amide to a solid phase resin is described in Scheme IV. In cases where a coupling partner is an amide, instead of an Fmoc-protected amino acid, the following procedure is used and is illustrated in Scheme XVII. Scheme XVII R5 OH and 3E2 HCTU, HOBT

DIPEA

[246] A mixture of 3D2 amino acid (1.5 eq), HCTU (1.5 eq), HOBT (1.5 eq) in DIPEA (1.5 eq) in dry DMF (6-8 ml / eq) was stirred at 20 ° C for 30 min. Then, the above mixture was added to Compound 3E2 (1 eq) and stirred at 20 ° C for 1.5 hours. After LCMS showed that the reaction was complete, the mixture was filtered and the residue was washed with DMF (3 x 10 ml / mmol) and DCM (3 x 10 ml / mmol) to give Compound 3El.

[247] General Method 8: The cleavage from the resin with 1% TFA is shown in Scheme XVIII. Scheme XVIII Rs y 0 ~ nR "'· ~ nRsa ~ - .. 1Iim ~~ 1? TR1 · º, R4 n 3E1 n R3 Ynn R2 O n R1 ~ 1% TFA

DCM ..

[248] Cleavage of the 3El Compound is achieved by repeated treatment of the resin with 1% TFA in CH 2 Cl 2 as shown in the following example. A mixture of Compound 3El (3 mmol) was treated with 1% TFA / DCM (3-4 mL / mmol) for 5 min and filtered. This operation was repeated three times. The filtrate was treated with a saturated solution of NaHCO 3 solution until pH ~ 7-8. The aqueous layer was adjusted to pH ~ 3-4 with citric acid. The mixture was extracted with DCM (6-8 ml / mmol) three times, then the combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated to give Compound 3F. The reported yields are based on the theoretical load of the chlorotrityl chloride resin.

NHTrt Me 0-tBu ~ O · 0 ~: ç · 0 ~ '9' H O H O '> - 1 OH O ~ O Me O BocHN ~ 129

F [2 4 9] Compound 129F: the compound was prepared using General Methods 6-8, as shown in Scheme XIX. A mixture of Trt resin (1 g, 1 mmol), Fmoc-Asn (Trt) -OH (1.2 g, 2 mmol) and DIPEA (258 mg, 2 mmol) in dry DCM (20 mL) was stirred at 25 ° C for 4 hours. The mixture was filtered and the cake was washed with DCM (2 x 30 ml), DMF (2 x 30 ml) and MeOH (2 x 30 ml, to stop the possible unreacted trityl resin). To the above resin about 20% piperidine / DMF (70 ml) was added to remove the Fmoc group. The mixture was stirred for 10 minutes and repeated three times. The mixture was then washed with DCM (2 x ml) and DMF (3 x 30 ml) to give Compound 129A2.

[250] A mixture of Fmoc-L-Ala-01-I (0.62 g, 2 mmol), HCTU (0.83 g, 2 mmol), HOBT (0.27 g, 2 mmol) and DIPEA (0 , 26 g, 2 mmol) in dry DMF (20 mL) was stirred at 25 ° C for minutes. Then, the above mixture was added to Compound 129A2 (1 mmol) and stirred at 25 ° C for 1.5 hours. After LCMS showed that the reaction was complete, the mixture was filtered and the residue was washed with DCM (2 x 30 ml) and DMF (3 x 30 ml). To the above resin, about 150 ml of 20% piperidine / DMF was added to remove the Fmoc group. The mixture was stirred for 10 minutes and repeated three times. The mixture was then washed with DCM (2 x 30 ml), DMF (3 x 30 ml) to give Compound 129B2.

[251] A mixture of Fmoc-L-Thr (tBu) -OH (2 mmol), HCTU (0.83 g, 2 mmol), HOBT (0.27 g, 2 mmol) and DIPEA (0.26 g, 2 mmol) in dry DMF (20 mL) was stirred at 25 ° C for 20 minutes. Then, the above mixture was added to Compound 129B2 (1 mmol) and stirred at 25 ° C for 1.5 hours. After LCMS showed that the reaction was complete, the mixture was filtered and the residue was washed with DCM (2 x 30 ml) and DMF (3 x 30 ml). To the above resin, about 150 ml of 20% piperidine / DMF was added to remove the Fmoc group. The mixture was stirred for 10 minutes and repeated three times. The mixture was then washed with DCM (2 x 30 ml), DMF (3 x 30 ml) to give Compound 129C2.

[252] A mixture of Fmoc-L-Lys (BOC) -OH (0.62 g, 2 mmol), HCTU (0.83 g, 2 mmol), HOBT (0.27 g, 2 mmol) and DIPEA ( 0.26 g, 2 mmol) in dry DMF (20 mL) was stirred at 25 ° C for 20 minutes. Then, the above mixture was added to Compound 129C2 (1 mmol) and stirred at 25 ° C for 1.5 hours. After LCMS showed that the reaction was complete, the mixture was filtered and the residue was washed with DCM (2 x 30 ml) and DMF (3 x 30 ml). About 150 ml of 20% piperidine / DMF were added to the above resin to remove the Fmoc group. The mixture was stirred for 10 minutes and repeated three times. The mixture was then washed with DCM (2 x 30 ml), DMF (3 x 30 ml) to give Compound 129D2.

[253] A mixture of 4- (4-butylphenyl) benzoic acid (1.5 eq), HCTU (1.5 eq), HOBT (1.5 eq) and DIPEA (1.5 eq) in dry DMF (6 -8 ml / eq) was stirred at 20 ° C for 30 min. Then, the above mixture was added to Compound 129D2 (1 eq) and stirred at 20 ° C for 1.5 hours. After LCMS showed that the reaction was complete, the mixture was filtered and the residue was washed with DMF (3 x 10 ml / mmol), DCM (3 x 10 ml / mmol), THF (3 x 10 ml / mmol) and petroleum ether (3 x 10 mL / mmol) to give Compound 129El.

[254] A mixture of Compound 129El (1 mmol) was treated with 1% TFA DCM (4 mL) for 5 min and filtered. This operation was repeated three times. The filtrate was treated with saturated NaHC0 3 solution until pH ~ 7-8. The aqueous layer was adjusted to pH ~ 3-4 with citric acid. The mixture was extracted with DCM (8 ml) three times, and then the combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated to give Compound 129F. MS (ESI) m / z 1067.4 (M + H) +.

Scheme XIX R, l. o ~ F1 ".0CHN- 1 (FmocHN ...._ ,. ÂOH 1 48 R 'O R1"' o H1Ny "- N ~ OY".}.

1.0IPEA

2. 20'l • piperidin: v '1, HCTU, HOBT Dl? EA. R 'H O \ d

2. 20'l • piperidine.o '482 2-dorotritil DMF OMF doride resin R8 0 ~ j FmocN ~ OH o 40 i R "Jl_ 4E2 R1 OH

1. HCTU, HOBT

OIPEA HCTU.HOBT

2. 20 '! ~ Piperidine.o' 402 OIP :: A

OMF 1% TFA OR ~ OR 'HO R3 HO R1 RyNy ~~ NyÂNJyo'f'.1 \ OC \ I Ry ~ y> l ~~~ yÂN ~' OH OR ~ RA Ó R2 H Ó ~ O R4 RA OR ' HO 4F 4E1

[255] Using the procedures described in General Methods 6-8 and Scheme XIX, the following carboxylic acids were prepared: Me ~ j ::: ..., -:> "IAo: çOIBu BocHN ~. ::: ... .1 u_Jt • N u_Jl • NO): HO ~ HO HO 132F Mo 133F BocHN MS (ESI) mlz 939.5 (M + H) "MS (ESI) m / 2: 1078 .5 (M • H) • ~ prrrt ~ u} -n ~~ -! n ~ "TrtH - Ol Ollo O BocHN._) 136F

Me Ma ~ ~ 1 IP 'o "' - yOtSu BocHN ~ o ~ o ~ 0n" 'lr ~ 0n 1

OH - o ,, ..

Me '~. l IP '~ 1: -) BocHN ~ 0Me: çOIBu ~ ._Jl. ~ ._Jl. 0 ~: ~ Me 142F

OH

M BocHN ~ _t •: çOH ~ .Jl: ~) /, - 'fiH ~:, .. 142F MS (ESI) m / z 925.4 (M + H) "H2N ~ ~ 143F

OH BocHN MS (ESI) m / z 925.4 (M .. Hr N.::::,.1 MS (ESI) rrJz 1090.S (M + Ht Me TrtHN ~ Je10t ~ .Jl r: H Cl ~ I ~ IP 'BocH "iz oo"', ç · ...: ~ '') (: ~~ ~ 1 ~ _.ll ~ _.ll OH ~: ~ '1,., ..-::' 1 O Me BocHN ..._.) 144F BoeHN ...._) 145F MS (ESI) rrJz 1081.4 (M + H) "BocHN ~ Ma ~ I ~ 0 ~ uc ~ J:; º" Ma Mo :: ,, ,. IP 'Mo OtBu BocHNZ ~ 1 ~ 0: ç ~ 0 "o

OH º 'o -......, "o! ::,. - the BocHN) 146F DocHN ...._) 147F MS (ESI) rr.Jz 966.6 (M + H)' MS (ESI) rrJz 965.4 (M + H) ° BocHN ~

M

IH OH O ~ 0: ç ~ Yl OH: ~ o ... ~) HBoc 148F MS (ESI) m / z 911.4 (M + H) "

~ "* OIBu TrtHNZ ~ oo ~ 'U ~ ~~ OH: No. No. BocHN ~ 151F MS (ESI) rnJz 987.5 (M + H)' ..., ~, PM • o ~ Otsu BocHNZ o ~ 1 ~ 0 ~ xr ~ rN o OH BocHN) 153F MS (ESI) mJz 953.5 (M .. Hr CI ~ HtN ~ ~ ~ ._ll 1 Me Me ~ '?' Oo 1 U._Jl jªOH: - ~ • N ~ .. . o H, N.) 155F 01 ~ Bu ~~ x; ~ ;? li • TrtHNZ ~ OH Mo HO - O Me Ny-1 ~ 0N OH "1 Me O BocHN) 156F BocHN .._.) 157F MS ( ESI) rrlz 915.5 (M • l · Boc • + H) "... ~ ~ ~ BocHNZ ~ ~.; Nx; ~.; N Me Bu 1 08- ... 1 _ .. N" Me O Me 159F

THE

OH 118 MS (ESI) mlz 881.6 (M + H) "Me BocHN) ~ ;;: y;, tt ~ º" tBuO ~ o 183F MS (ESI) rr / z 896.5 (M + H) 'Me .. BocHN , <; Me ... oo ~ ~ 0 ~ \ u0N - 0 Mo 0

OH BocilNJ 185F MS (ESI) mlz 853.5 (M + H) "

~ -A _._ ogOMo

N ':' '~ U-A_, CI ~ U_) l ~ Yº "ú';: ~ oH ~" Y NH OH = H = H l H Me "-NHB oc O Me 167F BocHN .._.). 166F MS (ESI) mlz 875.1 (M + Hf MS (ESI) m / z 945.3 (M + H) 'CI ~ BocHNZ o BocHNZ o U_Jl U_) l OH ~ ~: ~ "-NHBoc O Me O 168F 169F MS ( ESI) rrJz 946.1 (M + Ht uf ~ - \ Yt ~ "-NHª-- 1: ~ u) - ~ .Ay / ::) _- ~ .Jy'l: ~ '..., ... Me O: ........ O Me O 170F MS (ESl) m / z.611.S (M + Hf NHBoc

I 171F MS (ESI) m / z 840.9 (M + H) "Cl ~: r H ~ NHBoc 1 'ff" "oo!; ..... Cl ~ p H 1: V 1 o, çNHBoc o ;; M • M1 ~ 1 N_Á ~ _.Jl OH ~ N0N U_.JlN OH: ~: ~ iH ÕH ~ o ~ o ........ ~ o NHBoc 1 172F NHBoc 173F MS (ESI) mJz 817.4 (M + H) 'Me ~ I ~ BocHNZ M ~ I BocHNZ ~ i: V o u0n "lruJln) oM • yOIBu o Me o

OH BocHN :: r '~ o (Ng Ç Pnu) l ~ o M • o

OH 181F HN.J. HN, the Me 17'4F Me MS (ESI) m / z 1119.2 (M + Hr HN ~ s' .._. // 1 o li bo Me NHBoc ~ 0N-Ç ~~ - ~ Me ~ H ~>: ° 'ruJl ~~ OH _ ........ 1

H 182F - Me

H 1 ~ 1 ~ _ ,,

THE

The 183F Me The NHBoc M •. & MS (ESI) nVz 837.7 (M + Hf

[256] Using the procedures described in General Methods 6-8, the following carboxylic acids were prepared: Me 191E MS {ESI} mJz C67.4 {M • H} 'Me ~ 1 1 ~ ~ .Jl, ~ · ~ JM • Ot8u T?;: Uo ~ 1 ~

O ~ .Jl, ~ · ~ .Jl M • 0.Bu BocHN ~ "" l (i ~~: H "" l (i ~ -y: ~ OO) Mo O r.te O o O "" '! O Mo O BocHN 192G Boci <N ....,) 193G Mt ~ :: ... ~ j ~ 0rM ~ M • Mo ~ ~ tB..0 O "_.lM • x; Bu ~ _.li. .. Mox; O.O or "" l (, NO;: N

H 1 HO Mo HON "" lr '~ 0 ~ ~ 0 ~ H llocHN' \ OO.) O Mo O ...._ / 19-lG MS (ES!) RrJz881.4 {M • H) "BocHN 195G li '~ ::: ,, .. j I ~ ~ o "º Y-nXf' {n llocHN '\ ...._ / llo OtBu 196Q {N ~ Trt

N

OH Mo '= ~ v ~ "~

J

J BocHN llocHN o U. o 1970 NHTrt o MS (ESI) mz 1161.5 (M • H) 'MS (ESI) rrl% 1209.6 (M • Hr

OtBu TrtHM

~ = "lr =). ~ Vgu '-" vu) l ~ \ = J-2 "' li 1 BocHN 1 O BocHN

: =).) ~~ IH • ~ - 8 • H 0 O º) ... o) - BocMN .._ J 215F BocHN .._ J 21SF MS (ESI) rrlz 1on.4 (M + 11). MS (ESI) rrlz 1223.5 (M + H) '

NHll <> c 8ocHN ~ - ~ "'~~~ --- J-ç / n ~' (nooo 111e0tau º ~, Jtt fef ~ 0" 2210 ... & ocHN 11 2220 • (ESI) rr / z 950. - '(M .. H)' MS (ESI) rrlz 1008.5 (M • H) '230H MS (ESI) m / Z 1088.8 (M + Na)'

[257] General Method 9: The coupling of an aminoboronate ester to a carboxylic acid is described in Scheme XIX.

Scheme XIX

[258] Compound 3F (1 eq) 'HATU (2' eq) and aminoboronate ester 3Fl (1, 5 eq) were added to a round bottom flask, and cooled in an ice bath. DCM and DMF were added in a 3: 1 ratio (0.03-0.05 M). In cases where the solubility is limiting, additional DMF can be added. After 15-30 minutes, the reaction was allowed to warm to room temperature and stirred for 30 minutes. After LCMS analysis showed that the reaction was complete, the mixture was partitioned between DCM and water, and the aqueous layer was extracted twice with DCM. The combined organic layers were washed sequentially with diluted HCl (<0.1 M), NaHC0 3 solution and brine. The solvent was removed under reduced pressure. The solid residue was washed with acetonitrile to give the desired compound. In cases where there is excess DMF remaining, the residue was distributed between EA (300 mL / mmol) mL): water (100 mL / mmol). The organic layers were washed sequentially with water and brine, and dried over Na 2 SO 4 • The mixture was filtered and concentrated, and the resulting solid was washed with acetonitrile.

[259] General Method 10: Deprotection of acid-sensitive protecting groups (N-Boc, 0-t-butyl, and / or C (O) NH-trityl) with TFA and triethylsilane. A fully protected Compound 3G solution (100 mg, 0.070-0.12 mmol)

in TFA: DCM: TES (50: 45: 5) (1 ml) was stirred at room temperature for 30 min. When LC-MS analysis showed that the reaction was complete, TFA was evaporated and ELSD showed that the reaction was complete. The crude residue was then taken up in DMSO and purified by HPLC-prep. In cases where the mobile phase was acetonitrile / water with 0.1% TFA, the resulting salt is the TFA salt. In cases where the mobile phase was acetonitrile / water with 0.1% HCl, the resulting salt is the HCl salt.

[260] A representative example of General Methods 9 and is shown in Scheme XX. Scheme XX

[261] Compound 173: A vial containing Compound 173F (100 mg, 0.12 mmol), HATU (91 mg, 0.24 mmol), then 3F2 (47 mg, O, 18 mmol) was placed in an ice bath. DCM (2.4 ml) and DMF (0.80 ml) were added. To this mixture was added DIEA (46.2 mg, 0.358 mmol). After 15-30 minutes the reaction was warmed to room temperature and stirred for 30 minutes. After ELSD showed that the reaction was complete, water (1 ml) was added and the mixture was filtered. The filter cake was washed sequentially with water and petroleum ether to obtain compound 173-1 (70 mg, 56%).

[262] A solution of 173-1 compound (70 mg, 0.069 mmol) in TFA: DCM: TES (50: 45: 5) (1 mL) was stirred at 23 ° C for 2 hours until ELSD showed that the reaction was complete then TFA was evaporated. Then, the crude residue was taken up in DMSO and purified by preparative HPLC to give Compound 173 (13 mg, 23%).

[263] General Method 11: The deprotection of the pinanediol protection group to free boronic acid by transesterification with Ph (BOH) 2 is described in Scheme XXI. Scheme XXI

[264] A solution of pinanediol (0.05 mmol) in water (2 mL) was stirred for five minutes, until the compound dissolved and formed a clear solution. Ether (3 ml) and phenylboronic acid (3 eq) dissolved in water (1 ml) were added. The mixture was stirred at 25 ° C overnight. After LCMS analysis showed that the reaction was complete, the water layer was evaporated under reduced pressure. The crude residue was washed with Et 2 0 to obtain the free boronic acid (25.0 mg, yield: 74.6%). If further purification is required, the crude product was dissolved in DMSO and purified by preparative HPLC. In cases where the mobile phase was acetonitrile / water with 0.1% TFA, the resulting salt is the TFA salt. In cases where the mobile phase was acetonitrile / water with 0.1% HCl, the resulting salt is the HCl salt. A representative example is shown in Scheme XXII. Scheme XXII Cl ~ I :::, ... P o ~ NH2 o, çM • Mo M ~ • "'• r.ae o' · 0 ~ :::, ... 1 o 0 '! ~ ~ Me ~ o ~ '(it's .. Me PhB (OHh ether /: water NHz 173 CI ~ :::, ... 1 PO ~ NH2 O ~ Me Mo OH :::, ... 1 ~ 0 ~ ~ 0 ~ ~ yé ..OH '! Me Me NH, 177

[265] A solution of Compound 173 (9.0 mg, 0.011 mmol) in water (2 mL) was stirred for five minutes, until the compound dissolved and formed a clear solution. Ether (3 mL) and a solution of phenyl boronic acid (4.00 mg, 0.033 mmol) dissolved in water (1 mL) were added. The mixture was stirred at 23 ° C for 12 h. After LCMS showed that the reaction was complete, the water was evaporated. The crude residue was then washed with Et 2 0 to give Compound 177 (7.0 mg, yield: 93%) as an off-white solid.

[266] Using the procedures described in General Methods 9 and 10 for the preparation of boronate esters or General Methods 9, 10 and 11 for the preparation of boronic acids, the following boronate ester or boronic acid was prepared from the corresponding carboxylic acid described above:

'~ li • li H, N O lle?' =} n = yln r '-; _)) 5 Me ~') '~ 1-J ~ X ("uJ? OH ~ e.): •• i H • ... o: ... 13 HN) lfiN) '135 • MS (ESI) rrlz 901.4 (M + H) "MS (ESI) mh. 722.2 (M. H, O. Hr 11 ... t: çOK ~ ff ~ NH ~; ~ 110 U'i "" HH, N ~ "'° 3: JTº111 • ~ HY' O ~ ..,) l oU.'V '~ u_il ur "' • ~) i Jg,}. : H Íq H Íq Ih

J H1N 1.cQ MS (ESl) m1Z860.4 (M + H) '• ~ • 141 n Y io' O H, N MS (ESI) rr / z 83'.5 (M + 11) '

[267] Using the procedures described in General Methods 9 and 10 for the preparation of boronate esters or General Methods 9, 1 O, and 11 for the preparation of boronic acids, the following boronate esters or boronic acid of varying length were prepared at from the corresponding carboxylic acid, described above:

191 MS (ESI) rnl.t 62: 0.3 (M · H; iO • H) '

. ~~ '~ "' u ~ · ~ MS (ESl) ~ 04

923.4 ("1+ Ht uJ: çºH OH, ç · ll ij • n U -.) 1 .. o

U IM ~ -0. Me...

? 0 HOlle: çOH "] ('-.)! .. º J • n • uyt .. • H?; O •" u .., .. ••' "" \

J '.) ....., .. ~ se "...., ~ n lj'O H, N W Q. MS (ESl) ~ 08

959.4 (M + H) "MS (ESI) mlz207

086.5 (M • H) '

MS (ESI) mt.? 955.4 (M + H) 'MS (ESl) ~ 18

971.8 (M + H) '... ~ H ......-_.,. H_.ll y- · O MYtllAe ng ~ 0n'.SY ~ vr) -. T H H OMa OH ...

º g i H, N \ ..._ / iMe 21

O • li MS (ESI) m / z. 914.4 (M + Hr ~~ I '"~ JAr-Oy ~) ...' CN; ·" y • -... o • •• "o • ~ NH H, N ~ MS 220 Mo (ESI} mli 7 89. 3 1M. HP + H) ". ~~~ O ~., J.N 1 221 9-Y ~ _l "º 0 ,,. •" H 0 _ .; O H 9H · ~ · -; ~

OH "" '+ lf} ° m l 803.3 (M. H · "'

Examples 131-150

S ema XXIII

5- <N) o. "" 'C ~ N ~ () hi BocHNZ FmocHN .__) l ...

58 ~ to 00 ~,; .. CI ~

1.01 ::: H2N, ~. OY ':' \ 1. HCTU, HOBT OJ!> EA .. "" Ol <-. p1pen.-.... • 'd'm: u' Q ••. ·· 5A2 1-dorotritil OMF chloride resin o FmocHN ~ OH BocHN .._ / 50

1. HCTU, HOBT

OIPEA 1% TFA

OCM ZO% piperidin: ai

OMF

[268] Compound SG: The synthesis of Compound 5G is described in Scheme XXI II. The resin mixture of 2-chlorotrityl (0. 320 g, O, 416 mmol), DIEA (0. 215 g, 1.66 mmol) in dry DCM (15.0 mL) was added to a solution of Fmoc-L -Lis (Boc) -OH (0.389 g, 0.832 mmol) in dry DCM (10.0 mL) at 0 ° C. The mixture was then stirred for 5 hours at room temperature. The mixture was filtered and the cake was washed with DCM (20.0 ml x 3), DMF (20.0 ml x 3), MeOH (20.0 ml x 3). To the above resin, 20% piperidine / DMF (approximately 20.0 ml) was added to remove the Fmoc group. The mixture was stirred for 10 min, and the cycle was repeated three times. The mixture was then washed with DCM (20.0 ml x 3 ml) and DMF (20.0 ml x 3) to give Compound 5A2.

[269] To the mixture of Fmoc-L-Ala-OH (0.259 g, 0.832 mmol) in dry DMF (15.0 mL) were added (0.344 g, 0.832 mmol), HOBt (0.112 g, 0.832 mmol), DIEA (0.215 g, 1.66 mmol) at 0 ° C. Then, the mixture was stirred at 16ºC

192 / 2SS for 30 minutes. The mixture was added to the suspension of Compound SA2 (0. 416 mmol) in DMF (10.0 mL). The mixture was stirred at room temperature for 1.6 hours. After ELSD showed that the reaction was complete, the mixture was filtered. The cake was washed with DMF (3 x 20.0 ml), DCM (20.0 ml x 3). To the above resin, approximately 20.0 ml of 20% piperidine / DMF was added to remove the Fmoc group. The mixture was stirred for 10 min, and the cycle was repeated three times. The mixture was then washed with DCM (20.0 ml x 3 ml) and DMF (20.0 ml x 3) to give Compound SB2.

[270] Compound SC2 was made using the same method as described for Compound SB2 except that Fmoc-L-Thr (tBu) -OH was used in the coupling reaction instead of Fmoc-L-Ala-OH.

[271] Compound SD2 was made from Compound SC2 using the same method as for Compound SC2, except that Fmoc-L-Dab (Boc) -OH was used in the coupling reaction instead of Fmoc-L-Thr ( tBu) -OH.

[272] A mixture of Compound SD2 (2.00 mmol) in TFA / DCM (1%, 20.0 mL) was stirred at 1 ° C for 10 minutes. The mixture was then filtered and the filtrate was treated with saturated NaHC03 solution at pH ,,, 7 8. The mixture was treated with DCM (20.0 ml). To the aqueous layer, citric acid was added until pH 3-4. The mixture was extracted with DCM (20.0 ml x 3). The combined organic layers were washed with brine, dried over Na 2 SO4 and concentrated to give Compound SE (1.1 g, 61% S). MS (ESI) m / z 919.3 (M + Na) +.

[273] The compound SE (2SO mg, 0.279 mmol), HATU (212 mg,

0.558 mmol) and compound 3F2 (108 mg, 0.419 mmol) were placed in a flask in an ice bath, then DCM (2.40 mL) and DMF (0.800 mL) were added. DIEA (108 mg, 0.837 mmol) was then added to the mixture. The reaction mixture was stirred at -5 ° C for 30 minutes. The crude residue was taken up in DMSO. A second experiment from 250 mg of compound SE was repeated and combined with this experiment. The combined batches were purified by preparative HPLC to give Compound SF (200 mg, 81.4%) as a white solid. MS (ESI) m / z 1102.4 (M + H) +.

[274] To a solution of Compound SF (400 mg, 0.363 mmol) in MeCN (3 mL) was added Et 2 NH (79.6 mg, 1.09 mmol). The mixture was then stirred at 16ºC for 12 hours until TLC (DCM: MeOH 10: 1, Rf = 0.5) showed that the reaction was complete. The mixture was concentrated and the residue was purified by column chromatography to give Compound SG (280 mg, 87.8%). MS (ESI) m / z 880.6 (M + Na) +.

[275] General Method 12: Coupling of Compound SG with a carboxylic acid, in solution phase, followed by deprotection of acid-sensitive protection groups with TFA in the presence of a reducing agent. A specific example is shown in Scheme XXIV to illustrate this method. Scheme XXIV

[27 6] Compound 231: To the mixture of Compound 5G (60 mg, O, O68 iranol), 4- (4-t-butylphenyl) benzoic acid (17, 3 mg, O, 0683 mmoi), EDCI (26 , 2 mg, O, 137 mmol), HOBt 18, 4 mg, 0.137 mmol) in DMF (2.00 mL) was added DIEA (17.6 mg, 0.137 mmol). Then, the mixture was stirred at room temperature for 12 hours. When TLC analysis (DCM: MeOH 10: 1, Rf o, 5) showed that the reaction was complete, the mixture was diluted with water, filtered and the filter cake was washed with water, dried to generate Compound 231H ( 50 mg, yield: 63.3%) as a brown solid.

[277] A solution of Compound 231H (50.0 mg, 0.0448 mmol) in TFA: DCM: TES (50: 45: 5) (2.00 mL) was stirred at 12 ° C for 0.5 h, then TFA was removed and ELSD showed that the reaction was complete. The crude residue was taken up in DMSO and purified by preparative HPLC to give Compound 231 (6.3 mg, 16.4%) as an off-white solid. MS (ESI) m / z 860.6 (M + H) +.

[278] Using the procedures described in General Method 12, the following compounds were prepared:

"J: · .ly · ~ ~ ·· M ~ · M · ~ _ÂN - · ~ ~. FlC ~ I 'Nz!? 1 CFi M •: çOH) HH Me o · ~ <N: o M •: çOH OH l '"MS (ESI) .. H i oli H o" N .........- "N: o (' HH ,: ,,. Mi • Ol'U (M •• ,. ; ::, .. 'f?' j "- '" - ""' • 'li "Oo o •• ...

M •: çOH HiNZH áOH O ('NH2 MS (ESI) rrJz237872.1 (M + H) ° ~ _ÂN Ny' OH

THE

The UJ, NH, ('"oo." (ESI) o mlz .. MS ,,. (M • H20 • H)'

709.1 M •: çOH "" ZOH l M'1J • .. ••., H o ~ ...) l ~ Ny 'N ...) lN ~ HO: Me O Me ~ Hi / 239 MS (ESI) m / z 842.2 (M + H) 'Me OH OHzNZ á ~ ~ · - ~~ M • li: çH

H 'f?' MeH O li N ........, ...... NN: - 'O; ::, .. 1 N .........- "N: H; Ma H o M • 0 O ', 241 Ht NHz (ESI) m / z 874.3 (M +? $ Mo "" Z ~ · - .. 1 ~' f? '1 Ml: çOH: ") u MS ••.,. . "': -l_, u.) .. ~ u0n- \' i:" 'º "or & V MS (ESl) m / Z86 ~ 2.5 ~ ~ Yl ~ g ~ ~ H;" •• .. (' "'0 y ··· UJ yMo., NH1 (M ,,. + -6- O Me', NH. • MS (ESI) mlz 874. 243 8 (M + H)"

Example 151

[279] General Method 13: The synthesis of biaryl or an arylheteroaryl carboxylic acid from 1-bromo-4-butylbenzene and an aryl or heteroaryl boronic acid. An illustration of this method is described for 4- (4-butylphenyl) benzoic acid.

[280] A solution of l-bromo-4-butylbenzene (100 g, 0.472 mol), 4- (methoxycarbonyl) phenylboronic acid (82.0 g, 0.456 mol), 2 M Na 2 C0 3 (150 g, 1 , 42 mol) in toluene / EtOH (900 ml / 300 ml) was degassed with N2 three times,

then Pd (PPh 3) 4 (27, 2 g, 23, 6 mmol) was added. The resulting mixture was degassed with N2 three times and then heated to reflux for 5 hours. After TLC showed that the reaction was complete, toluene and EtOH were removed in vacuo. The residue was extracted with EA (30 ml x 3). The combined organic layers were washed with brine, dried with Na 2 SO 4 • The solvent was removed to give the crude product. The crude product was purified by column chromatography on silica gel eluted with PE, PE: EA (150: 1). The solvent was removed to give methyl 4 (4-butylphenyl) benzoate (105 g, yield: 86.0%), as a white solid.

[281] A mixture of methyl 4- (4-butylphenyl) benzoate (89.0 g, O, 332 mol), NaOH (26.6 g, O, 664 mol) in THF / H 2 0 (500 ml / 100 mL) was heated to reflux overnight. After TLC showed that the reaction was completed, THF was removed. The residue was adjusted to pH ~ 3-4 with 2N HCl solution. The resulting mixture was filtered and the cake was washed with water, dried to give 4- (4-butylphenyl) benzoic acid (60.0 g, yield: 71.1%), as a white solid. (ESI) m / z 255.0 (M + H) +.

[282] General Method 14: The synthesis of a biaryl or arylheteroaryl carboxylic acid from 4-butylbenzenoboronic acid or pinacol 4-butylbenzenoboronic acid and an aryl or heteroaryl halide. An illustration of this method is represented by Compound 248A. A solution of pinacol 4-butylbenzenoboronic acid ester (937 mg, 3.60 mmol) in dioxane / H 2 O (40 mL, v / v, 1/1) was added to Compound 14A (400 mg, 1.80 mmol) and K2 CO 3 (497 mg, 3.60 mmol). The mixture was then degassed with N2 3 times before the addition of Pd (dppf) Cl2 (132 mg, 0.180 mmol) and degassed with N2 3 times. The mixture was heated to reflux for 7 hours. The reaction mixture was cooled to room temperature and then concentrated after TLC had shown that the reaction was complete. The residue was adjusted to pH ~ 4-5 with 1 N HCl solution. After that, the resulting mixture was filtered and the filter cake was washed with water, dried to give Compound 248A (200 mg, yield: 42.6%), as a brown solid.

~, /, r) and C-0-M and _ o 241A

S 1

OH u oliley0! 8u ~ _.ll ~ U_.ll O \ MeMe

OH Y ~ i. ~ ::, A; .i :: --- & \ n O Qe ~ -HA-JU- (2_eq_) IO_IEA (-3e-q-) 1 BocHNJ 1980 DMF (1.5ml) IDCM ( 'mL) ~ Pd (OH) iMeOH TFAIDCWJEt ~ iH

[283] Compound 251: To a mixture of Compound 198G (100 mg, 0.112 mmol), HATU (85.1 mg, 0.224 mmol), and Compound 251A (61.4 mg, 0.168 mmol) in DCM (2.4 ml) and DMF (0.5 ml) at 0 ° C DIEA (43.3 mg, 0.336 mmol) was added After 15-30 min, the reaction was allowed to warm to room temperature and stirred for 30 min. After ELSD showed that the reaction was complete, the mixture was extracted with DCM (30 ml) and water (15 ml). The resulting mixture was extracted with DCM (30 ml x 2). The combined organic layers were washed with dilute hydrochloric acid HCl (<0.1 M), then NaHCO 3 solution, brine. The solvent was removed and the residue was extracted with EA (30-50 ml): water (10-15 ml). The organic layers were washed with water (2 ml), followed by brine, dried over Na 2 SO 4 • The mixture was filtered and the filtrate was concentrated. The crude residue was purified by means of prep-HPLC to give Compound 251H (50.0 mg, yield: 37.1%). MS (ESl) m / z 1206.7 (M + H) +.

[284] A suspension of Compound 251H (50.0 mg,

0.0415mmol) and 50% Pd (OHh (10.0 mg) in MeOH (2 mL) in H2 was stirred at 25 ° C overnight and ELSD showed that the reaction was complete. The catalyst was filtered and the solvent was evaporated, the crude residue was purified by preparative HPLC to give Compound 2511 (20.0 mg, yield: 43.2%>). MS (ESl) m / z 1116.6 (M + H) +.

[285] A solution of Compound 2511 (10.0 mg, 0.0090 mmol) in TFA: DCM: TES (50: 45: 5) (1 mL) was stirred at room temperature for 2 hours, then TFA was evaporated and ELSD showed that the reaction was completed. The crude residue was taken up in DMSO and purified by preparative HPLC to give Compound 251 (2.8 mg, yield: 33%). MS (ESl) m / z 960.8 (M + H) +. Example 152

[286] Compound 252: 252 g of the compound was prepared according to general methods 6 8. MS (ESI) m / z 1153.4. Compound 252 was prepared using the methods described for Compound 111 from Compound 252G and Compound K4. MS (ESI) m / z 852.2 (M + H) +. Example 153

H O o acetone ~ Boc "" 'N ~ OH l.AH / THF li cyanohydrin Boç_ .. "' (" 'H - - - - 1 .... Ma ii.e 253At 253A3

OH OH H ~ 1 Bo ~~ 0CN MoOHIHCI NH: iJMoOH Y "" cONH 2 Me Me 253A.C 253Ati

[287] Compound 253: To a mixture of Boc-L-Ala-OH (50.0 g, O, 265 mol), Compound 253B (16, 1 g, O, 265 mol), and DIEA (102.4 g , 0.794 mol) in DMF (600 mL) HOBt (39.9 g, 0.91 ml) and E DC I (6.6, 0 g, O, 4 4 ml) were added at O ° C. The mixture was stirred overnight at 26 ° C. After LCMS showed that the reaction was completed, the mixture was extracted with BuOMe mandate and H2 0. The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated to give Compound 253 A2 (50, O g, yield: 81.5%).

[288] A solution of LAH (2.16 g, 51.7 mmol) in dry THF (70 mL) was stirred with a superior stirrer and cooled to 15 ° C. A solution of Compound 253A2 (12.0 g, 51.7 mmol) in dry THF (80 mL) was added, with cooling to maintain the reaction temperature <5 ° C. The reaction mixture was stirred for 45 min and was stopped by the slow addition of EA (20 ml) maintaining the internal temperature <5ºC. The combined organic layers were washed with sat. aq. NaHC 0 and brine, dried with Na 2 SO 4, filtered and concentrated to give the

202 / 2SS Compound 2S3A3 (10.0 g, yield:> 90%).

[289] To a solution of Compound 2S3A3 (10.0 g, S7, 8 mmol) in dry DCM (100 mL) was added Et 3 N (7.01 g, 69.4 mmol) and acetone cyanohydrin ( 9.83 g, 116 mmol) at 26 ° C. The reaction mixture was stirred overnight at 26 ° C. After TLC showed that the reaction was completed, the reaction mixture was diluted with a 1 N aqueous solution of concentrated HCl (30 mL) and extracted with DCM. The combined organic layers were washed with H2 O and brine, dried over Na 2 SO 4, filtered and concentrated to give Compound 2S3A4 (4.00 g, yield: 34.6%).

[290] A mixture of Compound 2S3 A4 (3.00 g, 1S, O mmol) in HCl / MeOH (30 mL) was heated to reflux for 1 hour. After ELSD showed that the reaction was complete, HCl / MeOH was evaporated to give Compound 2S3 AS (3.00 g, yield:> 90%).

[291] A mixture of Compound 2S3 AS (3.00 g, 17.7 mmol) in NH 3 / THF (30 mL) in a sealed tube was heated to 100 ° C overnight. After ELSD showed that the reaction was complete, the mixture was evaporated to give Compound 253A6 (1.30 g, yield: 62.2%). MS (ESI) m / z 852.2 (M + H) +.

[292] To a solution of Compound 146F (18 mg, 0.02 mmol) in anhydrous DMF (1 mL) were added HATU (15 mg, 0.04 mmol), DIEA (8 µL, 0.06 mmol) and 253A (5 mg, 0.03 mmol). The mixture was stirred at room temperature overnight. After LCMS showed that the reaction was complete, crushed ice was added to the reaction mixture and after standing for about an hour a white solid was precipitated. The solid was filtered and dried to produce the

Compound 253 G. The solid was dissolved in anhydrous DCM (2 ml) and Dess Martin periodinane (DMP, 5 eq, 0.1 mmol, 42 mg) was added. The reaction mixture was stirred for 24h. After LCMS showed that the reaction was complete, the reaction mixture was diluted with DCM-EtOAc (1: 1), washed with saturated NaHC0 3 solution and brine, dried (Na 2 SO 4) and concentrated. The residue was purified by means of an ISCO column (DCM and 20% MeOH-DCM) to isolate 9 mg of Compound 253H as a white solid. To a solution of Compound 253H in dioxane (1 ml) was added 4N HCl in dioxane (0.3 ml) at 0 ° C and the resulting solution was stirred at room temperature for 2 h while warming up to the reaction temperature to room temperature. After LCMS showed that the reaction was complete, the material was left to stand for about 10 minutes. A gummy material formed and the supernatant dioxane were removed and dry ether was added and stirred for 5 min. The white precipitate was formed. The ether layer was removed and the solid was dried to produce Compound 253, a white solid, like the bis-HCl salt. MS (ESI) m / z 793.3 (M + H) +.

Example 154 [293) Compound 254: Compound 254A was prepared in a similar manner to Compound 253A using Boc-D-Ala-OH as the starting material. Compound 254 was prepared in a similar manner to Compound 253 from Compound

146F and Compound 254A. MS (ESI) m / z 793.4 (M + H) +. Example 155

H H Cbz-N ,, Cb & -N.-.

op.'H DMF, 85% op.'OMe 1N HCI, EtOH 60 6E Mo H2 N ,. CbzHNZ Mo O O rMo ~ 0N ~ 0N ~ OH O.) :: J'OMe 6F O \ H O Me H O CbzHN ..._ J 255F Ma CbzHNZ Me

H · Y-n ºJ- · 0 ~, (;

THE . oµ ,. THE

H Mo O ~ e OMe CbzHN 255G Mo CbzHNZ Me H O H ~ • H2 N0 ~ N0 ~~ N ,,,.

O CbzHN J- O 255G Me O · ri or "'' oMo 10% Pd-C ui.Zu) -.- <: ~.:..: H · ri o Me HO H2N J 255 O ,,? - N ,Oman

[294] Compound 255: Compound 6D (Tetrahedron (1983), Vol 39, N2 15, 2571-2575) was dissolved in DMF and treated with K2 CO 3 (1, 1 eq) and iodomethane (2, 5 eq) and left to stir for 4 hours. The reaction was then quenched by adding water and a small amount of brine and extracted 3x with EtOAc. The combined organic fractions were washed with 1% citric acid and brine, then dried over sodium sulfate and concentrated. The crude material was purified by ISCO silica gel chromatography (0-50% EtOAc in Hex, compound eluted at 40% EtOAc) to give Compound 6E 1 (75% yield). H-NMR (CDCl 3) ó 7.35 (m, 5H), 5.41 (broad s, lH), 5.112 (s, 2H), 4.61 (m, lH), 3.84 (m, lH) ), 3.81 (s, 3H).

[295] To a solution of Compound 6E in EtOH was added 1N HCl (2 eq). The solution was then placed under a nitrogen atmosphere and 10% Pd / C (50% by weight of starting material) was added. The solution was then placed under an atmosphere of hydrogen and hydrogen was allowed to bubble through the solution. After 3 hours, the mixture was filtered through celite and concentrated to give Crude Compound 6F.

[296] Compound 25SF was prepared according to General Methods 6 - 8. MS (ESI) m / z 963.2 (M + H) +.

[297] To a slightly cloudy solution of Compound 255F and Compound 6F (4 eq) in anhydrous DMF were added HATU (1, 2 eq) and DIEA (5 eq). The reaction was complete as assessed by LCMS after 10 min and water and DCM were added. The aqueous layer was extracted 3x with DCM, then the combined organic fractions were washed with water (2x) and then with brine. The solution was then dried over sodium sulfate and concentrated. The crude material was then passed through a silica plug to provide Compound 255G (75% yield) (MS (ESI) for (Cs7H72N 80u): m / z 1067, 5 (M + Na).

[298] To a cloudy solution of Compound 255G in EtOH was added 1N HCl (2 eq). The solution was placed under a nitrogen atmosphere, then 10% Pd / C (100%), by weight, of the starting material was added. The mixture was placed under an atmosphere of hydrogen and stirred overnight. The mixture was then filtered through celite and evaporated to obtain compound 255 by LCMS. MS (ESI) for m / z 815.4 (M + Na). Example 156 HaN ,,, (\ N / f "'' 'oMe O 6F HATU / OIEA Me ...

Me

[299] Compound 256: Compound 256F was prepared according to General Methods 6 - 8. MS (ESI) m / z 947.3 (M + H) +.

[300] To a solution of Compound 256F and Compound 6F (4 eq) in anhydrous DMF were added HATU (1.2 eq) and DIEA (5 eq). The reaction was complete as assessed by LCMS after min and water, a small amount of brine and EtOAc was added. The aqueous layer was extracted 3x with EtOAc, then the combined organic fractions were washed with diluted citric acid, water and then brine. The solution was then dried over sodium sulfate and concentrated. The crude material was purified by ISCO silica gel chromatography to provide Compound 256G (41% yield). MS (ESI) for m / z 799.4 (M + Na).

[301] To a solution of Compound 256G in EtOH was added 1N HCl (1, 9 eq). The solution was placed under a nitrogen atmosphere, then 10% Pd / C (100%), by weight, of the starting material was added. The mixture was then placed under an atmosphere of hydrogen and stirred overnight. The mixture was filtered through celite, then the diluted filtrate was checked by LCMS and found to give the correct mass (MS (ESI) for (C 41 H60 N 8 0 7): m / z 799.4 (M + N)). Example 157 o ~ Cbz- ~,. '· Br ~ Me LI Cbz-' '• n Pd / C, H2 o.:: = J'OH K2C ~. OMF, 85% orN'o \. 1N HCI, EtOH fr · OMe 60 7A O Mo Mo ...

Mo

[302] To a solution of Compound 60 in anhydrous DMF was added K2 CO 3 (1.1 eq) and methyl bromocetate (1.5 eq). The mixture was stirred at room temperature until TLC indicated complete consumption of the starting material, after 2.5 hours, then diluted citric acid and EtOAc were added. The aqueous layer was extracted 3x with EtOAc, then the combined organic layers were washed twice with water and then with brine. The combined organic solution was dried over sodium sulfate and concentrated to give the crude product, then purified by ISCO silica gel chromatography (0 to 65% EtOAc in hexanes - product eluted at 60% EtOAc) 1 to give Compound 7A (73% yield). H-NMR (CDCl 3) ó 7.35 (m, 5H), 5.31 (br s, 1H), 5.11 (s' 2H), 4.62 (m, 1H), 4.55 (s 2H), 3.99 (m, 1H), 3.79 (s, 3H), 3.67 (m, 1H).

[303] To a solution of Compound 7A in EtOH was added 1N HCl (2 eq). The solution was placed under a nitrogen atmosphere and 10% Pd / C (100% by weight of starting material) was added. The solution was then placed under an atmosphere of hydrogen and hydrogen was allowed to bubble through the solution. After 2 hours the mixture was filtered through celite and concentrated to give compound 7B.

[304] A solution of Compound 256F (10 eq) in anhydrous DMF was added to Compound 7B, then HATU (1.2 eq) and DIEA (10 eq) were added. The reaction was stirred at room temperature for 4.5 hours, then water and EtOAc were added. The aqueous layer was extracted 2x with EtOAc, then the combined organic layers were washed with water (2x), diluted citric acid, and brine, then dried over sodium sulfate and concentrated. The crude material was then purified by filtration through a silica plug to give Compound 257G (56% yield) (MS (ESI) to (Cs9H74Ns013}: m / z 1103, 2 (M + H)).

[305] To a solution of Compound 257G in EtOH was added 1N HCl (1, 9 eq). The solution was placed under a nitrogen atmosphere, then 10% Pd / C (100%, by weight, of the starting material) was added. The mixture was then placed under an atmosphere of hydrogen and stirred overnight. The mixture was filtered through celite, then the diluted filtrate was checked by LCMS and was found to give the correct product. MS (ESI) for (C43 H62 N8 0 9): m / z 8 5 7, 4 (M + Na). The filtrate was then concentrated to an 8 mg / ml solution in EtOH and again checked by LCMS which showed a mass spectrum identical to that of the diluted sample. Compound 257 was stored as an 8 mg / ml solution. Example 158

H Boc-N ~

DCC ... op'osn

SB

H Boc-N ,,, ..

P .. J 20% TFA ... O _.- 'oMo se 80

[306] To a solution of Boc-D-Ser-OH (1.5 g, 1 eq) in THF (54 ml) was added a solution of 0-benzylhydroxylamine (1.3 eq) in THF (3 ml ), H2 O (30 mL), and a solution of DCC (1.3 eq) in THF (3 mL). The solution was stirred at room temperature until LCMS analysis indicated that the starting material had been consumed (1 hour), at which point the THF was evaporated by rotary evaporation.

EtOAc and water were added to the residue and the aqueous layer was extracted 3x with EtOAc and the combined organic layers were evaporated.

The crude residue was then taken up in a small amount of EtOAc and filtered.

The filtrate was diluted with EtOAc, washed with 5% citric acid, saturated NaHC0 3 solution and brine, then dried over sodium sulfate and concentrated.

The crude residue was purified by chromatography on ISCO silica gel (20% to 90% EtOAc in Hex, product eluted at ~ 90% EtOAc) to give pure Compound SA (63% yield). [307] In a dry flame balloon over 4 A activated molecular sieves under Ar, a solution of Compound SA (1 eq) and triphenylphosphine (1.1 eq) in acetonitrile was treated with a solution of anhydrous CC1 4 (10 eq) in anhydrous AcCN and a solution of triethylamine (1.2 eq) in anhydrous AcCN. The mixture was left to stir overnight, then it was filtered through celite and concentrated. The crude material was purified by ISCO chromatography on silica gel (0-3% MeOH in DCM, product eluted at 2.9%) to give Compound BB (62% yield). [30B] To a solution of Compound BB (1 eq) in MeOH under Ar atmosphere was added Raney's Ni in water suspension. The solution was then placed under an H2 atmosphere and allowed to stir at room temperature for 7 hours or until TLC indicated complete consumption of the starting material. The mixture was then filtered through celite and the filtrate was concentrated. The crude material was purified by chromatography on ISCO silica gel (0 to 6% MeOH in DCM, product eluted at -1% MeOH) to produce Compound BC (79% yield).

[309] In a dry flame balloon under an Ar atmosphere, a solution of Compound BC (1 eq) in AcCN was heated to 50 ° C. The solution was then treated with cesium carbonate (1.2 eq) and methyl bromoacetate (1.5 eq). The mixture was stirred at 50ºC until TLC indicated the complete consumption of the materials, then the reaction was cooled and diluted with EtOAc and water. The aqueous layer was extracted 3x with EtOAc, then the combined organic layers were washed with brine and dried over sodium sulfate and concentrated. The crude material was purified by chromatography on ISCO silica gel (O to 10% MeOH in DCM, the product eluted at 6.5% MeOH) to give Compound BD (36% yield). 1 H-NMR (CDCl 3) o 7, 35 (m, 5H), 5, 41 (broad s, 1H), 5.112 (s, 2H), 4.61 (m, 1H), 3, B4 (m, 1H), 3, Bl

(s, 3H).

[310] Compound BD was treated with a 5: 1 mixture of DCM: TFA in an ice bath. After 2 hours the TLC indicated the complete consumption of the starting material, and the solvents were evaporated. The crude product was collected in DCM and evaporated by rotary evaporation 3x to give a crude compound which was used without further purification.

[311] Compound 258F was prepared using the procedures described in General Methods 6-8 and Scheme XIX.

[312] To a solution of BE Compound (5 eq) and Compound 258F (1 eq) in DMF were added HATU (1.2 eq) and DIEA (8 eq) and the reaction mixture was stirred at room temperature. After 4 hours, the mixture was diluted with water and EtOAc. The aqueous layer was extracted 3x with EtOAc, then the combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated. The crude material was purified by chromatography on ISCO silica gel (0 to 12%, MeOH in DCM, product eluted at -8% MeOH) to obtain the pure compound 258 g (49% yield). MS (ESI) m / z 1087.1 (M + H) +.

[313] To a solution of Compound 258 g in EtOH, under Ar, 1N HCl (1.9 eq) 10%) of Pd / C (100%) w / w) was added. The mixture was then placed under an H2 atmosphere and allowed to stir for 4 hours, at which point TLC indicated the complete consumption of the starting material. The mixture was filtered through celite and concentrated to give Compound 258 as a bis-hydrochloride salt. MS (ESI) m / z

819.3 (M + H) +. Example 159 º "U: NH BocHN ~ · Me ~, ~ ... 11 PdlC, • M • Hi o o · ~~~ ~~~ ~" '! "' ~" () 'NHISoc 259J ...

[314] Compound 259F is prepared using the procedures described in General Methods 6 - 8. MS (ESI) m / z 959.2 (M + H) +.

[315] To a solution of Compound 259F (100 mg, 0.104 mmol), HATU (79.0 mg, 0.208 mmol), and Compound 3F2 (40.4 mg, O, 156 mmol) in DCM (2.4 mL) and DMF (0.8 mL) at OºC DIEA (40.2 mg, 0.312 mmol) was added. After 15-30 min the reaction was allowed to warm to 25 ° C and stirred at 25 ° C for 30 min. After ELSD showed that the reaction was completed, the mixture was extracted with DCM (10 ml) and water (5 ml). The resulting mixture was extracted with DCM (5 ml x 2). The combined organic layers were washed with diluted HCl (<0.1 M), then NaHCO 3 solution, brine. The solvent was removed and the residue was extracted with EtOAc (30-50 ml): water (10-15 ml). The organic layers were washed with water (10 ml), brine, dried over Na 2 SO 4 • The mixture was filtered and the filtrate was concentrated. The residue was crystallized from acetonitrile to give Compound 259g (90.0 mg, yield: 74.3%). MS (ESI) m / z 1165.0 (M + H) +.

[316] To a mixture of Compound 259 g (190 mg, O, 163 mmol) in THF (2 mL) was added Pd / C (50.0 mg) and CH 3 COOH (O, 5 mL) under H2 • A The mixture was degassed with H2 three times before stirring at 25 ° C at 50 psi H2 • After 12 hours, LC-MS showed that the reaction was complete. The catalyst was filtered and the solvent was evaporated, the crude residue was purified by means of prep-HPLC to give Compound 259H (120 mg, yield: 68.5%).

[317] To a solution of Compound 259H (50.0 mg, 0.0466 mmol), HATU (35.4 mg, 0.0932 mmol) and Compound 259B (29.2 mg, 0.0932 mmol) in DCM (0.5 ml) and DMF (0.5 ml) at OºC DIEA (18.1 mg, 0.140 mmol) was added. The reaction was stirred for 2 hours at 0º C. After LCMS showed that the reaction was completed, the DCM was evaporated. The crude residue was taken up in DMF and purified by preparative HPLC to give compound 2591 (15.0 mg, yield: 23.4%).

[318] To a mixture of Compound 2591 (7.50 mg, 0.00548 mmol) in EtOAc (0.5 mL) was added Pd / C (10.0 mg) under

H2 • The mixture was degassed with H2 three times before stirring at 25 ° C under 50 psi H2 • After 12 hours, LC-MS showed that the reaction was complete. Then, the catalyst was filtered and the solvent was evaporated to give Compound 259J (5.0 mg, yield: 76.8%)

[319] A solution of Compound 259J (5.00 mg, 0.00421 mmol) in TFA: DCM: TES (50: 45: 5) (1 mL) was stirred at 25 ° C for 1 hour, then TFA was evaporated and ELSD showed that the reaction was completed. The crude residue was taken up in DMSO and purified by preparative HPLC to give Compound 259 (3.0 mg, yield: 71%). MS (ESI) m / z 989.3 (M + H) +. Example 160

[320] To a solution of Compound 259H (50.0 mg, 0.0466 mmol), HATU (35.4 mg, 0.0932 mmol), followed by D-Ala (P-UNF) (13, 5 mg, 0.932 mmol) in DCM (0.5 ml) and DMF (0.5 ml) at 0 ° C was added DIEA (18.1 mg, 0.140 mmol). The reaction was stirred for 2 hours at 0ºC. LCMS then showed that the reaction was completed and DCM evaporated. The crude residue was taken up in DMF and purified by preparative HPLC to give compound 2601 (40.0 mg, yield: 71.6%).

[321] To a solution of compound 2601 (40.0 mg, 0.0333 mmol) in TFA: DCM: TES (50: 45: 5) (1 mL), it was stirred at 25 ° C for 1 hour, then TFA was evaporated and ELSD showed that the reaction was completed. Then, the crude residue was washed with petroleum ether to give Compound 260 (15.0 mg, yield: 47.6%). MS (ESI) m / z 945.6 (M + H) +. Example 161 [322] [00312] The mixture of Compound 2 61F (10 mg, 0.0953 mmol) in EtOH (1.0 mL) was added PdC1 2 (0.2 mg), and Et 3 N (0, 1 mg, 0.000953 mmol), and Et 3 SiN (11.0 mg, 0.095 mmol) under N2 • The mixture was stirred overnight. After LCMS showed that the reaction was completed, the solvent was removed and the crude residue was taken up in DMSO and purified by preparative HPLC to give Compound 261 (3.0 mg, yield: 33%). MS (ESI) m / z 945.5.

Example 162 ~ OH triphosgene / OIEA Me ~ OC ~ JTHF 262A TrtHN ... J): ;; __; _ N, Ç \ j ó) HO • '1o HO • Mo ~ - = · ~ dr.O - ~ -M ~ - ~ -29-10_2_

2.1% TFAIDCM TrtHN BocHN ..., __ 12902 262A1 (YO ":;" H '("~ y - N ~~

H o "'•" OtBu

H o J:; º OH ~ o \ ~ l ~. Me ~ BocHNV 262F

[323] To a solution of triphosgene (47.7 mg, 0.162 mmol) in dry DCM (5.0 mL) was added slowly a solution of Compound 262A (110 mg, 0.487 mmol) and DIEA (0.503 g, 3.90 mmol) in THF (5.0 mL), at 0 ° C. The reaction mixture was allowed to stir at 20 ° C for 25 min. The Compound 262Al solution was used for the next step, directly without purification.

[324] Compound 129D2 was added to the Compound 2 62Al solution at 0 ° C. The reaction mixture was heated to 20 ° C and was stirred at 20 ° C for 4 hours. After ELSD showed that the reaction was complete, the mixture was filtered. The filter cake was washed with THF (20.0 ml x 3) and DCM (20.0 ml x 3) separately, and then dried. TFA / DCM (1%, 5.0 ml) was added and the mixture was stirred at 20 ° C for 5 min. The mixture was filtered and the filtrate was treated with saturated NaHC0 3 solution until pH

"= '7-8. The aqueous layer was adjusted with citric acid to pH" =' 3-4. The mixture was extracted with DCM (20.0 ml x 3). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated to give a residue that was purified by prep-HPLC to give Compound 262F (80.0 mg, yield: 61.6%). MS (ESI) m / z 1083.3 (M + H) +.

[325] Using the procedures described in General Methods 9 and 10, compound 262 was prepared from Compound 262F. MS (ESI) m / z 890.4 (M + H) +.

Example 163 NNH, ~ triphosgene! DIB. h ~ DCWTHF: ZIJA

[326] [00316] To a solution of triphosgene (47.7 mg, O, 162 mmol) in dry DCM (5 mL) was added a solution of Compound 263A (110 mg, 0.487 mmol) and DIEA (0.500 g, 3 , 90 mmol) in THF (5 mL slowly) at 0 ° C. The reaction mixture was allowed to stir at 20 ° C for 25 min. The solution

Compound 263Al was used directly in the next step without purification. [327] A solution of Compound 2 63Al and Compound 12 902 was mixed at O in THF (5 mL). The reaction mixture was heated to 20 ° C and was stirred at 20 ° C for 4 hours. After ELSO showed that the reaction was complete, the mixture was filtered. The filter cake was washed with THF (20 ml x 3) and OCM (20 ml x 3) sequentially, and then dried. TFA / OCM (1%, 5 ml) was added and the mixture was stirred at 20 ° C for 5 min. Then, the mixture was filtered and the filtrate was treated with a saturated NaHC0 3 solution, until pH "" 7-8. The aqueous layer was adjusted with citric acid to pH "" 3-4. The mixture was extracted with OCM (20 ml x 3). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated to give a residue, which was purified by prep-HPLC to give Compound 263F (80.0 mg, yield: 61.7%). MS (ESI) m / z 1082.4 (M + H) +.

[328] Using the procedures described in General Methods 9 and 10, compound 263 was prepared from Compound 263F. MS (ESI) m / z 889.4 (M + H) +. Example 164

[329] A solution of Compound 263Al (10.0 mL, about 0.480 mmol) and Compound 15002 (prepared according to

General Methods 5 and 6, 0.400 g, 0.200 mmol) was stirred at 0 ° C. The reaction mixture was heated to 20 ° C and was stirred at 20 ° C for 4 hours. After ELSD showed that the reaction was complete, the mixture was filtered. The cake was washed with THF (20 ml x 3) and DCM (20 ml x 3) sequentially, and then dried. TFA / DCM (1%, 5 ml) was added and the mixture was stirred at 2 ° C for 5 min. The mixture was filtered and the filtrate was treated with saturated NaHC0 3 solution until pH ~ 7-8. The aqueous layer was adjusted with citric acid to pH ~ 3-4. The mixture was extracted with DCM (20 ml x 3). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated to give a residue, which was purified by prep-HPLC to give Compound 264F (80.0 mg, yield: 42.0%). MS (ESI) m / z 954.5 (M + H) +.

[330] Using the procedures described in General Methods 9, 10 and 11, compound 264 was prepared from Compound 264F. Example 165 o Mt N., _) LN xr OtBu o U., _) LN ~ NHBoc o ~ + e;: · l.9aae ~ · ~ NHBoc -J H1 \ H m02 \ •• H ..... , 215A _ _ _..., .. so, c1 2.1% TFAIOC) 'l__JM s ..,. U ._,) l º •.; : çu0 ~ OtBu.; 0 ~

OH 0 li • "BocHll ..._ j 2S5F '11t

[331] [00321] Using the procedures described in

General Methods 9, 10 and 11, compound 265 was prepared from Compound 265F. MS (ESI) m / z 732.4 (M - H20 + H) +.

Example 166 ~ ~ ~ --v Me 266A1

H

HH, N00Mo 'i ~ o NHBoc ~' tl- 166 ~ H 266A2 ... ~~ 1 o "'• yOIBu aoeHNZ ~ .Generous methods 9 and 10 0 1 ~ 0 ~ ry ~ 0 ~ OH (O Me O NHBoc 2MF Me ~ I 11, N ~ ~ Me Mo oM • yOH O O '<~ 1 ~ 0 ~.) "~ 0 ~ ~ yé (28' ... ... NHz

[332] A solution of l-bromo-4-butylbenzene (50.0 g, 0.333 mol), 4-formylphenylboronic acid (47.2 g, 0.222 mol), Na 2 CO 3 (70.6 g, 0.666 mol) in toluene / THF / H 20 (200 mL / 200 mL / 200 mL) was degassed with N2 three times, then Pd (PPh 3) 4 (12.8 g, 11.2 mmol) was added. The resulting mixture was degassed with N2 three times and then heated to reflux for 5 hours. After TLC showed that the reaction was completed, toluene and THF were removed in vacuo. The residue was extracted with EA (30 ml x 3). The combined organic layers were washed with brine, dried with Na 2 SO 4 • The solvent was removed to give the crude product. The crude product was purified by silica gel column chromatography eluted with PE. The solvent was removed to give Compound 266Al (20.0 g, yield: 37.8%), as a yellow oil.

[333] To a mixture of Compound 266A2 (0.8 g, 3.45 mmol) and Compound 266Al (0.862 g, 3.62 mmol) in DCM (2 mL) were added DIEA (O, 3 lg, 2, 3 mmol) and Na2S04. After stirring for 4 h, the mixture was filtered and the filtrate was concentrated to give a residue. The residue was dissolved in MeOH (5 ml) and NaBH 4 (144 mg, 3.79 mmol) was added at OºC. The mixture was heated to 26ºC. After 2 hours, TLC (PE / EA = 1/1, Rf = 0.1) showed that the reaction was complete. The reaction was quenched with water (1 ml), concentrated and purified by column chromatography (PE / EA = 1: 1) to produce Compound 266A3 (2 g, crude). MS (ESI) m / z 455.1 (M + H) +.

[334] To a mixture of Compound 266A3 (1.60 g, crude) in MeOH (2 mL) was added to Boc 20 (900 mg, 4.13 mmol). The mixture was stirred at 24 ° C for 12h. TLC (PE / EA = 1/1, Rf = O, 5) showed that the reaction was completed. The solvent was concentrated to give a residue which was purified by column chromatography (PE / EA = 1: 1) to give Compound 266A4 (1.30 g, 66.7%) as a colorless oil. MS (ESI) m / z 577.0 (M + Na) +.

[335] To a mixture of Compound 266A4 (1, 30 g, 2, 35 mmol) in THF (5 mL) was added LiOH (0.296 g, 7.04 mmol) in H2 O (5 mL). The reaction was stirred at 30 ° C for 36 hours. TLC (PE / EA = 1/1, Rf = 0.6) showed that the reaction was completed. The solvent was acidified to pH - 3-4 with 1 N HCl, extracted with DCM (20.0 ml x 4). The organic layer was dried, filtered and concentrated to give Compound 266A5 (0.9 g, 70, 9%) as a yellow oil. MS (ESI) m / z 563, 3 (M +

Na) +.

[336] Using Compound 266A5 and the procedures described in General Methods 6-8 and Scheme XIX, Compound 266F was prepared. MS (ESI) m / z 997.6 (M + H) +.

[337] Using the procedures described in General Methods 9 and 10, compound 266 was prepared from Compound 266F. MS (ESI) m / z 846.4 (M + H) +. Example 167

[338] Using the procedure described in General Procedure 11, Compound 267 was prepared from Compound 266 MS (ESI) m / z 694.3 (M - H2 0 + H) +. Example 168: M: General ethics 9e10

[339] Using the procedures described in General Methods 6-8 and Scheme XIX, Compound 268F was prepared. MS (ESI) m / z 923.1 (M + H) + ~ Using the procedures described in General Methods 9 and 10, compound 268 was prepared from Compound 268F. MS (ESI) m / z 872.3 (M + H) +.

Example 169

~ v! General ethics Mo OtBv BocHJol ~ 9e10 ~ ~ n: ç: ~ O H O ~ H N .._) l. OH N ... H ~ \ _ ~ H \ _lk ...., _ ,, O Mo O o 269F (340] Using the procedures described in General Methods 6-8 and Scheme XIX, Compound 269F was prepared. (ESI) m / z 923.2 (M + H) +. MS (ESI) m / z 923.1 (M + H) +. Using the procedures described in General Methods 9 and 10, compound 269 was prepared at from Compound 269F MS (ESI) m / z 872.1 (M + H) + Example 170

N 1 -Jº: ç ° "u; · zOH Bcx:

N H

O •: Me

N H

270F Me (341] To a mixture of Compound 266Al (0.5 g, 2 mmol) and methyl 3-aminopropanoate (0.3 g, 2.2 mmol) in DCM (2 ml) was added DIEA (O, 3 g, 2.3 mmol) and Na 2 SO 4 • After stirring for 4 h, the mixture was filtered and the filtrate was concentrated.The residue was dissolved in MeOH (5 mL) and NaBH4 (84 mg, 2.2 mmol ) was added to the solution at 0 ° C. The mixture was warmed to room temperature. After 2 hours, TLC (PE / EA = 10/1, R f = 0.1) showed that the reaction was complete. quenched with water (1 mL), concentrated to give a solid (0.7 g, crude) used in the next step without further purification. This material was treated with Boc 2 0 (0.5 g, 2.3 mmol) in MeOH (5 mL), was stirred at 26ºC for 5h TLC (DCM / MeOH = 10/1, Rf = 0.7) showed that the reaction was complete The solvent was concentrated to obtain a residue, which was purified by column chromatography (PE) to give compound 270A2 (0.65 g, 73%) as a colorless oil MS (ESI) m / z 44 8.2 (M + Na) +.

[342] To a mixture of Compound 270A2 (0.68 g, 2 mmol) in THF (5 mL) was added LiOH (96 mg, 2.3 mmol) in water (5 mL). The mixture was stirred at 26 ° C for 2h. TLC (PE / EA = 5/1, Rf = 0.1) showed that the reaction was complete. The volatiles were removed in vacuo and the aqueous mixture was acidified to pH = 3 - 4 with 0.3 N HCl and extracted with DCM (20 ml x 3). The organic layer was dried, filtered and concentrated to give Compound 270A3 (0.4 g, 84%) as a white solid.

[343] Using the procedures described in General Methods 6-8 and Scheme XIX, Compound 270F was prepared from Compound 2 7 0A3. MS (ESI) m / z 890, 5 (M + Na) +. Using the procedures described in General Methods 9 and 10 O, Compound 27 O was prepared from Compound 270F. MS (ESI) m / z 817.7 (M + H) +. Example 171 o o "-" ~ • ~ Mo ~ H ~~ ... .. ~., H j '<: l ~. 0 LIÓH '<: l ~ · íl .. 2MA1 1-aBH; .H' '""' "O - '<: l ,,:; O Mo ~ I ::: ,, .. - :?' Boc: oM • yOH Boc: HN ~ o ::: ,, .. 1 ~ ___. Jl. ~ "'Lr ~ 0 ~ OH 271F O Me O

[344] To a mixture of Compound 266Al (0.5 g, 2 mmol) and methyl 3-aminobutanoate (0.34 g, 2.2 mmol) in DCM (2 mL) was added DIEA (O, 3 lg, 2, 3 mmol) and Na 2 SO 4 • After stirring for 4 h, the mixture was filtered and the filtrate was concentrated to obtain a residue, which was dissolved in MeOH (5 ml). NaBH 4 (84 mg, 2.2 mmol) was added to it at OºC. Then, the mixture was heated to 26ºC. After 2 hours, TLC (PE / EA = 10/1, Rf = 0.1) showed that the reaction was complete. The reaction was quenched with water (1 ml), concentrated to give a solid (0.7 g, crude) used in the next step without further purification. This material was treated with Boc 20 (0.5 g, 2.3 mmol) in MeOH (5 ml), was stirred at room temperature for 5 h. TLC (DCM / MeOH 10/1, Rf = 0.7) showed that the reaction was complete. The solvent was concentrated to obtain a residue, which was purified by column chromatography (petroleum ether) to produce Compound 271A2 (0.45 g, 73%) as a colorless oil. MS (ESI) m / z 462.1 (M + Na) +.

[345] To a mixture of Compound 270A2 (0.45 g, 2 mmol) in THF (5 mL) was added LiOH (96 mg, 2.3 mmol) in water (5 mL). The mixture was stirred at room temperature for 2 hours. TLC (PE / EA 5/1, Rf O, 1) showed that the reaction was complete. The volatiles were removed in vacuo and the aqueous mixture was acidified to pH = 3 - 4 with 0.3 N HCl, extracted with DCM (20 ml x 3). The organic layer was dried, filtered and concentrated to give Compound 271A3 (0.4 g, 84%) as a white solid.

[346] Using the procedures described in General Methods 6-8 and Scheme XIX, Compound 271F was prepared from Compound 271A3. MS (ESI) m / z 881, 8 (M + Na) +. Using the procedures described in General Methods 9 and 10, compound 271 was prepared from Compound 271F. MS (ESI) m / z 831.8 (M + H) +. Example 172 Mo 0Me ~ OtBu BocHNZ

THE

N ~ 0 • N

OH H .; H N O Me O 272F Me o

[347] Compound 272F was prepared using the procedures described in General Methods 6-8 and Scheme XIX, Compound 272F. MS (ESI) m / z 822.5 Using the procedures described in General Methods 9 and 10, Compound 271 was prepared from Compound 271F. MS (ESI) m / z 831.8 (M + H) +. Example 173

Ma BocHN ~ oM •: çOtr :: O N N ~ _ N OH H • H N o Me o 273F Me ,, __, fYº "uJ") u ~ i ~ ·· ~ T ~~ = ~~ = N _.,. the 273 Me O Ma

[348] To the mixture of Compound 266Al (1.10 g, 4.62 mmol) in dry DCM (20 mL) Compound 273A (0.762 g, 4.85 mmol), DIEA (0.686 g, 5.32 mmol) and Na 2 S0 4 at 24 ºC. The mixture was stirred at 24 ° C for 2 hours. The mixture was filtered and the filtrate was evaporated. The residue was dissolved in dry MeOH (10 ml), cooled to 0 ° C and then NaBH 4 (184 mg, 4.85 mmol) was added in portions. The mixture was stirred at 24 ° C for 2 hours.

After LCMS showed that the reaction was complete, MeOH was evaporated. The crude product was purified by chromatography on silica gel, then the mixture was in EA / HCl for 3 minutes and evaporated. The solid was washed with EA to give Compound 273Al of pure product (450 mg, yield: 25.7%).

[349] To a solution of Compound 273Al (450 mg, 1.19 mmol) in THF / H 2 0 (10 mL / 2 mL) was added LiOH.H 2 0 (100 mg, 2.37 mmol) at 21 ° C . The mixture was stirred overnight at 21 ° C. After TLC showed that the reaction was completed, the THF was evaporated and the mixture was extracted with EA. 1 N HCl was added to the aqueous layer until pH - 3-

4. The mixture was extracted with EA, the organic layers were combined, dried with filtrates and concentrated to give Compound 273A2 (260 mg, yield: 62.2%).

[350] Using the procedures described in General Methods 6-8 and Scheme XIX, Compound 273F was prepared from Compound 273A2. MS (ESI) m / z 808.2 (M + Na) +. Using the procedures described in General Methods 9 and 10, compound 273 was prepared from Compound 273F. MS (ESI) m / z 857.3 (M + H) +. Example 174 Fmoc. ~ J ..: OMe Fmoc-NM \ OMo Fmoc-NM 11 '- \ Boc? O ~ \. OMe

H Mo OH ("~ ~~ ~ NBoc OHH2) - 274A1 274A2 274A3 274A4 274A5

[351] To a solution of Compound 274Al (1.00 g, 2.47 mmol), compound 266Al (679 mg, 2.85 mmol) and DIEA (719 mg, 5.57 mmol) in dry DCM (50 mL) Na 2 SO 4 (10 g) was added. The mixture was stirred at 25 ° C for 4 hours, filtered and the filtrate was evaporated. To the residue, dry MeOH (50 mL) and NaBH 4 (108 mg, 2.84 mmol) were added at 0 ° C. The reaction mixture was stirred at 25 ° C for 30 minutes. After LCMS showed that the reaction was completed, 1 N HCl was added to pH - 7. The solution was evaporated to give Compound 274A2 (1, 00 g, yield: 68, 4%) as a light yellow solid. MS (ESI) m / z 591.9 (M + H) +.

[352] To a solution of Compound 274A2 (1.00 g, 1.69 mmol) in dry MeOH (20 mL) was added 1N HCl until pH ~ 6-7, followed by the addition of DIEA until pH ~ 7- 8. To the mixture, Boc 20 (0.732 g, 3.39 mmol) was added at 24 ° C. The mixture was stirred overnight at 24 ° C. After LCMS showed that the reaction was complete, MeOH was evaporated and the crude product was purified by chromatography on silica gel (EP: EA = 15: 1) to give Compound 274A3 (0.680 g, yield: 58.3% ). MS (ESI) m / z 713.4 (M + Na) +.

[353] To a solution of Compound 274A3 (0.680 g, 0.985 mmol) in THF / H 20 (10 mL / 3 mL) was added LiOH.H20 (0.166 g, 3.94 mmol) at 24 ° C. The mixture was stirred overnight at 24 ° C. After TLC showed that the reaction was complete, the THF was evaporated. The mixture was extracted with PE and H2O. To the aqueous layer, 1N HCl was added until pH ~ 4-5. The aqueous mixture was extracted with EA (10 ml x 3). The organic layers were combined, dried with Na 2 SO 4 and concentrated to give Compound 274A4 (0.400 g, yield: 89.3%).

[354] To a solution of Compound 274A4 (0.400 g, 0.880 mmol) in DCM (15 mL) was added Boc 20 (0.228 g, 1.06 mmol) and Et 3 N (0.267 g, 2.64 mmol) at 24ºC. The mixture was stirred for 2 hours at 24ºC. After LCMS showed that the reaction was complete, the DCM was evaporated. The crude product was washed with PE. The polyethylene layer was evaporated to give Compound 274A5 (380 mg, 77.9%).

[355] Using the procedures described in General Methods 6-8 and Scheme XIX, Compound 274F was prepared from Compound 274A5. MS (ESI) m / z 1011.2 (M + Na) +. Using the procedures described in General Methods 9 and 10, Compound 274 was prepared from Compound 274F. MS (ESI) m / z 860.2 (M + H) +. Example 175 Fmoc-NH

H

O Fmoc-NK FmocHN} -. (((M ~ // "" - ~ OMa BoeiO (~~ ~~ (M ~ ~ NBoc - "----- ~ Boc Mo Me3SnOH / OCE //" "- ' - :: H ~ NH -;:;: 274A3 275A4 275A5

[356] To a solution of Compound 274A3 (1.00 g, 1.69 mmol) in MeOH (50.0 mL) was added Boc 20 (527 mg, 2.44 mmol). The reaction was stirred at 25ºC for 4 hours. After LCMS showed that the reaction was complete, the solvent was evaporated and the residue purified by silica gel column chromatography to give Compound 275A4 (0.580 g, yield: 49.7%) as a white solid.

[357] To a solution of Compound 275A4 (0.580 g, 0.840 mmol) in DCE (20.0 mL) was added Me 3 SnOH (1.18 g, 6.50 mmol). The reaction was stirred at 70ºC for 4 hours. After LCMS showed that the reaction was complete, the mixture was cooled to 0 ° C and treated with 1 M NaH 2 P0 4 (60.0 mL). The mixture was extracted with DCM (30.0 mL x 2). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give Compound 27 5A5 (0. 550 g, yield: 96.4%) as a white solid. MS (ESI) m / z 699.0 (M + Na) +.

[358] Using the procedures described in General Methods 6-8 and Scheme XIX, Compound 275F was prepared from Compound 275A5. MS (ESI) m / z 953.1 (M + Na) +. Using the procedures described in General Methods 9 and 10, Compound 275 was prepared from Compound 275F. MS (ESI) m / z 902.4 (M + H) +. Example 176 Using the same

OH procedures that _) - BocHN • Compound 274A5 M ~ <-0-oJ "" 27flA5

Me O y- ·· H OtSu BoeHNZ

The BocHN ~~ "" lrN ~~ OH '?' '! O Me O ~ 1 NBoc 276F

[359] Using the procedures described in Example 174, compound 277A5 was prepared from Compound 276Al. Using the procedures described in General Methods 6-8 and Scheme XIX, Compound 276F was prepared from Compound 276A5. MS (ESI) m / z 997.2 (M + Na) +. Using the procedures described in General Methods 9 and 10, compound 276 was prepared from Compound 276F. MS (ESI) m / z 846.2 (M + H) +.

Example 177 Using the same Using the same procedures as the procedure. Compound 275A5 Compound 274A3 IH'fO Me OtBu BocHNZ HN ~~~~~~ OH? 'i o ... o ~ j NBoc 277F

[360] Using the procedures described in Examples 174 and 175, Compound 277A5 was prepared from Compound 277Al. MS (ESI) m / z 663.1 (M + H) +. Using the procedures described in General Methods 6-8 and Scheme XIX, Compound 277F was prepared from Compound 277A5. MS (ESI) m / z 939.5 (M + Na) +. Using the procedures described in General Methods 9 and 10, Compound 277 was prepared from Compound 277F. MS (ESI) m / z 888.2 (M + H) +. Example 178 HCIH, N) FmocHN ~ o, ~: HATU / DMF ~: H) \ _M: - 9 'Lff c9-01.:":J LIOHITHF / H20 Me 278A3 HN o 278A2 FmocHN-S-c1 -} -oH 2 279A1 o c9-01 .: o:; 9A4 FmoQiN ": J -} - oH z •. the "fly ~ f2 ~; fr see it ~ ~ l \ _ ...

The H BocHN

OHM ~ lolle o 'Me HATU (2 eq) / () lEA (3 oq) I FmocHN .__) l 11 .._)! .., N., _,) ~ OMl' (0.8 mL) IOCM (2 • mL)! ~; ~: '-., OMe O Me 1 271G NHBoc

[361] To a solution of Compound 278Al (1.00 g, 2.39 mmol), 4- (4-butylphenyl) benzoic acid (O, 7 2 8 g, 2. 8 mmol) and NaHC0 3 (0.742 g, 8.84 mmol) in dry THF (30 mL) and

DMF (30 ml) HATU (1.09 g, 2.89 mmol) was added. The mixture was stirred at 25 ° C until LCMS indicated that the reaction was finished (5 hours). The THF was evaporated and the mixture was poured into water (100 ml) and extracted with DCM (80 ml x 2). The combined organic layers were evaporated and purified by silica gel column chromatography to give Compound 278A2 (800 mg, yield: 54.4%).

[362] A mixture of Compound 278A2 (800 mg, 1.29 mmol) and LiOH (108 mg, 2.58 mmol) in THF / H 2 0 (30 mL / 10 mL) was stirred at 10 ° C. LCMS showed that the reaction was completed after 2 hours, at which point the THF was evaporated. The mixture was extracted with EP (30 ml x 3), the aqueous layers were pH adjusted to ~ 3-4 with a 1 N HCl solution. The resulting mixture was filtered and the cake was washed with water and dried to give the Compound 278A3 (400 mg, yield: 91.0%), as a white solid.

[363] The mixture of Compound 278A3 (400 mg, 1.05 mmol) in THF / H 2 0 (100 ml / 100 ml) was added NaHCO 3 (176 mg, 2.10 mmol). The mixture was cooled to 0 ° C and a solution of Fmoc-OSu (354 mg, 1.05 mmol) in THF (100 ml) was added dropwise over 8 hours. After stirring for an additional 2 hours at 10 ° C, CL-EM showed that the reaction was complete and the THF was evaporated. The mixture was extracted with EP (30 ml x 3) and the aqueous layers were adjusted to pH ~ 4-5 with 1 N HCl solution. The resulting mixture was filtered and the filter cake was washed with water and dried to give Compound 278A4 (600 mg, yield: 94.9%), as a white solid. MS (ESI) m / z 605.1 (M + H) +.

[364] Using the procedures described in General Methods 6-8 and Scheme XIX, Compound 278F was prepared from Compound 278A4. MS (ESI) m / z 1104.1 (M + H) +.

[365] To a solution of Compound 278F (200 mg, 0.181 mmol), HATU (138 mg, O, 362 mmol), and 3F2 (70, 3 mg, O, 272 mmol) in DCM (2.4 mL) and DMF (0.8 ml) DIEA (70.0 mg, 0.543 mmol) was added. After 15-30 minutes the reaction was allowed to warm to 15 ° C and stirred for 30 minutes.

After LCMS showed that the reaction was completed, water (1 ml) was added and the mixture was filtered, the filter cake was washed with water and petroleum ether, to obtain Compound 278G as a crude product (180 mg , yield: 75.9%).

[366] To a mixture of Compound 278G (160 mg, 0.122 mmol) in CH 3 CN (5 mL) was added Et 2 NH (26.7 mg, O, 366 mmol). The mixture was stirred at 10 ° C for 17 hours.

After LCMS showed that the reaction was complete, CH 3 CN was removed. The residue was dissolved in MeOH and purified by means of prep-HPLC to give Compound 278H (50.0 mg, yield: 37.7%).

[367] A solution of Compound 278H (25.0 mg, 0.0230 mmol) in TFA: DCM: TES (50: 45: 5) (1 mL) was stirred at 10 ° C for 20 minutes, then TFA was evaporated and LCMS showed that the reaction was completed. The crude residue was dissolved in MeOH and purified by means of prep-HPLC to give Compound 278 (5.60 mg, yield: 27.5%): MS (ESI) m / z 887.6 (M + H) + .

Example 179

H0t3t DIEAJHOAc

[368] Using the procedure described in General Method 10 for the preparation of boronate esters, the boronate ester compound 279 was prepared from Compound 279G (1.5 mg, yield: 18.3%). MS (ESI) m / z 929.2 (M + H) +.

BIOLOGICAL DATA Example 180 Determination of Minimum Inhibitory Concentration - Method A

[369] The in vitro antimicrobial activity of each compound was determined by measuring the minimum inhibitory concentrations (MICs), using the broth micro-dilution technique approved by the Institute of Clinical and Laboratory Standards (CLSI). Antibacterial activity was measured against two strains of bacteria: 1) strain of Staphylococcus aureus 300 methicillin resistant USA (NRS384) and 2) a strain of Escherichia coli MC4100 IMP-4213, in which the transcription of the gene encoding SPase was placed under the control of an inducible tetracycline promoter in order to decrease the levels of expression of

SPase. The cells were inoculated into Trypyticase Soy Agar or Luria Agar containing 16 ng / ml anhydrotetracycline, respectively, and cultured at 35 ° C for 20 hours. Inocular suspensions were made by scraping cells in 1 mL of test medium (Mueller Hinton broth adjusted with cation supplemented with 0.002% v / v Tween-80) and diluting to a final 006oonrn of 0.01.

[370] Test compounds were prepared in OMSO, at a concentration of 10 mg / ml. These compound standards were diluted in assay medium to a concentration of 64 µg / mL and a series of 9 1: 2 dilutions were made in the same medium, in 96 wells of bottom microtiter in U plates. Inoculum suspensions were added to the two serial serial dilutions of the test compounds to a final density of 006 μm of O, 0005 and incubated stationary at 35 ° C for 22 hours, after which the plates were examined visually. MICs were recorded as the lowest concentration of test compound that completely prevented bacterial growth. The results are listed in Table 1. Table 1: Antimicrobial Activity in Total Cell Bacterial Assays CIM Compound (µg / mL) CIM (µg / mL) E. coli s. aureus 108> 64 64 103 NO> 64 104 NO 8 105> 64> 64 110> 64> 64

109> 64> 64 128> 64> 64 111> 64> 64 122> 64 40 112> 64> 64 124> 64> 64 102> 64> 64 101> 64> 64 113 NO NO 125 NO NO 117> 64> 64 116> 64> 64 115> 64> 64 118 11 0.71 127 1.6 16 126 1.4 16 119> 64> 64 120 32> 64 121 0.5 0.25 CSC = not determined Determination of the Minimum Inhibitory Concentration - Method B

[371] The in vitro antimicrobial activity of each compound was determined by measuring minimum inhibitory concentrations (MICs), using the broth micro-dilution technique approved by the Institute of Clinical and Laboratory Standards (CLSI). Antibacterial activity was measured against two strains of bacteria: 1) strain of methicillin-resistant Staphylococcus aureus (MRS A)

USA300 (NRS384) and 2) strain of Escherichia coli MC4100 IMP-4213, which houses an LptD mutation. Inocula were prepared by scraping cells in 1 ml of assay medium (Cation-adjusted Mueller Hinton broth supplemented with 0.002% v / v Tween-80) and diluted to a final OD6oonm of 0.01.

[372] Test compounds were prepared in DMSO, at a concentration of 10 mg / ml. These compound standards were diluted in assay medium to a concentration of 64 µg / mL and a series of 9 1: 2 dilutions were made in the same medium, in 96-well U-bottom microtiter plates. The bacterial inoculums were added to the two serial dilutions of the folding test compounds to a final density of OD 6oonm of O, 0005 and incubated stationary at 35 ° C for 22 hours, after which the plates were examined visually. MICs were recorded as the lowest concentration of test compound that completely prevented bacterial growth. The results are listed in Table 2. Table 2: Antimicrobial activities in bacterial full cell assays

CIM CIM CIM CIM Compound (µg / mL) (µg / mL) Compound (µg / mL) (µg / mL) E. coli s. aureus E. coli s. aureus 129 0.91 0.74 130 11 64 131 0.44 0.45 132 1 0.21 133 0.79 1.4 134 1.4 0.87 135 16 3.2 136 1 1.4 137 23 16 138> 64 5 139 2 1 140 8 1

145 5 3.2 146 0.25 0.4

147 0.31 0.25 148 0.4 0.23

14 9 0.31 0.28 150 0.5 0.3

151 1.2 0.71 152 0.5 0.4

154 32 2.8 155 NO NO

156 0.5 0.31 157 4 2

158 5 5.7 159 16 1

160 64 2.8 161 0.71 0.63

162 0! 5 0.4 163> 64 4

164 1 1.4 165 0.63 0.63

166 0.5 0.63 167 4 1.7

168 1 0.79 169 11 3.2

170 0.4 2 171 0.25 0.71

172 8 8 173 2 2

174 0.5 0.25 175 2 1.2

176 8 16 177 2 2

178 0.25 0.063 179 0.5 2

180 1 1 181 0.5 0.4

182 0.71 4 183 1 1

184 0.13 0.25 185 0.71 4

186 0.13 0.13 187 2.8 8

188 8 16 18 9 64> 64

190> 64 64 191 16 1 20

192 16 0.59 193 5 0.16

194 6.3 0.71 195 32 1.2

196 2.5 0.66 197 1 0.3

198 5 0.5 199> 64 7

200 64> 64 201 64 4.6

202 23 1.1 203 32 1.4

204 4.6 0.45 205 32 2

206 2 0.5 207 2 0.099

208 4 0.31 209 2.5 1

210 4 0.71 211 32 0.71

212 5 0.84 213 1.3 0.22

214 5.7 0.35 215 4 0.5

216 4 0.21 217 1.6 0.35

218 1.3 0.5 219 64 5

220 4 0.5 221 8 1

222 2 1.4 223 ND ND ND

224 2.8 0.13 225 2 0.57

226 25 2.8 227 13 8

228 2.8 5.7 229 32 64

230 20 2 231 0.5 0.5

232 0.25 0.31 233 1 0.5

234 0.5 0.4 235 0.5 0.25

236 8 2 237 2 0.71

238 0.35 0.35 239 2 0.71

240 4 0.71 241 0.18 0.25

242 11 1.4 243 2 0.5

244 64 45 245 0.5 0.35

246 64 23 247 0.5 0.5

248 0.25 0.25 249 1 0.35

250 0.71 0.35 251> 64 3.4

252> 64 5 253 11 8

254 11 8 255 ND ND

256 ND ND 257 ND ND

258 23> 64 259 4 11

260 1 4 261 0.79 0.71

262 8 2.8 263 2 0.71 264 NO NO 265 4 0.13 266 1 0.5 267 0.25 0.13 268 16 1 269 8 0.5 270 8 0.5 271 11 0.5 272 32 0.71 273 8 0.088 274 16 0.13 275 32 1 276 16 0.5 277 32 0.5 278 16 4 279 8 11 ND = Not determined.

Enzyme Inhibition Assay

[373] Full-length E. coli Bis-tagged Spase proteins were expressed in E. coli BL2I (OE3) containing the plasmid pET23-lepB. Briefly, overnight saturated cultures grown in 20 mL of Luria-Bertani medium supplemented with ampicillin were subcultured in 1.5 L of Luria-Bertani medium, and agitated at 37ºC to an optical density at 600 nm of 0.4- 0.5 have been achieved. Protein expression was induced with isopropyl ~ -0-1- thiogalactopyranoside (ITPG) at a final concentration of 0.5 µM, and purified using nickel affinity chromatography.

[374] The full-length S. aureus Bis-tagged SPase protein was similarly expressed from E. coli BL2 I (OE3) containing the plasmid pCOFI-SaSpsB and purified in a similar way to E. coli protein with the following exceptions. The SPase protein was solubilized using 300 mM NaCl, 20 mM Tris, pH 8.06, 5 mM imidazole, 10% glycerol, 1% Triton X-100, before purification on NiNTA Superf low resin and protein bound to the resin was washed in a similar buffer, containing 1% Elugent in place of Triton X-100 before the protein eluted in wash buffer supplemented with 300 mM imidazole. The purity of the protein was evaluated to over 95% through visual inspection of SDS-PAGE followed by Comassie staining. All protein concentrations were determined by the BCA assay.

[375] The peptidase enzyme activity of the above protein signal was measured using two fluorogenic peptide substrates (decanoyl-LSSPAYN02AtADKabzPD and decaniol-LTPTAYN02AiASKKabzDD), where abz is the 2-aminobenzamide fluorescence donor 3-yin02 receptor is YN02 nitrotyrosine, and the cleavage site is indicated with an arrow. Enzyme mix solution was prepared by diluting 2.5 nM of Escherichia coli SPase protein or Staphylococcus aureus in reaction buffer consisting of 20 mM P0 4 pH 7.4, 100 mM NaCl, and 1% Elugent ™ or octyl detergent phenoxypolyethoxyethanol at a concentration of 0.25% or 0.0625%. The reactions were initiated by adding substrate to a final concentration of 20 µM. The progress of the reaction was monitored by measuring the increase in the fluorescence signal (excitation at 314 nm, emission at 416 nm) using a SpectraMax M2 microplate fluorescence reader. To determine the IC50 values of test compounds, stock solutions of the compounds were prepared in DMSO, at a concentration of 1 mM. Serial three-fold dilutions of test compounds, starting at 10 µM, were prepared in an enzyme mixture solution and incubated at room temperature for 10 minutes. After this incubation, the fluorogenic substrate was added to a final concentration of 20 µM and the increase in fluorescence, which corresponds to substrate cleavage, was monitored continuously at room temperature for 1 hour. The initial reaction rates were calculated based on the rate of increase in fluorescence during the reaction. The reaction rates were plotted as a function of the concentration of the compound, and the IC 50 values are the determined nonlinear regression analysis (SoftMaxPro 5.4, Molecular Oevices ™) of the sigmoidal dose-response curve. The results are listed in the Table

3.

Table 3: Inhibition activities (ICSO) in activity assays Biochemical spase IC50 IC50 IC50 (nM) IC50 (nM) Compound (nM) Compound (nM) s. aureus s. aureus E. coli E. coli 101 11000 86 102 18000 9.7 103 11000 110 104 8900 18 105 NO NO 108 20000 2100 109 50000 4900 110 NO 150 111 4900 18000 112 31000 3400 113 50000 470 114 50000 390 115 1000 170 116 310 310 38 117 300 350 118 1100 9.4 119 290 59 120 1600 100 121 NO NO 122 1500 7.6 123 220 42 124 810 83 125 730 55 126 17 6 127 12 3.7 128 3000 670

133 15 170 134 8.7 120

135 31 25 136 14 39

137 1200 26000 138 1000 1100

139 3.4 8.5 140 50 52

141 33 23 142 15 34

143 250 180 144 18 36

145 39 240 146 12 160

147 14 98 148 7.4 140 149 3.9 129 150 6 270

151 8.8 38 152 25 350

154 14 8.1 155 39 250

156 5.5 97 157 130 1000

158 33 400 159 240 86

160 2100 900 161 60 300

162 12 200 163 240 310

164 44 120 165 120 410

166 36 350 167 5.2 190

168 5.4 250 169 3.9 87 170 10 530 171 27 520 172 20 750 173 69 550 174 59 130 175 5r5 110

176 56 1200 177 70 640

178 3.1 58 17 9 22 570

180 11 280 181 5.4 18

182 35 1100 183 20 610 184 5.9 300 185 41 580

188 120 2900 189 430 7700

194 16 4.7 195 19 2.6

196 8.8 5.7 197 11 6.2

198 42 8.9 199 4.5 1.4

200 5200 1200 201 8 1.9

202 7.1 3.5 203 130 21

204 33 13 205 210 20

206 6.3 5.2 207 87 13

208 20 5.7 209 12 15

210 56 16 211 50 000 36 212 26 12 213 6.8 7.7

214 77 17 215 77 17

216 29 4.1 217 15 14

218 6.9 13 219 560 46 220 36 7 221 62 130 222 6.6 24 223 NO NO 224 55 12 225 7.1 4

226 440 140 227 550 850

228 360 270 229 290 220 230 390 150 231 4.5 95 232 5 140 233 29 220 234 8.3 53 235 21 50 1

236 28 130 237 16 210

238 4.6 33 239 17 670

240 28 88 241 2.1 42 242 21 54 243 10 80 244 350 1100 245 8.7 130 246 55 290 247 17 110

250 8.4 110 251 9200 18 252 3000 8.7 253 4800 2100 254 1200 660 255 NO NO 256 NO NO 257 NO NO 258 50000 50000 259 2.6 32 260 5.6 83 261 41 280 262 37 15 263 88 72 264 NO NO 265 120 17 266 22 160 267 11 33 268 1600 81 269 1800 340 270 650 120 271 200 16 272 1300 50 273 470 9.8 274 1700 35 275 1500 110 276 2000 110 277 680 110 278 800 2300 279 530 7400 ND = Not determined.

Example 181 Clinical Trial of the Safety and Efficacy of Compounds of Formula (I), (I,), (II), (II '), (III) or (III') in patients with diarrhea associated with C. Difficile

[376] Objective: The present study aims to determine the safety and efficacy of the compounds presented here for the treatment of symptoms of diarrhea associated with e. difficile and decrease the risk of recurrent diarrhea episodes. The compounds are evaluated against the current standard antibiotic treatment, so that all patients will receive the active medication. All care related to the study is provided including medical appointments, physical examinations, laboratory tests and study medication. The total extension of participation is approximately 10 weeks.

[377] Patients: eligible individuals will be men and women 18 years of age or older.

[378] Criteria: Inclusion criteria: Be at least 18 years of age; having mild to moderate active C. difficile (CDAD) diarrhea; being able to tolerate oral medication; not be pregnant or breastfeeding; and sign and date the consent form.

[379] Study Design: This is a randomized, double-blind, active control study of the efficacy, safety and tolerability of a compound of Formula (I), (I '), (II), (II'), ( III) or (III '), in patients with diarrhea associated with c. difficile. Example 182 Clinical Trial Comparison of a Compound of Formula (I), (I '), (II), (II'), (III) or (III ') with Vancomycin for the treatment of MRSA Osteomyelitis

[380] Objective: This study aims to verify the efficacy of compounds presented here, in comparison with vancomycin, for the treatment of methicillin-resistant Staphylococcus aureus osteomyelitis (MRSA).

[381] Patients: eligible individuals will be men and women 18 years of age or older.

[382] Criteria: Inclusion criteria: MRSA proven in culture, obtained in the operating room or sterile biopsy procedure of the bone site.

The site of infection and sampling is both within the bone and in a place of deep soft tissue that adjoins bone; Or radiographic abnormality compatible with osteomyelitis in conjunction with MRSA positive blood culture;

surgical debridement of the infection site, when necessary; patient and able to prove written informed consent; and the patient is able to receive outpatient parenteral therapy for 12 weeks.

Exclusion criteria: Hypersensitivity to a compound of Formula (I), (I '),

(II), (II '), (III) or (III') or vancomycin; S. aureus resistant to a compound of Formula (I), (I '), (II), (II'), (III) or (III ') or vancomycin; osteomyelitis that develops directly from a chronic open wound; polymicrobial culture (the only exception is if the

Coagulase-negative Staphylococcus is present in the culture and the clinical evaluation is that this is a contaminant); individual has a positive pregnancy test at the start of the study; renal baseline or liver failure that would prevent the administration of study drugs; use of injectable drugs active without safety conditions to administer intravenous antibiotics for 3 months; and predict antibiotic use for more than 14 days for an infection with the exception of osteomyelitis.

[383] Study Design: This is an open, randomized, active control, efficacy test study comparing vancomycin, with a compound of Formula (1), (I '), (II), (II') , (III) or (III '), for the treatment of MRSA osteomyelitis. Example 183 Clinical Trial to Evaluate a Compound of Formula (I), (I '), (II), (II), (III) or (III') in Serious Infections Selected by Causes of Vancomycin-Resistant Enterococcus (VRE) [3 8 4] Objective: This study aims to determine the safety and efficacy of a compound of formula (I), (I '), (II), (II), (III) or (III') in the treatment selected serious infections caused by VRE.

[385] Patients: eligible individuals will be men and women 18 years of age or older.

[386] Criteria: Inclusion criteria: Isolation of one of the following bacteria resistant to multiple antibiotics: Enterococcus faecium resistant to vancomycin, Enterococcus faecalis resistant to vancomycin alone or as part of a polymicrobial infection; and have a confirmed diagnosis of a serious infection (for example, bacteremia [unless due to an excluded infection], complicated intra-abdominal infection, complicated skin and skin structure infection, or pneumonia) and require administration of antibiotic therapy ( IV)

intravenous. Exclusion criteria: Individuals with any concomitant condition or taking any concomitant medication that, in the investigator's opinion, may impair the assessment of a response or make it unlikely that the contemplated course of therapy or follow-up assessment will be completed or will continue. substantially increase the risks associated with the individual's participation in the study. Expected length of antibiotic therapy for less than and 7 days. [3 8 7] Study Design: This is a randomized, double-blind, safety and efficacy study of a compound of Formula (I), (I '), (II), (II'), (III) or (III ') in the treatment of selected severe infections caused by VRE.

Pharmaceutical Compositions Parenteral Composition

[388] In order to prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 reg of compound of Formula (I), (I '), (II), (II'), (III), or (III ') they are dissolved in DMSO and then mixed with mL of 0.9% sterile saline. The mixture is incorporated into a dosage unit form suitable for administration by injection.

[389] In another embodiment, the following ingredients are mixed to form an injectable formulation: Ingredient Amount Compound of Formula (I) '(I') '(II), (II'), 1.2 g

(III) or (III ') Sodium acetate buffer solution (o 4 M) 2.0 mL HCl (1 N) or NaOH (1 M) q.s. to appropriate pH Water (distilled, sterile) q. s. up to 20 mL

[390] All the above ingredients, except water, are combined and agitated and, if necessary, with slight heating if necessary. A sufficient amount of water is then added. Oral composition

[391] In order to prepare a pharmaceutical composition for oral delivery, 100 mg of a Compound of Formula I), (I '), (II), (II'), (III) or (III ') are mixed with 750 mg of starch. The mixture is incorporated into an oral dosage unit, such as a hard gelatin capsule, which is suitable for oral administration.

[392] In another embodiment, the following ingredients are mixed together and pressed into individual tablets. Ingredient Amount per tablet, mg Compound of Formula (I) I (I ') I (II) I 200 (II') I (III) or (III ') Corn starch 50 Cascarmellose sodium 25 Lactose 120 Magnesium stearate 5

[393] In yet another embodiment, the following ingredients are intimately mixed and loaded into a hard gelatin capsule. Ingredient Amount per tablet, mg Compound of Formula (I) '(I') '(II), 200 (II'), (III) or (III ') Lactose, lyophilized 148 Magnesium stearate 2

[394] In yet another embodiment, the following ingredients are mixed to form a solution / suspension for oral administration: Ingredient Amount Compound of Formula (I) '(I') '(II), 1 g (II'), (III) or (III ') Sodium Carbonate Anhydrous 50 Ethanol (200 proof), USP 10 mL Purified water, USP 90 mL Aspartame 0.003 g Topical gel composition

[395] In order to prepare a topical gel pharmaceutical composition, 100 mg of a compound of Formula (I), (I '), (II), (II'), (III) or (III ') are mixed with 1.75 g of hydroxypropylcellulose, 10 ml of propylene glycol, 10 ml of isopropyl myristate and 100 ml of purified alcohol USP. The resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration.

[396] Although preferred embodiments of the present description have been presented and described herein, it will be obvious to those skilled in the art, 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 is to be understood that various alternatives to the embodiments described herein can be employed in the practice of the invention.

It is intended that the following claims define the scope of the invention and that the methods and structures within the scope of these claims and their equivalents are hereby covered.

Claims (21)

1. Compound, characterized by having the structure of Formula (I): Formula (I) in which: R1 is selected from: R2, R4, R10, R11, R12, and R13 are each, independently, -H, -CH3, -CH (CH3) 2, -C (CH3) 3, - CH (CH3) (CH2CH3), -CH2CH ( CH3) 2, -CH2OH, -CH (OH) (CH3), -CH2CF3, -CH2C (O) OH, -CH2C (O) OR25, -CH2CH2C (O) OH, -CH2CH2C (O) OR25, - CH2C ( O) NH2, -CH2CH2C (O) NH2, -CH2CH2C (O) N (H) C (H) (CH3) CO2H, - CH2CH2C (O) N (H) C (H) (CO2H) CH2CO2H, -CH2NR21R22, - (CH2) 2NR21R22, - (CH2) 3NR21R22, - (CH2) 4NR21R22, - (CH2) 4N (R25) 3, - (CH2) 4N (H) C (O) (2,3-dihydroxybenzene), C1-C8 optionally substituted alkyl, C1-C8 optionally substituted heteroalkyl, C3-C8 optionally substituted cycloalkyl, - CH2-C3-C8 optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, R3 is methyl, ethyl, isopropyl , or cyclopropyl; R5 is H, methyl, ethyl, or -CH2OH; or R5 and R24 together with the boron atom form a 5- or 6-membered ring containing boron; R6 is -C (= O) H, -CH2C (= O) H, -C (= O) NHCH2C (= O) H, - C (= O) C (= O) N (R14) 2, -B (OR23) (OR24), or ; or R5 and R6 together with the carbon atom form Rx is H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted C3-C8 cycloalkyl; or Rx and R2 together with the nitrogen atom form an optionally substituted nitrogen-containing ring; Ry is H or methyl; or Ry and R5 together with the nitrogen atom form an optionally substituted nitrogen-containing ring; Rz is -NR15R16, -CH2-NR15R16, or - (CH2) 2-NR15R16; R7 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, or a straight or branched alkyl chain of about 1-22 carbon atoms, optionally comprising within the alkyl chain, or at the end of the alkyl chain, a optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or optionally substituted where Z is a bond, O, S, NH, CH2, NHCH2, or C≡C; R8 is a bond, -O, or -N (R17) -, optionally substituted aryl or optionally substituted heteroaryl; R9 is -CH2OH, -CH2CH (CH3) 2, R14, R15, and R16 are each, independently, H, or C1-C4 alkyl; R17 is H, methyl, ethyl, isopropyl or cyclopropyl; R18, R19, and R20 are each, independently, H, or a methyl group; each R21 is, independently, H or C1-C4 alkyl; each R22 is, independently, H, C1-C4 alkyl, C (= NH) (NH2), or -CH (= NH); R23 and R24 are each independently H, or C1-C4 alkyl, or R23 and R24 together with the boron atom form a 5- or 6-membered ring containing optionally substituted boron; each R25 is independently, C1-C6 alkyl; R26 is H, C1-C4 alkyl, C1-C4 alkoxy, -CH2C (O) OR25, or - OCH2C (O) OR25; n is 0 or 1; p is 0 or 1; and q is 0 or 1; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. Compound according to claim 1, characterized in that R1 is Compound according to claim 2, characterized in that R8 is a bond. Compound according to claim 3, characterized in that R2, R4, R10, R11, R12, and R13 are each, independently, H, -CH3, -CH (CH3) 2, -C (CH3) 3, - CH (CH3) (CH2CH3), -CH2CH (CH3) 2, -CH2OH, -CH (OH) (CH3), -CH2CF3, -CH2C (O) OH, -CH2CH2C (O) OH, -CH2C (O) NH2 , -CH2CH2C (O) NH2, - CH2NH2, - (CH2) 2NH2, - (CH2) 3NH2, - (CH2) 4NH2, Compound according to claim 4, characterized in that R2, R4, R10, R11, R12, and R13 are each, independently, H, -CH3, -CH2CH (CH3) 2, -CH2OH, - CH (OH) (CH3), -CH2CH2C (O) OH, -CH2C (O) NH2, -CH2CH2C (O) NH2, - CH2NH2, - (CH2) 2NH2, - (CH2) 3NH2, - (CH2) 4NH2, or. Compound according to claim 5, characterized in that n is 1 and p is 0. Compound according to claim 6, characterized in that it has the structure of Formula (Ib): Formula Ib; wherein R2, R4, and R12 are each, independently, - CH2CH (CH3) 2, - (CH2) 3NH2 or (CH2) 4NH2. Compound according to claim 1, characterized in that R1 is Compound according to claim 8, characterized in that R2, R4, R12 and R13 are each, independently, -H, -CH3, -CH (CH3) 2, -C (CH3) 3, - CH (CH3) (CH2CH3), -CH2CH (CH3) 2, -CH2OH, -CH (OH) (CH3), -CH2CF3, -CH2C (O) OH, -CH2CH2C (O) OH, -CH2C (O) NH2, -CH2CH2C ( O) NH2, - CH2NH2, - (CH2) 2NH2, - (CH2) 3NH2, - (CH2) 4NH2, Compound according to claim 9, characterized in that R2, R4, R12 and R13 are each independently -H, -CH3, -CH2CH (CH3) 2, -CH2OH, - CH (OH) (CH3), -CH2CH2C (O) OH, -CH2C (O) NH2, -CH2CH2C (O) NH2, - CH2NH2, - (CH2) 2NH2, - (CH2) 3NH2, - (CH2) 4NH2,. Compound according to claim 10, characterized in that n is 0. Compound according to claim 11, characterized in that R8 is a bond. Compound according to claim 12, characterized in that it has the structure of Formula (Ic): Formula (Ic); where R2, R4, and R12 are each, independently, - CH2CH (CH3) 2, -CH (OH) (CH3), CH2C (O) NH2, -CH2CH2C (O) NH2, - CH2NH2, - (CH2) 2NH2, - (CH2) 3NH2, or - (CH2) 4NH2. Compound according to claim 1, characterized in that R1 is A compound according to claim 14, characterized in that R2 and R4 are each independently -H, -CH3, -CH (CH3) 2, -C (CH3) 3, -CH (CH3) (CH2CH3), -CH2CH (CH3) 2, -CH2OH, -CH (OH) (CH3), -CH2CF3, -CH2C (O) OH, -CH2CH2C (O) OH, - CH2C (O) NH2, -CH2CH2C (O) NH2, -CH2NH2, - (CH2) 2NH2, - (CH2) 3NH2, - (CH2) 4NH2, A compound according to claim 15, characterized in that q is 1; and R8 is a link. A compound according to claim 16, characterized in that it has the structure of Formula (Id): Formula (Id); where Rz is NH2; and R2 and R4 are each independently - CH2CH (CH3) 2, -CH (OH) (CH3), CH2C (O) NH2, -CH2CH2C (O) NH2, - CH2NH2, - (CH2) 2NH2, - ( CH2) 3NH2, or - (CH2) 4NH2. Pharmaceutical composition, characterized in that it comprises a compound as defined in claim 1 and a pharmaceutically acceptable excipient. 19. Use of a compound as defined in claim 1, characterized in that it is in the preparation of a pharmaceutical composition for treating a bacterial infection in a mammal, wherein said composition is supplied to the mammal with a frequency and of sufficient duration to provide a beneficial effect for the mammal. 20. Use according to claim 19, characterized in that the bacterial infection is an infection involving Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas Alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyi, Entermon, tymon, Salmonella tyati, Salmonella , Klebsiella pneumoniae, Klebsiella oxytocin, Serratia marcescens, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Acinetobacter calyaceticus, acinetobacter, acinetobacteria, acinetobacteria intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainf uenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Paste urella haemolytica, Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeais, Bacteria, Neisseria gisorrhoeais, Gardneris, distasonis, Homologous group 3452A of Bacteroides, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecal, Staocylococcus, Staphylococcus, Staphylococcus, Staphyloccus hyicus, Staphylococcus haemolyticus, Staphylococcus hominis or Staphylococcus saccharolyticus. Use according to claim 19, characterized in that the pharmaceutical composition further comprises a second therapeutic agent.