ANTIBACTERIAL AGENTS

1. CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit under 35 U.S.C, §119(e) of U.S. Provisional Patent Application No. 61/645,439, filed May 10, 2012, The foregoing application is incorporated herein by reference In its entirety,

IS. BACKGROUND OF THE INVENTION

A, Field of the Invention

This invention pertains generally to treating infections caused by gram- negative bacteria. More specifically, the invention described herein pertains to treating gram-negative infections by inhibiting activity of UDP-3-0-(R-3-hydroxydacaneyl}-N~ acety (glucosamine deacetylase (LpxC). The present invention provides small molecule inhibitors of LpxC, pharmaceutical formulations containing such inhibitors, methods of treating subjects with such pharmaceutical formulations, and methods of preparing such pharmaceutical formulations and inhibitors. The invention described herein pertains \Q traa ing gram-negative infections by administering compounds capable of inhibiting activity of UDP-3-0-(R-3-hydroxydecanoy!)-N-acet l9iuc §a.mine deacetylase (LpxC), either alone or in combination with administering a second antibacterial compound.

B. Introduction

Over the past several decades, the frequency of antimicrobial resistance and its association with serious infectious diseases have increased at alarming rates. The problem of antibacterial resistance is compounded by the existence of bacterial strains resistant to multiple antlbactsriate. Thus there is a need for new antibacterial®, particularly antibacterial with novel mechanisms of action. A previously unexploited but highly conserved target, LpxC, provides a new opportunity for developing broad-spectrum antibacterial small molecules thai comprise a new class of active bactericidal chemical entities that should encounter iittle, if any, naturally- occurring, target-related resistance. LpxC {the enzyme uridyidiphospho-3~0-(R.- hydraxyd@canoyf}-N-acetyiglucQsamlne deacetylase) is present across all Gram- negative bacterial species of interest and is tnvotvecj in the first committed step in outer membrane biosynthesis. Thus LpxC is essential for survival and presents an ideal target for antibiotic activity in Gram-negative bacterial species.

Researchers have identified some compounds with antibacterial activity that target lipid A biosynthesis. For example, Jackman et al. (J. Biol. Chem. _r 2000,

275(15), 11002-11009); Wyei aff et ai. (Trends in Microbiology. 1998, 8(4), 154-159);

U.S. Patent Application Publication No. 2001/0053555 (published 20 December 2001 , corresponding to International: PCT Publication No, WO 98/18754, published 7 May

1998): international PCT Publication No. WO 00/61134 (published 19 October 2000); U.S. Patent Application Publication No, 2004/0229955 (published 18 November 2004);

Internationa! PCT Publication No. WO 2008 027468 (published 6 March 2008);

International PCT Publication No. WO 2008/105515 (published 4 September 2008);

I ternationa! PCT Publication No. WO 2008/154042 (published 18 December 2008);

International PCT Publication No. WO 2009/158369 (published 30 December 2009): International PCT Publicatio No. WO 2010/017060 (published 11 February 2010):

International PCT Publication No. WO 2010/Q243S6 (published 4 March 2010);

International PCT Publication No. WO 2010/031750 (published 25 March 2010);

Internationa! PCT Publication No. WO 2010/032147 (published 25 March 2010);

international PCT Publication No. WO 2010/100475 (published 10 September 2010); Internationa! PCT Publication No. WO 201 1/045703 (published 21 April 2011);

International PCT Publication No, WO 201 1/073845 (published 23 June 201 1): and

Internationa! PCT Publication No. WO 20 1/132712 (published 27 October 201 1 } ail disclose compounds having antibacterial ami- LpxC activity. The commercial

development of these LpxC inhibitors has been complicated by toxicity of these compounds in mammalian animals at concentrations at or near those required for antibacterial activity.

Although there have been advances in the field, there remains a need for LpxC inhibitors that have activity as bactericidal agents against gram-negative bacteria and have an acceptable efficacy and toxicify tole ance profile, it is, accordingly, an object of this invention to provide compounds and combinations of such compounds for use in the preparation of non-toxic antibacterials and other pharmaceuticals capable of inhibiting gram-negative bacterial infections.

Ill BRIEF SUMMA Y OF THE INVENTION

The present invention provides novel compounds, pharmaceutical formulations induding the compounds, methods of inhibiting UDP-3-0-(R-3- hydroxydecanoyl)-N-acety}giucosarnine deaceiyiase (LpxC), and methods of treating gram-negative bacterial infections,

In one aspect, the invention provides compounds of formula I:

and stereoisomers and, pharmaceutically acceptable salts thereof, wherein

A is selected from the group consisting of:

(a) substituted C Ce aikyl, wherein at least one substituent is hydroxy; and

(b) substituted C ₃ -C ₆ cyc!oalkyl, wherein at least one substituent is selected from hydroxy and hydroxyalkyi;

G is selected from the group consisting of:

(a) ~C=C-~;

(b) -CH=CH-C2C~;

c) -C≡C-CH=CH-;

phenyl; and

D is selected from the group consisting of:

(a) wherein W is N or *-0 ^' ; i d) . wherein

R ¹ and R ² are each independently selected from hydrogen and methyl;

and

E is -C(CH ₃ ) ₂ SCH ₃₎ -C(CH ₃ ) ₂ S(0)CH ₃ , -C(CH _s ) ₂ S(0) ₂ CH _; , or - C(0)NHCH ₃ .

In one aspect, the in compounds of formula li: and stereoisomers and pharmaceutically acceptable salts thereof, wherein

A is selected from the group consisting of:

fa) substituted C _t -C _e alkyl. wherein at least one substiiueni is hydroxy; and

(b) substituted C C _e cycloalkyi, wherein at least one substituent is

selected from hydroxy and hydroxyalkyi;

G is selected from the group consisting of:

(b) -CH=CH-CSC~;

(c) -CSC-CH=CH-;

(g) phenyl; and D is selected from the group consisting of:

wherein

Q Is O or NR, wherein B. is hydrogen or an unsubstituted Ci-C ₃ alkyi; R ' and R ² independently are selected from the group consisting of

hydrogen, and substituted or unsubstituted C C ₃ alky!, or R ¹ and R ² , together with the carbon atom to which they are attached, form an unsubstituted C _; C _e cycloalkyi group or an unsubstituted

4-6 membered heterocyclic group; and

R ^:> is selected from the group consisting of hydr ogen, substituted or unsubstituted C _r Ci-aik i, substituted or unsubstituted cycloalkyi, substituted or unsubstituted cycloaikyialkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryialkyl, substituted or unsubstituted heterocyc!yl, substituted or unsubstituted heterocydyiaikyi, substituted or unsubstituted heteroary!, and substituted or unsubstituted heteroaryiaikyi. In another aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula I, or a stereoisomer or

pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. In another aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula II, or a stereoisomer or

pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. in another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of an antibacterisi! compound of Formula i, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. In another aspect, the present invention provides a pharmaceutical composition comprising art effective amount of an antibacterial compound of Formula if or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

In another aspect, the present Invention provides a method of inhibiting a deacety!ase enzyme in gram-negative bacteria, thereby affecting bacterial growth, comprising administering to a subject in need of such inhibition an LpxC-inhtbitory compound of Formula I or a stereoisomer or pharmaceutically acceptable salt thereof, in another aspect, the present invention provides a method of inhibiting a deaoefylase enzyme in gram-negative bacteria, thereby affecting bacterial growth, comprising administering to a subject in need of such inhibition an LpxC-inhibitory compound cf Formula II or a stereoisomer or pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of inhibiting LpxC. thereby modulating the virulence of a bacterial infection, comprising

administering to a subject in need of such inhibition an LpxC-in bi ^' iory compound of Formula I or a stereoisomer or pharmaceutically acceptable salt thereof. In another aspect, the present invention provides a method of inhibiting LpxG, thereby modulating the virulence of a bacterial infection, comprising administering to a subject in need of such inhibition an LpxC -inhibitory compound of Formula II or a stereoisomer or pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method for treating a subject having a bacterial infection comprising administering to the subject in need thereof an antibacterialiy effective amount of a compound of Formula I. or a

stereoisomer or pharmaceutically acceptable salt thereof. In another aspect, the present invention provides a method for treating a subject having: a bacterial infection comprising administering to the subject in need thereof an antlbacteriaily effective amount of a compound of Formula II, or a stereoisomer or pharmaceutically acceptable salt thereof. In a more specific embodiment of the method of treatment, the bacterial infection is a gram-negative bacterial infection, in a further specific embodiment the subject is a mamma! and in certain embodiments, a human.

In another aspect, the present invention provides a method of

administering an antibacterial!/ effective amount of a compound of Formute i. or a stereoisomer or pharmaceuticaiiy acceptable salt thereof, to a subject infected with fermentative or non-fermentative gram-negative bacteria, in another aspect, the present invention provides a method of administering an antibacterially effective amount of a compound of Formula II, or a stereoisomer or pharmaceuticaiiy acceptable salt thereof, to a subject infected with a fermentative or non-fermentative gram- negative bacteria. Examples of such bacteria include Pseuclomonas aeruginosa, Stenolmphomonas maftop ila. Burkholdem cepacia, Aicaiigenes xyfosoxidsns, Enterobact.eriaceae, Haemophilus, F nsiisceilaeeae (e.g., Francisoei!e tu!ar&nsis) and Neisseria species.

i another aspect, the present invention provides a method of administering an aniibacterial!y effective amount of a compound of Formula I, or a stereoisomer or pharmaceuticaiiy acceptable salt thereof, to a subject infected with gram-negative bacteria. In another aspect, the present invention provides a method of administering an antibacterially effective amount of a compound of Formula ii, or a stereoisomer or pharmaceutically acceptable sa!t thereof, to a subject infected with gram-negative bacteria. Examples of such bacteria include Enterohacienaceae, such as Se atia, Proteus.. Klebsiella, Enterobecter Citt'obmeter, Salmonella, Providemia, Yersinia (e.g., Yersinia pestis), Morganel!a. Cedecea, Edwardsi&lia species and

Escherichia coll.

These and other aspects of the invention will be evident upon reference to the following detailed description.

IV. DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel compounds, methods for inhibiting LpxC in gram-negative bacteria, and novel methods for treating bacteria! infections. The compounds provided herein can be formulated into pharmaceutical formulations and medicaments that are useful in the methods of the invention. The invention also provides for the use of the compounds in preparing medicaments and pharmaceutical formulations, for use of the compounds n inhibiting LpxC, and for use of the compounds sn treating bacteria! infections in a subject. The invention further provides compositions arsd methods for treating gram-negative infections by administering compounds capable of inhibiting activity of UDP-3-CKR~3>h drox decano l}-N- aceiylglucosarnine deaceiylase (LpxC), either alone or in combination with, administering a second antibacterial compound

A. Definitions

The following abbreviations and definitions are used throughout this application:

"LPXC" is an abbreviation that stands for UDP-3-0-( -3<- hyc roxydeca n oyi)~N-ac@tyigiuQosamine deaeetyiase.

As used herein, the following definitions shall apply unless otherwise indicated.

"Aikyi" refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and preferably 1 to 8 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl {CH;H, ethyl (CH ₃ CH ), ^p o l (CH ₃ CH ₂ CH } _} iSGprcpy! ((CH ₃ )iCH->. «-butyl {CH _S CH ₂ CH ₂ CH ₂ -}. isobutyl ((CH ₃ ) ₂ CHCHri. sec-butyl ((CH*KCH _s CH _a )CH-), /- utyi ((CH ₃ ) ₃ C-) _f n-pen l {CH ^. ₃ CH ₂ CH ₂ CH _S GH ₂ -), and neapentyl ((CH _s ) ₃ CCH ).

"Alkoxy" refers to the group -G-alkyi, wherein alkyl m as defined herein, Aikoxy includes methoxy, ethaxy, n-propcxy, isopropoxy, n-buioxy, f-hutoxy, sec-buioxy, n-pentoxy, and the like.

"Amino" refers to the group -NH ₂ .

"Primary alcohol ^' ' refers to the group -alkyl-OH. wherein the hydroxy! radical is connected to a primary carbon. Examples include -CH ₂ OH ihydroxymethyl), - CH ₂ CH ₂ OH {hydroxymethyi) and ~CH(CH _a )CH _a OH (1 -hydroxypropan-2-yl).

^' ' lken l" refers to straight chain or branched hydrocarbyl groups having from .2 to 6 carbon atoms and preferably 2 to 4 carbon atoms and having at least 1 and preferably from 1 to £ sites of vinyl C>G-C<) unsaturation. Such groups are exemplified by vinyl a!lyi, and bui~3~en-1 ~yl Included within this term are the cis an trans isomers or mixtures of these isomers.

"Aikynyi" refers to straight or branched monovalent hydroearbyl groups having from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at least 1 and preferably from 1 to 2 sites of acetylenic -C=C- unsaturation. Examples of such aik nyl groups include aeetylsnyl CsCH), and propargy! (-CH ₂ CsCH).

"Carboxyl" or "oarbo y ^' ' refers to -COOH or salts thereof.

"Cyano" or "nitrite" refers to the group. ~C ,

"Cyctoalkyi" refers to cyclic a!kyl groups of from 3 to 13 carbon atoms having single. Examples of cyc!oalkyl groups include cyctopropyl, cyciobutyi.

cyclopentyl, cyc!oociyi, and the like.

"Guanidino" refers to the group -NHC(=NH}NH ₂ .

"Halo" or ^' 'halogen" refers to fiuoro, chforo, bromo, and sodo and is typically fiuoro or ch!cro.

"Hydroxy" or "hydroxy!" refers to the group -OH.

"Heterocvcie." "heterocyclic," and "heierocycivi ^" refer to a saturated or unsaturated group having ¾ single ring, and having from 3 to 15 ring atoms, including 1 to 4 hetero atoms. These ring atoms are selected from the group consisting of nSrogen, sulfur, or oxygen. In one implementation, the nitrogen and/or sulfur stom(s) of the heterocyclic group are optionally oxidized to provide for the N-cxide. -8(0}-. or ~ SOj- moieties.

"Nitro" refers to the group -N0 ₂ .

"NftrosQ" refers to the group -NO.

"Oxo" refers to the atom (=0).

"Substituted" refers to a group having one or more hydrogens replaced with subslituents selected from the group consisting of aikoxy, acyi. acyiamino, acyloxy, amino, aminocarbcnyi. amlnothlocarbonyl. aminocarbonylamino,

aminothiocarbonylamino _. , aminocarbonyloxy, amidino, carboxyl, carboxyl ester, (carboxyl esSer)amino, (carboxyl estenoxy, c ano, guanidino, halo, hydroxy, nitro, S0 ₃ H, sulfonyl, suifony!oxy, tbioacyi, thiol, and alky!lhm wherein said substiiuenfs are as defined herein. In certain substituted cyclic groups, "substituted" also refers to a group having two hydrogens replaced with a single doubie bonded oxygen atom (an oxo group) or a single double bonded suifur atom fthioxo). In some implementations, the substituted group has 1 to 3 of the aforementioned substituersts. in other implementations, the substituted group has 1 to 2 of the aforementioned substttuents

"Suifor l" refers to the group ^S0 ₂ ^» aikyl, -80 ₂ -substituted slkyi, -SO alkenyi, -SOr-substituted alkenyi, wherein aik l, substituted alkyl, a!kenyi, substituted alkenyi, alkynyl, and substituted alkynyl are as defined herein. Sulfonyi includes groups such as methyi-S0 ₂ -.

^:i SuJfoQylo y' refers to the group -GSOi-a!kyl, -QSO _r substituted aikyl, -OSO _r alkenyl, -OSO substituted alkenyi, -OS0 ₂ -aikynyt, -OSO substltuted alkynyl wherein alkyl. substituted alkyl, alkenyi, substituted alkenyi, aikynyi, and substituted alkynyl are as defined herein.

"Thioacyr refers to the groups H-C(8}-, alkyl- GtS)-, substituted alkyl-C(S)~, alkonyi-C(S)-, substituted alkenyi~C(S)-, alkynyi-C(S)-, and substituted aikynyl-C(S)-, wherein aikyl, substituted alkyl, alkenyi, substituted alkenyi, alkynyl, and substituted alkynyl are as defined herein.

' hjgf refers io the group -SH.

"Thioxo* refers to the atom (~S).

"Aikyithio" refers to the group ~S-alkyl _f wherein aikyl is as defined herein. In other implementations, suifur may be oxidized to -3(OK The sulfoxide may exist as one or more stereoisomers.

Unless indicated otherwise, the nomenclature of sufostif uents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjsceni functionality toward the point of attachment. For example, the substituent "aryialkyioxycarbonyr refers to the group {ary!}-(a!ky!)-0 C(Oh

Generally, reference to a certain element such as hydrogen or H is meant to include all isotopes of tha element. For example, if a substii uent group is defined to include hydrogen or H, it also Includes deuterium and tritium.

The subject invention also includes isotopically-iafeeied compounds of the present invention, thai are structurally identical to those disclosed herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as ² H, ³ H, ^* ¾, ¹⁴ C, ^;5 N. ^iS 0, ¹⁷ 0, ³¹ P, ^¾ P, ³ ¾, ¹⁵ F and ³ ¾5, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically

acceptable salts of said compounds and of said prodrugs that contain the

aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain rsotoptcaily labeled compounds of the present invention, for example those into which radioactive isotopes such as H and ¹ C are incorporated, are useful in drug and/or substrate tissue distribution assays. Trit!ated, s.e., ³ H, and carbon-14, i.e.. isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e.. ^' Ή, may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopica!ly labeled compounds of this invention and prodrugs thereof can generally b prepared by carrying out known or referenced procedures and by substituting a readily available isotopieai!y Iabeied reagent for a non-isotopicaily iabeied reagent.

"Stereoisomer" and "stereoisomers" refer to compounds thai have same atomic connectivity but different atomic arrangement in space. Stereoisomers include els-trans isomers, E and Z isomers, enantlomers, and diastereomers.

"Tautomer' refers to alternate forms of a molecule that differ in the position of a proton, such as enoi-keto and imine-enamine tautomers, or the tautomeric forms of heter aryi groups containing a -N=C(H}-NH- ring atom arrangement, such as pyrazoles, imidazoles, benzimidazoles, tnasoies, and tetrazoleg. A person of ordinary skill in the art would recognize that other tautomeric ring atom arrangements are possible.

''Su ject" refers to human and non-human animals, especially

mammals. Tharrnaceutfcaily acceptable salt ^* refers to pharmaceutically acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraa!kyiarn nonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, rnaieata oxalate, phosphate, sulfate and the like.

^armiet Uiica!l^ and ^K therapeutic¾jly _, effective amount" refer to an amount of a compound sufficient to treat a specified disorder or disease or one or more of Its symptoms and/or to prevent the occurrence of the disease or disorder.

"Co-administration" can be in the form of a single formulation

(combining, for example, a compound of the present invention and a second antibacterial agent with pharmaceutically acceptable ex pients, optionally segregating the two active ingredients in different exeipierrt mixtures designed to independently control their respective release rates and durations) or by independent administration of separate formulations containing the active agents. "Co-adm lustration" further includes concurrent administration (administration of a compound of the present invention and a second antibacterial agent at the same time) and time varied ad ^' ministration (administration of a compound of the present invention at a time different from that of the second antibacterial agent), as long as both the compound of the present invention and the second antibacterial agent are present in the body in therapeutically effective concentrations during at least partially overlapping times.

The term "antibacterial agent" refers to agents thai have either bactericidal or bacteriostatic activity. The term Inhibiting the growth" indicates that the rate of increase in the numbers of a population of a particular bacterium is reduced. Thus, the term includes situations in which the bacterial population increases but at a reduced rat©, as well as situations where the growth of the population is stopped, as well as situations where the numbers of the bacteria In the population are reduced or the population even eliminated. If an enzyme activity assay is used to screen for inhibitors, one can make modifications In uptake/efflux, solubility, half-life, etc. to compounds In order to correlate enzyme inhibition with growth inhibition, The activity of antibacterial agents is not necessarily limited to bacteria but may also encompass activity against parasites, virus, and fungi.

Unless the context requires otherwise, throughout the specification and claims which follow, the word "comprise" and variations thereof, such as. "comprises" and "comprising" are to be construed in an open, inclusive sense, that Is as "including, but not limited to".

Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described In connection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the phrases In one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily ail referring to the same embodiment. Furthermore, the particular features, structures, or c aracteristics may be combined in any suitable manner in one or more embodiments, B. Compounds, Compositions and Use Thereof

in one aspect, the invention provides compounds of formula I:

and stereoisomers, pharmaceutically acceptable salts, and esters thereof, wherein A is selected from the group consisting of:

(a) substituted CrC _e aikyi, wherein at least one subsf!tuenf is hydroxy; and

( ) substituted C ₃ -C ₃ cycloaikyL wherein at least one substiiuent is

selected from hydroxy and hydroxyaikyi.

G is selected from the group consisting of:

(a) -CSC-;

(b) -CH-CH~CsC~;

(c) -0£C -CH-CH- ^» :

(g) phenyl; and

D is selected sting of:

(a) n W is or hf-O".

R ¹ and R ² are each independently selected from hydrogen and methyl;

and

E is -C(CH ₃ ) ₂ SCH ₃ , -C(CH ₃ ) ₂ S(0)CH ₃ , -C(CH"} _? S(0} _S CH ₃ or - C(0)NHCH _S .

In one aspect, the in compounds of formula II: lers, pharmaceutically acceptable salts, and esters thereof, wherein

?d from the group consisting of:

substituted Ci-C _ti alkyi, wherein at least one substituent is hydroxy; and

substituted C ₃ -C ₅ cycloalky!, wherein at least one substituent is selected from hydroxy and hydroxyalkyl;

3d from the group consisting of: (b) -CH=CH-C≡C~;

(c) ~Cse-CH=CH~;

(g) phenyl; and

D s selected from the group consisting of:

Bin

Q is O or MR, wherein is hydrogen or an unsubstituted C C ₃ aikyl;

1 and R ² independently are selecied from the group consisting of

hydrogen, and substituted or unsubstituted C<-C ₃ aikyl, or R ¹ and R\ together with the carbon atom to which they are attached, form an unsubstituted C ₃ -C ₈ cy oalkyi group or an unsubstituted 4-6 membered heterocyclic group; and

R ^a is selected from the group consisting of hydrogen, substituted or unsubstituted C C¾-aikyi _v substituted or unsubstituted cycioalky!, substituted or unsubstituted cycloaikyfaikyl, substituted or unsubstituted aryl, substituted or unsubstituted aryiaikyl, substituted or unsubstituted heterocyelyi, substituted or unsubstituted heterocyciyialkyi. substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylaiky!. In certain embodiments, A is substituted Ci~ ¾ alky!, wherein at ieast one substituent is hydroxy, In certain embodiments, A i$ substituted d-C ₃ alkyi, wherein at least two substltuente are hydroxy. For example, in certain embodiments A is hydroxymethyi, hy roxyethyi, hydroxy-propyl or dihydroxpropyl,

In other embodiments, A is substituted C%~C cycioalkyi, wherein at teast one substituent is selected from hydroxy and hydroxyafkyi. In certain embodiments, A is substituted C ₃ -O _s cycioalkyi, wherein at least one substituent is hydroxy methyl- For example, in certain embodiments A is hydroxymethylcyciopropyi. in other

embodiments, A is substituted C ₃ -C _e cycioalkyi, wherein at least one substiuent is hydroxy.

in certain embodiments. 0 is -CsC-CsC-.

In certain embodiments of compounds of Formula W is N or N*-Q ^" . In other embodiments of compounds of n still other embodiments of compounds of Formula I. D n stii other embodiments of compounds of Formula f, D

embodiments, W is hydrogen. Similarly, in certain embodiments, R ² is hydrogen. In certain embodiments of compounds of Formula i, E is -CCCH ₃ / ₂ SCH3. in other embodiments, E is ~GiCH;0 _a SiO} _: CH ₃ . In still other embodiments, E is - C(CH ₃ ) ₂ S(0)CH ₃ , In still other embodiments, E is ~G{0)NHCH ₃ .

The compounds of the invention include the compounds of Table ! below. _1i oxs _yii - _•

to

SUBSTITUTE SHEET (RLTLE 26)

_{(l tt} aname _'.

C0

Compounds of the present invention cart be readily synthesized using the methods described herein, or other methods, that are welt known in the art. For example, the synthesis of hxdroxamic acids or similar scaffolds having a wide variety of su siituents are comprehensively reviewed in Kline, T. _: et al , "Potent, novel in vitro inhibitors of the Pseudomonas aeruginosa deacetyiase LpxC" J. Med C em. 2002, 48(14), 31 12-29; U.S. Patent No. 6,925,659:; Ftrrung, M. C„ et ai., ^! \ Convenient Procedure for the Preparation of Amino Acid Hydroxamates from Esters" J, Org. Own. if is, 60, 8084-8085; Nhu, K. _s et at, "A New and Efficient Solid Phase Synthesis of Hydroxamic Acids" J. Org. C &m. 997, 62, 7088-7089; Internationa PCT Publication No. W098/ 8754; Mellon 3. L , et al, "N-Fmoc-amtnoxy-2-chlorirityi

Polystyrene Resin: A Facile Solid-phase Methodology for the Synthesis of Hydroxarmo Acids" Tetrahedron Lett 1997. 38, 3311-3314; Khan, S. L et ai., "A Facile and Convenient Solid-phase Procedure for Synthesizing Nucleoside Hydroxarme Acids ^* T&rahedron Lett 1938, 39, 8031-8034; Zhang, Y., et ai., "Design, Combinatorial Chemical Synthesis, and in vitro Characterization of Novel Urea Based Gelaiinase inhibitors" Bioorg. M&d. C em. Lett 1999, 9. 2823-2826; ito, Y., et a!., "Synthetic Reactions by Complex Catalysts, XXXI, A Novel and Versatile Method of Heterocycie Synthesis" J. Am Chem. Soc. 1973, 95, 4447-4448; ito, Y., et af„ "Synthetic Reactions by Complex Catalysts XXXV" Syn. C m un. 1974, 4, 97-103; Witte, H. _: et ai., "Cy ische Imidsaurester a us Nitriten und Aminoa!kohoien* Uebigs Ann Chew., 1974, 998-1009; Pattenden, β. , et aL "Nsturally Occurring Linear Fused Thiazoiine-Thiazoie Containing Metabolites; Tola! Synthesis of (-} Dldehydrornirsbszoie A, a Cytotoxic Alkaloid from Blue-Green Algae" J. Chem. Soc. Perkin Trans 1993, t, 1629-1636; Boyce, R. J., et a!., "Total Synthesis of Thlangazo!o, A Novel Naturally Occurring HiV- Inhibitor from Poiyangium sp." Tetrahedron 1095, 51 , 7321-7330; Gaieotti, N., et ai., "Synthesis of Peptidyl Aldehydes from Thiazoiines" Telmhedmn, Lett 1997, 38, 2459- 2462; Charette, A. B., et a!., "Mild Method for the Synthesis of Thiazoiines from Secondary and Tertiary Amides" J. Org. Chem. 1998, 63, 908-909; Bergeron, R. J., et a!,, "Effects of C-4 Stereochemistry and C-4' Hydroxyiatron on the iron Clearing:

Efficiency and Toxicity of Desferrfthioctn Analogues" J. Meet. Cham, 1999, 42, 2432- 2440; Raman, P. , et ai., "Titanium (!V)-medlated Tandem Deproteetion- cyclodehydraiion of Protected Cysteine N-Arnides; Biomimetic Synthesis of Thiazoiine- and Thiazole-coniaining Heisrocycies ^* Org. Lett 2000, 2, 3283-3292; Fernandez. X., et aL "Novel Synthesis of 2-Thioazolines" Tstrahe&on Lett. 2000, 41 3381 -3384; and Wipf, P., et a!., "G. Thiolysls of Oxaxolihenes: A New, Selective Method for the Direct 5 Conversion of Peptide Oxazo!snes into Thiazoli-nes" Tetra eamn left. 1995, 36, 6395- 8398, which are incorporated herein by reference.

In- another aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula I, or a stereoisomer or

pharrnaceufieaiiy aecepiable sail thereof, and a pharmaceutically acceptable carrier ø? 10 diluent.

In another aspect, the invention provides a method of inhibiting a deacetylase enzyme in a gram-negative bacteria, thereby affecting bacterial growth, comprising administering to a subject in need of such ^' inhibition a compound of Formula I or a stereoisomer or pharmaceutically acceptable salt thereof.

I S In another aspect, the invention provides a method of inhibiting LpxG, thereby modulating the Virulence of a bacterial infection, comprising administering to a subject in need of such inhibition a compound of Formula I or a stereoisomer or pharmaceutically acceptable salt thereof In certain embodiments of the method of inhibiting LpxC using a compound of the present invention, the IC _S0 value of the

20 compound is less than or equal to 10 i with respect to LpxC. In other embodiments, the IC«.o value is less than or equal to 1 μΜ, is less than or equal to 0.1 \M, is less than or equal to 0.050 μΜ. is less than or equal to 0.030 μ , is less than or equai to 0.025 μ , or is less than or equal to 0.0 0 μ .

in another aspect, the invention provides a method for treating a subject

25 having a gram-negative bacterial infection comprising administering to the subject in need thereof an antibacterial!/ effective amount of a compound of Formula I or a stereoisomer or pharmaceutically acceptable salt thereof.

In another aspect, the Invention provides a method of administering a therapeutically effective amount of a compound of Formula I or a stereoisomer or

30 pharmaceutically acceptable salt thereof to a subject infected with a fermentative or non-fermentative gram-negative bacteria. Examples of fermentative or non- fermentative gram-negative bacteria include Pseudomonas aeruginosa,

Stewfrophomon m&ftop iia, Burkhoideria cepacia, Alca!igenes xylosoxkiaos, Ent&rQbactenaceae.. Haemophil s Franoiscei!acea® (e,g„ Franasoeiia iuiarensis} and Neisseria spec/as,

in another aspect, the invention provides a method of administering an inhibitory amount of a compound described herein to gram-negative bacteria, such as Enterohaote ceae which is selected from the group consisting of organisms such as Serrate, Proteus, Klebsiella. Enterobact&r, Citrob&cter, Salmonella Ptwktencia, Yersinia (e.g.. Yersinia p ils), ^organella, Cedecea, Edwarxlsiella s ecies and Escherichia coll,

In certain embodiments, the subject may be a mamma!, and in some embodiments, a human.

Bacteria! infections susceptible to treatment according to the present invention include primary infections and co-infections caused by a species of bacteria and one or more additional infectious agents such as, for example, bacteria, virus, parasite and fungus.

Compounds of the invention can be used for treating conditions caused by the bacterial production of endotoxin and, in particular, by gram-negative bacteria and bacteria that use LpxC in the biosynthesis of (^polysaccharide (LPS) or endotoxin.

Compounds of the invention also are useful in treating conditions that are caused or exacerbated by the bacterial production of lipid A and LPS or endotoxin, such as sepsis, septic shock, systemic inflammation, localized inflammation, chronic obstructive pulmonary disease (COPD) and acute exacerbations of chronic bronchitis (AECB). For these conditions, treatment includes the administration of a compound of the invention, or a combination of compounds of the invention, optionally with a second agent wherein the second agent is a second antibacterial agent or a non-antibacterial agent

For sepsis, septic shock, systemic inflammation, localized inflammation, chronic obstructive pulmonary disease (COPD) and acute exacerbations of chronic bronchitis (AECB), representative non-antibacterial agents include antientiotoxins including endotoxin receptor-binding antibodies endotoxin-hinding antibodies, anii- CD14-bindlng protein antibodies, antilipopoiysaccharide-binding protein antibodies and tyrosine kinase inhibitors.

In treatment of serious or chronic respiratory tract infections, compounds of the present Invention may also be used with non-antibsoisrial agents administered via inhalation. Representative non-anlihactenai agents used in this treatment include anti-inflammatory steroids, non-steroidal anti-inflammatory agents, branch iodilators, mucolytics, anti-asthma therapeutics and !uog fluid surfactants. In particular, the non-antibacterial agent may be albuterol, ^albuterol, budesonide, beciomethasone, dexamethasone, netiooromii,. bec tethasorte, fluticasone, fiunisolide, triamcinolone, ibuprofin, rofecoxib, naproxen, ceieeoxib, nedocroml, ipratropium, metaproterenol, ptrbuterol, salmeterol, formoterol, Indacaterol.

bronchiodilators, mucolytics, calfactant, beracfanf, porac ant alia, surfaxin or ptd ozyrne (also called dornase alfa).

Compounds of the invention can be used alone or in combination with a second antibacterial agent for the treatment of a serious or chronic respiratory tract .infection including serious lung and nosocomial Infections such as those caused by E erobacier aerogen&s, Entetvbact&r cloacae, Escherichia coft, Klebsiella

pneumoniae, Kfeb&tella oxyiaca, Proteus mimbiiis, S&rraita marcescens,

Sienotrophomonas maitophilia, Pseudomoms aeruginosa, Burkhoideria cepacia,

Aica enes xylosoxidans, Flavobastmum meningasetpffcum. Provideocia stuartR and Cltmbacler reundi, community lung infections such as those caused by Haemophilus Influenzae, L&gion&tia species, Moraxeile catarrh ai/s, Branha ella caierrh&!is, Entembaoier species, Klebsiella species, and Proieus species. Infections caused by other bacterial species such as Neisseria species, Shigella species, Salmonella species, Helicobacter pylori Vlbrionaceae and Bordeieiia species, as well as infections caused by a Brucella species, Fr cisel!a iularensis and/or Yersinia P&stis.

When used for treating subjects infected with gram-negative bacterial infections, compounds of the present invention ca be used to sensitize gram-negative bacteria to the effects of a second agent. The present invention provides novel combinations of compounds including a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof, as well as methods for treating subjects infected with gram-negative bacteria. The novel combinations provided herein can be formulated into

pharmaceutical formulations and medicaments that are useful in the methods of the invention. The invention also provides for the use of the novel combinations in preparing medicaments and pharmaceutical formulations, for use of the combinations in treating bacteria! infections in a subject

In one embodiment a second antibacterial agent is used in combination with a compound of Formula I, or stereoisomer or pharmaceutically acceptable salt thereof. Examples of suitable second antibactieral agents include, but are not limited to, vancomycin, iinezolid _« azithromycin, irnipenem, teicopianin, daptomycin, clindamycin, rifampin, cefotaxime, geniamiein, novobiocin or teiavancin. In one such embodiment, the antibacterial agent is vancomycin, teicopianin* rifampin, azithromycin, te!avancin or novobiocin. In certain embodiments the second antibacterial agent is vancomycin or rifampin. In some embodiments of the invention, the second

antibacterial agent and/or the compound of Formula I, or stereoisomer or

pharmaceutically acceptable salt thereof, is administered at a sub-therapeutic dose, wherein a subtherapeutic dose is a dose that would be insufficient to treat bacterial infections, if administered alone.

Pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of Formula i.. er a stereoisomer or pharmaceutically acceptable salt thereof, formulated together with one or more pharmaceutically acceptable carriers or diluents. As used herein, the term

"pharmaceutically acceptable carrier means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. 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 earboxymethyi cellulose, ethyl cellulose and cellulose acetate, powdered tragacanth; malt; gelatin; talc excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; saffiowet oil: sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oteate and ethyl laurate; agar; buffering agents such m magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;

isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium iaury! sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present In the composition, according to the judgment of the ramiuSator, The pharmaceutical compositions of this invention can be administered to humans and other animate orally, rectally _. . parenteral^ (as by intravenous, intramuscular or subcutaneous injection}, intraeisiemaily, intravagina v, intraperitoneally, topically (as by powders, ointments, or drops), bucaiiy, or as an oral or nasal spray, or a liquid aerosol or dry powder

formulation for inhalation.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemuisions, solutions, suspensions, syrups a d elixirs, in addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubiliiing agents and ernulsifiers such as ethyl alcohol, isopropyi alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butytene glycol, dimefhylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol ietrahydrofurfury! alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents,

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending, agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic

parenterally acceptable diluent or solvent, for example, as a solution in 13-butanedioi. Among; the acceptable vehicles and solvents that may be employed are water, Ringer's solution, 1 % lidocaine, U.S.P, and isotonic sodium chloride solution, in addition, sterile, fixed oils are corwenttonally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or digiywides. in addition, fatty acids such as oleic acid are used in the preparation of injeeiabies.

The injectable formulations can be sterilized., for example, by filtration through a bacterial-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 prior to use.

In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution thai, In turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenteraily administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle, injectable depot forms are made by forming mlcrcencapsuie matrices of the drug in biodegradable polymers such as polylactide-poiygiycolide. Depending upon 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

poiy(orthoesters) and poly anhydrides). Depot injectable formulations may also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues,

Compositions for recta! or vaginal administration are preferably suppositories that can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at bod

temperature and therefore melt in the rectum or vagina! cavity and release the active compound.

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 inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicaicium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, niannitol and silicic acid, b) binders such as, for example, cafboxymethylc llulos , alginates, gelatin, poiyvinyipyrroiidmone, sucrose, and acacia, c) humectanis such as glycerol, d) disintegrating agents such as agar-agar, calctum carbonate, potato or tapioca starch, alginie 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, acetyl alcohol and glycerol monosiearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, sold polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactase or milk sugar as well as high molecular weight polyethylene glycols and the like.

The solid dosage forms of tablets, dragees, capsules, pills, and

granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredients) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The antibacterial 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 controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is norma! practice, additional substances other than inert diluents, e g., tafotefing lubricants and other taoieting aids such a magnesium stearate and macrocrystalline cellulose, in the case of capsuiss, tablets and pills, the dosage forms may also comprise: buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredients) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding com ositions thai can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulations, ear drops, and the like arealso contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, exe enis such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonitss, silicic acid, talc and zinc oxide, or mixtures thereof.

Compositions of the invention may also be formulated for delivery as a liquid aerosol or inhaiable dry powder. Liquid aerosol formulations may be nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles where bacteria reside in subjects with bronchial infections, such as chronic bronchitis and pneumonia. Pathogenic bacteria are commonly present throughout airways down to bronchi, bronehioii and lung parenebema, particularly in terminal and respiratory bronchioles. During exacerbation of infection, bacteria can also be present in alveoli. Liquid aerosol and inhaiable dry powder formulations are preferably delivered throughout the endobronchial tree to the terminal bronchioles and eventually to the parenchymal tissue.

Aerosolized formulations of the invention may be delivered using an aerosol forming device, such as a jet, vibrating porous plate or ultrasonic nebulizer, preferably selected to allow the formation of a aerosol particles having with a mass medium average diameter predominantly between 1 to 5 μτη. Further, the formulation preferably has balanced osmoiarity ionic strength and chloride concentration, and the smallest aeroso!izabie volume able to deliver effective dose of the compounds of the invention to the site of the Infection. Additionally, the aerosolized formulation preferably does not impair negatively the functionality of the airways and does not cause undesirable side effects

Aerosolizatipn devices suitable for administration of aerosol formuiations of the invention include, for example, jet, vibrating porous plate, ultrasonic nebulizers and energized dry powder inhalers, thai are able to nebulize the formulation of the invention into aerosol particle size predominantly in the size range from 1 -5 prn. Predominantly in t is application means that at least 70% ut preferably more than

90% of ail generated aerosol panicles are t to 5 prn range. A jet nebulizer works by air pressure to break a liquid solution info aerosol droplets. Vibrating porous plate nebulizers work by using a sonic vacuum produced by a rapidly vibrating porous plate to extrude a solvent droplet through a porous piate. An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets. A variety of suitable devices are available, including, for example, Aero Neb and AeroDose vibrating porous piate nebulizers (AeroGen, Inc., Sunnyvale, Calif,), Sidestream? nebulizers (Medic-Aid Ltd. , West Sussex, England), Pan LC? and Pari LC Star? jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Va.), and Aerosonic

(DeViiblss Me izlnische Produkte (Deutschland) GmbH, Heiden, Germany) and U!fraA!re? (Omron Healthcare, inc., Vernon Hills, III.) ultrasonic nebulizers.

Compounds of the invention may also be formulated for use as topical powders and sprays that can contain, in addition to the compounds of this invention, excipiente such as lactose, talc, silicic acid, aluminum: hydroxide, calcium silicates and polyarnide powder, or mixtures of these substances. Sprays can additionally contain customary propellents such as chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlled delivery of compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

According to the methods of treatment of the present invention, bacteria infections are treated or prevented in a subject such as a human or lower mammal by administering to the subject a therapeutically effective amount of a compound of

Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof, in such amounts and for such time as is necessary to achieve the desired result. By a

"therapeutically effective amount' ^' of a compound of the invention is meant a sufficient amount of the compound to treat bacterial infections, at a reasonable benefit/risk ratio applicable to any medical treatment, it will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend upon 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 age, body weight, general health, se and diet of the subject; the time of

administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.

The total daily dose of the compounds of this invention administered to a human or other mammal in single or in divided doses can be in amounts, for example, from 0.01 to 200 mg/kg body weight or more usually from 0.1 to 50 mg kg body weight. In certain embodiments, the total daily dose administered to a human or other mammal is from 1.0 to 100 mg/kg body weight or from 5,0 to 25 mg/kg body weight. Single dose compositions may contain such amounts or submultip!es thereof to make up the daily dose, !n general treatment regimens according to the present invention comprise administration to a subject in need of such treatment from about 10 mg to about 15 g of the compound(s) of this invention per day in single or multiple doses, more usually, from 100 mg to 5 o, and even more usually from 250 mg to 1 g per day in single or multiple doses. Methods of formulation are well known in the art and are disclosed,, for sample, n Remington: The Science and Practice of Pharmacy, Mack Publishing Company, Easiori Pa. , 18th Edition (1 §95). Pharmaceutical compositions for use in thepresent invention can be in the form of sterile, non-pyrogenle liquid solutions or suspensions, coated capsules, suppositories, lyophtfeed powders, transdermal patches or other forms known in the art.

A "kit" as used in the instant application includes a container for containing the pharmaceutical compositions and may also include divided containers such as a divided bottle or a divided foil packet. The container can be in any conventional shape or form as known in the art that is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar, a resealable bag (for example, to hold a "refill* of tablets for placement into a different container}, or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule. The container employed can depend on the exact dosage form involved, for example a conventional cardboard box would not generally be used to hold a liquid suspension, It is feasible thai more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle that is in turn contained within a box.

An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses have the size and shape of individual tablets or capsules to be packed or may have the size and shape to accommodate multiple tablets and/or capsules to be packed. Next, the tablets or capsules are placed in the recesses accordingly and trie sheet of relatively stiff material is sealed against the plastic foil at the face of the foil that Is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are individually sealed or collectively sealed, as desired, in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at th place of the recess. The tablet Of capsule can then be removed via said opening.

If maybe desirable to provide a written memory aid, where the written memory aid is of the type containing information and/of instructions for the physician, pharmacist or other health care provider, or subject, e.g. , in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen that the tablets or capsules so specified should be Ingested or a card that contains the same type of information. Another example of such a memory aid is a calendar printed on the card e.g., as follows "First Week, Monday, Tuesday/' sic . . .

"Second Week, Monday, Tuesday . . .* etc. Other variations of memory aids will be readily apparent. A "daily dose* can be a single tablet or capsule or several tablets or capsules to be taken on a given day. When the kit contains separate compositions, a daily dose of one or more compositions of the kit can consist of one tablet or capsule while a daily dose of another one or more compositions of the kit can consist of several tablets or capsules.

Another specific embodiment of a kit is a dispenser designed to

dispense the dally doses one at a time In the order ot their intended use. Preferably, the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen. An example of such a memory-aid is a mechanical counter, that indicates the number of daily doses that has been dispensed. Another example of such a memory-aid is a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal that, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.

The kits of the present invention ma also include, in addition to a compound of the present invention, one or more additional pharmaceutically active compounds. For example, the additional compound second ants bacterial. The additional compounds may be administered in the same dosage form as the compound of the present invention or in a different dosage form. Likewise, the additional compounds can be administered at the same time as the compound of the present invention or at different times. Compositions of the present compounds may also be used in

combination with other known antibacterial agents of similar spectrum to (1 ) enhance treatment of severe gram-negative infections covered by the spectrum of this

compound or (2) add coverage in severe infections in which multiple organisms are suspected which another agen of a different spectrum may be required in auditor i to this compound. Potential agents include members of the aminoglycosides, penicillins, cephalosporins, fluoroquinolones, rn.ac.rol ides, glycopeptides, lipopeptides and Qxazoiidinones, The treatment can involve administering a composition having both a compound of the present invention a d a seco d antibacterial compound or administration of a compound of the present inventive compounds followed by Or preceded by administration of a second antibacterial agent.

The foregoing may be better understood by reference to the following examples, thai are presented for illustration and not to limit the scope of the inventive concepts.

V. EXAMPLES

HPLC: Angilent 1200; Mobile Phase: A: water(0.G1 TFA) B:ACN(0.01 %TFA); Column: ZORBAX. SB-C 18, Sum, 4.6*150mm; Oven Temperature; 5Q°C

LCfVlS: Angiieni 1200; Mobile Phase: A: water(0.O1 %TFA) B:ACN(0-.O1 %TFA) _S

Column; Sun re€18 3,5um, 4.6*50mm; Oven Temperature; 50°C

GCMS. Agilent instrument (789QA Series gas chromatograph with a Mass Selective Detector 5875C; injector volume: 1 mL; initial column temperature; 4CT C; final coiumn temperature; 250C; ramp time: 8.4 min; gas flow rate: 1 ,2 mL/r in; coiumn; 5% phenyl methyl silox, M deLAgilent 1 091 $-433:3250, dimensions: 30. Q m ^* 250u m ^' 0.25 urn) HMR Bruker AVANCE ill 40Q?vlHz, UrtraShield-PlusT Digital NMR

A, Compound synthesis

Referring to the examples that follow, compounds of the present invention were characterized by high performance liquid chromatography (HPLC) using a Waters Millenium chromatography system with a 2690 Separation Module ( iiford, Mass.) or an Agilent 1200; Mobile Phase; A; water(Q.0 %TFA) B:ACN(0.01 %TFA): Column: ZORBAX S8-C18, Sum, 4.6*160mm; Oven Temperature: 50°C or an Agilent 1100 series chromatography system (Santa Clara, Ca), The analytical columns were Phenomena* Luna C18(2> reversed phase, ι θμπ , 100 A, axia packed, 2,0x50mrn and the preparative columns were phenomenex Luna C1 S(2) reversed phase, 1 Gprn, 100 A, axia packed, 21. *250 or 50x250mm. A gradient el utton was used, typically starting with 00% water and progressing to 100% acetonitrifc over a varying lengths of time All solvents contained 0.1 % acetic acid (AcOH). Compounds were detected by ultraviolet light (LIV) absorption at either 220 or 254 nm. In some instances, purity was assessed by thin layer chromatography (TLC) using glass or plastic hacked silica gel plates, such as, for example, Baker-Flex Silica Gel 1 B2-F flexible sheets. TLC results were readily detected visually under ultraviolet light, or by employing well known iodine vapor and other various staining techniques

Mass spectrometry analysis was performed on one of throe LGMS instruments: a Waters System. (Alliance NT HPLC and a Micromass ZQ mass spectrometer; Column: Eclipse XDB-C-18, 2.1 x50 mm; solvent system: 5-95% (or 35- 95%, or 65-95% or 95-95%) acetonitrile In water with 0.06%TFA; flow rate 0,6 mL/min; molecular weight range 500-1500: cone Voltage 20 V; cofumn temperature 40° C.) or a Hewlett Packard System (Series 1100 HPLC; Column: Eclipse XD8-C18, 2.1 50 mm: solvent system: -95% acetonifn!e in water with 0.05% TFA; flow rate 0.4 mL/min; molecular weight range 150-850; cone Voltage 50 V; column temperature 30 ^c' G). or an Agilent System (Series 1 100 HPLC; Column: Waters Sunfire C18 reversed phase, 2.5pm, 100 A, 2.1x50mm; solvent system; 1 -95% acetomthie In water with 0.1 % TFA; flow rate 0.5 mL/min, molecular weight range 150-1500; cone Voltage 70 V; column temperature 35* C), or an Agilent 1200; Mobile Phase' A:water<0.01 %TFA)

B:ACN(0.01 %TFA}, Column: SunFire CI 8 3. Sum, 4.6*50mm Oven Temperature: 50°C. All masses are reported as those of the protonated parent ions.

GCMS analysis was performed on a Hewiet Packard instrument (HP68S0 Series gas chromatograph with a Mass Selective Detector 5973; injector volume: 1 lit; initial column temperature: 50* C; final column temperature: 250C, ramp time; 20 mln; gas flow rate: 1 mL/min; column: 5% phenyl methyl siioxane, Model #HP 190915-443, dimensions: 30.0 m 25 m x 0.25 m), or Agilent instrument (7S90A Series gas chromatograph with a Mass Selective Detector 5975C; injector volume 1 rrjL; initial column temperature: 40* C; final column temperature: 250C; ramp time: 8.4 ■ nin; gas flow rate; 1,2 mL/min; -column: 5% phenyl methyl silox, o del :Agi Sent 19081 s- 433:3250, dimensions: 30.0 m ^' 2S0u m ^* 0.25 urn).

Nuclear magnetic resonance (NMR) analysis was performed with a Varian 300 MHz MR (Palo Alto, Calif ), and a Varian Unity Enova 400 MHz NMR spectrometer (Pa!o Alto, Ca!if.}, or Brisker AVANCE ill 400MHz, UltraShield-PiusTM Digital NIVIR. The spectral reference was either IMS or the known chemical shift of the solvent. Some compound samples were run at elevated temperatures (e.g. 75° C.) to promote increased sample solubility,

Proce ure 1 (C-C coupling reaction using CuCi-C&diot):

Hydroxylamine hydrochloride {0.23 rnrnoL 0.06 eq) and CuCI (0.08, 0,02 eq) were dissolved in 23% aqueous -butvlamine (1 ml) and the resulting solution was cooled to OX. A solution of the a kyne (4.3 mmol, 1.1 eq) in 23% aqueous n-butylamtne (2 ml) was then added. The bromo-alfcyne (3.92 mmei) and hydroxylamine hydrochloride (0,23 mmol. 0.06 eq) we e dissolved in 23% aqueous n-butylamine (2 ml) and THF (3 ml), and they were slowly added to the reaction mixture. The reaction was stirred for 1 hr, followed by quenching with EtOAc and water. The organic layer was separated and washed with brine, dried over sjSO. , filtered and concentrated under reduced pressure to yield the desired coupled product.

Procedure 2 (Boc eprot&ction using TP A}: To the Boc-protected compound (3.39 mmol) at O was added a TFA;DCSv] solution (9 mL 2: 1) and the reaction was stirred for 1 hr. The reaction was concentrated under reduced pressure to yield a crude residue, which was aseoiroped wit I PA twice to yield the desired de rotected product.

Procedure 3 (tfydroxmmt® formation); To a stirring solution of the ester (3.38 mmol) in I PA (4 mL) at OX was slowly added 50% aqueous hydroxylamine (40 eq), and the reaction was stirred overnight The reaction was quenched with AcOH (0.12 mol, 20 eq) or until the pH was 8. The vol tiies were removed under reduced pressure, and the resulting solution was purified by RP HPLC,

ProcBdum 4A (formation of ims s in reductive simtmn to NHMe);

To a stirring solution of the amine (2.37 g, 7.20 mmol) in DMF (14.39 mL) was added Pi P EA (1 .88 mL, 10.79 mrnol) followed by formaldehyde (37% in water} (1 .07 mL, 14.39 mrnol) and the reaction: was stirred for 2 nr. The excess aldehyde was quenched with w-butylamine (30% in water) (2.63 g, 10,79 mmof) and stirred for 1 hr. The reaction mixture was diluted with water, and !yophi!ized to yield the desired irnine,

Procedure 48 {reduction to amine- in reductive ammation to

N Me): To a stirring solution of the imine (3.86 g, 11.60 rnmoi) in THF (23.17 mL) and Me OH (2,439 mL) was added acetic acid (133 mL 23.20 mrno!) followed b sodium cyanoborohydride (10.94 g, 174 mmol) and the reaction was stirred for 1 hr. The reaction mixture was diluted with water (7 mL) and concentrated under reduced pressure to yield the m ne.

Eth ny!tfime hyisfiane (82.4 g, 0,84 mol) was added dropwise over 10 min under a nitrogen atmosphere to a solution of methyl 4-bromobenzoate (150 g, 0.7 mol), PdC¾ (PPh ₃ ) ₂ (15 g, 0.021 mol) and Cu! (13 g, 0.07 mol) in TEA (1.5 L) and the reaction was siirsd at 90¾ for 30 minutes. Solids were collected by filtration and washed with EtOAc (5 x 500 mL). The filtrate was concentrated under reduced pressure to give a residue, which was distilled under reduced pressure to yield methyl 4-C(trimethylsify!) ethynyl) benzoate (INT-12) as an off-white solid (156 g, 96%),

To a solution of methyl 4-((trimethylsiiyl) ethynyljbenzoate (155 g, 0.67 mol) in methanol (800 ml) was added dropwtee KOH/methanoi (18 g/250 mL) keeping the temperature below 1Q°C. The reaction mixture was allowed to warm to room temperature for 5 min and was then neutralized with 2M HCi. Methyl 4- ethynylbenzoate (INT-1.3) was collected by filtration as a w ite solid (97 g ₍ 90%). MS: m z ca!cd for 0 _1(ί Η ₈ 0 ₂ 160,0, found [M+Hf 161 .

88

To a solution of methyl 4-ethynyibenzoate (50 g _: 0,31 rno!) in acetone (750 mL) was added AgNOs (5 g, 28,7 mmoS) and the reaction mixture was stirred for 1 hr. NBS (61.2 g. 0,34 mol) was added and the reaction mixture was stirred at room temperature for 20 hr, filtered and concentrated under reduced pressure. The residue was diluted in EA, and washed with Iced 20% H ₂ S0 . The organic layer was washed with water and brine, dried (Na-SC^), filtered, concentrated under reduced pressure to give a residue, which was recrysiailized from ivleOH (1 mL 4 g) to yield methyl 4~ (bromoethynyl) benzoate (INT-1.4) as an off-yellow solid (67 g, 90%). H HMR (400 MHz, CDCU) 5 7,98 (d, J = 8.8 Hz, 2H), 7,51 (d, J = 8.8 Hz, 2M), 3,92 (s, 3H).

To a solution of methyl 4-ibromoethynyf) benzoate (67 g, 280 rnmoi) in CH ₃ QH/THF/H ₂ 05/5/1 (1100 mL) was added aOH (44.84 g) and the reaction mixture was stirred at 25°C for 3 hr. The volatiies were removed under reduced pressure and the resulting solution was neutralized with 1 N MCI to pH 3-5. Solids were collected by filtration, washed with water and dned at 50°C for 5 hr to yield 4- (bromoeihyrw!) benzoic acid (INT-1) (61g, 93%),

1 W- e,¥o,¾y»2 _" ^^^^

diynyf}pheny -1,@ n&phihyridm@-4"carhox8mfd@ (1)

To a stirring solution of 4-arn;no~3-broroopyridine (1,1, 173 mg _: 1 mmol) and ₃ N (132 mg, 1.3 mmol) in DCM (5 mL) was added dropwise pivaioyl chloride (133 nig, 1.1 mmol), and the reaction was stirred at room temperature for 3 hr. The mixture was washed with water (2 x), NaHC0 , brine, dried and concentrated under reduced pressure to give the product 12 as a solid, MS; /z caicd for CioH ₃ BrN ₂ 0 256.02/258.02, found [ +Hf 257/259.

A mixture of compound 1,2 (5 g, 19.4 mmoi) and 10%Pd/C (500 mg> in

MeOH (70 rnl) was stirred under H ₂ (1 atm) at room temperature overnight , The Pd/C was removed by filtration and the solvent was concentrated under reduced pressure to yield a crude, which was dissolved in EtOAc. The organic layer was washed with NaHC0 ₃ , brine, dried and concentrated under reduced pressure to give the product 13 as a solid.. MS: m/z caicd for C _{1 e} H ₄ N ₂ 0 178.11 , found ( +Η 179.

1 ,4

To a solution of compound 13 (5.34 g, 30 mmoi) in TH (200 ml) st - ?8 ^:0 C was added dropwise / BuLi (47 ml, 75 mmoi) and the reaction was stirred for 3 hr at -10°C. The reaction was cooled to ~78 ^e C and a solution of diethyl oxalate (22 g, 150 mmoi) In THF (20 rnl) was added dropwise and the mixture was stirred overnight at room temperature. NH ₄ CI was added, and the reaction was extracted with EtOAc, washed with brine, dried, concentrated under reduced pressure and purified by flash chromatography (silica gel/EtOAc PE 1 :10-1:8) to give the product 1.4 as a solid. MS: m/z caicd for C ₁₄ H ₁₈ N ₂ 0 ₄ 278.13, found [M+Hf 279.

1.6

Compound 1.7 was synthesized according to the procedure described in International PCT Patent Application Publication No. WO2012/154204.

1 -(4-({trimethytstiy8)et yn yS)phertyl)ethanone- (1.9)

Reagent W Eq. mmol g. mL

Compound 1 ,8 198 1 .0 101 20 g ethynyl(trimeihyl}siiane 98 1.4 141 13.8 g

Pdi PPh ;j.;Ci; 701 0.05 5.1 3.6 g

CU! 190 0.1 1 Q 1 .9

TEA 300 ml.

To a stirring solution of compound 1 ,8 (20 g, 101 mmol } _: Pd(PPh ₃ ) ₂ C½ ( 3.6 g, 141 mmol ), Cul (1.9 g, 10 mmol ) in TEA ( 300 mL } under argon was added ethynyl(trimethy!)siiane (13.8 g, 141 mmol ) at 90°C and the reaction mixture was stirred at 80°C for 4 hr. The solids were removed by filtration, and rinsed with ethyl acetate (3 x 80 mL), The filtrate was concentrated under reduced pressure to give a crude, which was purified by flash chromatography (silica gel/ ethyl acetate in petroleum ether 5%-10% v/v) to give compound 1.9 as a yellow oil (19 g, 90%). ¹ H

HUR (400 MHz, D SO-d _e ) o 7.92 (d, J = 8, 2H), 7.56 (d. J - 8, 2H), 2.58 (s, 3H).. 0.23 is, 9H). ^« {4-eth »y!phenyl)eihanone (i .10)

To a stirring solution of compound 1.9 (19 g _s 88 rnrnoi) in MeOH (200 mL) was added a solution of KOH (2.46 g, 44 mrnoi) in MeOH (20 mL) at 10°C and the mixture was stirred at room temperature for 1 hr. AeOH was added until the pH was 7. and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL), washed with 5% aqueous NaHCOa (100 mL), brine (1 Q0 mL), dried, and concentrated under reduced pressure to give compound 1.10 as a white solid (12 g, 95%). ¹ H N R (400 MHz, DMSO-efe) δ 7.95 (d, J = 8, 2H), 7.82 (d, J = 8, 2H), 4.49 (s, 1 H), 2.59 (s, 3 M),

To a stirring solution of compound 1.10 (12 g, 83.3 mmoi) in acetone (200 mL) was added AgjSSO* (1 .34 g, 7.9 mmoi) and the the reaction was stirred for 30 mm. MBS (17.7 g, 99.96 mmoi ) was then added and the reaction mixture was stirred at 2G*C for 14 hr. Solids were removed by filtration and the filtrate was concentrated under reduced pressure to give a crude, which was purified by flash chromatography (silica get/ ethyl acetate in petroleum ether 5%-10% v/v) to give compound 1.11 as a white solid (14 g, 76 %). Ή N R (400 MHz, DM8O-0¾ δ 7.95 (d, J = B, 2H )., 7.62 ¾ J ~ 8, 2H), 2.58 (s, 3 H ).

To a stirring solution of compound 1.11 (1.0 g, 4.5 mmol), compound

1.7 (648 mg, 6.75 rnmoi), Pd(PPh ₃ ) ₂ CI ₂ (158 rng, 0.22 mmol), and Cu! (90 mg, 0.45 mmol) in THF (30 mL) under argon was added TEA (1.16 g, 9 mmol) and the mixture was stirred at 20°C for 14 hr. SoHds were removed by filtration and rinsed with ethyl acetate (3 x 80 mL), the filtrate was concentrated under reduced pressure to yield a crude, which was purified by Hash chromatography (silica gel/ ethyl acetate in petroleum ether 15%-50% v/v) to give compound 1.12 as a yellow solid (450 mg, 42%). MS; m z calcd for 238.1 found [ +H] ⁺ 239. ^f H NMR (400 MHz, CDCSs) δ 7.89 (d, J - 8.4, 2H). 7.53 (d, J = 8.4, 2H), 3.61 (dd, J ^~ 6, 1 1.6, 1 H ), 3.51 (dd, J = 6.8, 1 1.6, 1 H), 2.59 (s. 3H), 1.57-1.82 {rn, 1 H), 1.49 (brs, 1 H), 1.37- 1.41 (m, 1 H), 106-1.10 (m, 1 H), 0.88-0.93 (m, 1 H).

1.12

To a stirring solution of compound 14 (139 mg, 0.5 mmol) in EtOH (10 mL) was added KOH ( 12 mg, 2.0 mmol, 4 fvl), and the reaction was heated at 100°C for 3 hr. Racemic compound 1, 12 (178.5 mg, 0.75 rnmoi) was added and the mixture was stirred overnight at 100 C. The solvent was concentrated under reduced pressure. Water was added, and the reaction was washed with Ei ₂ 0. The reaction mixture was adjusted to pH 1-2 with acetic acid, and the resulting solids e e collected by filtration and dried to yield the desired product 1.13. MS: rn z caicd for C ₂ 3H _lf iN-/¾ 368.12, found [ +H 369.

To a stirnng solution of compound 1.13 (184 mg, 0.5 mmoi) in DMF (10 rnL) was added _z CO (138 rng,. 1 ,0 mmoi), followed by iodomethane (74.55 rng, 0.52 mmoi) and the reaction was stirred overnight at roorn temperature. The reaction was quenched with water, extracted with EtOAc, washed with brine, dried, concentrated under reduced pressure to give a crude, which was purified by flash chromatography

(silica gel/ PE:EtOAc 1.5:1-1 : 1 .5) to yield a solid, which was recrystaiiized from EA/PE

(1 :5) to give the desired product 1.14. MS: m/z catcd for Cz ^ ^O} 382.13, found

[ +Hf 383.

compound 1 0 OH

Compound f 4 (500 mg) was converted to W-hydroxy-2-(4-(((?r<8/?s)-2- (hydroxymethyl)cyciopropy!)buta-1 _: 3-dlyn~1 -yl)phenyl)-1.6-naphthyridine-4- carboxamide (1 , 339 mg, 58%) using Procedure 3: MS: m/z calcd for C ₂ sH ₁ 7 ₃ 0 ₃

333.13, found [M+Hf 384.

2, N-hyd xy~4*(4~( ((trans)~2-( ydroxymethyt) cyclopropyijbuta- 1, 3-

To a stirring solution of co pound Z 1 (2 c 8 g , 0.15 mol), compound

2,2 (45.7 g , 0.18 mo!) and PdC!a(PPh _a } ₂ (5.26 g, 7.5 mmof) in 1 ,4-dioxane (500 ml), was added KOAc (22.0 g _t 0.225 mo!) under an argon atmosphere and the mixture was stirred at 80 ^C C for 15 fir. The solvent was removed under reduced pressure, and the residue was diluted with PE (500 nL). Solids were removed by filtration, and the filtrate was concentrated under reduced pressure to give a crude, which was purified by flash chromatography (siiica gel/ FE:EA 1 Q- 1) to give 4-(4 _t 4,5,5-tetramethy!-1 3.2- dioxgborolan-2-yi)ben2aid©hyd« (2.3, 32.5 g, 95%) as a white solid.

To a stirring solution of compound 2.3 (32.4 g,. 0.14 mol). compound 2,4 (32.2 g, 0.17 mol) and Pd(PPh ₂ ) ₄ (8.08 g, 7 ram of) in 1 ,4-dioxane/nrietrianoi (800 rnL 1 :1) was added Na ₂ CO _s (22.3 g,u.21 mol) under an argon atmosphere and the mixture was stirred at 80°C for 15 nr. The solvent was removed under reduced pressure and the resulting residue was diluted with wafer (500 rnL) and extracted with EtOAc (3 x 500 ml). The combined organic layers were dried and concentrated under reduced pressure to give a crude, which was purified by flash chromatography (silica gel/ ΡΕ.ΈΑ 2: 1) to give ethyl 4-(4-formylphenyl picolinate (2.5, 14.2 g, 40%) as a yellow solid.

To a stirring solution of compound 2.5 (12.7 g, 50 mmoi) in CHsOH (300 mL) was added the Besimann reagent (14.4 g. 75 mmoi) followed by ₂ C0 ₃ (20.8 g, 150 mmoi) and the reaction was stirred, for 5 hr. The reaction mixture was diluted with water (o ^' QQ mL.) and extracted with Et ₂ 0 (3 x 300 mL). The combined organic layers were dried and concentrated under reduced pressure to give a crude, which was purified by flash chromatograph (silica gei/ PE:Et _s O 10:1-5:1) to give methyl 4-(4~ ethynyipheny!)picolinate (2.S, 4.0 g, 33.9%) as a white solid.

2,7 2,S

To a stirring solution of rac.em.ic compound 2,7 (4.8 g, 50 mmol) and

AgNOg (0.85 g, 5 mmol) in acetone (200 mL) was added NBS (10.7 g, 60 mmoi) under an argon atmosphere and the mixture was stirred at room temperature for 15 hr. The mixture was filtered and the residue was taken up with acetone, the combined organic layers were concentrated under reduced pressure to give a crude, which was purified by flash chromatography (silica gei/ P£:EA 5: 1 ) to give {l-tmns-

(bromoethynyi)cyciopropyi)methanoi {2,8, 5 2 g, 60%) as a colorless oil.

2.6 IHF

To a stirring solution of compound 2.6 (1.77 g, 7.5 mmoi), Pd(PPhs) ₂ Clg (262 mg, 0.37 mmoi), Cul (143 mg, 0.75 mmoi). and DIPEA (2.9 g, 22.5 mmol) in THF (50 mL) was added compound 2,8 (1.84 g, 10.5 mmoi) under an argon atmosphere, and the mixture was stirred at room temperature for 5 hr. The solvent was removed under reduced pressure, and the resulting residue was diluted with water (100 ml) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried and concentrated under reduced pressure to give a red oil, which was purified by flash chromatography (silica gei/ PE:EA 5: 1 -3: 1) to yie!d methyl 4-(4-C((fr ?s)-2- (hydroxymethy yciopropyObuta-l^-diyn-i-yOpheny^picotinate (2.9 _: 570 mg, 2:3%}: MS; m/z ca!cc for C-H ₁₇ N0 ₃ 331.12, found [ -H-!f 332 _: 'H-NMR (D SO-d*. 400 MHz} 0 8.77 (d, J=5,6 Hz, 1H). 8.30 is. 1H), 7.S9 (d, J=5.6 Hz, 1 H), 7.90 (d, J-8.4 Hz, 2H), 7.67 (d, ,/~8.4 Hz, 2H), 4.72 (t, J~5.6 Hz, 1 H), 3.91 ($, 3H), 3.44 (m, H), 3.24 (m, 1H), 1.45 (m, 2H), 0.88 (m, 2H).

Methyl 4^(4-({{fra«s)-2~{ yclfoxymet y!)cyciopropyl)buta-1.3-diyn-1 - yl)phenyl)picolinaie (2,9, S00 mg) was treated according to Procedure 3 to give N~ hydroxy-4-(4-«(? -ans)-2-(hydro>rymsthyl)cydopropy})buta-1 ,3-diyn-l - yl)phenyl)picolinamide (2, 157 mg, 31%) MS: /S: ca!cd for C ₂ gH, _e N ₂ 0 ₃ 332,12, found [ ÷Hj ^" 333.1.

y "4 _' ({(tr@m)~2~(hy ^' € my^ (3}

To a stirnng suspension of < ?)-2-amino-3-mercapto-3-methylbuianoic add (3.1, 9 g, B0.3 mmo!) in D F (20 mL) was added BQC-anhydfide (14.0 mL, 60.3 mmoi) followed by TEA (8.41 mL, 63.3 mrnoi) and the reaction mixture was stirred for 18 hr. Excess solvent was removed under reduced pressure. The. crude product was treated with methyl iodide (18.83 g, 133 mrnoi) in DMF (20 mL) and Cs ₂ C0 ₃ (43.2 g. 1 3 mmol) at room temperature for 18 hr. Water (100 mL) was added and the product as extracted with ethyl acetate (2 x 200 mL), dried (Na _K $Cc,) and concentrated under reduced pressure to give compound 3.2 (12.62 g) as a white solid. Subsequent BOG deprotection was achieved by treatment with TFA (20 mL) in CH2CJ2 (20 mL) for 5 hr. The solvent was removed under reduced pressure to give the desired product 3,3 (8.2 g).

A stirring solution of racemic ((im/?¾--2-ethynyte clopiOpyS)methanoi

(17, 1 1 g, 106 mmoi). copper(l) chloride (0.20 g, 2 03 rnmci), and hydroxyl-amln hydrochloride (0.42 g, 6.08 mmoi) in 30% aqueous butylamiise (156 ml) was poured into a 1 L jacketed reactor and cooled to 0 ^' "C A solution of 4-(bromoethynyi}benzoic acid (fflT*1, 22.81 g, 101 mmoi) and hydroxylarnine hydrochloride (0,42 g, 6. OS mmoi) in 30% aqueous butytamine (11 1 ml.) was then added dropwise and the reaction was stirred for 2 nr. The reaction mixture was washed with T6E (2 x 230 ml..) and the aqueous layer was diluted with methyl THF (460 ml). The solution was cooled to 0°C and acidified by dropwise addition of B HCi (100 mi) to pH 1. The reaction mixture was filtered through Celite, and washed with rnethyf-THF (230 ml). The two layers were partitioned and the a ueous layer was back-extracted with methyi-TBF (230 m!_}.

The organic layers were washed with 2M HCi (2 x 230 mU, water (230 ml), and brine (230 mi), dried over i^SO . and filtered. The organic layer was concentrated under reduced pressure until the solution turned cloudy, then heptane (230 ml) was added. The resulting solution was concentrated under reduced pressure to 5 volumes and then additional heptane (230 mL) was added. The resulting solution was concentrated to 5 volumes to give a slurr The solids were collected by filtration, washed with heptane (50 mL), and dried under reduced pressure to yield 4-(((imns)-2- (hydroxymethyl)cyclopropyl)buta-l ,3-diyn-1 -yl)b©nzoic acid {3.4, 3.96 g). MS: mfz caicd for C*H,zO» 240.08, found Π ΤΗΓ 239.1. ^; H N (D SO-cfe. 400 MHz) δ 13.18 { , 1H), 7.85 (d, 2H), 7.61 id, 2H), 4.72 (t. 1H), 3.39-3.52 (m, 1H), 3.21 -3.32 (m, 1 HV 1.41-1.51 (fti, 2H) _: 0.81-0.99 {m, 2H).

98

compound 3

To a stirring solution of triethylamine (1.06 g, 10.52 mmoi), and {R}- methyl 2-amino-3-methyl-3-(methyithio)but8noate (3,3. 1.88 g, 10.52 mmof) was added a solution of racemic 4-({(irans}"2-(hydroxymethyl)cyclopropyi)buta- ,3-diyrt-1- 5 yi)benzoic acid (3.4, 2.5 g, 10.52 mmoi) in D F (40 mL), followed by 2-(3H- [1 ,2,3JtriazGlo[4,5~b]pyridin-3-yl)-1 , 1 ,3,3-tetramethylisouronium

hexafiuofOpnosphate(V) (4 g, 10.52 mmoi) and the reaction was stirred for 2 hr. Wafer (100 ml) was added and the mixture was extracted with ethyl acetate (2 x 100 ml), dried (Na ₂ S0 ₄ ) and concentrated under reduced pressure to yield a crude, which was 10 purified by flash chromatography (silica gel/ ethyl acetate 10-40% in hexanest to yield the corresponding ester 3,5 (2.6 g), which was converted to ^"((.¾-1-(hydroxyamsna)- 3-methyi-3-(methyltf)io)-1-oxobutan-2-yl}-4-(((if¾ns)-2-

(hydroxymethyi)cyc!opropy!)buta-1 ,3-diyn-l -yl)benzamide (3) using Procedure 3. MS: m z caic for C ₂ iH _{2 2} 0«S 400.15. found [M+Hf 4G1.

1 -5

4. N~i(2R)-1~lhy€iroxyammo}~3~m& y^ diynyt)henzamide (4)

·> _< ··> compound 3 compound 4

To a stirring solution of A/-((i?)-1-(hydroxyamino)-3-methyl-3- (methyithio)- -oxobutan-2-ylH-(({ira/?s)-2 ^« (hydroxyn ethyf)cydopropyl)buta-1 ,3-diyn-1 - yi)benzarnide (3, 0.2 g, 0.50 mmol) in acetonitrile water (20 mL) was added 30% aqueous hydrogen peroxide (0.015 mL, 0.50 mmol) and the reaction mixture was stirred at room temperature for 18 hr. The reaction mixture was !ycphylized to afford

(hydroxymethyi)cyc!opropy!}buta-1 ,3-diyn-1 -yi)benzamide (4, 200 mg, 449 rnmoL 90%). MS: m/z caicd for 0 _{ί ;} Η _.¾ Ν ₂ 0 ₅ 3 416.14, found [M+H] ⁺ 417.

5, N~{(i ,'Bmmo)'3-m&thyl-3"(!

oxobutm'2'yi}^((tr^m)-2^hydrox methyl)c clKipfopyl)buts-1 _f 3 _'

diy iyi}foetszamid0 {$}

/V-((R)-1-(hydroxyamino)-3-rnethyi-3-(rnethyithio)-1-oxobuta n-2-yi)-4- (((tra is)-2-(hydroxymelhy!)cyciopropyl)buta-1,3-diyn-1-yl)benzamid e (3, 120 mg, 0.3 mmo!) in 22% acetonitrile -water (100 mL) was treated with 30% peracetic acid (1 mL) overnight at room temperature. The reaction was lyophtlized to afford A/-(( )-1- (hydroxyaniino)-3-methyi-3-(methy!sulfony!)-i-oxobutan-2-yiH -(((irans)-2- (hydroxymethyl)cyclcpropyi)buta-1 ,3-diyn-1 -yDbenzamide (5, 130 mg). MS: m/z caicd for ¾,H _S4 N ₂ 0 ₅ S 432.14, found [M+Hf 433.

6, ~({S}~3-aminc~1~(hydro y@minG}-3-m®t yl-1~oxQ {({traiis}-2-{ y roxym'e^yi}cyciQpropyl)ethynyi)^2'naphthamide (6)

OH

To a stirring solution of 6-bromo~2- naphthoic acid (§.1, 1 ,0 g, 4.0 mmol), racemic ((iran«)-2-ethyny!cyciopropyi)methano {1.7, 0.5 g, 5.2 mmol), copper(l) iodide {30 mg, 0.16 mmol} and pa!ladium(lf) bis(tripheo iphosphine} dleh!oride (56 mg, 0.08 mmol) in tetrahydrofuran (7.5 ml) under a nitrogen atmosphere was added triethyiamine (2.5 ml) and the reaction was stirred for 1 week. The reaction was partitioned between 2N aqueous sodium hydroxide and ethyl acetate. The aqueous layer was acidified with cane HCi and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium chloride and dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 6-{((irans)-2- (hydroxymeihyl)cyciopropyi)ethynyi}-2-naphthoic add 1.0 g, 94%).

To a stirring suspension of (S)-m thyl-2-amino-3-((fert- butoxycarboriyl)arniriO)-3-methy!buianoate oxalate (6,3. 1.0 g, 4.9 mrnoi) and 6- ({{frao5)-2-(hydfoxymethyl)cyc!opropyi)ethyny!}-2-naphthoic acid (6.2, 1.0 g« 3.8 mrnoi) in ACN (10 ml) at 0*C was added tnethy!emine (2.1 ml, IS mrnoi), foil owed by the portionwsse addition of a solution of HATU (3.0 g, 7.9 mmol) in ACN (10 mL} and the reaction mixture was stirred at 0°C for 75 n ^' tn. The reaction was concentrated under reduced pressure to yield a residue, which was partitioned between MTBE and water. The organic iayer was washed with 1M citric acid, water, saturated sodium bicarbonate (2 x), saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure, to give (S)-methy! 3-((½ri- butoxycarbonyl)amino)-2-(6->(({fc*3 ?s)-2-{hydroxymeth l)cyc!opfopyi)ethynyl}-2- naphth3mido)-3-methyfbutanoaie (0.4), which was carried through to the next step without further purification.

To a stirring solution of (S)-methyi 3-((fetf-butoxycarbony!)am

(0,4) in methanol (10 mL) was added 4N HCi in dioxane (10 rnL) and the reaction mixture was stirred at ri for 2 hr, then at 4 ^C 'C overnight The mixture was concentrated under reduced pressure to give a residue, which was partitioned between water and MTBE. The aqueous layer was basified with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give (S)-methyl 3-amino-2-(6-(((frans)-2-

(hydroxymethyi}cyclopropyl)ethynyl)-2-naphthamido)-3-rnet hylbutanoate (β,5, 1.2 g,

3.0 mmo!, 79%).

Compound 6,5 (1.2 g) was treated according to Procedure 3 to yield the desired compound /V-((S)-3-amino-i -(hydroxyamino)-3-methyl~1 -oxobutan-2-yl)-6- {((?ra/?s)-2-{hydroxymethyi}cyciopropyi)ethynyi)-2-naphthami de (6, 400 mg, 1.01 mrnol 33.3 % yield). MS: m/z caicd for C ₂₂ H ₂₅ N ₃ 0 395.18, found [M+Hf 306.2

{({tram}-2~{!v/ roxyffleihyi)cyciQprQp

carfooxamh

7.1 To a stirring solution of 6· bromo enzo[b]thiophene-2-carboxylic acid (7.1. 1.0 g _t 3.9 mrnci) in DMF (7.5 mL) under a nitrogen atmosphere were added racemic ¾iraris)-2-ethynylcyciopropyi)meihano! (1.7, 935 mg, 9.7 mmol), oopper(!) iodide (30 mg, 0.16 mmol) and palladiurrKH) bisitnphenylphosphine} dichiorido (56 mg, 0.08 mmol), followed by triethy!amine (2.5 mL) and the reaction was stirred at room temperature for 1 hr, and then at 40 C for 20 nr. The reaction mixture was partitioned between 2N aqueous sodium hydroxide and ethyl acetate. The aqueous layer was acidified with co e HCI and extracted with ethyl acetate. The resulting organic layer was washed with water, saturated sodium chioride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 6-(((irens -2-

(hydroxymethyl)c ciopfopyl)ethynyi)benzo{bJth,iophen$-2-car oxyiic acid (7,2, 900 mg, 3.3 mmol, 85%).

To a stirring solution of (S)-roethyi 2-aroino-3«((te/f- butoxycarbonyl)amino)-3-methyibutanoate oxalate S.3 (1.4 g, 4.3 mmol), e-(((irans)-2- (hydroxymethyl)cyclopropy ethyny!)ber^o[b}thiop ene-2-carbox5rtic acid (7.2, 900 mg, 3,3 mmol) in ACN (10 mL) at Q ^e C was added triethyiamine (1.8 mL, 13 mmol), followed by the portionwise addition of a suspension of HATU (2.6 g, 6.9 mmol) in ACN (10 ml), and the reaction mixture was stirred at 0 ^a C for 105 min. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between MTBE and water. The organic layer was washed with 1 citric acid, water, saturated sodium bicarbonate (2 x), saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give (S)-methyl :i-((i&tt- butoxycartx>ny])amino)-2-(6-(((*f^

[b]ihiophene-2--carboxarnido)-3-rnethylbutanoate (7.3), which was carried through to the next step without further purification.

To a stirring solution of (S)-methyi 3~(<teff-butaxycarbonyl)amino) 2-(6~

(d ^> Y?ifts)-2-( y :ra^

rnethyibutanoate (7.3) in methanol (10 mL) was added 4H HCi in dioxane (10 mL) and the reaction was stirred at room temperature for 2 hr, then at 4°C overnight. The reaction mixture was concentrated under reduced pressure to yield a residue, which was partitioned between water and MTBE. The aqueous layer was foasified with saturated sodium bicarbonate and extracted with ethyi acetate. The organic layer was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give (S)-methyl 3-amino-2-(6-((( far?s)~2- {hydroxymethyi}cyclopropyl)ethyny!>bensoib] hiophene-2-«^6rboxamWo)-3-' methyibutanoate (7.4, 880 mg ₍ 2.2 mrnoi, 67%)..

Compound 7.4 (0.86 g) was treated according to Procedure 3 to yield the desired compound W-((S}-3-amino-1-(hydrQxya-miho)-3-methyl-1-oxobutan-2-yi)-8 -

({(irans)~2~(hydroxymethyl)cycto^ (7, 16.3 mg, 0.041 mrnoi, 1 ,85 % yield). MS: m/z caicd for 401 .14, found IM+Hf 402.2. a. N1^ rox _' 2^4-{({1R,2R}'2^ rox m@i y!}cy i0pr&pyi}but '

1,3-dfynyi}bmmmido M3-meih imaiQ mf€i (8)

8.1

To a stirring solution of diethyl 2-{(ieri-butoxycarbonyf)amjrjo}rinal nates

( .f, 0.93 mL 3.63 mmoi) in methanol (10 mL) was added 40% meihanamine in water (Q.32 mL, 3.63 mrnol) and the reaction was stirred at room temperature for 2? days. The reaction was concentrated under reduced pressure to give an oil which was purified by flash chromatography (silica ge!/ 10% MeOH/DCM) to provide compound 8.2 (592 mg, 66.2% yield). MS: rnfz calcd for C ₁₀ H _ls N ₂ O ₅ 246.12, found [M+Na] ⁺ 260.1

8.2

Compound 8.2 (0,59 g _; 2,40 mmoi) was dissolved in DC (3 ml), and

TFA (3 mL) and the reaction was stirred for 30 min. The reaction mixture was concentrated under reduced pressure to give compound $,3 (0.88 g), which was carried through to the next step without further purification. MS: m/z calcd for

C _s H ^. _iC ¾ ¾ 146.07, found | +Hf 147.1

The synthesis of compound 8.14 was carried out as described in

Internationa! PCT Patent Application Publication No. WQ2012/154204.

To a stirring solution of compound 8.3 (375 mg. 1.44 mmoi) in ACN (3 niL) was added compound 8.14 (315 mg, 1.31 mmoi), followed by DIPEA (1 .01 mL, 5.77 mmoi) and the reaction mixture was cooled to 0°C. HATU (548 mg, 1.44 mmoi) was added and the reaction was allowed to warm to room temperature. After 1 nr solids were collected by filtration, and washed with ACN to yield compound 8.15 (200 mg, 41.4% yield), MS: m z caicd for C ₂₀ H ₂₀ N ₂ O ₃ 368.14, found [ +Hf 369.1.

To a stirring solution of compound 8.15 (200 mg, 0.54 mmoi) in THF (1 .0 ml) and methanol (1 mi.) was added dropwise over 1 rnin a solution of 50% hydroxamic acid in water (1 mi) and the reaction was stirred at room temperature for 3 hr, The reaction mixture was concentrated under reduced pressure to give a crude, which was purified by RP HPLC (0, 1 % AcOH in water and ACN) to give N1-hydroxy-2- (4-(({l ,2 >2 hydroxymethy!)cyc{opropyi)buta-1 _i 3-di n I)ben2amiclo}-N3- methyl alonamide (6, 47.7 mg, 23.8% yield). MS: m/z calcd for C ₉ H _1¾ N _a O _s 369.13, found fM+Hf 370.1. ¹ H NMR (D SO-de, 400 MHz) δ 10.84 fbr, 1 H), 9.06 ($, 1 H>, 8,57 (d, 1H) _: 8.02 (d. I N), 7.89 (ci, 2H), 7.60 ( , 2H), 4.99 fd, IN), 4,70 (t. 1 H). 3.43-3.37 (m, 1H), 3.20-3.22 (m, 1 H), 2.60 (d, 3H), 1.46-1.41 {m, 2H), 0,94-0.86 (m, 2H).

9. N-hydroxy~4~(4~( { (i ans}~2~{hytfr&xym@thyi)cyc prQpyf}bitta~

A solution of 2-(4~bromophenyi5©thanol (20,0 g, 100 moi) in CH ₂ CI ₂ (10 ml) was added dropwise io a solution of imidazole (22.4 mg, 0.33 mmoi), PPf¼ (33.3 g, 127 mmoi), and \ ₂ (32,5 g,130 mmoi) in CH ₂ Ci ₂ (50 mL) at 0°C, and the reaction was warmed to room temperature and stirred overnight. The reaction mixture was washed with saturated aqueous sodium ihiosufaie {2 x 50 mL), brine, dried over Na _? S04, filtered and concentrated under reduced pressure to give a crude, which was purified by flash chromatography (silica gel/ PE) to yield 1-bromo- - 2-iodoethyl)ben2ene (9.2. 22.7 g, 73%) as a white solid. Ή NMR (400 MHz, CQGI ₃ ) d ^" 3.13 (t. J = 7.6 Hz, 2H), 3.32 (t, J = 7.6 Hz, 2H), 7,07 (d, J ~ 8,0 Hz, 2H). 7.44 (d _: J = 8,2 Hz, 2H).

Methyl 4H 4-bf0mophef¾yi -2-meihyi-2^meiii:yisuifonyS butenoat®

Compound 9.3 was synthesized according to the procedure described in

WQ 201 1045703.

To a stirring suspension of methyl 4-(4-bromophenyl)-2-methyi-2- (mefhyisu fonyi)butanoafe (9,3, 6.36 g, 18.23 rnmol),

bis(tripheny!phosphine)palladjum(lf) chloride (1.28 mg, 1.82 mmoi) and copper(!) iodide (347 mg, 1.82 mmoi) in triethyiamine (30 ml.) was added ethyny!frimethy!si!ane (0.92 mL, 6.49 mmol) and the reaction mixture was heated to 80°C briefly, and then allowed to stir at room temperature for 18 hr. Volatites were removed under reduced pressure and the resulting residue was purified by fiash chromaiography (silica gel/ 15- 50% ElOAe/hexanes) to yield methyl 2-mei-hyi-2-(methyisu!fonyl)-4-(4-

((trimethyfeiiyl)ethynyl)phertyi)butar»oate (9.4, 4,0 g, 59.9% yield), MS: /z caicd for C _1s H ₂₈ 0,SSi 386.13, found [ +Hf 367.2.

B.4

I o a stirring solution of methyl 2-methy -2-(methyisuSfonyi)~4~(4-

((trimet yl ilyi)ethynyhphenyl)buta:noate {9,4, 4.4 g, 12.0 mmoi) in methanol (80 mL) was added K ₂ CO _s (100 m 0,720 mmoi) and†hs reaction was stirred at room temperature for 3 hr. The reaction mixture was filtered through ee!ite, concentrated under reduced pressure to give a residue, which was dissolved in DC _f filtered and concentrated under reduced pressure to yield methyl 4T4-ethynyiphenyl)~2-m hyi:-2- (methylsulfonyl)hutanoaie (ill, 2,49 g, 70.5%), MS: m/z caicd for Ci ₅ H ₁₈ 0. ₄ S 294,09, found [M+Hf 29S.2.

To a stirring solution of methyl 4-(4-ethynylphenyi -2~methy!-2- (methylsulionyl)butanoate {9.B., 2.49 g, 8.46 mmoi) and silver nitrate (144 mg _: 0.85 mmoi) in acetone (24 niL) was added NBS (2.5 g, 14.33 mmoi} and the reaction was stirred at room iernperatufe for 1.5 hr, Solvent was removed under reduced pressure to give a residue, which was purified by flash chromatography (silica gel 30~§O% EiOAc/bexanes) to yield methyl 4-(4-{ romo@thynyl)pnenyi)~2~methyP2- (methy!sulfonyf)bt(tanoate (9,6, 150 mg, 0.40 mmoi, 4.75%). MS: mfz ea!ed for C ₁₅ H ₁₇ Br0 ₄ S 372.0/374,0, found [ +Hf 373.0/375.0.

To a stirring solution of racemlc ( frans)-2-ethyny!cyclopropyl)met anol (17) in rt-butyiamine (750 pL, 30% in 1 :1 water THF) at -10*0 was added a solution of copper chloride (4 mg) in «-butyiamine (300 pL _« 30% in 1 : 1 water/THF) and NH ₂ OH ( 12 pL of 50% in water) and the reaction was stirred for 10 min. A solution of methyl 4- (4-(bromoethyny!)phenyi)-2-methyi-2-(met yteuifonyl)butanoate (9,6) in n-butylamine (750 pL, 30% sn i ; 1 water/THF) and NH-/0H (12 pi of 50% in water, 0,201 mmoi) at - 10°C was then added- dropwfee over 10 min and the reaction was stirred at -10°C for 10 min. The reaction mixture was diluted with EtOAc (10 mL) and washed with 1 M citric acid (5 mL) . The organic layer was washed with water (2 x § mL), sodium bicarbonate (5 mL), brine (5 ml), dried over Na^O* and concentrated under reduced pressure to give a thick oil (9.?)., which was carried through to the next step without further purification. MS; mfz cased for C ₂ iH ₂₄ 0sS 388, 13. found [ +Hj* 389.2.

To a stirring solution of methyl 4-(4~((f?/¾/ s)-2- (hydr ^Q xymethyl)cyclopropy!)fouta- ,3^ butanoate (9.7) in isopropanol (1.3 ml) at QPC was added h droxylamine (948 μΐ, 5.44 rnmoi. 50% in water) and the reaction was stirred at room temperature overnight. The reaction mixture was neutralized with AcOH (884 μί. 15.44 mmoi) and

concentrated under reduced pressure to give a crude, which as purified by P-HPLC (0-30% ACN in water) to yield W-hydrox -4-(4-(((ter ⁾ s)-2~(hydroxymethyl)cydopropy!) buta-l ,3-dtynyi}phenyf)-2-methyf-2-(rneihy!sulfonyi)biftanam!de (9, 22.6 mg. 22.6% yield). MS: rn/z caicd for C _¾i; H, _:: NO,S 389.13, found [ +H 3S0.2,

8. Antimicrobial Activity

1. Bacterial Screens md Cultures

Bacterial isolates were cultivated from -70° C. frozen stocks by overnight passages at 35" C in ambient air on Mueiier-Hinton agar (Beokfon Dickinson, Franklin Lakes, NJ). Clinical isolates tested were obtained from various geographically diverse hospitals in the US and abroad (Focus Diagnostics, Hemdon, VA and J i, North Liberty, IA). Quality control strains were from the American. Type Culture Collection (ATCC; Rockvil!e. Md.}.

2. St scepitbHity T img

Minimum Inhibitory Concentrations ( ICs) were determined by the broth micfodilution method in accordance with the Clinical and Laboratory Standards Institute (CLS!) guidelines. In brief, organism suspensions were adjusted to a 0.5 Mcfariand standard to yield a final inoculum between 3x10 ^s and 7x10" colony-forming units (CFU}/mL. Drug dilutions and inocuia were made in sterile, cation adjusted ueiler-Hinton Broth (Becktcn Dickinson). An inoculum volume of 100 uL was added to wells containing 100 uL of broth with 2-fold serial dilutions of drug. All inoculated mlcrodilution trays were incubated in ambient air at 35° C for 18-24 hr. Following incubation, t e lowest concentration of the drug that prevented visible growth (OD600 nm < 0.05) was recorded as the MIC. Performance of the assay was monitored by the use of laboratory quality-control strains and levofioxacin, a compound with a defined MIC spectrum, in accordance with CLSI guidelines. Typically, compounds of the present invention have MIC values of 0.03 - 32 pg/ml. To this end, data for certain representative compounds is shown in Tab!© il below.

Table St: Inhibitory Concentrations ( iCs) cmpc . AECO AKPN APAE

1 A A C

2 A C C

3 A A A

4 A C A

5 A A A

§ B C A.

7 B C B

8 A A A

9 A B A

MIC Key:

A = MfC's of 1 ,0 pg/mL or less

B ~ MIC's of greater than 10 pg/mL to 8.0 pg/mL

C = MIC's of greater than 8.0 pg/mL to 16.0 μα/ml

D - MIC's of greater than 16.0 pg/mL

* AECO is Escherichia coff ATCC25922. AKPN is Klebsiella pneumonia ATCC43816. APAE is Pseudomonm aeruginosa ATCC27853. it should be understood that the organic compounds according to the invention may exhibit the phenomenon of tautomerism. As the chemical structures within this specification can only represent one of the possible tautomeric forms, it should be understood that the invention encompasses any tautomeric form of the drawn structure. Furthermore, while particular embodiments of the present invention have been shown and described herein for purposes of frustration, it will be understood, of course, that the invention is not limited thereto since modifications may b made by persons skilled in the art, particularly in light of the foregoing teachings, without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.

All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification are incorporated herein by reference, in their entirety to the extent not inconsistent with the present description.