OA16551A

OA16551A - Fluoro-pyridinone derivatives useful as antibacterial agents.

Info

Publication number: OA16551A
Application number: OA1201300364
Authority: OA
Inventors: Mathew Frank BROWN; Ye Che; Michael Joseph Melnick; Justin Ian Montgomery; Mark Stephen Plummer; Loren Michael PRICE; Usa Reilly
Original assignee: Pfizer Inc.
Priority date: 2011-03-07
Filing date: 2012-02-22
Publication date: 2015-10-22

Abstract

The present invention is directed to a new class of hydroxamic acid derivatives, their use as LpxC inhibitors and, more specifically, their use to treat bacterial infections.

Description

This invention relates to novel hydroxamic acid dérivatives. The invention also relates to methods of using such compounds in the treatment of bacterial infections (especially Gram-negative infections) and to pharmaceutical compositions containing such compounds.

Backqround of the Invention

Infection by Gram-negative bacteria such as Pseudomonas aeruginosa, Extended Spectrum β-lactamase producing (ESBL) Entgerobacteriaceae, and Acinetobacter baumannii is a major health problem, especially in the case of hospitalacquired infections. In addition, there is an increasing level of résistance to current antibiotic thérapies, which severely limits treatment options. For example, in 2002, 33% of Pseudomonas aeruginosa infections from intensive care units were résistant to fluoroquinolones, while résistance to imipenem was 22% (CID 42: 657-68, 2006). In addition, multi-drug résistant (MDR) infections are also increasing; in the case of Pseudomonas aeruginosa, MDR increased from 4% in 1992 to 14% in 2002 (Biochem Pharm 71: 991, 2006).

Gram-negative bacteria are unique in that their outer membrane contains lipopolysaccharide (LPS), which is crucial for maintaining membrane integrity, and is essential for bacterial viability (reviewed in Ann. Rev. Biochem 76: 295-329, 2007). The major lipid component of LPS is Lipid A, and inhibition of Lipid A biosynthesis is léthal to bacteria. Lipid A is synthesized on the cytoplasmic surface of the bacterial inner membrane via a pathway that consists of nine different enzymes. These enzymes are highly conserved in most Gram-negative bacteria. LpxC [UDP-3-O-(R-3hydroxymyristoyl)- N-acetylglucosamine deacetylase] is the enzyme that catalyzes the first committed step in the Lipid A biosynthetic pathway, the removal of the N-acetyl group of UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine. LpxC is a Zn²⁺ dépendent enzyme that has no mammalian homologue, making it a good target for the development of novel antibiotics. Several inhibitors of LpxC with low nM affinity hâve been reported (Biochemistry 45: 7940-48, 2006).

Summary of the Invention

A new class of LpxC inhibitors has been discovered. These compounds, or their pharmaceutically acceptable salts, can be represented by Formula I below:

E-----D'

in which:

R¹ is represented by C1-C3 alkyl;

R² is represented by hydrogen or C1-C3 alkyl;

R³ is represented by hydrogen, halogen, hydroxy, cyano, C^C^Ikyl, C^Cgalkoxy, trifluoromethyl or trifluoromethoxy;

T is represented by ethynyl, optionally substituted (C₆-C₁₀)aryl or optionally substituted heteroaryl;

D is absent, or is represented by -(CH2)r. -(CH₂)_n-O-(CH₂)_p-, or a bond;

r is represented by the integer 1,2, or 3;

n and p are each independently represented by the integer 0,1, or 2;

E is absent, or is represented by a substituent selected from the group consisting of:

i) (C₃_C₁₀)cycloalkyl, optionally substituted;

ii) (C₆-C₁₀)aryl optionally substituted;

iii) heteroaryl, optionally substituted; and iv) heterocyclic, optionally substituted;

with the proviso that:

) if E is absent, then D is also absent;

2) T is not represented by unsubstituted phenyl; when E and D both are absent, R³is hydrogen and R¹ and R² are each methyl.

The compounds of Formula I exhibit antibacterial activity, especially against Gram-negative organisms. They may be used to treat bacterial infections in mammals,

especially humans. The compounds may also be used for veterinary applications, such as treating infections in livestock and companion animais.

The compounds of Formula I are useful for treating a variety of infections; especially Gram-negative infections including nosocomial pneumonie, urinary tract infections, systemic infections (bacteremia and sepsis), skin and soft tissue infections, surgical infections, intraabdominal infections, lung infections (including those in patients with cystic fibrosis), Hélicobacter pylori (and relief of associated gastric complications such as peptic ulcer disease, gastric carcinogenesis, etc.), endocarditis, diabeticfoot infections, osteomyelitis, and central nervous system infections.

In order to simplify administration, the compounds will typically be admixed with at least one excipient and formulated into a pharmaceutical dosage form. Examples of such dosage forms include tablets, capsules, solutions/suspensions for injection, aérosols for inhalation, cream/ointments for topical, otic or ophthalmic use, and solutions/suspensions for oral ingestion.

Detailed Description of the Invention

The headings within this document are only being utilized to expedite its review by the reader. They should not be construed as limiting the invention or claims in any manner.

Définitions and Exemplification

As used throughout this application, including the claims, the following terms have the meanings defined below, unless specifically indicated otherwise. The plural and singular should be treated as interchangeable, other than the indication of number:

a. “C-i - C3 alkyl” refers to a branched or straight chained alkyl group containing from 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, or isopropyl, etc.

b. “C^ C₃ alkoxy refers to a straight or branched chain alkoxy group containing from 1 to 3 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, etc.

c. halogen” refers to a chlorine, fluorine, iodine, or bromine atom.

d. “C,. C₆ alkyl refers to a branched or straight chained alkyl group containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, etc.

e. “C^ C₆ alkyl, optionally substituted refers to a branched or straight chained alkyl group containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, etc. Such an alkyl group may be optionally substituted, in which up to 3 hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, cyano, sulfonamide, imino, OR⁴,

-SR⁴, and -NR⁴R⁵ in which R⁴ and R⁵ are each independently represented by hydrogen or C1-C3 alkyl.

f. “C^ C₆ alkoxy refers to a straight or branched chain alkoxy group containing from 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, nbutoxy, isobutoxy, pentoxy, etc.

g. “C^ C₆ alkoxy, optionally substituted” refers to a straight or branched chain alkoxy group containing from 1 to 6 carbon atoms, such as methoxy, ethoxy, npropoxy, isopropoxy, n-butoxy, isobutoxy, pentoxy, etc. Such an alkoxy group may be optionally substituted, in which up to 3 hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, cyano, sulfonamide, imino, -OR⁴, -SR⁴, and -NR⁴R⁵ in which R⁴ and R⁵ are each independently represented by hydrogen or C1-C3 alkyl.

h. “(C₆-C₁₀)aryr means a cyclic, aromatic hydrocarbon containing from 6 to 10 carbon atoms. Examples of such aryl groups include phenyl, naphthyl, etc.

i. “(C₆-C₁₀)aryl optionally substituted means a cyclic, aromatic hydrocarbon as defined above. Such an aryl moiety may be optionally substituted with up to 4 non-hydrogen substituents, each substituent is independently selected from the group consisting of halogen, cyano, nitro, hydroxy, (C^-C₆)alkyl optionally substituted, (C^Cgjalkoxy optionally substituted, trifluoromethyl, trifluromethoxy, phosphate, -SO₂NR⁴R⁵, -(CH2)m-NR⁵-C(O)-R⁴, -(CH2)_m-C(O)-N-R⁴R⁵, -C(O)-R⁴,C(O)-O-R⁴, -SR⁴, -SO₂R⁴ and -NR⁴R⁵, in which m, R⁴ and R⁵ are as defined above and each M independently represents an integer from 0-4. These substituents may be the same or different and may be located at any position of the ring, that is chemically permissible. Phenyl optionally substituted refers to a phenyl ring substituted as described above.

j. “heteroaryl” refers to an aromatic ring having one, or more, heteroatoms selected from oxygen, nitrogen and sulfur. More specifically, it refers to a 5- or 6membered ring containing 1,2,3, or 4 nitrogen atoms; 1 oxygen atom; 1 sulfur atom; 1 nitrogen and 1 sulfur atom; 1 nitrogen and 1 oxygen atom; 2 nitrogen atoms and 1 oxygen atom; or 2 nitrogen atoms and 1 sulfur atom. The 5-membered ring has 2 double bonds and the 6- membered ring has 3 double bonds (hereinafter a “5- to 6-membered heteroaryl”). The term “heteroaryl” also

includes bicyclic groups in which the heteroaryl ring is fused to a benzene ring, heterocyclic ring, a cycloalkyl ring, or another heteroaryl ring. Examples of such heteroaryl ring Systems include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazoîyl, oxazolyl, indolyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, benzofuran, tetrazole, isoquinolinyl, oxadiazolyl, thiadiazolyl, isothiazolyl, isoxazolyl, triazolyl, benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 7-benzimidazolyl, or benzothiazolyl.

k. “heteroaryl, optionally substituted,” refers to a heteroaryl moiety as defined immediately above, in which up to 4 carbon atoms of the heteroaryl moiety may be substituted with a substituent, each substituent is independently selected from the group consisting of halogen, cyano, nitro, hydroxy, (C₁-C_e)alkyl optionally substituted, (C^C^alkoxy optionally substituted, trifluoromethyl, trifluromethoxy, phosphate, -SO₂NR⁴R⁵, -(CH2)m-N-C(O)-R⁴, -(CH2)m-C(O)-N-R⁴R⁵,

-C(O)-R⁴, -C(O)-O-R⁴, -SR⁴, -SO₂R⁴ and -NR⁴R⁵, in which m, R⁴ and R⁵ are as defined above. These substituents may be the same or different and may be located at any position of the ring, that is chemically permissible.

Any reference to an optionally substituted 5- to 6- membered heteroaryl refers to 5- to 6-membered heteroaryl ring as described in définition j, having the substitution pattern described immediately above.

l. “(C3-C10) cycloalkyl” refers to a saturated or partially saturated monocyclic, bicyclic, bridged bicyclic or tricyclic alkyl radical wherein each cyclic moiety has 3 to 10 carbon atoms. Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and the like.

m. “(C3-C10) cycloalkyl” optionally substituted refers to a (C3-C10) cycloalkyl moiety as described above. Such a cycloalkyl group may be optionally substituted, in which up to 4 hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, cyano, nitro, hydroxy, (C^C^alkyl optionally substituted, (C^C^alkoxy optionally substituted, trifluoromethyl, trifluromethoxy, phosphate, oxo, -SO₂NR⁴R⁵, -(CH2)m-NR⁵-C(O)-R⁴, -(CH2)_m-C(O)-N-R⁴R⁵, C(O)-R⁴, -C(O)-O-R⁴, -SR⁴, -SO₂R⁴ and -NR⁴R⁵, in which M, R⁴ and R⁵ are as defined above. These substituents may be the same or different and may be located at any position of the ring, that is chemically permissible.

n. '‘(C3-Ce) cycloalkyl refers to a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl moiety, any of which may be optionally substituted as described above, if chemically permissible.

o. “heterocycle or “heterocyclic ring” refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6-, 7-, 8-, 9-, or 10- membered ring containing 1,2, or 3 nitrogen atoms; 1 oxygen atom;

sulfur atom; 1 nitrogen and 1 sulfur atom; 1 nitrogen and 1 oxygen atom;

oxygen atoms in non-adjacent positions; 1 oxygen and 1 sulfur atom in nonadjacent positions; or 2 sulfur atoms in non-adjacent positions. The 5-membered ring has 0 to 1 double bonds, the 6- and 7-membered rings hâve 0 to 2 double bonds, and the 8, 9, or 10 membered rings may hâve 0,1,2, or 3 double bonds. The term “heterocyclic also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring, a cyclohexane or cyclopentane ring or another heterocyclic ring (for example, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl and the like). Heterocyclics include: pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, azepane, azocane, morpholinyl, isochromyl, quinolinyl, tetrahydrotriazine, tetrahydropyrazole, dihydro-oxathiol-4-yl, dihydro-1Hisoindole, tetrahydro-oxazolyl, tetrahydro-oxazinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl.

p. heterocyclic, optionally substituted refers to a heterocyclic moiety as defined immediately above, in which up to 4 carbon atoms of the heterocycle moiety may be substituted with a substituent, each substituent is independently selected from the group consisting of halogen, cyano, nitro, hydroxy, (C^CgJalkyl optionally substituted, (C^Cgjalkoxy optionally substituted, trifluoromethyl, trifluromethoxy, pentafluoro sulfonyl, phosphate, oxo, SO₂NR⁴R⁵, -(CH2)m-N-C(O)-R⁴, -(CH2)_mC(O)-N-R⁴R⁵, -C(O)-R⁴, -C(O)-O-R⁴, -SR⁴, -SO₂R⁴ and -NR⁴R⁵, in which m, R⁴ and R are as defined above. These substituents may be the same or different and may be located at any position of the ring that is chemically permissible. Any nitrogen atom within such a heterocyclic ring may optionally be substituted with (Ci-C₆) alkyl, or any other substituent listed above, if such a substitution is chemically permissible. Any sulfur atom in the ring may be further substituted with 1 or 2 oxygen atoms (if such a substitution is chemically permissible).

V

q. therapeutically effective amount refers to an amount of a compound of Formula I that, when administered to a patient, provides the desired effect; i.e., lessening in the severity of the symptoms associated with a bacterial infection, decreasing the number of bacteria in the affected tissue, and/or preventing bacteria in the affected tissue from increasing in number( localized or systemic).

r. “patient refers to warm blooded animais such as for example, livestock, guinea pigs, mice, rats, gerbils, cats, rabbits, dogs, monkeys, chimpanzees, and humans.

s. treat” refers to the ability of the compounds to relieve, alleviate or slow the progression of the patients bacterial infection (or condition) or any tissue damage associated with the disease.

t. pharmaceutically acceptable” indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingrédients comprising a formulation, and/or the mammal being treated therewith.

u. “isomer'’ means “stereoisomer and “géométrie isomer” as defined below.

v. “stereoisomer” means compounds that possess one or more chiral centers and each center may exist in the R or S configuration. Stereoisomers include ail diastereomeric, enantiomeric and epimeric forms as well as racemates and mixtures thereof.

w. “géométrie isomer’’ means compounds that may exist in cis, trans, anti, entgegen (E), and zusammen (Z) forms as well as mixtures thereof.

x. Compounds of “Formula I”, “formula I, formula (I)’’ and “compounds of the invention” are being used interchangeably throughout the application and should be treated as synonyms.

y. The terms pyridone and “pyridinone hâve been used interchangeably within this application. No différence or distinction is meant, unless otherwise noted. One skilled in the art will readily understand this.

The phrase “pharmaceutically acceptable salt(s)”, as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be présent in the compounds of the présent invention. The compounds of the présent invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to préparé pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts,

i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate,

îsonrcotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e·, 1,r-methylene-bis-(2-hydroxy-

3-naphthoate)] salts. The compounds of the présent invention that include a basic moiety, such as an amino group, may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.

The invention also relates to base addition salts of the compounds of the invention. The chemical bases that may be used as reagents to préparé these pharmaceutically acceptable base salts are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali métal cations (e.g., potassium and sodium) and alkaline earth métal cations (e.g., calcium and magnésium), ammonium or water-soluble amine addition salts such as Nmethylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.

Suitable base salts are formed from bases which form non-toxic salts. Non limiting examples of suitable base salts include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnésium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Sélection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for making pharmaceutically acceptable salts of compounds of the invention are known to one of skill in the art.

Certain of the compounds of the formula (I) may exist as géométrie isomers. The compounds of the formula (I) may possess one or more asymmetric centers, thus existing as two or more stereoisomeric forms. The présent invention includes ail the individual stereoisomers and géométrie isomers of the compounds of formula (I) and mixtures thereof. Individual enantiomers can be obtained by chiral séparation or using the relevant enantiomer in the synthesis.

In addition, the compounds of the présent invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, éthanol and the like. In general, the solvated forms are considered équivalent to the unsolvated forms for the purposes of the présent invention. The compounds may also

exist in one or more crystalline states, i.e. polymorphe, or they may exist as amorphous solids. Ail such forms are encompassed by the ciaims.

The invention also relates to prodrugs of the compounds of the invention. Thus certain dérivatives of compounds of the invention which may hâve little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of the invention having the desired activity, for example, by hydrolytic cleavage. Such dérivatives are referred to as “'prodrugs”. Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Sériés (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug

Design, Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical

Association).

This invention also encompasses compounds of the invention containing protective groups. One skilled in the art will also appreciate that compounds of the invention can also be prepared with certain protecting groups that are useful for purification or storage and can be removed before administration to a patient. The protection and deprotection of functional groups is described in “Protective Groups in Organic Chemistry”, edited by J.W.F. McOmie, Plénum Press (1973) and Protective Groups in Organic Synthesis”, 3rd édition, T.W. Greene and P.G.M. Wuts, WileyInterscience (1999).

The présent invention also includes isotopically-labeled compounds, which are identical to those recited in formula I, 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, fluorine and chlorine, such as, but not limited to, ²H, ³H, ¹³C, ¹⁴C, ^1SN, ¹⁷0,¹⁸0,³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶CI, respectively. Compounds of the présent invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopicallylabeled compounds of the présent invention, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of préparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., ²H, can 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.

Isotopicaily-labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the

Examples below, by substituting a readily available isotopicaily-labeled reagent for a non-isotopically-labeled reagent.

Ail of the compounds of Formula I contain a sulfonyl moiety as depicted below:

SO₂-R¹ _H

This sulfonyl moiety will always be substituted with a lower alkyl moiety. Typically it will be methyl. The carbon atom adjacent to the sulfonyl may optionally be substituted, as represented by R². Typically both R¹ and R² will be methyl.

As is readily apparent to one skilled in the art, the carbon adjacent to the sulfonyl moiety is a chiral center. Therefore, the compounds can exist as the racemate, as the S-enantiomer, or as the R-enantiomer. In a further embodiment, the compounds may be prepared and administered as the R-enantiomer, as depicted below:

As is readily apparent to one skilled in the art, the compounds as synthesized will rarely be présent exclusively as a single enantiomer. The opposite enantiomer (i.e the Senantiomer) may be présent in minor amounts (i.e. “substantially pure”). This minor amount can be up to 10 w/w%, more typically no greater than 5 w/w%, in a further embodiment no greater than 1 w/w%, or more specifically, no greater than 0.5 w/w%.

Ali of the compounds of Formula I contain a pyridinone moiety as depicted below:

xZ

This pyridinone ring will be connected to the rest of the molécule via the 1 - and 4positions as depicted above. Position 3 will always be substituted with a fluoro moiety as depicted above. The pyridinone moiety may be optionally substituted, as depicted by the R³ moiety. R³ may represent one non-hydrogen substituent, as defined above. This non-hydrogen substituent may be located at either position 2 or 5 of the pyridinone ring. Typically R³ will represent hydrogen.

T will always be présent in the molécule. It will be represented by ethynyl, aryl or heteroaryl (either ring system may be substituted as defined above.) Typically, T will be represented by phenyl, which may be optionally substituted. When T is heteroaryl, it will be linked to the pyridinone via a carbon-carbon bond (i.e. the heteroatom(s) will not be bonded to the pyridinone). If E is présent, and D represents a bond, then it may represent any chemically permissible bond, i.e carbon-carbon, carbon-nitrogen, etc.

The presence of D and E are optional. If présent, D will typically be a bond and E will be represented by either a 5- to 6-membered heteroaryl or a (C₃-C₆) cycloalkyl, either of which may be optionally substituted as defined above.

More spécifie embodiments of the invention include compounds of Formula I in which:

a) R¹ is methyl;

b) R² is methyl;

c) R³ is hydrogen;

d) the compound is présent as the R-enantiomer (i.e. substantially pure);

e) T is phenyl, which may be optionally substituted and D and E are both absent; and

f) T is phenyl, D is a bond and E is either C3-C₆ cycloalkyl or a 5- to 6membered heteroaryl, either of which may be optionally substituted.

A further embodiment of the invention is directed to compounds of Formula I, substantially pure in which:

a) R¹ and R² are each methyl, R³ is hydrogen, and T, D and E are as defined;

•y

b) R¹ and R² are each methyl, R³ is hydrogen, T is optionally substituted phenyl and both E and D are absent;

c) R¹ and R² are each methyl, R³ is hydrogen, T is optionally substituted phenyl, D is a bond and E is a 5- to 6-membered heteroaryl, which may be optionally substituted; and

d) R¹ and R² are each methyl, R³ is hydrogen, T is optionally substituted phenyl, D is a bond and E is Ca-Ce cycloalkyl, which may be optionally substituted.

In a further embodiment, the invention is directed to a subgenus represented by formula la below, in which the molécule is présent as the R-enantiomer (i.e. the Senantiomer may optionally be présent in minor amounts). As depicted below, R¹ and R²are methyl, R³ is hydrogen, both E and D are absent and T is substituted phenyl. More specifically R^a is represented by one or more substituents selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, fluorine, chlorine, hydroxy, trifluoromethyl and trifluoromethoxy.

In a further embodiment, the invention is directed to a subgenus represented by formula lb below, in which the molécule is présent as the R-enantiomer (i.e. the Senantiomer may optionally be présent as a minor impurity). As depicted below, R¹ and R² are methyl, R³ is hydrogen, T is phenyl, D is a bond and E is a 5- to 6-membered heteroaryl, which may be optionally substituted.

In a more spécifie embodiment of the invention, the LpxC inhibitor is the following compound, or its pharmaceutically acceptable sait:

Synthesis

The compounds of Formula I can be prepared by a variety of methods that are analogously known in the art. The reaction schemes presented below illustrate two alternative methods for preparing these compounds. Others, including modifications thereof, will be readily apparent to one skilled in the art.

The synthesis of the compounds of Formula I is depicted below in Scheme A.

The first step is to carry out the N-alkylation depicted in Step A. The pyridinone of structure 1 is reacted with the sulfonyl dérivative of structure 2 generating the intermediate of structure 3. Structure 3 can be further derivatized to generate the compounds of Formula I. Two alternative synthèses are depicted (Option A or B), but the reader will readily note they are variations of the same synthesis. The only différence is the order in which the steps are carried out.

Initially in Option A, the halide, depicted by X, at the 4-position of the pyridinone of structure 3 is displaced by the desired terminal moiety E-D-T-M¹, in which M¹ is a métal species, such as a boron dérivative suitable for undergoing a typical crosscoupling such as a Suzuki-Miyaura reaction. Hydrolysis, or removal, of the ethyl protecting group (or other suitable protecting groups) in Step C affords the compound of structure 5. The terminal carboxylic acid of structure 5 is then converted to the protected hydroxamic acid dérivative as depicted by structure 8. Deprotection of the protected hydroxamic acid dérivative of structure 8, as depicted in Step H, affords the final product of Formula I. While these reactions are well known to one skilled in the art, they are discussed in greater detail below.

Initially, in Option B of Scheme A, the ethyl protecting group (or other conventional protecting groups) is removed from the pyridinone of structure 3 generating the compound of structure 6 as depicted in Step E. In Step F, the terminal carboxylic acid of structure 6 is converted to the protected hydroxamic acid dérivative of structure 7 via amidation conditions. In Step G, the halide function at the 4-position on the pyridinone moiety is then directly displaced by the desired terminal moiety, E-D-TM¹, via a coupling reaction to afford the protected hydroxamic acid dérivatives of structure 8. As before, deprotection of the protected hydroxamic acid dérivatives, as depicted in Step H, affords the compounds of Formula I.

The N-alkylation depicted above in Step A can be carried out using techniques well known to one skilled in the art. One of the starting materials is the 2-pyridinone dérivative of structure 1. In this pyridinone, X will represented by a halide and R³ will be represented by the same moiety as is desired in the final product. Many of these pyridinone dérivatives are known in the art and the remainder can be produced using synthetic techniques analogously known in the art. The reader’s attention is directed to Tet. Lett. (2005) Vol 46, 7917, for a description of such techniques. Préparation 2 infra, also illustrâtes their préparation.

The other reactant in the N-alkylation depicted in Step A is the protected alkyl sulfonate of structure 2, in which R¹ and R² are represented by the same moiety as is desired in the final product. An ethyl protecting group is portrayed, but any standard protecting group may be substituted. These alkyl sulfonates are also known in the art. The reader’s attention is directed to Journal of Organic Chemistry, (1980) Vol 45, 8, 1486-1489 for a description of their préparation. Préparation 1 infra, also illustrâtes their préparation

The N-alkylation can be carried out as is known in the art. Typically, équivalent amounts of the compounds of structure 1 and 2 are contacted in a mixture of aprotic and protic solvents, such as tetrahydrofuran and f-butanol, in the presence of a base such as potassium carbonate, césium carbonate, sodium carbonate, sodium hydride, etc. A transfer agent, such as tetrabutyl ammonium bromide, can be utilized, if desired. The reactants are typically heated and the reaction is allowed to proceed to completion. The desired product of structure 3 can be isolated by methods known in the art. If desired, the product of structure 3 can be purified, or alternatively the crude can be used in the next step of the reaction. Préparation 2 infra, illustrâtes such an Nalkylation.

Scheme A illustrâtes how to incorporate the hydroxamic acid moiety into the molécules. Initially, the protecting group is removed from the carboxylic acid, thereby generating the intermediate of structure 5 and 6, as depicted in Step C (Option A) and Step E (Option B) respectively. The manner in which this is accomplished will vary with the identity of the actual protecting group and is well known to those skilled in the art. The reader’s attention is directed to McOmie or Greene supra, for a discussion of potential protecting groups and methods for their removal. Préparation 2 infra describes how to remove an ethyl moiety as depicted in Scheme A.

In Steps F and D, the hydroxamic acid moiety as depicted, is incorporated into the molécule. A protected hydroxylamine source may be used followed by a subséquent deprotection reaction (alternatively, hydroxylamine may be directly incorporated to eliminate the deprotection steps). In either case the hydroxamic acid is

Y

incorporated into the molécule using standard amidation reactions. For example, the compound of structure 5 (Option A) or 6 (Option B) may be contacted with an excess of oxalyl chloride, in an aprotic solvent such as dichloromethane for a sufficient period of time to allow the formation of the corresponding acid chloride, followed by the addition of an excess of either hydroxylamine or protected hydroxylamine. The reaction is then allowed to proceed to completion and the protected intermediates of structure 7 (Option B) or 8 (Option A) is isolated from the reaction medium and purified as is known in the art. As mentioned above, any deprotection may be carried out as is known in the art (See Greene or McOmie supra). Alternatively, the amide can be formed using the amide coupling reagent, 1,T-carbonyldiimidazole (CDI), 2-chloro-4,6-dimethoxy-1,3,5triazine (CDMT), or 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), as is known in the art.

Scheme A also depicts how to incorporate the terminal moiety, E-D-T, into the molécule. Regardless of whether Option A or Option B is chosen, a coupling reaction is ultimately carried out to attach the terminal moiety, E-D-T, to the 4-position of the pyridinone intermediate. In Scheme A, the co-reactant is depicted as E-D-T-M¹, where E-D-T-M¹ represents the same moiety as desired in the final product, except that it will be substituted with a métal (or metalloid) such as magnésium, copper, boronic ester/acid, etc. at the desired point of attachment to the pyridinone intermediate of structure 3 or 7 (i.e. the other reactant). The terminal groups encompassed by Formula I, i.e E-D-T, are either known in the art or can be prepared by methods analogously known in the art.

The coupling reaction can be carried out by a variety of techniques. The SuzukiMiyaura strategy can be used to form the carbon-carbon bond. In such a reaction M¹will be represented by a boronic acid/ester. Equivalent molar amounts of the reactants will be contacted in a solvent such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4dioxane, water, toluene, or a mixture thereof in the presence of a transition métal catalyst such as a free or resin bound palladium or nickel species, together with a base such as sodium carbonate, potassium carbonate, césium fluoride, césium carbonate, etc. The reaction mixture can be heated by microwave or by other conventional techniques until adéquate conversion is achieved. Once complété, the desired product may be isolated and recovered from the reaction and further purified as is known in the art. Analogously, the Castro-Stevens or Sonogashira-Hagihara strategy can be employed; the T moiety will be a suitable terminal acetylene species reacted in the presence of copper sait such as copper iodide. In such a reaction M¹ can be

represented by the in situ generated cuprate species. Equivalent molar amounts of the reactants will be contacted in a solvent such as tetrahydrofuran, 2methyltetrahydrofuran, dimethylformamide or a mixture thereof in the presence of a transition métal catalyst such as free or resin bound palladium or nickel, together with an appropriate base such as a suitable organic base for example N,Ndiisopropylethylamine. The reaction mixture can be heated by microwave or by other conventional techniques until adéquate conversion is achieved. Once complété, the desired product may be isolated and recovered from the reaction and further purified as is known in the art.

The reaction schemes depicted above for producîng the compound of Formula I, are merely illustrative. As is readily apparent to one skilled in the art, they may be modified depending upon the spécifie compound, availability of reagents, etc.

Medical and Veterinary Uses

The compounds may be used for the treatment or prévention of infectious disorders, especially those caused by susceptible and multi-drug résistant (MDR) Gramnegative bacteria. Examples of such Gram-negative bacteria include Acinetobacter baumannii, Acinetobacter spp., Achromobacter spp., Aeromonas spp., Bacteroides fragilis, Bordetella spp., Borrelia spp,, Brucella spp., Campylobacter spp., Citrobacter diversus (koseri), Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Francisella tularensis, Fusobacterium spp., Haemophilus influenzae (βlactamase positive and négative), Hélicobacter pylori, Klebsiella oxytoca, Klebsiella pneumoniae (including those encoding extended-spectrum β-lactamases (hereinafter ESBLs), Légionella pneumophila, Moraxella catarrhalis (β-lactamase positive and négative), Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitidis, Proteus vulgaris, Porphyromonas spp., Prevotella spp., Mannheimia haemolyticus, Pasteurella spp., Proteus mirabilis, Providencia spp., Pseudomonas aeruginosa, Pseudomonas spp., Salmonella spp., Shigella spp., Serratia marcescens, Treponema spp., Burkholderia cepacia, Vibrio spp., Yersinia spp., and Stenotrophomonas mulophilia. Examples of other gram négative organisms include members of the Enterobacteriaceae that express ESBLs; KPCs, CTX-M, metallo-p-lactamases (such as NDM-1, for example), and AmpC-type beta-lactamases that confer résistance to currently available cephalosporins, cephamycins, carbapenems, and beta-lactam/betalactamase inhibitor combinations.

In a more spécifie embodiment, the Gram-negative bacteria are selected from the group consisting of Acinetobacter baumannii, Acinetobacter spp.,Citrobacter spp., Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Serratia marcescens, Stenotrophomonas maltophilia, Pseudomonas aeruginosa and members of the Enterobacteriaceae and Pseudomonas that express ESBLs, KPCs, CTX-M, metallo-p-lactamases, and AmpC-type betalactamases that confer résistance to currently available cephalosporins, cephamycins, carbapenems, and beta-lactam/beta-lactamase inhibitor combinations.

Examples of infections that may be treated with the compounds of Formula I include nosocomial pneumonia, urinary tract infections, systemic infections (bacteremia and sepsis), skin and soft tissue infections, surgical infections, intraabdominal infections, lung infections in patients with cystic fibrosis, patients suffering from lung infections, endocarditis, diabetic foot infections, osteomyelitis, and central nervous system infections.

In addition, the compounds can be used to treat Hélicobacter pylori infections in the Gl tract of humans (and other mammals). Elimination of these bacteria is associated with improved health outcomes including fewer dyspeptic symptoms, reduced peptic ulcer récurrence and rebleeding, reduced risk of gastric cancer, etc. A more detailed discussion of eradicating H. pylori and its impact on gastrointestinal illness may be found at: www.informahealthcare.com. Expert Opin. Drug Saf. (2008) 7(3).

In order to exhibit this anti-infective activity, the compounds need to be administered in a therapeutically effective amount. A therapeutically effective amount is meant to describe a sufficient quantity of the compound to treat the infection, at a reasonable benefit/risk ratio applicable to any such medical treatment. It will be understood, however, that the attending physician, within the scope of sound medical judgment, will décidé the total daily dosage of the compound. The spécifie therapeutically effective dose level for any particular patient will dépend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the spécifie compound employed; the spécifie composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excrétion of the spécifie compound employed; the duration of the treatment; drugs used in combination or coincidental with the spécifie compound employed; and like factors well known in the medical arts. As a general guideline however, the total daily dose will typically range from about 0.1mg/kg/day to about

5000mg/kg/day in single or in divided doses. Typically, dosages for humans will range from about 10 mg to about 3000 mg per day, in a single or multiple doses.

Any route typically used to treat infectious illnesses, including oral, parentéral, topical, rectal, transmucosal, and intestinal, can be used to administer the compounds. Parentéral administrations include injections to generate a systemic effect or injections directly into to the afflicted area. Examples of parentéral administrations are subcutaneous, intravenous, intramuscular, intradermal, intrathecal, and intraocular, intranasal, intravetricular injections or infusions techniques. Topical administrations include the treatment of areas readily accessible by local application, such as, for example, eyes, ears including external and middle ear infections, vaginal, open wound, skin including the surface skin and the underneath dermal structures, or lower intestinal tract. Transmucosal administration includes nasal aérosol or inhalation applications. Formulations

Compounds of the invention can be formulated for administration in any way for use in human or veterinary medicine, by analogy with other bioactive agents such as antibiotics. Such methods are known in the art and are summarized below.

The composition can be formulated for administration by any route known in the art, such as subdermal, by-inhalation, oral, topical or parentéral. The compositions may be in any form known in the art, including but not limited to tablets, capsules, powders, granules, lozenges, creams or liquid préparations, such as oral or stérile parentéral solutions or suspensions.

The topical formulations of the présent invention can be presented as, for instance, ointments, creams or lotions, ophthalmic ointments/drops and otic drops, impregnated dressings and aérosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug pénétration and émollients, etc. Such topical formulations may also contain conventional carriers, such as cream or ointment bases and éthanol or oleyl alcohol for lotions. Such carriers may be présent, for example, from about 1% up to about 98% of the formulation.

Tablets and capsules for oral administration may be in unit dose présentation form, and may contain conventional excipients such as binding agents, for example acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnésium stéarate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.

The tablets may be coated according to methods well known in normal pharmaceutical practice.

Oral liquid préparations may be in the form of, for example, aqueous or oily suspensions, solutions, émulsions, syrups or élixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid préparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stéarate gel or hydrogenated edible fats, emulsifyîng agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerin, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavoring or coloring agents.

For parentéral administration, fluid unit dosage forms are prepared utilizing the compound and a stérile vehicle, water being typical. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle or other suitable solvent. In preparing solutions, the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, agents such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parentéral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the stérile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The compositions may contain, for example, from about 0.1 % by weight, to about 100% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will contain, for example, from about 0.5-1000 mg of the active ingrédient. The dosage as employed for adult human treatment will range, for example, from about 10 to 3000 mg per day, depending on the route and frequency of administration.

If desired, the compounds of the invention may be administered in combination with one or more additional antibacterial agents (“the additional active agent”). Such use of compounds of the invention in combination with an additional active agent may be for simultaneous, separate or sequential use.

The Examples and préparations provided below further illustrate and exemplify the compounds of the présent invention and methods of preparing such compounds. It is to be understood that the scope of the présent invention is not limited in any way by the scope of the following Examples and préparations. In the following Examples molécules with a single chiral center, unless otherwise noted, exist as a racemic mixture. Those molécules with two or more chiral centers, unless otherwise noted, exist as a racemic mixture of diastereomers. Single enantiomers/diastereomers may be obtained by methods known to those skilled in the art.

EXAMPLES

Experimental Procedures

Experiments were generally carried out under an inert atmosphère (nitrogen or argon), particularly in cases where oxygen- or moisture-sensitive reagents or intermediates were employed. Commercial solvents and reagents were generally used without further purification, including anhydrous solvents where appropriate (generally Sure-Seal™ products from the Aldrich Chemical Company, Milwaukee, Wisconsin). Mass spectrometry data is reported from either liquid chromatography-mass spectrometry (LCMS) or atmospheric pressure chemical ionization (APCI). Chemical shifts for nuclear magnetic résonance (NMR) data are expressed in parts per million (ppm, δ) referenced to residual peaks from the deuterated solvents employed. Melting points are uncorrected. Low Resolution Mass Spectra (LRMS) were recorded on either a Hewlett Packard 5989®, utilizing chemical ionization (ammonium), ora Fisons (or Micro Mass) Atmospheric Pressure Chemical Ionization (APCI) platform which uses a 50/50 mixture of acetonitrile/water with 0.1% formic acid as the ionizing agent. Room or ambient température refers to 20-25°C.

For synthèses referencing procedures in other Examples, reaction conditions (length of reaction and température) may vary. In general, reactions were followed by thin layer chromatography or mass spectrometry, and subjected to work-up when appropriate. Purifications may vary between experiments: in general, solvents and the solvent ratios used for eluents/gradients were chosen to provide appropriate R₍s or rétention times.

In the discussion above and in the Examples below, the foliowing abbreviations hâve the foliowing meanings. If an abbreviation is not defined, it has its generally accepted meaning.

	Ac	=	acetate
5	ACN	=	acetonitrile
	AC₃O		acetic anhydride
	APCI	=	atmospheric pressure chemîcal ionization
	Aq.	=	aqueous
	9-BBN	=	9-Borabicyclo[3.3.1]nonane
10	bd	=	broad doublet
	bm	=	broad multiplet
	bs	=	broad singlet
	BOC	=	tert-butoxycarbonyl
	°C	=	degrees celsius
15	CBZ	=	benzyloxycarbonyl
	CDI	=	1,1 ’-carbonyldiimidazole
	CDMT	=	2-chloro-4,6-dimethoxy-1,3,5-triazine
	cm	=	centimeter
	d	=	doublet
20	DCC	=	1,3-dicyclohexylcarbodiimide
	DCM	=	dichloromethane
	dd	=	doublet of doublets
	ddd	=	doublet of doublets of doublets
	DIAD	=	diisopropyl azodicarboxylate
25	DME	=	dimethyl ether
	DMF	=	dimethylformamide
	DMA	=	dimethylacetamîde
	DMAP	=	4-dimethylaminopyridine
	DMSO	=	dimethyl sulfoxide
30	dq	=	doublet of quartets
	dt	=	doublet of triplets
	EDCI	=	1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
	eq.	=	équivalents
	EtO	=	ethoxy
35	Et₂O	=	diethyl ether

	16551 24
EtOAc	ethyl acetate
g GCMS	grams gas chromatography mass spectromety
h ¹H	hours proton
HATU	(2-(7-aza-1 H-benzotriazole-1 -yl)-1,1,3,3-tetramethyluronium hexafluorophosphate)
HCl	hydrochloric acid
H₂N-OTHP = HOBT	0-tetrahydro-2H-pyran-2-yl-hydroxylamine Hydroxybenzotriazole
HPLC	high pressure liquid chromatography
Hz =	hertz
IPA	isopropanol
J	coupling constant
KOAc	potassium acetate
K3PO4	potassium phosphate
L	liter
LCMS	liquid chromatography mass spectrometry
LDA	lithium diisopropylamide
LG	leaving group
LiHMDS	lithium hexamethyldisilazide/ lithium bis(trimethylsilyl)amide
m =	multiplet
M	molar
M%	mole percent
max =	maximum
mCPBA	meta-chloroperbenzoic acid
MeOH	methanol
meq = MeTHF	milliequivalent 2-methyltetrahydrofuran
mg MgSO₄MHz	milligram magnésium sulfate mégahertz
min	minutes
mL	milliliter
mm =	millimeter

mmol	=	millimole
MS	=	mass spectrometry
MTBE	=	methyl tert-butyl ether
m/z	=	mass to charge ratio
N	=	normality
NaHCO₃	=	sodium bicarbonate
Na₂SC>4	=	sodium sulfate
NH₄CI	=	ammonium chloride
NMM	=	A/-methylmorpholine
NMP	=	1 -methyl-2-pyrrolidinone
NMR	=	nuclear magnetic résonance
Pd	=	palladium
Pd EnCat™	=	palladium acetate and BINAP, microencapsulated in polyurea matrix 0.39mmol/g Pd loading BINAP 0.25, Pd 1.0
Pd(dppf)CI₂	⁼	bis(diphenylphosphino)ferrocenepalladium(ll) chloride Pd(dppf)CI₂ dichloromethane complex
Pd(PPh₃)₄	=	tetrakîs(triphenylphosphine)palladium(0)
ppt	=	precipitate
p-TLC	=	préparative thin layer chromatography
PyBop	—	benzotriazole-l-yl-oxy-trispyrrolidinophosphonium hexafluorophosphate
q	-	quartet
R_f	=	rétention factor
rt	=	room température
s	=	singlet
sat.	=	saturated
tor tr		triplet
TBAB	=	tetrabutylammoinum bromide
TBS	s	tert-butyldimethylsilyl
TFA	=	trifluoroacetic acid
THF	=	tetrahydrofuran
THP	=	tetrahyropyranyl
TLC	=	thin layer chromatography
TMS	=	trimethylsilyl
TPP	=	triphenylphosphine

ΤΡΡΟ pL triphenylphosphine oxide microliter

PREPARATION OF STARTING MATERIALS

Préparation 1

Synthesis ofTemplate 1 (Tl): Ethvl 4-bromo-2-methvl-2-(methvlsulfonvl)butanoate and individual enantiomers (R) and (S).

MeO_zS,

Step A)

Ethyl 2-(methylsuifonvl)Dropanoate

Sodium methanesulfinate (103 g, 937 mmol) was combined with ethyl 2chloropropionate (109 g, 892 mmol) in éthanol (350 mL) in a 500 mL one neck round bottom flask. The reaction was heated to 77 °C for 20 h, and then allowed to cool to room température. The solids were removed by filtration through celite, and the filter pad was washed with éthanol. The combined filtrâtes were concentrated in vacuo. The crude product was suspended in diethyl ether (250 mL), and solids were removed by filtration. The filtrate was concentrated in vacuo to afford the title compound as a pale yellow oil (51 g, 73%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.32 (t, J=7.05 Hz, 3 H) 1.67 (d, J=7.47 Hz, 3 H) 3.05 (s, 3 H) 3.83 - 3.92 (m, 1 H) 4.18 - 4.37 (m, 2 H).

Step B) Ethyl 4-bromo-2-methvl-2-(methvlsulfonvl) butanoate

Sodium hydride (60% dispersion in minerai oil, 2.33 g, 58.3 mmol) was washed with hexanes (2x10 mL) in a 100 mLtwo neck round bottom flask under nitrogen then suspended in DMF (30 mL). The suspension was treated dropwise with ethyl 2(methylsulfonyl)propanoate (10.0 g, 55.49 mmol) in DMF (10 mL). The mixture was stirred 30 min at RT, cooled to 0 °C, and treated drop-wise with 1,2-dibromoethane (5.17 mL, 58.8). The mixture was allowed to warm to room température while stirring overnight. The mixture was quenched with saturated aq ammonium chloride (100 mL) and extracted with diethyl ether (4x50 mL). Combined organics were washed with 50% saturated sodium chloride (4x50 mL), dried (MgSO₄), and concentrated in vacuo. Crude material was purified via silica chromatography (350 g, 230-400 mesh) and an eluent of EtOAc in hexanes (10-20%) to afford the title compound as a pale yellow oil

(7.9 g, 50%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (t, J=7.05 Hz, 3 H)

1.64 (s, 3 H) 2.49 - 2.59 (m, 1 H) 2.78 (ddd, J=13.89, 10.16, 6.64 Hz, 1 H) 3.05 (s, 3 H)

3.33 - 3.41 (m, 1 H) 3.46 - 3.54 (m, 1 H) 4.22 - 4.37 (m, 2 H).

Step C) Chiral séparation of Ethvl 4-bromo-2-methyl-2-(methvlsulfonvl)butanoate Crude ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (1.82 kg) was purified via flash chromatography using an LP-600 column and toluene as the eluent to afford pure ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (1.63 kg). The purified material was dissolved in éthanol (75 g/L) and resolved via chiral column chromatography (conditions listed in Table 1) on MCC-2 to afford enantiomer #1 (738.4 g, rt = 4.719 min, [a]₅89²⁰ - +14.1°) at 99% ee and enantiomer #2 (763.8 g, rt = 4.040 min) at 95% ee. Purity of the enantiomers was determined via chiral HPLC, 4.6x250 mm Chiralpak AD, 10μ column, 215 nm wavelength, mobile phase: éthanol, isocratic elution at 1 mL/min at ambient température.

Table 1

Stationary Phase	ChiralPak AD, 20μ
Column Dimension/Temp	5x10cm/30 °C
Mobile Phase	100% éthanol
Feed Concentration	75 g/L in mobile phase
Feed Rate	4.0 mL/min
Eluent Rate	90.5 mL/min
Raffinate Rate	35.6 mL/min
Extract Rate	58.9 mL/min
Recycling Rate	262 mL/min
Period Time	1.0 min

Enantiomer #1 was determined to be ethyl (2R)-4-bromo-2-methyl-2(methylsulfonyl)butanoate, Template 1 (T1).

Préparation 2

Scheme B illustrâtes the préparation of ethyl (2R)-4-(5-fluoro-4-iodo-2oxopyridin-1 (2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate (T2) and (2R)-4-(5-fluoro-4iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methyisulfonyl)-N-(tetrahydro-2H-pyran-2yloxy)butanamide (T3) and the corresponding racemic and diastereomeric mixtures ethyl 4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate

(T4) and 4-(5-fluoro-4-iodo-2-oxopyridin-1 (2H)-yl)-2-methyl-2-(methylsulfonyl)-N(tetrahydro-2H-pyran-2-yloxy)butanamide (T5).

il

III

T2

Synthesis ofTemplate 3 (T3): (2R)-4-i5-Fluoro-4-iodo-2-oxopyridin-1(2H)-vlÎ-2methvl-2-(methvlsulfonvl)-N-(tetrahvdro-2H-Dvran-2-yloxv)butanamide

Step A) Compound III: 5-Fluoro-4-iodopyridin-2(1H)-one

Concentrated HCl (50 mL) was added to a mixture of 2,5-difluoro-4-iodopyridine (2.0 g, 8.3 mmol) in 1,4-dioxane (350 mL) and water (100 mL). The mixture was heated to reflux and stirred at this température overnight. The reaction was concentrated to dryness and the residue was triturated in water (20 ml_).The solids were collected via filtration and washed with water (2x30 mL) and hexanes (3x30 mL). The solid was dried under vacuum to afford the title compound as a yellow solid (1.0 g, 50%). MS (LCMS) m/z 240.0 (M+1). ¹H NMR (400 MHz, DMSO-cfe) δ ppm 7.02 (d, J=5.07 Hz, 1 H) 7.68 (d, J=2.34 Hz, 1 H) 11.50 (br. s., 1 H).

Step B) Template 2 (T2): Ethyl (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-vl)-2methvl-2- (methylsu If onyl) butanoate

Césium carbonate (1.77 g, 5.44 mmol) was added to a suspension of 5-fluoro-4iodopyridin-2(1 H)-one (1.00 g, 4.2 mmol) and ethyl (2R)-4-bromo-2-methyl-2(methylsulfonyl)butanoate (1.56 g, 5.44 mmol) in anhydrous THF (45 mL). The reaction was heated to 70 °C and stirred at this température overnight. The reaction was quenched with water (100 mL) and extracted with EtOAc (2x100 mL). The combined organics were washed with brine (100 mL), dried (MgSO₄), filtered, and concentrated. The crude product was purified via flash chromatography using a Varian SF15-24g column and an eluent of EtOAc in n-heptane (30-80%) to afford the title compound as a yellow residue (691 mg, 37%). MS (LCMS) m/z 446.0 (M+1). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (t, 3 H) 1.75 (s, 3 H) 2.37 - 2.57 (m, 2 H) 3.10 (s, 3 H) 3.83 - 4.02 (m, 1 H) 4.16 - 4.37 (m, 3 H) 7.15 (d, 1 H) 7.20 (d, J=3.32 Hz, 1 H).

Step C) Compound IV: (2R)-4-(5-Fluoro-4-iodo-2-oxoDvridin-1 (2H)-vl)-2-methyl-2(methylsulfonyl)butanoic acid

Potassium hydroxide (669 mg, 7.7 mmol) was added to a solution of ethyl (2R)-4-(5fluoro-4-iodo-2-oxopyridin-1 (2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate (691 mg, 1.55 mmol) in 2-methyltetrahydrofuran:water (2:1 22.5 mL) and the solution was stirred at 70°C for 2 h. The reaction was diluted with 1 N aq NaOH (50 mL). The organics were separated and the aqueous layer was washed with EtOAc (2x50 mL), and acidified to a pH of 3 using 3 M aqueous HCl. The aqueous layer was extracted with EtOAc (3x60 mL), dried (MgSO₄), filtered and concentrated to afford a yellow-white solid (290 mg, 44.8%). MS (LCMS) m/z 418.0. ¹H NMR (400 MHz, DMSO-cf₆) δ ppm 1.53 (s, 3 H) 2.08 - 2.20 (m, 1 H) 2.36 - 2.48 (m, 1 H) 3.13 (s, 3 H) 3.79 - 4.02 (m, 2 H) 7.03 (d, J=6.05 Hz, 1 H) 7.96 (d, J=4.29 Hz, 1 H) 13.82 (br. s„ 1 H).

Step D) Template 3 (T3): (2R)-4-(5-Fluoro-4-iodo-2-oxoDvridin-1 (2H)-vl)-2-methyl· 2-(methvlsulfonyl)-N-(tetrahvdro-2H-pyran-2-vloxy)butanamide

N-Methylmorpholine (120 uL, 1.1 mmol) was added to a solution of CDMT (178 mg,

1.01 mmol) and (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1 (2H)-yl)-2-methyl-2(methylsulfonyl)butanoic acid (280 mg, 0.762 mmol) in 2-methyltetrahydrofuran (7.60 mL) and the reaction was stirred at rt for 1 h. THP-hydroxylamine (117 mg, 1.00 mmol) was added to the reaction and the reaction was stirred overnight at rt. The reaction was quenched with water (50 mL) and the aqueous layer was extracted with EtOAc (3x50 mL). The combined organics were washed with brine (50 mL), dried (MgSO₄), filtered,

X

and concentrated to afford the title compound as an off-white solid (399.8 mg) MS (LCMS) 515.0 (M-1).

Example 1 (2R)-4-f5-Fluoro-2-oxo-4-r4-(2H-tetrazol-2-yl)phenvllDvridin-1(2H)-yl}-2-methyl-2(methvlsulfonvl)-N-(tetrahvdro-2H-pyran-2-vloxv)butanamide

NHOH

Step A) 2-r4-(4,4.5,5-Tetramethvl-1,3.2-dioxaborolan-2-vl)Dhenyl1-2H-tetrazole Pd(dppf)CI₂ (70.2 mg, 0.10 mmol) was added to a suspension of 4,4,4^,5,5,5^5octamethyl-2,2'-bi-1,3,2-dioxaborolane (291 mg, 1.15 mmol), 2-(4-bromophenyl)-2Htetrazole (215 mg, 0.96 mmol), and potassium acetate (191 mg, 1.91 mmol) in 1,4dioxane (4.78 mL). The resulting suspension was heated to 80 °C and stirred at this température overnight. The reaction was allowed to cool, filtered through celite, and concentrated in vacuo. The crude product was purified via flash chromatography using a 40g silica gel Redisep column and an eluent of EtOAc in n-heptane (0-50%) to afford the title compound as a light yellow solid (258 mg, 99%). MS (LCMS) m/z 273.2 (M+1). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (s, 12 H) 7.66 - 7.73 (m, 2 H) 7.96 8.02 (m, 2 H) 9.01 (s, 1 H).

Step B) (2R)-445-Fluoro-2-oxo-444-(2H-Îetrazol-2-vl)phenvllpyridin-1(2H)-vl}-2methvl“2-(methylsulfonyl)-N-itetrahydro-2H-pyran-2-vloxv)butanamide

Pd EnCat™ (317 mg, 0.10 mmol) was added to a mixture of potassium carbonate (393 mg, 2.84 mmol), 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-tetrazole (258.4 mg, 0.95 mmol), and (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1 (2H)-yl)-2-methyl-2(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (490 mg, 0.95 mmol), T3, in 1,4-dioxane:water (4:1,10 mL). The réaction was heated to 80 °C and stirred at this température overnight. The reaction was filtered through celite, and the filter pad was washed with methanol (250 mL). The combined filtrâtes were concentrated under reduced pressure, and the resulting crude material was purified via flash chromatography using an eluent of EtOAc in n-heptane (20-100%) and methanol in y

EtOAc (0-10%) to afford the title compound as a light tan solid (500 mg, 98%). MS (LCMS) m/z 534.4 (M-1).O

Step C) (2R)-4-f5-Fluoro-2-oxo-4-r4-(2H-tetrazol-2-vl)ohenyl1ovridin-1(2H)-vl}-Nhydroxy-2-methvl-2-(methvlsulfonvl)butanamide

Hydrochloric acid (4.0 M in 1,4-dioxane, 1.7 mL, 6.63 mmol) was added to a solution of (2Fi)-4-{5-flijoro-2-oxo-4-[4-(2H-Îetrazol-2-yl)phenyl]pyridin-1 (2H)-yl}-2-methyl-2(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (500 mg, 0.94 mmol) in dichloromethane'.methanol (5:1,6 mL) at room température. The reaction was stirred for 1 h then was concentrated under reduced pressure affording a residue, which was triturated in diethyl ether:pentane (1:1) overnight. The solid was collected via filtration and dried under reduced pressure to afford the title compound as a solid (340 mg, 76%). MS (LCMS) m/z 451.0 (M+1). ¹H NMR (400 MHz, DMSO-d_e) δ ppm 1.56 (s, 3 H) 2.09 - 2.21 (m, 1 H) 2.42 - 2.45 (m, 1 H) 3.09 (s, 3 H) 3.78 (m, J=11.80, 11.80, 5.20 Hz, 1 H) 3.97 - 4.10 (m, 1 H) 6.63 (d, J=7.61 Hz, 1 H) 7.84 (dd, J=8.68, 1.66 Hz, 2 H) 8.00-8.15 (m, 3 H) 10.16 (s, 1 H) 11.08 (br. s., 1 H).

Example 2

2R)-4-[5-Fluoro-4-(2-fluoro-3-methvlphenvl)-2-oxopvridin-1(2H)-vll-N-hydroxv-2-methvl2-(methvlsulfonvl)butanamide

NHOH

Step A) (2R)-4-f5-Fluoro-4-(2“fluoro-3-methylphenvn-2-oxopyridin-1(2H)-vn-2methvl-2-(methvlsulfonvl)-N-(tetrahvdro-2H-pvran-2-vloxy)butanamide

The title compound (470 mg, 48.7%) was obtained as a solid from (2-fluoro-3methylphenyl)boronic acid (388 mg, 2.52 mmol) using a procedure analogous to thaï described for (2R)-4-(5-Îluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1 (2H)-yl}-2methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, Example 1, Step B. MS (LCMS) m/z 499 (M + 1 ). ¹H NMR (400 MHz, METHANOL-t/₄) δ ppm 1.49 -1.57 (m, 3 H) 1.59 (d, J = 3.71 Hz, 3 H) 1.64 - 1.74 (m, 3 H) 2.16 - 2.26 (m, 1 H) 2.27 - 2.31 (m, 3 H) 3.10 (d, J = 5.66 Hz, 3 H) 3.31 (s, 1 H) 3.47 - 3.55 (m, 1 H) 3.72 - 3.88 (m, 1 H)

3.90 (s, 1 H) 3.99 - 4.15 (m, 2 H) 4.94 - 4.99 (m, 1 H) 6.47 (d, J = 7.22 Hz, 1 H) 7.20 7.26 (m, 1 H) 7.26 - 7.32 (m, 1 H) 7.40 - 7.47 (m, 1 H) 8.01 (dd, J = 11.90, 5.85 Hz, 1 H)

11.52 (d, J = 3.51 Hz, 1 H).

Step B) (2R)-4-r5-Fluoro-4-(2-fluoro-3-methvlDhenvD-2-oxODyridin-1(2H)-vll-Nhvdroxy-2-methvl-2-(methvlsulfonyl)butanamide

The title compound (185 mg, 46.6%) was obtained as a solid from (2R)-4-[5-fluoro-4-(2fluoro-3-methylphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro2H-pyran-2-yloxy)butanamide (477 mg, 0.957 mmol) using a procedure analogous to that described for (2R)-4-(5-fluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1 (2H)-yl}~ N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, Example 1, Step C. MS (LCMS) m/z 415 (M + 1) ¹H NMR (400 MHz, DMSO-d_e) δ ppm 1.54 (s, 3 H) 2.13 (ddd, J = 13.03, 11.07, 4.78 Hz, 1 H) 2.40 - 2.45 (m, 1 H) 3.08 (s, 3 H) 3.76 (td, J = 11.81,5.07 Hz, 1 H) 4.02 (td, J = 11.85, 5.17 Hz, 1 H) 6.53 (d, J = 7.61 Hz, 1 H) 7.45 - 7.64 (m, 4 H) 8.02 (d, J = 6.63 Hz, 1 H) 9.11 9.26 (m, 1 H) 11.00 - 11.13 (m, 1 H).

Example 3 (2R)-4-r4-(4-Chlorophenvl)-5-fluoro-2-oxopvridin-1(2H)-vll-N-hvdroxv-2-methyl-2(methvlsulfonvl)butanamide ci

Step A) (2R)-4-r4-(4-Chlorophenvl)-5-fluoro-2-oxopyridin-1 (2H)-vll-2-methvl-2(methvlsuifonvl)-N-(tetrahvdro-2H-pvran-2-vloxv)butanamide

The title compound (870 mg, 59.8%) was obtained as a solid from (4chlorophenyl)boronic acid (610 mg, 4.36 mmol) using a procedure analogous to that described for (2R)-445'fluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1 (2H)-yl}-2methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, Example 1, Step B. MS (LCMS) m/z 502 (M+1). ¹H NMR (400 MHz, DMSO-cfe) δ ppm 1.17 -1.28 (m, 2 H) 1.45 -1.53 (m, 3 H) 1.56 (d, J = 3.71 Hz, 3 H) 1.60 -1.72 (m, 3 H) 2.08 - 2.23 (m, 1 H)3.07 (d, J = 6.44 Hz, 3 H) 3.48 (d, J = 11.12 Hz, 1 H) 3.67 - 3.85 (m, 1 H) 3.96 - 4.12 (m, 2 H) 4.88 - 4.97 (m, 1 H) 6.53 (d, J = 7.61 Hz, 1 H) 7.50 - 7.62 (m, 3 H) 8.00 (dd, 7=13.07, 6.63 Hz, 1 H) 11.50 (s, 1 H).

x/

Step B) (2R)-4-[4-(4-Chloroohenvl)-5-fluoro-2-oxopyridin-1(2H)-vn-N-hydroxv-2methvl-2-(methylsulfonyl)butanamide

The title compound (340 mg, 47.0%) was obtained as a solid from (2R)-4-[4-(4chlorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro2H-pyran-2-yloxy)butanamide (870 mg, 1.74 mmol) using a procedure analogous to that described for (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1 (2H)-yl}-Nhydroxy-2-methyl-2-(methylsulfonyl)butanamide, Example 1, Step C. MS (LCMS) m/z 417 (M + 1). ¹H NMR (400 MHz, DMSO-d_e) δ ppm 1.54 (s, 3 H) 2.13 (ddd, J = 13.12, 11.27, 5.07 Hz, 1 H) 2.37 - 2.45 (m, 1 H) 3.08 (s, 3 H) 3.76 (td, J = 11.90, 5.07 Hz, 1 H) 3.93 - 4.12 (m, 1 H) 6.53 (d, J = 7.61 Hz, 1 H) 7.49 - 7.66 (m, 4 H) 8.02 (d, J = 6.63 Hz, 1 H) 9.21 (s, 1 H) 10.95-11.17 (m, 1 H).

Example 4 (2R)-4-r5-Fluoro-4-(2-fluorophenyl)-2-oxopyridin-1(2H)-vH-N-hvdroxv-2-methvl-2(methylsulfonvl)butanamide

Step A) (2R)-4-f5-Fluoro-4-(2-fluoroohenvl)-2-oxoovridin-1 (2H)-yll-2-methyl-2(methylsulfonvO-N-(tetrahvdro-2H-pvran-2-vloxy)butanamide

The title compound (230 mg, 81.7%) was obtained as a solid from (2fluorophenyl)boronic acid (122 mg, 0.871 mmol) using a procedure analogous to that described for (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1 (2H)-yl}-2methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, Example 1, Step B. MS (LCMS) m/z 485 (M+1). ¹H NMR (400 MHz, DMS0-d₆) δ ppm 1.21-1.28 (m, 2 H) 1.48 -1.56 (m, 3 H) 1.58 (d, J = 3.71 Hz, 3 H) 1.63 -1.74 (m, 3 H) 2.15 - 2.26 (m, 1 H) 3.10 (d, J = 5.66 Hz, 3 H) 3.34 (br. s., 1 H) 3.51 (d, J = 10.73 Hz, 1 H) 3.71 - 3.88 (m, 1 H) 3.99 - 4.15 (m, 2 H) 4.94 - 4.99 (m, 1 H) 6.50 (d, J = 7.02 Hz, 1 H) 7.31 - 7.40 (m, 2 H) 7.46 - 7.53 (m, 1 H) 7.56 (m, J=7.76, 7.76, 5.56, 1.76 Hz, 1 H) 8.01 (dd, J = 11.90, 5.85 Hz, 1 H) 11.51 (d, J = 3.32 Hz, 1 H).

Step B) (2R)-4-[5-Fluoro-4-(2-fluorophenvl)-2-oxopvridin-1(2H)-vll-N-hvdroxy-2methyl-2-(methylsulfonyl)butanamide

The title compound (68 mg, 36.0%) was obtained as a solid from (2R)-4-[5-fluoro-4-(2fluorophenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2Hpyran-2-yloxy)butanamide (230 mg, 0.475 mmol) using a procedure analogous to that described for (2R)-4-[5-Îluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1 (2H)-yl}-Nhydroxy-2-methyl-2-(methylsulfonyl)butanamide,-Example 1, Step C. MS (LCMS) m/z 401 (M+1). ¹H NMR (400 MHz, DMSO-d₆) Ô ppm 1.58 (s, 3 H) 2.18 (td, J = 12.15, 4.98 Hz, 1 H) 2.47 (m, 1 H) 3.12 (s, 3 H) 3.79 (td, J = 11.85, 5.17 Hz, 1 H) 4.07 (td, J = 11.81, 4.68 Hz, 1 H) 6.50 (d, J = 7.02 Hz, 1 H) 7.30 - 7.44 (m, 2 H) 7.46 - 7.64 (m, 2 H) 8.04 (d, J = 6.05 Hz, 1 H) 9.20 - 9.32 (m, 1 H) 10.99 -11.17 (m, 1 H).

Example 5 (2R)-4-r4-(2.3-Dihvdro-1-benzofuran-5-yl)-5-fluoro-2-oxopyridin-1(2H)-vll-N-hvdroxv-2methvl-2-(methvlsulfonvl)butanamide

ΝΗΟΗ

Step A) (2R)-4-f4-(2,3-Dihvdro-1-benzofuran-5-vl)-5-fluoro-2-oxopyridin-1 (2H)-vl12-methvl-2-(methylsulfonyl)-N-(tetrahvdro-2H-pyran-2-vloxy)butanamide

The title compound (198 mg, 61.0%) was obtained as a solid from 2,3-dihydro-l benzofuran-5-ylboronic acid (153 mg, 0.871 mmol) using a procedure analogous to that described for (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1 (2H)-yl}-2methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,-Example 1, Step B. MS (LCMS) m/z 509 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.46 -1.56 (m, 2 H) 1.58 (d, J = 4.10 Hz, 3 H) 1.63-1.76 (m, 3 H) 2.12-2.27 (m, 1 H) 2.40-2.48 (m, 1 H) 3.10 (d, J = 6.05 Hz, 3 H) 3.23 (t, J=8.78 Hz, 2 H) 3.35 (br. s, 1 H) 3.51 (d, J = 12.10 Hz, 1 H) 3.67 - 3.88 (m, 1 H) 3.98 - 4.15 (m, 2 H) 4.59 (t, J = 8.78 Hz, 2 H) 4.96 (d, J = 2.73 Hz, 1 H) 6.46 (d, J = 7.81 Hz, 1 H) 6.81 - 6.92 (m, 1 H) 7.28 - 7.39 (m, 1 H) 7.47 (s, 1 H) 7.96 (dd, J=12.78, 6.73 Hz, 1 H) 11.55 (s, 1 H).

Step B) (2R)-4-r4-(2.3-Dihvdro-1-benzofuran-5-vl)-5-fluoro-2-oxopvridin-1 (2H)-vl1N-hvdroxv-2-methvl-2-(methvlsulfonvl)butanamide

The title compound (165 mg, 53.0%) was obtained as a solid from (2R)-4-[4-(2,3dihydro-1-benzofuran-5-yl)-5-fluoro-2-oxopyridin-1 (2H)-yl]-2-methyl-2-(methylsulfonyl)16551

N-(tetrahydro-2H-pyran-2-yloxy)butanamide (198 mg, 0.389 mmol) using a procedure analogous to that described for (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-tetrazol-2yl)phenyl]pyridin-1 (2H)-ylJ-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,-Example 1, Step C. MS (LCMS) m/z 425 (M+1). ¹H NMR (400 MHz, DMSO-cfe) δ ppm 1.57 (s, 3 H) 2.16 (dd, J = 5.56, 1.07 Hz, 1 H) 2.36 - 2.49 (m, 1 H) 3.11 (s, 3 H) 3.23 (t, J = 8.59 Hz, 2 H) 3.66 - 3.86 (m, 1 H) 4.04 (dd, J = 6.15, 0.88 Hz, 1 H) 4.59 (t, J = 8.78 Hz, 2 H)

6.45 (d, J = 7.81 Hz, 1 H) 6.87 (d, J = 8.39 Hz, 1 H) 7.34 (dd, J = 8.20, 1.95 Hz, 1 H)

7.46 (s, 1 H) 7.98 (d, J = 6.83 Hz, 1 H) 9.15 - 9.31 (m, 1 H) 11.01 -11.19 (m, 1 H).

Example 6 (2R)-4-r4-(3,4-DifluoroDhenvl)-5-fluoro-2-oxoDyridin-1 (2H)-vll-N-hydroxy-2-methyl-2(methylsulfonvl)butanamide

NHOH

Step A) (2R)-4-r4-(3.4-DifluoroDhenvlÎ-5-fluoro-2-oxoDvridin-1(2H)-vll-2methyl-2(methvlsulfonyl)-N-(tetrahydro-2H-Dyran-2-vloxv)butanamide

The title compound (760 mg, 52.1%) was obtained as a solid from (3,4difluorophenyl)boronic acid (596 mg, 3.78 mmol) using a procedure analogous to that described for (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1 (2H)-yl}-2methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, Example 1, Step B. MS (LCMS) m/z 503 (M+1).

Step B) (2R)-4-r4~(3,4-Difluorophenyl)-5-fluoro-2-oxoDvridin-1(2H)-yri-N-hvdroxy-2methvl-2-(methvlsulfonyl)butanamide

The title compound (350 mg, 55.0%) was obtained as a solid from (2R)-4-[4-(3,4difluorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N(tetrahydro-2H-pyran-2-yloxy)butanamide (760 mg, 1.51 mmol) using a procedure analogous to that described for (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-tetrazol-2yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, Example 1, Step C. MS (LCMS) m/z 419 (M+1). ¹H NMR (400 MHz, DMSO-cfe) δ ppm 1.57 (s, 3 H) 2.06 - 2.25 (m, 1 H) 2.38 - 2.48 (m, 1 H) 3.11 (s, 3 H) 3.68 - 3.87 (m, 1 H) 3.96 16551

4.18 (m, 1 H) 6.60 (d, J = 7.61 Hz, 1 H) 7.37 - 7.52 (m, 1 H) 7.52 - 7.65 (m, 1 H) 7.65

7.84 (m, 1 H) 8.06 (d, J = 6.63 Hz, 1 H) 9.13 - 9.39 (m, 1 H) 11.08 (s, 1 H).

Example 7 (2R)-4-{5-Fluoro-2-oxo-4-r4-(2,2,2-trifluoroethoxv)Dhenvr|pvridin-1 (2H)-vll-N-hvdroxv-2methvl-2“(methylsulfonvl)butanamide

NHOH

Step A) (2R)-4-f5-Fluoro-2-oxo-4-f4-(2,2,2-trifluoroethoxv)phenvllpyridin-1(2H)-vl}2-meÎhvl-2-(methylsulfonvl)-N-(tetrahvdro-2H-pyran-2-vloxy)butanamide

The title compound (860 mg, 78.6%) was obtained as a solid from [4-(2,2,2trifluoroethoxy)phenyl]boronic acid (554 mg, 2.52 mmol) using a procedure analogous to that described for (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1 (2H)yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, Example 1, Step B. MS (LCMS) m/z 565 (M+1).

Step B) (2R)-445-FÎuoro-2-oxo-4-[4-(2.2.2-trifluoroethoxv)phenvl]pvridin-1(2H)-vl)N-hvdroxv-2-meÎhyl-2-(methvlsulfonvl)butanamide

The title compound (310 mg, 42.3%) was obtained as a solid from (2R)-4-(5-fluoro-2oxo-4-[4-(2,2,2-trifluoroethoxy)phenyl]pyridin-1 (2H)-yl}-2-methyl-2-(methylsulfonyl)-N(tetrahydro-2H-pyran-2-yloxy)butanamide (860 mg, 1.52 mmol) using a procedure analogous to that described for (2R)-4-(5-fluoro-2-oxo-4-[4-(2H-tetrazol-2yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide_I Example 1, Step C. MS (LCMS) m/z 419 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.54 (s, 3 H) 2.06 - 2.22 (m, 1 H) 2.37 - 2.45 (m, 1 H) 3.08 (s, 3 H) 3.74 (td, J = 11.76, 4.98 Hz, 1 H) 3.93 - 4.10 (m, 1 H) 4.81 (q, J = 8.98 Hz, 2 H) 6.49 (d, J = 7.61 Hz, 1 H) 7.16 (d, J = 8.98 Hz, 2 H) 7.49 - 7.62 (m, 2 H) 7.98 (d, J = 6.63 Hz, 1 H) 9.21 (br. s., 1 H) 11.07 (s,

Example 8 (2RÎ-4-f4-(3.4-Dihydro-2H-chromen-6-yl)-5-Îluoro-2-oxopyridin-1 (2H)-vl1-N-hvdroxv-2methyl-2-(methvlsulfonvl)butanamide

NHOH

Step A) (2R)-4-r4-(3.4-Dihvdro-2H-chromen-6-yl)-5-fluoro-2-oxoDvridin-1 (2H)-yl1-2methvl-2-(methylsulfonvl)-N-(tetrahydro-2H-Dvran-2-yloxv)butanamide

The title compound (500 mg, 82.3%) was obtained as a solid from 3,4-dihydro-2Hchromen-6-ylboronic acid (228 mg, 1.28 mmol) using a procedure analogous to that described for (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridÎn-1 (2H)-yl}-2methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, Example 1, Step B. MS (LCMS) m/z 523 (M+1).

Step B) (2R)-444-(3,4-Dihvdro-2H-chromen-6-yl)-5-fluoro-2-oxopyridin-1(2H)-yllN-hvdroxy-2-methyl-2-(methvlsulfonvl)butanamide

The title compound (240 mg, 57.1%) was obtained as a solid from (2R)-4-(4-(3,4dihydro-2H-chromen-6-yl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N(tetrahydro-2H-pyran-2-yloxy)butanamide (500 mg, 0.957 mmol) using a procedure analogous to that described for (2R)-4-(5-fluoro-2-oxo-4-[4-(2H-tetrazol-2yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(meÎhylsulfonyl)butanamide, Example 1, Step C. MS (LCMS) m/z 439 (M+1). ¹H NMR (400 MHz, DMSO-d_e) δ ppm 1.52 (s, 3 H) 1.83-1.97 (m, 2 H) 2.12 (ddd, J = 13.03, 11.27, 5.17 Hz, 1 H) 2.34-2.44 (m, 1 H) 2.75 (t, J = 6.34 Hz, 2 H) 3.07 (s, 3 H) 3.71 (td, 7= 11.76, 5.17 Hz, 1 H) 3.92-4.07 (m, 1 H) 4.08 - 4.20 (m, 2 H) 6.42 (d, J = 7.61 Hz, 1 H) 6.79 (d, J = 8.39 Hz, 1 H) 7.20 - 7.32 (m, 2 H) 7.94 (d, J = 6.83 Hz, 1 H) 9.20 (br. s., 1 H) 11.07 (s, 1 H).

Example 9 (2R)-4-{5-Fluoro-4-f4-(methvlthio)phenyl1-2-oxoDvridin-1 (2Η)-νΙΑΝ-Ι^Γθχν-2-ΓΤΐθΐΐΊνΙ-2(methylsulfonvDbutanamide

ΝΗΟΗ

Step A) Ethyl (2R)-4-(5-fluoro-4-[4-(methylthio)ohenyl1-2~oxoovridin-1 (2Η)-νΙΕ2methyl-2-(methvlsulfonvl)butanoate

1,4-Dioxane (10 ml) and 3 M aq K3PO4 (1.12 mL, 3.3 mmol) was added to a flask containing [4-(methyîthio)phenyl]boronic acid (0.283 g, 1.68 mmol), Pd(dppf)Cl2 (82 mg, 0.112 mmol) and ethyl (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2(methylsulfonyl)butanoate, T2, (500 mg, 1.12 mmol) that was previously flushed with nitrogen. The mixture was heated to 60 °C and stirred at this température for 1 h. The reaction mixture was diluted with EtOAc and washed with water. The organics were dried (MgSO₄), filtered, and concentrated. The crude product was purified via flash chromatography on a 40 g silica column and an eluent of EtOAc in n-heptane (0-100%) to afford the title compound as a gum (492 mg, 99%). MS (LCMS) m/z 442.1 (M+1). ¹H NMR (400 MHz, CHLOROFORM-7) δ ppm 1.17 -1.27 (m, 3 H) 1.74 (s, 3 H) 2.38 - 2.61 (m, 5 H) 3.09 (s, 3 H) 3.88 - 4.02 (m, 1 H) 4.17 - 4.32 (m, 3 H) 6.57 (d, 7=7.61 Hz, 1 H) 7.21 - 7.34 (m, 3 H) 7.37 - 7.48 (m, 2 H).

Step B) /2Η)-445-ΡΙυθΓθ-444-(πΊθίΐΊνΙϋΊΐο)ρΙ'ΐθπνΙΐ-2-οχορνπΡίη-1(2Η)-νΙΕ2-ΓηθίΐΊνΙ2-(methvlsulfonvl)butanoic acid

Lithium hydroxide monohydrate (165 mg, 6.68 mmol) was added to a solution of ethyl (2R)-4-{5-fluoro-4-[4-(methylthio)phenyl]-2-oxopyridin-1 (2H)-yl}-2-methyl-2(methylsulfonyl)butanoate (0.492 g, 1.12mmol) in THF:water (1:1,14 mL) and the réaction was allowed to stir at rt for 18 h. The reaction mixture was acidified using 4 M aq HCl to afford a precipitate. The solid was collected via filtration and dried under vacuum to afford the title compound as a solid (339 mg, 73%). MS (LCMS) m/z 414.1 (M+1). ¹H NMR (400 MHz, DMSO-d_e)Cô ppm 1.54 (s, 3 H) 2.17 (ddd, 7=13.42, 10.00, 5.07 Hz, 1 H) 2.41 - 2.45 (m, 1 H) 2.49 (s, 3 H), 3.14 (s, 3 H) 3.78 - 4.15 (m, 2 H) 6.46 (d, 7=7.81 Hz, 1 H) 7.28 - 7.39 (m, 2 H) 7.43 - 7.55 (m, 2 H) 8.01 (d, 7=6.83 Hz, 1 H).

Step C) (2RÎ-4-f5-Fluoro-4-[4-(meÎhylthio)phenvn-2-oxopyridin-1(2H)-vl}-2-methyl2-(methvlsulfonvl)-N-(tetrahydro-2H-pvran-2-vloxy)butanamide

/V,A/-Diisopropylethylamine (450 uL, 2.45 mmol), 0-(tetrahydro-2H-pyran-2yl)hydroxylamine (192 mg, 1.64 mmol) and HATU (447 mg, 1.23 mmol) were added to a solution of (2R)-4-{5-fluoro-4-[4-(methylthio)phenyl]-2-oxopyridin-1 (2H)-yl}-2-methyl-2(methylsulfonyl)butanoic acid (339 mg, 0.82 mmol) in DMF (10 mL). The reaction was allowed to stir at rt for 18 h. The reaction mixture was diluted with EtOAc and washed with brine. The organics were dried (MgSO^, filtered and concentrated. The crude residue was purified via flash chromatography using a 40 g silica column and an eluent of EtOAc in n-heptane (0-100%) to afford the title compound (420 mg, 100%). MS (LCMS) m/z 511.4 (M-1).

Step D) (2R)-445-Fluoro-4-ί4-(meΐhvlthio)DhenyΠ-2-oxoDvridiπ-1(2H)-vll·Nhvdroxv-2-methyl-2-(methylsulfonvl)butanamide

Aqueous HCl (4 M, 3 mL) was added to a solution of 2R)-4-(5-fluoro-4-[4(methylthio)phenyl]-2-oxopyridin-1 (2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro2H-pyran-2-yloxy)butanamide (437 mg, 0.852 mmol) in THF (10 mL) and the reaction was allowed to stir at rt for 3 h. The reaction mixture was concentrated and then azeotroped with EtOAc and n-heptane several times to give the title compound as an off-white solid (233 mg, 64%). MS (LCMS) m/z 429.1 (M+1). ¹H NMR (400 MHz, METHANOL-cQ δ ppm 1.69 (s, 3 H) 2.37 (ddd, J=13.51, 10.59, 5.17 Hz, 1 H) 2.51 (s, 3 H) 2.57 - 2.74 (m, 1 H) 2.82 (s, 3 H) 3.09 (s, 3 H) 3.97 (ddd, J=13.12, 10.59, 5.56 Hz, 1 H) 4.27 (ddd, J=13.03, 10.49, 5.17 Hz, 1 H) 6.68 (d, J=7.22 Hz, 1 H) 7.25 - 7.40 (m, 2 H) 7.47 - 7.59 (m, 2 H) 7.90 (d, J=6.05 Hz, 1 H).

Example 10 (2R)-4-[4-(4-EthoxyDhenvl)-5-fluoro-2-oxoDvridin-1(2H)-vl1-N-hydroxy-2-methvl-2(methvlsulfonyl)butanamide

Step A) Ethvl (2R)-4-(4-(4-ethoxvphenvl)-5-fluoro-2-oxopyridin-1 (2H)-yll-2-methvl2-(methylsulfonyl)butanoate

The title compound (320 mg, 64%) was obtained as a gum from (4ethoxyphenyl)boronic acid (280 mg, 1.68 mmol) using a procedure analogous to that

described for ethyl (2R)-4-{5-fluoro-4-[4-(methylthio)phenyl]-2-oxopyridin-1 (2H)-yl}-2meÎhyl-2-(methylsulfonyl)butanoate, Example 9, Step A. MS (LCMS) m/z 440.3 (M+1). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.22 (t, J=7.12 Hz, 3 H) 1.40 (t, J=7.02 Hz, 3 H) 1.73 (s, 3 H) 2.36 - 2.61 (m, 2 H) 3.09 (s, 3 H) 3.85 - 3.98 (m, 1 H) 4.07 (dd, J=14.93, 7.12 Hz, 2 H) 4.25 (m, 3 H) 6.51 - 6.58 (m, 1 H) 6.93 (d, J=8.98 Hz, 3 H) 7.22 -

7.31 (m, 1 H) 7.44 (d, J=7.02 Hz, 1 H).

Step B) (2R)-4-r4-(4-EthoxvDhenvl)-5-fluoro-2-oxopvridin-1(2H)-vl1-2-methvl-2(methvlsulfonvl)butanoic acid

Lithium hydroxide (108 mg, 4.37 mmol) was added to a solution of ethyl (2R)-4-[4-(4ethoxyphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoate (320 mg, 0.728 mmol) in tetrahydrofuran:water (1:1, 20 mL) and the reaction was allowed to stir at rt until complété. The reaction mixture was acidified with 4 M aq HCl and extracted with EtOAc. The combined organic layers were dried (MgSO₄), filtered and concentrated to afford the title compound as a solid (220 mg, 73%). MS (LCMS) m/z 412.2 (M+1). ¹H NMR (400 MHz, DMSO-d_e) δ ppm 1.26-1.40 (m, 3 H) 1.54 (s, 3 H) 2.07 - 2.26 (m, 1 H) 2.43 (d, J=6.24 Hz, 1 H) 3.14 (s, 3 H) 3.83 - 4.15 (m, 4 H) 6.42 (d, J=7.81 Hz, 1 H) 6.93 - 7.07 (m, 2 H) 7.50 (dd, J=8.68, 1.85 Hz, 2 H) 7.97 (d, J=6.83 Hz, 1 H).

Step C) (2R)-4-r4-(4-Ethoxyphenyl)-5-fluoro-2-oxoDyridin-1 (2H)-vl1-2-meÎhvl-2(methvlsulfonvl)-N-(tetrahydro-2H-pyran-2-vloxv)butanamide

The title compound (273 mg, 100%) was obtained from (2R)-4-[4-(4-ethoxyphenyl)-5fluoro-2-oxopyridin-1 (2H)-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (220 mg, 0.535 mmol) using a procedure analogous to that described for (2R)-4-{5-fluoro-4-[4(methylthio)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro2H-pyran-2-yloxy)butanamide, Example 9, Step C. MS (LCMS) m/z 509.4 (M+1).

Step D) (2R)-4-f4-(4-Ethoxvphenyl)-5-fluoro-2-oxopvridin-1(2H)-vll-N-hvdroxv-2methyl-2-(methylsulfonyl)butanamide

The title compound (205 mg, 83%) was obtained as a solid from (2R)-4-[4-(4ethoxyphenyl)-5-fluoro-2-oxopyridin-1 (2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro2H-pyran-2-yloxy)butanamide (297 mg, 0.582 mmol) using a procedure analogous to that described for (2R)-4-(5-fluoro-4-[4-(methylthio)phenyl]-2-oxopyridin-1 (2H)-y IJ-Nhydroxy-2-methyl-2-(methylsulfonyl)butanamide, Example 9, Step D. MS (LCMS) m/z

427.2 (M+1). ¹H NMR (400 MHz, METHANOL-cf₄) δ ppm 1.40 (t, J=6.93 Hz, 3 H) 1.69 (s, 3 H) 2.28 - 2.42 (m, 1 H) 2.54 - 2.69 (m, 1 H) 3.09 (s, 3 H) 3.86 - 3.99 (m, 1 H) 4.09 (q, J=7.02 Hz, 2 H) 4.18 - 4.32 (m, 1 H) 6.60 (d, J=7.42 Hz, 1 H) 7.01 (d, J=8.96 Hz, 2

H) 7.54 (dd, J=8.78, 1.56 Hz, 2 H) 7.82 (d, J=6.24 Hz, 1 H).

Example 11 (2R)-4-[5-Fluoro-2-oxo-4-(4-propvlphenyl)pyridin-1 (2Η)-νΠ-Ν4ινάΓθχν-2-ιτΐ6ΐΐΊνΙ-2(methylsulfonvl)butanamide

Step A) (2R)-4-r5-Fluoro-2-oxo-4-(4-propylphenvl)pvridin-1(2H)-vll-2-methyl-2(methylsulfonvl)-N-(tetrahvdro-2H-ovran-2-vloxy)butanamide

The title compound (75.5 mg, 21%) was obtained as a solid from (2R)-4-(5-fluoro-4iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2yloxy)butanamide, T3, (360 mg, 0.697 mmol) and (4-propylphenyl)boronic acid (171 mg, 1.04 mmol) using a procedure analogous to that described for ethyl (2R)-4-{5fluoro-4-[4-(methylthio)phenyl]-2-oxopyridin-1 (2H)-yl}-2-methyl-2(methylsulfonyl)butanoate, Example 9, Step A. MS (LCMS) m/z 507.4(M-1),

Step B) (2R)-4-[5-Fluoro-2-oxo-4-(4-propvlphenyl)pyridin-'l(2H)-vll-N-hydroxy-2methyl-2-(methvlsulfonyl)butanamide

The title compound (58 mg, 94%) was obtained as a solid from (2R)-4-[5-fluoro-2-oxo-4(4-propylphenyl)pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2yloxy)butanamide (75 mg, 0.15 mmol) using a procedure analogous to that described for (2R)-4-(5-fluoro-4-[4-(methylthio)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl2-(methylsulfonyl)butanamide, Example 9, Step D. MS (LCMS) m/z 425.2 (M+1). ¹H NMR (400 MHz, METHANOL-af₄) δ ppm 0.89 - 1.00 (m, 3 H) 1.57 - 1.76 (m, 5 H) 2.29 2.45 (m, 1 H) 2.55 - 2.69 (m, 3 H) 3.09 (s, 3 H) 3.86 - 4.04 (m, 1 H) 4.17 - 4.34 (m, 1 H)

6.63 (d, J=7.02 Hz, 1 H) 7.31 (d, J=8.00 Hz, 2 H) 7.44 - 7.55 (m, 2 H) 7.85 (d, J=5.85 Hz, 1 H).

K/

Example 12 (2R)-4-{5-Fluoro-2-oxo-4-[4-(pentafluoro-6À-sulfanyl)phenvllpyridin-1 (2H)-yn-N-hvdroxy2-methyl-2-(methvlsulfonvl)butanamide

NHOH

Step A) (2R)-4-(5-Fluoro-2-oxo-4-i4-(penÎafluoro-6X-sulfanvl)Dhenvllpvridin-1(2H)vl]-2-meÎhvl-2-(methvlsulfonvl)-N-(tetrahvdro-2H-pvran-2yloxy)butanamide

1,4-Dioxane was added to 1 -bromo-4-(pentafluoro-6X-sulfanyl)benzene (500 mg, 1.77 mmol), 4,4,4^,)4',5,5,5’,5’-octamethyl-2,2^l-bi-1,3l2-dioxaborolane (628 mg, 2.47 mmol), potassium acetate (347 mg, 3.53 mmol) and Pd(dppf)CI₂ (130 mg, 0.177 mmol). The mixture was heated to 80 °C and stirred at this température for 3 h. (2R)-4-(5-fluoro-4iodo^-oxopyridin-lfëHJ-yO-Z-methyl^-imethylsulfonyO-N-itetrahydro-^H-pyran^yloxy)butanamide, T3, (456 mg, 0.883 mmol) and aq Na₂CC>3 (2.0 N, 1.77 mL, 3.53 mmol) were added and the reaction was stirred at 80 °C ovemight. The mixture was diluted with EtOAc and washed with brine. The organics were dried (MgSO₄), filtered, and concentrated. The crude residue was purified via flash chromatography using a 40 g silica column and an eluent of EtOAc in n-heptane (0-100%) to afford the title compound (205 mg, 39.2%). MS(LCMS) m/z 591.4 (M-1).

Step B) (2R)-4-Î5-Fluoro-2-oxo-4-r4-(pentafluoro-6Â-sulfanvl)phenvllpyridin-1(2H)yl}-N-hvdroxv-2-methvl-2-(methvlsulfonvl)butanamide

Aqueous HCl (1.0 M) was added to a solution of (2R)-4-{5-fluoro-2-oxo-4-[4(pentafluoro-6X-sulfanyl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N(tetrahydro-2H-pyran-2-yloxy)butanamide (81 mg, 0.14 mmol) and the réaction was stirred at rt ovemight. The réaction was concentrated in vacuo to afford the title compound as a solid (70 mg, 100%). MS(LCMS) m/z 509.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1,58 (s, 3 H) 2.06 - 2.26 (m, 1 H) 3.11 (s, 3 H) 3.70 - 3.89 (m, 1 H) 3.97 - 4.14 (m, 1 H) 6.64 (d, J=7.41 Hz, 1 H) 7.81 (d, 2 H) 8.04 (d, J=8.78 Hz, 2 H) 8.11 (d, J=6.44 Hz, 1 H).

Example 13 (2R)-445-Fluoro-4-(3-methvlphenvl)-2-oxopyridin-1 (2H)-vH-N-hydroxv-2-methvl-2(methylsulfonyl)butanamide

NHOH

Step A) (2R)-4-[5-Fluoro-4-(3-methvlphenvl)-2-oxopyridin-1(2H)-yl1-2-methyl-2(methylsulfonvl)-N-(tetrahvdro-2H-pyran-2-vloxy)butanamide

The title compound (510 mg, 55%) was obtained as a gum from (3methylphenyl)boronic acid (384 mg, 2.82 mmol) using a procedure analogous to that described for (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1 (2H)-yl}-2methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, Example 1, Step B. MS (LCMS) m/z 479.4 (M-1 ).

Step B) (2R)-4-[5-Fluoro-4-(3-methvlphenvD-2-oxoDvridin-1 (2l~0-vH-N-hvdroxv-2methvl-2-(methylsulfonyl)butanamide

The title compound (255 mg, 61%) was obtained as a solid from (2R)-4-[5-fluoro-4-(3methylphenyl)-2-oxopyridin-1 (2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2Hpyran-2-yloxy)butanamide (510 mg, 1.06 mmol) using a procedure analogous to that described for (2R)-4-{5-fluoro-4-[4-(methylthio)phenyl]-2-oxopyridin-1 (2H)-yl}-Nhydroxy-2-methyl-2-(methylsulfonyl)butanamide, Example 9, Step D. MS (LCMS) m/z 397.1 (M+1). ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.70 (s, 3 H) 2.28 - 2.44 (m, 4 H) 2.62 (dd, J=10.44, 5.37 Hz, 1 H) 3.09 (s, 3 H) 3.96 (ddd, J=12.98, 10.63, 5.46 Hz, 1 H) 4.19 - 4.35 (m, 1 H) 6.64 (d, J=7.22 Hz, 1 H) 7.27 - 7.45 (m, 4 H) 7.88 (d, J=5.85 Hz, 1 H).

Example 14 (2R)-4-r5-Fluoro-4-(4-fluoro-3-methvlDhenyl)-2-oxopvridin-1(2HÎ-vll-N-hvdroxv-2-methvl2-(methvlsulfonvl)butanamide

ΝΗΟΗ

Step A) /'2R)-4-r5-Fluoro-4-(4-fluoro-3-methylphenyl)-2-oxopvridin-1(2H)-vl1-2methvl^-imethvIsulfonvD-N-ftetrahvdro^H-Dvran^-vloxylbutanamide

The title compound (360 mg, 38%) was obtained as a gum from (4-fluoro-3methylphenyl)boronic acid (434 mg, 2.82 mmol) using a procedure analogous to that described for (2R)-4-(5-fluoro-2-oxo-4-[4-(2H-Îetrazol-2-yl)phenyl]pyridin-1 (2H)-yl}~2methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, Example 1, Step B. MS (LCMS) m/z 497.0 (M-1).

Step B) (2R)-4-F5-Fluoro-4-(4-fluoro-3-methy|phenvl)-2-oxopyridin-1 (2H)-yl|-Nhydroxv-2-methyl-2-(methvlsulfonvl)butanamide

The title compound (271 mg, 91%) was obtained as a white solid from (2R)-4-(5-fluoro-

4-(4-fluoro-3-methylphenyl)-2-oxopyridin-1 (2H)-yl]-2-methyl-2-(methylsulfonyl)-N(tetrahydro-2H-pyran-2-yloxy)butanamide (360 mg, 0.722 mmol) using a procedure analogous to that described for (2R)-4~(5-fluoro-4-[4-(methylthio)phenyl]-2-oxopyridin1 (2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, Example 9, Step D. MS (LCMS) m/z 415.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.54 (s, 3 H) 2.13 (ddd, J=13.12, 11.17, 4.98 Hz, 1 H) 2.26 (s, 3 H) 2.40-2.45 (m, 1 H) 3.08 (s, 3 H) 3.75 (td, J=11.85, 5.17 Hz, 1 H) 4.02 (td, J=11.85, 4.98 Hz, 1 H) 6.49 (d, J=7.61 Hz, 1 H) 7.20 7.28 (m, 1 H) 7.38 - 7.45 (m, 1 H) 7.50 (d, J=7.41 Hz, 1 H) 8.01 (d, J=6.63 Hz, 1 H).

Example 15

5-Fluoro-1-r(3R)-3-(hydroxvamino)-3-(methylsulfonvl)butyn-4-f4-(oxetan-3vloxv)phenvnpvridin-2(1 H)-one

Step A) 3-(4-Bromophenoxy)oxetane

4-Bromophenol (2.5g, 14.5 mmol) and K2CO3 (5.45g, 39.4 mmol) were added to a solution ot oxetan-3-yl 4-methylbenzenesulfonate (3.00g, 13.1 mmol) in DMF (10 mL) in a sealed tube. The reaction was heated to 100 °C and stirred at this température for 24 h. The reaction was diluted with EtOAc and washed with water. The organic layer was dried (MgSO₄), filtered and concentrated to afford the title compound. MS (GCMS) m/z 228. This material was used in subséquent steps without further purification.

Step B) 4_l4,5.5-TetrameÎhvl-2-r4-(oxetan-3-vloxv)Dhenyl]-1,3.2-dioxaborolane The title compound (3.11 g, 86%) was obtained from 3-(4-bromophenoxy)oxetane (3.00 g, 13.1 mmol) using a procedure analogous to that described for 2-[4-(4,4,5,5tetramethyM ,3,2-dioxaborolan-2-yl)phenyl]-2H-tetrazole, Example 1, Step A. MS (GCMS) m/z 276. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.31 (s, 12 H) 4.70 4.79 (m, 2 H) 4.91 - 5.00 (m, 2 H) 5.18 - 5.27 (m, 1 H) 6.67 (d, J=8.78 Hz, 2 H) 7.73 (d, J=8.78 Hz, 2 H).

Step C) 5-Fluoro-1-i(3R)-3-(methylsulfonvl)-3-[(tetrahydro-2H-Dyran-2vloxy)amÎno1butyl)-444-(oxetan-3-vloxv)DhenvllDyridin-2(1H)-one

1,4-Dioxane (20 mL) and water (5 mL) were added to a flask containing (2R)-4-(5fluoro-4-iodo-2-oxopyridin-1 (2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2Hpyran-2-yloxy)butanamide, T3 (287 mg, 0.56 mmol), 4,4,5,5-tetramethyl-2-[4-(oxetan-3yloxy)phenyl]-1,3,2-dioxaborolane (301 mg, 1.09 mmol), Pd(PPh3)₄ (65 mg, 0.06 mmol), and potassium carbonate (230 mg, 1.67 mmol), which was previously flushed with N2.

The mixture was heated to 80 °C and stirred ai that température overnight. The reaction was concentrated and purified via flash chromatography using two 12 g silica gel columns. The first column was eluted with methanol in dichloromethane (0-20%). The second column was eluted with EtOAc in n-heptane (0-100%) followed by methanol in dichloromethane (0-20%) to afford the title compound as a solid (164 mg, 54%). MS (LCMS) m/z 537.4 (M-1).

Step D) 5-Fluoro-1-r(3R)-3-(hydroxvamino)-3-(methvlsulfonyl)butyll-4-[4-(oxetan-3vloxy)phenyl]pyridin-2(1 H)-one

Trifluoroacetic acid (1 mL) was added to a solution of 5-fluoro-1-{(3R)-3(methylsulfonyl)-3-[(tetrahydro-2H-pyran-2-yloxy)amino]butyl}-4-[4-(oxetan-3yioxy)phenyl]pyridin-2(1 H)-one (164 mg, 0.304 mmol) in DCM (10 mL). The reaction was allowed to stir at rt overnight and then concentrated under vacuum. The residue was re-dissolved in dichloromethane and n-heptane and concentrated again to afford the title compound as a solid. (113 mg, 82%). MS (LCMS) m/z 455.1 (M+1). ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.69 (s, 3 H) 2.35 (ddd, /=13.66, 10.63, 5.17 Hz, 1 H) 2.53 - 2.67 (m, 1 H) 3.09 (s, 3 H) 3.91 (ddd, /=12.98, 10.63, 5.27 Hz, 1 H) 4.16 4.30 (m, 1 H) 4.69 (dd, /=7.51, 4.78 Hz, 2 H) 5.02 (t, /=6.73 Hz, 2 H) 5.33 (t, /=5.46 Hz, 1 H) 6.58 (d, /=7.42 Hz, 1 H) 6.85 - 6.91 (m, 2 H) 7.55 (dd, /=8.68, 1.85 Hz, 2 H) 7.80 (d, /=6.24 Hz, 1 H).

Example 16 (2R)-4-r4-(4-Chloro-2-fluorophenvl)-5-fluoro-2-oxopvridin-1i2H)-vn-N-hydroxv-2-methvl·

2-(methylsulfonvl)butanamide

ΝΗΟΗ

Step A) (2R)-4-r4-(4-Chloro-2-fluoroDhenvl)-5-fluoro-2-oxoDvridin-1(2H)-vll-2methvl-2-(methylsulfonyl)butanoic acid

To a 3 L flask with mechanical stirring was added ethyl (2R)-4-(5-fluoro-4-iodo-2oxopyridin-1 (2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate, T2 (100 g, 225 mmol), (4chloro-2-fluorophenyl)boronic acid (25.5 g, 146 mmol) and Pd(dppf)₂CI₂ (4.93 g, 6.74 mmol). The flask was purged with N₂, then degassed 2-methyltetrahydrofuran (1 L) and 3 M aq K3PO4 (225 mL, 674 mmol) were added. The reaction mixture was heated to 75 °C and stirred at this température for 30 min. Additional (4-chloro-2fluorophenyl)boronic acid (25.5 g, 146 mmol) was added and the reaction was allowed to heat for 1.5 h. The mixture was allowed to cool to rt and the aqueous layer was separated. The organic layer was passed through a celite pad and placed back in the reaction vessel. Lithium hydroxide (28 g, 667 mmol) in water (700 mL) was added and the mixture was heated to 50 °C and stirred at this température for 1 h. The mixture was allowed to cool and the aqueous layer separated. Celite was added to the aqueous layer and the mixture was filtered through a plug of celite. The filtrate was placed in a flask with overhead stirrer and carefully acidified with 4 M aq HCl and heated to 50 °C with stirring until a precipitate formed. The solid was collected via filtration and dried under vacuum to afford the title compound as a tan solid (68.7 g, 74%). MS (LCMS) m/z

420.6 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.54 (s, 3 H) 2.18 (ddd, J=13.17,

10.24, 5.07 Hz, 1 H) 2.41 - 2.45 (m, 1 H) 3.10 - 3.19 (s, 3 H) 3.87 - 4.08 (m, 2 H) 6.47 (d, J=7.02 Hz, 1 H) 7.42 (dd, J=8.39, 1.95 Hz, 1 H) 7.48 - 7.56 (m, 1 H) 7.60 (dd,

J=9.95, 1.95 Hz, 1 H) 8.06 (d, J=6.05 Hz, 1 H).

Step B) (2R)-4-[4-(4-Chloro-2-fluorophenvlÎ-5-fluoro-2-oxopyridin-1(2H)-vn-2methyl-2-(methvlsulfonvl)-N-(Îetrahvdro-2H-pyran-2-vloxv)butanamide N-Methylmorpholine (54 mL, 491 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (43.1 g, 245 mmol) were added to a solution of (2R)-4-[4-(4-chloro-2-fluorophenyl)-5fluoro-2-oxopyridin-1 (2H)-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (68.7 g, 164 mmol) in 2-methyltetrahydrofuran (1 L) and the réaction was stirred at rt for 2 h. O(Tetrahydro-2H-pyran-2-yl)hydroxylamine (28.8 g, 245 mmol) was added and the reaction was allowed to stir at rt for 1 h. The mixture was filtered and the filtrate was concentrated. The crude residue was purified via column chromatography using silica gel and eluting with 40% EtOAc in n-heptane (4L) and EtOAc (6L). The desired fractions were combined and concentrated to afford the title compound as a white gummy solid. (74.82g, 88%). MS (LCMS) m/z 517.9 (M-1).

Step C) (2R)-4-[4-(4-Chloro-2-fluorophenvl)-5-fluoro-2-oxopyridin-1(2H)-vl1-Nhydroxy-2-methvl-2-(methvlsulfonyl)butanamide

Water (312 mL) and 1 N aq HCl (23.9 mL, 23.9 mmol) were added to a solution of (2R)4-[4-(4-chloro-2-fluorophenyl)-5-fluoro-2-oxopyridin-1 (2H)-yl]-2-methyl-2(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (74.7 g, 144.1 mmol) in éthanol (126 mL). The reaction was heated to 70 °C and stirred at this température overnight. The reaction was allowed to cool and the solid was collected via filtration and washed with water until the filtrate had a pH of ~5. The solid was dried under vacuum to afford the title compound as a white solid (46.48 g, 74%). MS (LCMS) m/z 435.6 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.56 (s, 3 H) 2.09 - 2.21 (m, 1 H) 2.44 (d, J=5.27 Hz, 1 H) 3.10 (s, 3 H) 3.77 (td, J=11.90, 5.07 Hz, 1 H) 4.04 (td, J=11.95, 4.98 Hz, 1 H) 6.51 (d, J=7.02 Hz, 1 H) 7.44 (dd, J=8.29, 2.05 Hz, 1 H) 7.50 - 7.56 (m, 1 H) 7.62 (dd, J=9.95, 1.95 Hz, 1 H) 8.04 (d, J=5.85 Hz, 1 H) 9.22 (s, 1 H) 11.05 (s, 1 H).

Example 17 (2RÎ-4-r5-fluoro-4-(2-fluoro-3-methoxyphenvl)-2-oxoDvridin-1(2H)-vl1-N-hydroxy-2· methvl-2-(methvlsulfonyl)butanamide

Step A) (2R)-4-r5-Fluoro-4-(2-fluoro-3-meÎhoxvphenvl)-2-oxopvridin-1(2H)-vl1-2methyl-2-(methvlsulfonvl)butanoic acid ,r-Bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (5.90 g, 7.22 mmol) was added to a mixture of ethyl (2R)-4-(5-fluoro-4-iodo-2oxopyridin-1 (2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate, T2 (29.63 g, 66.55 mmol), (2-fluoro-3-methoxyphenyl)boronic acid (18.50 g, 108.9 mmol) and potassium phosphate tribasic (54.5 g, 205 mmol) in 2-methyltetrahydrofuran (450 mL) and deionized water (225 mL). The mixture was heated to 60 °C and stirred at this température overnight. The reaction was allowed to cool to rt. The aqueous layer was separated from the organics and the organics were washed with water (200 mL) and brine (200 mL), dried (MgSO₄), and filtered. Darco® G-60 -100 mesh, powder was added to the filtrate and was stirred for 1 h. Solids were removed via filtration over celite and the filtered pad was washed with EtOAc (-300 mL). The combined filtrâtes were concentrated to afford a red oil (30.62 g). The oil was dissolved in 2methyltetrahydrofuran (450 mL) and deionized water (225 mL). Potassium hydroxide (26.1 g, 465 mmol) was added to the mixture and the reaction was heated to 50 °C and stirred at this température overnight. The reaction was allowed to cool to rt. The aqueous layer was separated and washed with diethyl ether (2x200 mL). The aqueous layer was slowly acidified while stirring using concentrated HCl to a pH of 1 and the suspension was stirred for 1 h. The suspension was filtered and the solids were washed with water (3x100 mL) and hexanes (3x300 mL). The solids were dried in vacuo to afford the title compound as a tan solid (26.49 g, 94.54%). MS (LCMS) m/z 416.0 (M+1). ¹H NMR (400 MHz, DMSO-cfe) δ ppm 1.57 (s, 3 H) 2.14-2.28 (m, 0 H) 2.42 - 2.54 (m, 1 H) 3.18 (s, 3 H) 3.88 (s, 3 H) 3.90 - 4.09 (m, 2 H) 6.44 (d, J=7.03 Hz, 1 H) 6.92 - 7.04 (m, 1 H) 7.20 - 7.36 (m, 2 H) 8.06 (d, J=5.95 Hz, 1 H) 13.90 (br. s., 1 H).

Step B) (2R)-4-r5-Fluoro-4-(2-fluoro-3-methoxvphenvl)-2-oxopyridin-1(2H)-vl1-2methvl-2-(methvlsulfonvl)-N-(tetrahvdro-2H-pyran-2-vloxv)butanamide /V-Methylmorpholine (11 mL, 96.2 mmol) was added to a solution of CDMT (13.5 g, 116 mmol) and (2R)-4-[5-fluoro-4-(2-fluoro-3-methoxyphenyl)-2-oxopyridin-1 (2H)-yl]-2xZ methyl-2-(methylsulfonyl)butanoic acid (26.49 g, 63.77 mmol) in 2methyltetrahydrofuran (640 mL) and the reaction was stirred for 2 h. THPhydroxylamine (13.5 g, 116 mmol) was added to the reaction and the reaction was stirred overnight at rt. The reaction was quenched with saturated aqueous sodium bicarbonate (500 mL). The organic layer was separated and washed with water (300 mL) and brine (300 mL), then dried (MgSO₄), and filtered. Darco G-60,-100 mesh, powder was added to the filtrate and the suspension was stirred for 1 h. The charcoal was removed via filtration through a celite pad and the filter pad was washed with EtOAc (1 L). The filtrate was concentrated to afford the title compound as a yellowishwhite solid (30.49, 92.93%). MS (LCMS) m/z 513.9 (M-1).

Step C) (2R)-4-r5-Fluoro-4-f2-fluoro-3-methoxvphenvl)-2-oxopyridin-1(2H)-yl]-Nhydroxv-2-methvl-2-(methylsuÎfonyl)butanamide

Pyridinium p-toluenesulfonate (190 mg, 0.76 mmol) was added to a solution of (2R)-4[5-fluoro-4-(2-fluoro-3-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (777 mg, 1.51 mmol) in éthanol (15 mL). The reaction was heated to 50 °C and stirred at this température overnight. Additional pyridinium p-toluenesulfonate (118 mg, 0.47 mmol) was added to the solution and the reaction was heated at 60 °C for 3 h. The reaction was allowed to cool to rt and the precipitate was collected via filtration. The solid was washed with éthanol (15 mL) and hexanes (15 mL) and dried in vacuo to afford the title compound as a white solid (413 mg, 63.5%). MS (LCMS) m/z 431.0 (M+1). ¹H NMR (400 MHz, DMSO-tfe) δ ppm 1.57 (s, 1 H) 2.08 - 2.25 (m, 0 H) 2.41 - 2.56 (m, 1 H) 3.02 - 3.19 (m, 3 H) 3.71 - 3.85 (m, 1 H) 3.88 (s, 3 H) 3.98 - 4.13 (m, 1 H) 6.47 (d, 4=7.02 Hz, 1 H) 6.93 7.08 (m, 1 H) 7.19 - 7.36 (m, 2 H) 8.04 (d, 4=5.66 Hz, 1 H) 9.24 (d, 4=1.56 Hz, 1 H) 11.07 (d, J=1.56 Hz, 1 H).

Example 18 (2R)-4-Γ5-Fluoro-444-Γ(trans-4-hvdroxvcvclohexvl)methoxylphenvll·2-oxopyridin-1(2H)vl1-N-hvdroxv-2-methvl-2-(methvlsulfonyl)butanamide

o o

Step A) Ethyl 4-(tetrahvdro-2H-pvran-2-vloxv)cvclohexanecarboxvlate Pyridinium-4-toluenesulfonate (2.57 g, 10.2 mmol) was added to a solution of ethyl 4hydroxycyclohexanecarboxylate (8.8 g, 51.10 mmol) and 3,4-dihydro-2H-pyran (8.60 g, 102 mmol) in DCM (200 mL) and the reaction was stirred at rt for 16 h. The réaction was quenched with saturated aq NaHCC>3. The layers were separated and the organic layer was washed with water. The organic layer was dried (Na₂SO4), filtered, and concentrated. Purification via flash chromatography on a 200 g siiica column using an eluent of EtOAc in hexanes (5-10%) afforded the title compound as a clear oil (11.1 g, 85%).

Step B) fcls-4-(Tetrahydro-2H-pvran-2-vloxv)cyclohexvl1methanol and i+Z-Mtrans4- (tetrahvd ro-2H-pyran-2-vloxv) cyclohexvll methano I

Sodium borohydride (3.69 g, 97.5 mmol) was added to a solution of ethyl 4-(tetrahydro2H-pyran-2-yloxy)cyclohexanecarboxylate (2.50 g, 9.75 mmol) in éthanol (100 mL) at 0 °C. The reaction was allowed to warm to rt as the ice bath expired. After 2 days the reaction was cooled to 0 °C and quenched by the addition of 1 N aq HCl until the effervescence ceased, pH 5-6. The reaction was concentrated and the resulting residue was partitioned between EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried (MgSO₄), filtered, and concentrated. Purification on a siiica gel 100g column and an eluent of EtOAc in hexanes (10-40%) afforded the two sets of enantiomers as clear oils.

Î+/-)-rcis-4-(tetrahydro-2H-pvran-2-vloxv)cyclohexyrimethanol (387 mg, 18%).

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.30 -1.65 (m, 12 H) 1.64 -1.76 (m, 1 H) 1.76 -1.94 (m, 3 H) 3.33 - 3.64 (m, 3 H) 3.80 - 4.01 (m, 2 H) 4.59 - 4.75 (m, 1 H).

(+/-Î-ftrans-4-(teÎrahvdro-2H-pvran-2-vloxv)cvclohexyl1methanol (824, 39.4%) ’HNMR (400 MHz, CHLOROFORM-d) δ ppm 0.86-1.11 (m, 2 H) 1.16 -1.31 (m, 1 H)

1.31 -1.64 (m, 7 H) 1.64-1.77 (m, 1 H) 1.78-1.93 (m, 3 H) 1.99-2.14 (m, 2 H) 3.353.67 (m, 4 H) 3.80 - 4.04 (m, 1 H) 4.63 - 4.79 (m, 1 H).

Step C) 2-[(trans-4-fr4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2vl)phenoxylmeÎhvl}cyclohexvl)oxv1tetrahvdro-2H-ovran

Diisopropyl azodicarboxylate (2.1 mL, 10.5 mmol) was added to a solution of [trans-4(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methanol (2.05 g, 9.57 mmol), 4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.3 g, 10.7 mmol), triphenylphosphine (2.76 g, 10.5 mmol), and triethylamine (1.5 mL,10.5 mmol) in THF (150 mL) at 0 °C. The reaction was allowed to warm to rt and stirred overnight. Water (200 mL) was added and the reaction was extracted with EtOAc (600 mL). The organics were washed with 1 M aq NaOH (4x100 mL), brine, then dried (Na₂SO4), filtered and concentrated under reduced pressure. The crude residue was purified via flash chromatography using an eluent of 20% EtOAc in hexanes to afford the title compound as a white solid (1.9 g, 48%). MS (APCI) m/z 417.3 (M+1).

Step D) Ethyl (2RÎ-4-r5-fluoro-2-oxo-4-(4-4[trans-4-(tetrahydro-2H-oyran-2yloxylcvclohexvllmethoxvlDhenvnDyridin-lfëHI-vIl^-methyl^(methylsulfonyl)butanoate

Pd(dppf)CI₂ (350 mg, 0.431 mmol) was added to a solution of ethyl (2R)-4-(5-fluoro-4iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate (1.6 g, 3.6 mmol), 2[(trans-4-{[4-(4,4,5_I5-tetramethyl·1,3,2-dioxaborolan-2yl)phenoxy]methyl}cyclohexyl)oxy]tetrahydro-2H-pyran (1.9 g, 4.49 mmol), and potassium phosphate tribasic (2.9 g, 10.8 mmol) in 2-methyl tetrahydrofuran/water (5:1, 240 mL). The reaction mixture was heated to 80 °C and stirred at this température for 16 h. The reaction was allowed to cool to rt, and water (50 mL) was added. The mixture was extracted with EtOAc (3x150 mL). The combined organic phases were dried (Na₂SO₄), filtered, and concentrated under reduced pressure to afford the title compound as a light tan solid (1.4 g, 64%). MS (LCMS) m/z 608.2 (M+1 ).

Step E) (2R)-4-[5-Fluoro-2-oxo-4-(4-fftrans-4-itetrahvdro-2H-pyran-2νΙοχν)ονοΙοίΊθχνΙ1ΐ'ηθίΐΊθχν]-ρΐΊ6ηνΙ)ρνπΡίη-1(2Η)-νΠ-2-ππ6ΐΙ^,ΊνΙ-2(methylsulfonyl)butanoic acid

Aqueous lithium hydroxide (2.0 M, 5.8 mL, 2.3 mmol) was added to a solution of ethyl (2R)-4-[5-fluoro-2-oxo-4-(4-([trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methoxy}phenyl)pyridin-1 (2H)-yl]-2-methyl-2-(methylsulfonyl)butanoate (1.4 g, 2.3 mmol) in éthanol (40 mL). The reaction was heated to 50 °C for 3 h. The reaction was allowed to cool to ambient température and then acidified to a pH of ~3 with 1.0 N aq. HCl. The mixture was extracted with EtOAc (3x150 mL). The combined organic phases were kZ dried (Na₂SO4), filtered, and concentrated under reduced pressure to afford the title compound as a white solid (1.28 g, 98%). MS (LCMS) m/z 580.3 (M+1).

Step F) (2R)-4-f5-Fluoro-2-oxo-4-(4-(rtrans-4-(tetrahvdro-2H-Dyran-2vloxv)cvclohexvrimethoxv)~Dhenvl)Dvridin-1 (2H)-vll-2-methvl-2(methvlsulfonvl)-N-(tetrahydro-2H-Dvran-2-vloxv)butanamide N-Methyl morpholine (340 uL, 3.09 mmol) was added to a suspension of (2R)-4-[5fluoro-2-oxo-4-(4-{[trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methoxy}phenyl)pyridin-1 (2H)-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (1.28 g, 2.21 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (510 mg, 2.87 mmol) in 2-methyltetrahydrofuran (30 mL) and the réaction was stirred for 1 h at rt. O-(Tetrahydro-2H-pyran-2yl)hydroxylamine (61 mg, 0.52 mmol) was added, and the reaction was stirred overnight at rt. Water (50 mL) was added, and the mixture was extracted with EtOAc (3x150 mL). The combined organic phases were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude material was purified via flash chromatography using an eluent of EtOAc in n-heptane (75-100%) to afford the title compound as a light brown residue (700 mg, 46%). MS (LCMS) m/z 677.4 (M+1).

Step G) (2R)-4-i5-fluoro-4-f4-[(trans-4-hvdroxvcvclohexvl)methoxv]Dhenyl}-2oxoDvridin-1(2H)-vll-N-hvdroxy-2-methvl-2-(methylsulfonvl)butanamide Hydrochloric acid (4.0 M in 1,4-dioxane, 1.7 mL, 6.63 mmol) was added to a solution of (2R)-4-[5-fluoro-2-oxo-4-(4-([trans-4-(tetrahydro-2H-pyran-2yloxy)cyclohexyl]methoxy}phenyl)-pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N(tetrahydro-2H-pyran-2-yloxy)butanamide (450 mg, 0.66 mmol) in 1,4dioxane:DCM:water (2:2:1,5 mL) at room température. After 1 h, the reaction was concentrated under reduced pressure. The crude residue was triturated in éthanol (10 mL) overnight. The solid was collected via filtration, washed with éthanol (5 mL), and dried under reduced pressure to afford the title compound as a white solid (110 mg, 33%). MS (LCMS) m/z 511.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.97-1.19 (m, 4 H) 1.54 (s, 3 H) 1.58 - 1.72 (m, 1 H) 1.72 - 1.89 (m, 4 H) 2.04 - 2.23 (m, 1 H) 2.41 (m, 1 H) 3.08 (s, 3 H) 3.18 - 3.40 (m, 1 H) 3.65 - 3.84 (m, 3 H) 4.01 (td, /=11.61,4.88 Hz, 1 H) 4.49 (br. s„ 1 H) 6.45 (d, /=7.81 Hz, 1 H) 6.94 - 7.06 (m, 2 H) 7.36 - 7.54 (m, 2 H) 7.96 (d,/=6.83 Hz, 1 H) 9.21 (s, 1 H) 11.07 (s, 1 H) 11.12 (s, 1 H).

y

Example 19 (2R)-4-r5-Fluoro-4-(3-fluoro-4-methoxvphenvh-2-oxoovridin-1(2H)-yl1-N-hvdroxv-2methyl-2-(methvlsulfonyl)butanamide

Step A) (2R)-4-r5-Fluoro-4-(3-fluoro-4-methoxvphenvl)-2-oxopyridin-1(2H)-vll-2methyl-2-(methvlsulfonvl)-N-(tetrahvdro-2H-pyran-2-yloxv)butanamide

Pd Encat™ (580 mg, 0.17 mmol) was added to a mixture of potassium carbonate (723 mg, 5.2 mmol), (3-fluoro-4-methoxyphenyl)boronic acid (318 mg, 2.1 mmol), and (2R)-4(5-fluoro-4-iodo-2-oxopyridin-1 (2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2Hpyran-2-yloxy)butanamide, T3, (900 mg, 1.7 mmol) in 1,4-dioxane:water (5:1,24 mL). The reaction was heated to 80 °C and allowed to stir at this température ovemight. The reaction was filtered through a pad of celite, which was washed with methanol (250 mL). The filtrate was concentrated under reduced pressure, and the resulting crude material was purified via flash chromatography using an eluent of EtOAc in heptanes (20-100%), then 10% methanol in EtOAc to provide the title compound as a light tan residue (800 mg, 99%). MS (LCMS) m/z 495.1 (M-1).

Step B) (2R)-4-f5-Fluoro-4-(3-fluoro-4-methoxvphenvl)-2-oxoovridin-1 (2H)-vl1-Nhydroxy-2-methvl-2-(methvlsulfonvl)butanamide

The title compound (400 mg, 58%) was obtained as a solid from (2R)-4-[5-fluoro-4-(3fluoro-4-methoxyphenyl)-2-oxopyridin-1 (2H)-yl]-2-methyl-2-(methylsulfonyl)-N(tetrahydro-2H-pyran-2-yloxy)butanamide (800 mg, 1.65 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-4-{4-[(trans-4hydroxycyclohexyl)methoxy]phenyl}-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2(methylsulfonyl)butanamide, Example 18, Step G. MS (LCMS) m/z 413.1 (M+1). ¹H NMR (400 MHz, DMSO-d_e) δ ppm 1.54 (s, 3 H) 2.06 - 2.18 (m, 1 H) 2.38 - 2.47 (m, 1 H) 3.08 (s, 3 H) 3.74 (td, 7=12.00, 4.88 Hz, 1 H) 3.87 (s, 3 H) 4.02 (td, 7=11.85, 4.98 Hz, 1 H) 6.52 (d, 7=7.81 Hz, 1 H) 7.21 - 7.31 (m, 1 H) 7.34 - 7.51 (m, 2 H) 7.99 (d, 7=6.83 Hz, 1 H) 9.20(8,1 H) 11.06 (br. s, 1 H).

kZ (2R)-4-r5-Fluoro-2-oxo-4-(4-pvrimidin-2-vlohenyl)pvridin-1(2H)-vl1-N-hvdroxy-2-methvl54

Example 20

2-(methvlsulfonvl)butanamide

MeO₂S_t

Step A) 2-r4-(4.4.5.5-Tetramethvl-1,3,2-dioxaborolan-2-vl)phenvllpyrimidine

A degassed solution of 2-bromopyrimidine (1.5 g, 9.4 mmol), 2,2'-(1,4phenylene)bis(4,4_l5_l5-tetramethyl-1,3,2-dioxaborolane) (5.1 g, 16.0 mmol), 1.0 M aq K3PO4 (28.3 mL, 28.3 mmol), and Pd(PPh₃)₄ (330 mg, 0.31 mmol) in DMF (140 mL) was heated to 80 °C and stirred at this température for 16 h. Water (100 mL) was added to the reaction mixture and was extracted with EtOAc (3x200 mL). The combined organic phases were dried (Na₂SO4), filtered, and concentrated under reduced pressure. The crude material was purified via flash chromatography using an eluent of 17% EtOAc in π-heptane to afford the title compound as a white solid (0.7 g, 28%). MS (LCMS) m/z 283.1 (M+1). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (s, 12 H) 7.19 (t, 7=4.68 Hz, 1 H) 7.93 (d, 7=8.00 Hz, 2 H) 8.43 (d, 7=7.81 Hz, 2 H) 8.81 (d, 7=4.68 Hz, 2 H).

Step B) Ethyl (2R)-4-(5-Fluoro-2-oxo-4-(4-pyrimidin-2-vlphenvl)pvridin-1 (2H)-yl]-2methyl-2-(methylsulfonvl)butanoate

The title compound (278 mg, 87%) was obtained as a light tan solid from 2-(4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidine (270 mg, 0.94 mmol) and ethyl (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1 (2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate_l T2, (300 mg, 0.67 mmol) using a procedure analogous to that described for the préparation of ethyl (2R)-4-[5-fluoro-2-oxo-4-(4-([trans-4-(tetrahydro-2H-pyran-2yloxy)cyclohexyl]methoxy}phenyl)pyridin-1(2H)-yl]-2-methyl-2(methylsulfonyl)butanoate, Example 18, Step D. MS (LCMS) m/z 474.2 (M+1).

Step C) (2R)-4-(5-Fluoro-2-oxo-4-(4-pvrimidin-2-vlphenvl)pvridin-1(2H)-vl]-2methyl-2-(methylsulfonvl)butanoic acid

The title compound (250 mg, 98%) was obtained as a light brown gum from ethyl (2R)4-[5-fluoro-2-oxo-4-(4-pyrimidin-2-ylphenyl)pyridin-1(2H)-yl]-2-methyl-2(methylsulfonyl)butanoate (270 mg, 0.57 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-2-oxo-4-(4-{[trans-4-(tetrahydro-2Hpyran-2-yloxy)cyclohexyl]methoxy}-phenyl)pyridin-1(2H)-yl]-2-methyl-2(methylsulfonyl)butanoic acid, Example 18, Step E. MS (LCMS) m/z 446.1 (M+1). ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.73 (s, 3 H) 2.39 - 2.51 (m, 1 H) 2.62 - 2.75 (m, 1 H) 3.17 (s, 3 H) 4.20 - 4.46 (m, 2 H) 6.86 (d, J=7.02 Hz, 1 H) 7.65 (t, J=5.07 Hz, 1 H) 7.83 (d, J=7.02 Hz, 2 H) 8.09 (d, J=5.85 Hz, 1 H) 8.53 (d, J=8.39 Hz, 2 H) 9.06 (d, J=4.88 Hz, 2 H).

Step D) (2R)-4-r5-Fluoro-2-oxo-4-(4-Dyrimidin-2-vlDhenyl)Dvridin-1(2H)-yri-2methvl-2-(methvlsulfonvl)-N-(tetrahvdro-2H-pyran-2-vloxv)butanamide The title compound (290 mg, 94%) was obtained as a light brown gum from (2R)-4-[5fluoro-2-oxo-4-(4-pyrimidin-2-ylphenyl)pyridin-1(2H)-yl]-2-methyl-2(methylsulfonyl)butanoic acid (250 mg, 0.56 mmol) and O-(tetrahydro-2H-pyran-2yl)hydroxylamine (87 mg, 0.74 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-2-oxo-4-(4-{[trans-4-(tetrahydro-2H-pyran-2yloxy)cyclohexyl]methoxy}-phenyl)pyridin-1 (2H)-yl]-2-methyl-2-(methylsulfonyl)-N(tetrahydro-2H-pyran-2-yloxy)butanamide, Example 18, Step F. MS (LCMS) m/z 543.0 (M+1).

Step E) (2R)-4-[5-Fluoro-2-oxo-4-(4-pyrimidin-2-vlphenvl)pvridin-1 (2H)-vl]-Nhydroxv-2-methyl-2-(methylsulfonvl)butanamide

The title compound (80 mg, 30%) was obtained as a tan solid from (2R)-4-[5-fluoro-2oxo-4-(4-pyrimidin-2-ylphenyl)pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N(tetrahydro-2H-pyran-2-yloxy)butanamide (312 mg, 0.57 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-4-(4-[(trans-4hydroxycyclohexyl)methoxy]phenyl}-2-oxopyridin-1 (2H)-yl]-N-hydroxy-2-methyl-2(methylsulfonyl)butanamide, Example 18, Step G. MS (LCMS) m/z 461.1 (M+1). ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.70 (s, 3 H) 2.31 - 2.45 (m, 1 H) 2.56 - 2.71 (m, 1 H) 3.10 (s, 3 H) 3.87 - 4.01 (m, 1 H) 4.19 - 4.33 (m, 1 H) 6.70 (d, J=7.42 Hz, 1 H)

7.38 (t, J=4.88 Hz, 1 H) 7.73 (dd, J=8.59, 1.76 Hz, 2 H) 7.87 (d, J=6.05 Hz, 1 H) 8.53 (d, J=8.59 Hz, 2 H) 8.87 (d, J=4.88 Hz, 2 H).

A

Example 21 (2R)-4-f5-Fluoro-4-r4-(5-methoxvpyrimidin-2-yl)phenvll-2-oxopvridin-1 (2Η)-νΙ}-Νhvd roxy-2-methyl-2- (meth visu Ifonvl) butanam id e

Step A) 5-Methoxy-2-r4-(4,4.5.5-tetramethvl-1.3.2-dîoxaborolan-2yl)phenvllpyrimidine

The title compound (700 mg, 17%) was obtained as a white solid from 2-chloro-5methoxypyrimidine (1.85 g, 12.8 mmol) and 2,2-(1,4-phenylene)bis(4,4,5,5-tetramethyl-

1,3,2-dioxaborolane) (6.9 g, 21.0 mmol) using a procedure analogous to that described for the préparation of 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl]pyrimidine, Example 20, Step A. MS (LCMS) m/z 313.1 (M+1). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (s, 12 H) 3.93 (s, 3 H) 7.83 - 7.90 (m, 2 H) 8.28 8.34 (m, 2 H) 8.45 (s, 2 H).

Step B) (2R)-4-f5-Fluoro-4-[4-(5-methoxypvrimidin-2-vl)phenvl]-2-oxopvridin1 (2H)-vl)-2-methvl-2-(methvlsulfonyl)-N-(tetrahydro-2H-pyran-2vloxy)butanamide

The title compound (900 mg, 95%) was obtained as a tan solid from 5-methoxy-2-[4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidine (719 mg, 2.3 mmol) and (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yi)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro2H-pyran-2-yloxy)butanamide, T3, (850 mg, 1.65 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2oxopyridin-1 (2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2yloxyjbutanamide, Example 19 Step A. MS (LCMS) m/z 573.2 (M+1).

Step C) (2R)-445-Fluoro-4-r4-(5-methoxvpvrimidin-2Vl)phenyll-2-oxoovridin1(2H)-vll-N-hvdroxy-2-methvl-2-(methylsulfonyl)butanamide

The title compound (50 mg, 6%) was obtained as a light brown solid from (2R)-4-{5fluoro-4-[4-(5-methoxypyrimidin-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2xZ (methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (900 mg, 1.57 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-4-{4[(trans-4-hydroxycyclohexyl)methoxy]phenyl}-2-oxopyridin-1(2H)-yl]-N-hydroxy-2methyl-2-(methylsulfonyl)butanamide, Example 18, Step G. MS (LCMS) m/z 491.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.53 (s, 3 H) 2.08 - 2.19 (m, 1 H) 2.39 2.48 (m, 1 H) 3.07 (s, 3 H) 3.69 - 3.78 (m, 1 H) 3.92 (s, 3 H) 3.96 - 4.08 (m, 1 H) 6.56 (d, J=7.71 Hz, 1 H) 7.67 (m, J=8.70, 2.00 Hz, 2 H) 8.01 (d, J=6.54 Hz, 1 H) 8.34 - 8.38 (m, 2 H) 8.64 (s, 2 H) 9.19 (br. d, J=1.80 Hz, 1 H) 11.04 (br. d, J=1.90 Hz, 1 H).

Example 22 (2R)-4-i5-Fluoro-4-r4-(4-methoxv-2H-1,2.3-triazol-2-vl)phenvH-2-oxopvridin-1 (2H)-vl)-Nh vd roxy-2-methvl-2- (methvlsu Ifonvl) butanam ide

Step A) 2-(4-Bromophenvl)-4-methoxv-2H-1.2.3-triazole

Césium carbonate (4.5 g, 13.7 mmol) was added to a solution of 2-(4-bromophenyl)-2H-

1,2,3-triazol-4-ol (1.1 g, 4.6 mmol) and methyl iodide (0.36 mL, 5.7 mmol) in THF (50 mL). The reaction was heated to 60 °C and stirred at this température for 16 h. Water (20 mL) was added to the reaction, and the resulting mixture was extracted with EtOAc (2x150 mL). The combined organic phases were dried over potassium carbonate, filtered, and concentrated under reduced pressure to afford the title compound as a tan solid (1.1 g, 95%). ¹H NMR (400 MHz, METHANOL-O4) δ ppm 3.98 (s, 3 H) 7.39 (s, 1 H) 7.55 - 7.62 (m, 2 H) 7.79 - 7.86 (m, 2 H).

Step B) 4-Methoxv-2-r4-(4.4.5,5-tetramethyl-1.3.2-dioxaborolan-2-vl)phenvll-2H-

1,2,3-triazole

Pd(dppf)Cl2 (0.71 g, 0.87 mmol) was added to a mixture of 2-(4-bromophenyl)-4methoxy-2H-1,2,3-triazole (1.1 g, 2.6 mmol), 4,4,4',4',5,5,5’,5'-octamethyl-2,2^,-bi-1,3,2dioxaborolane (1.3 g, 5.2 mmol), potassium acetate (1.3 g, 13.0 mmol), in 2-methyl tetrahydrofuramwater (5:1, 60 mL). The reaction was heated to 80 °C and stirred at this température for 16 h. The reaction was allowed to cool to rt, and water (50 mL) was

V added. The reaction was filtered through celite, which was washed with EtOAc (150 mL). The filtrate was concentrated under reduced pressure, and the resulting crude material was purified by flash chromatography using an eluent of EtOAc in n-heptane (10-60%) to afford the title compound as a light tan solid (1.2 g, 92%). MS (LCMS) m/z 302.3 (M+1). ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.33 (s, 12 H) 4.01 (s, 3 H) 7.40 (s, 1 H) 7.78 - 7.84 (m, 2 H) 7.88 - 7.95 (m, 2 H).

Step C) (2R)-4-{5-Fluoro-4-r4-(4-methoxv-2H-1.2,3-triazol-2-yl)Dhenvl1-2oxopvridin-1(2H)-vll·2-methvl-2-(methvlsulfonvl)-N-(tetrahvdro-2H-pvraπ2-yloxy)butanamide

The title compound (1.15 mg, 88%) was obtained as tan solid from 4-methoxy-2-[4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-1,2,3-triazole (0.98 g, 1.4 mmol) and (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N(tetrahydro-2H-pyran-2-yloxy)butanamide, T3, (1.2 g, 2.3 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-4-(3-fluoro-4methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2Hpyran-2-yloxy)butanamide, Example 19 Step A. MS (LCMS) m/z 562.0 (M+1).

Step D) (2R)-4-f5-Fluoro-4-f4-(4-methoxv-2H-1,2_t3-Îriazol-2-vl)Dhenvn-2oxoDvridin-1(2H)-yl}-N-hvdroxv-2-methvl-2-(methylsulfonyl)butanamide

The title compound (700 mg, 70%) was obtained as a light tan solid from (2R)-4-(5fluoro-4-[4-(4-methoxy-2H-1,2,3-triazol-2-yl)phenyl]-2-oxopyridin“1 (2H)-yl}-2-methyl-2(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (1.15 g, 2.04 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-4-{4[(trans-4-hydroxycyclohexyl)methoxy]phenyl}-2-oxopyridin-1 (2H)-yl]-N-hydroxy-2methyl-2-(methylsulfonyl)butanamide, Example 18, Step G. MS (LCMS) m/z 480.2 (M+1). Ή NMR (400 MHz, DMSO-cf₆) δ ppm 1.53 (s, 3 H) 2.07 - 2.18 (m, 1 H) 2.39 2.48 (m, 1 H) 3.06 (s, 3 H) 3.69 - 3.77 (m, 1 H) 3.95 (s, 3 H) 3.97 - 4.08 (m, 1 H) 6.54 (d, J=7.62 Hz, 1 H) 7.65 - 7.73 (m, 2 H) 7.75 (s, 1 H) 7.90 - 7.98 (m, 2 H) 8.03 (d, J=6.64 Hz, 1 H) 11.06 (br. s., 1 H).

Example 23 (2R)-4-(5-Fluoro-4-[4-(4-methvl-2H-1,2.3-triazol-2-vl)Dhenvl1-2-oxQDvridin-1 (2H)-vl}-Nhydroxv-2-methvl-2-(methvlsulfonvl)butanamide

Step A) 4-Methyl-2-(4-(4.4,5,5-tetramethyl-1,3.2-dioxaborolan-2-vl)phenvl)-2H-

1,2,3-triazole

Pd(dppf)CI₂ ( 592 mg, 0.718 mmol) was added to a solution of potassium acetate (705 mg, 7.18 mmol), 2-(4-bromophenyl)-4-methyl-2H-1,2,3-triazole (600 mg, 2.52 mmol), and 4,4,4',4',5,5,5',5^l-octamethyl-2,2'-bi-1,3,2-dioxaborolane (729 mg, 2.87 mmol) in

1,4-dioxane (20 mL). The reaction was heated to 80 °C and stirred at this température for 16 h. The reaction was filtered through celite, and the filter pad was washed with EtOAc (150 mL). The combined filtrâtes were concentrated under reduced pressure, and the crude material was purified via flash chromatography using EtOAc in n-heptane (10-60%) to afford the title compound as a light tan solid (720 mg, 98%). MS (LCMS) m/z 286.2 (M+1). ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.32 (s, 12 H) 2.36 (s, 3 H) 7.66 (s, 1 H) 7.77 - 7.84 (m, 2 H) 7.92 - 8.00 (m, 2 H).

Step B) (2R)-4-i5-Fluoro-4-r4-(4-methvl-2H-1.2,3-triazol-2-vDnhenyil-2-oxopvridin1 (2Η)-νΙ)-2-Γη6ΐΡνΙ-2-(ΐ'η6ΐΙ~ινΐ3υΙίοηνΙ)-Ν-(ΐθΐΓ3ΐ~^Γθ-2Η-ρνΓ3η-2yloxylbutanamide

The title compound (0.99 g, 98%) was obtained as a tan gum from 4-methyl-2-(4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2H-1,2,3-triazole (0.70 g, 2.4 mmol) and (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1 (2H)-yl)-2-methyl-2-(methylsulfonyl)-N(tetrahydro-2H-pyran-2-yloxy)butanamide, T3, (0.90 g, 2.0 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-4-(3-fluoro-4methoxyphenyl)-2-oxopyridin-1 (2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2Hpyran-2-yloxy)butanamide, Example 19, Step A. MS (LCMS) m/z 546.5 (M+1).

Step C) (2R)-4-i5-Fluoro-4-r4-(4-methyl-2H-1,2,3-triazol-2-vl)phenvn-2-oxopyridin1 (2H)-yll·N-hvdroxv-2-meΐhyl-2-(methylsulfonvl)butanamide

The title compound (450 mg, 53%) was obtained as a tan solid from (2R)-4~(5-fluoro-4[4-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl]-2-oxopyridin-1 (2H)-yl}-2-methyl-2(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (0.99 g, 1.81 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-4-{416551 [(trans-4-hydroxycyclohexyl)methoxy]phenyl}-2-oxopyridin-1(2H)-yl]-N-hydroxy-2methyl-2-(methylsulfonyl)butanamide, Example 18, Step G. MS (LCMS) m/z 464.2 (M+1). ¹H NMR (400 MHz, DMSO-d_e) δ ppm 1.53 (s, 3 H) 2.06 - 2.20 (m, 1 H) 2.33 (br. s, 3 H) 2.38 - 2.49 (m, 1 H) 3.06 (s, 3 H) 3.68 - 3.80 (m, 1 H) 3.90 - 4.11 (m, 1 H) 6.55 (d, J=7.61 Hz, 1 H) 7.65 - 7.76 (m, 2 H) 7.90 (br. s, 1 H) 7.96 - 8.10 (m, 2 H) 11.05 (br. s., 1 H).

Example 24 (2R)-4-(5-Fluoro-2-oxo-4-quinoxalin-6-vlpvridin-1 (2H)-vl)-N-hvdroxy-2-methvl-2(methvlsulfonvl)butanamide

Step A) (2R)-4-(5-Fluoro-2-oxo-4-quinoxalin-6-vlpvridin-1 (2H)-vl)-2-methvl-2(methylsulfonyl)-N-(tetrahvdro-2H-pyran-2-vloxv)butanamide

The title compound (480 mg, 95%) was obtained as a light brown gum from 6-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline (347 mg, 1.36 mmol) and (2R)-4-(5fluoro-4-iodo-2-oxopyridin-1 (2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2Hpyran-2-yloxy)butanamide, T3, (500 mg, 0.97 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2yloxy)butanamide, Example 19 Step A. MS (LCMS) m/z 517.1 (M+1).

Step B) (2R)-4-i5-Fluoro-2-oxo-4-quinoxalin-6-vlpyridin-1 (2H)-vl)-N-hydroxy-2methvl-2-(methylsulfonyl)butanamide

The title compound (110 mg, 28%) was obtained as a light tan solid from (2R)-4-(5fluoro-2-oxo-4-quinoxar[n-6-ylpyridin-1 (2H)-yl)-2-methyl-2-(methylsulfonyl)-N(tetrahydro-2H-pyran-2-yloxy)butanamide (0.48 g, 0.93 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-4-(4-[(trans-4hydroxycyclohexyl)methoxy]phenyl}-2-oxopyridin-1 (2H)-yl]-N-hydroxy-2-methyl-2(methylsulfonyl)butanamide, Example 18, Step G. MS (LCMS) m/z 433.2 (M+1). ¹H NMR (400 MHz, DMSO-d_e) δ ppm 1.54 (s, 3 H) 2.09 - 2.19 (m, 1 H) 2.44 - 2.52 (m, 1 H) 3.07 (s, 3 H) 3.73 - 3.84 (m, 1 H) 4.04 (m, 1 H) 6.71 (d, J=7.61 Hz, 1 H) 7.99 (dt,

A

H) 8.89 9.05 (m, 2 H) 9.20 (br. s., 1 H) 11.03 (br. s., 1 H).

Example 25 (2R)-4-Î5-Fluoro-4-(3-methoxvphenvl)-2-oxopyridin-1(2H)-yll-N-hvdroxv-2-methvl-2(methylsulfonyl)butanamide

NHOH

Step A) (2R)-4-r5-Fluoro-4-(3-methoxyphenvl)-2-oxopvridin-1 (2H)-vll-2-methvl-2(methylsulfonvl)-N-(tetrahydro-2H-pyran-2-yloxv)butanamide

The title compound (800 mg, 99%) was otained as a light tan gum from (3methoxyphenyljboronic acid (318 mg, 2.09 mmol) and (2R)-4-(5-fluoro-4-iodo-2oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2yloxy)butanamide, T3, (900 mg, 1.74 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2yloxy)butanamide, Example 19, Step A. MS (LCMS) m/z 495.1 (M+1).

Step B) (2R)-445-Fluoro-4-(3-methoxvohenvl)-2-oxopvridin-1 (2H)-vl1-N-hvdroxv-2methyl-2-(methylsulfonyl)butanamide

The title compound (400 mg, 58%) was obtained as a tan solid from (2R)-4-[5-fluoro-4(3-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2Hpyran-2-yloxy)butanamide (0.82 g, 1.65 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fiuoro-4-{4-[(trans-4hydroxycyclohexyl)methoxy]phenyl}-2-oxopyridin-1 (2H)-yl]-N-hydroxy-2-methyl-2(methylsulfonyl)butanamide, Example 18, Step G. MS (LCMS) m/z 413.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.52 (s, 3 H) 2.05 - 2.18 (m, 1 H) 2.36 - 2.50 (m, 1 H) 3.06 (S, 3 H) 3.66 - 3.78 (m, 4 H) 3.95 - 4.08 (m, 1 H) 6.50 (d, J=7.61 Hz, 1 H) 6.98 7.11 (m, 3 H) 7.32-7.40 (m, 1 H) 7.98 (d, J=6.54 Hz, 1 H) 9.18 (br. s., 1 H) 11.04 (s, 1 H).

Example 26 (2Η)-4-ί5-ΡΙυοΓθ-2-οχο-4-[4-(2Η-1.2,3-ΐΓί3ΖθΙ-2-νΙΪρΐΊ6ηνΙ1ρνπόίη-1(2Ηΐ-νΙ>-Ν-Κν(ΐΓθχν-2methyl-2-(methvlsulfonvl)butanamide

Step A) 2-[4-{4,4.5.5-Tetramethvl-1,3,2-dioxaborolan-2-vÎ)phenvl1-2H-1,2,3-triazole Pd(dppf)CI₂ (280 mg, 0.343 mmol) was added to a mixture of 2-(4-bromophenyl)-2H-

1,2,3-triazole (255 mg, 1.14 mmol), 4,4,4^,,4',5,5,5^,,5'-octamethyl-2,2'-bi-1,3,2dioxaborolane (350 mg, 1.38 mmol), and potassium acetate (340 mg, 3.46 mmol) in 1,4dioxane (10 mL). The reaction was heated to 80 °C and stirred at this température ovemight. The reaction was allowed to cool to rt and was diluted with EtOAc (30 mL) and brine (30 mL). The mixture was filtered through celite, and the organic layer was separated from the filtrate. The aqueous layer was extracted with EtOAc (2x30 mL) and the organics were combined, dried (MgSO₄), filtered and concentrated. The crude material was purified via flash chromatography using an Analogix SF15-12g column and an eluent of EtOAc in n-heptane (0-10%) to afford the title compound as an orange solid (240.6 mg, 78.0%). MS (LCMS) m/z 272.4 (M+1). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.37 (s, 12 H) 7.83 (s, 2 H) 7.94 (d, 2 H) 8.10 (d, J=8.59 Hz, 2 H).

Step B) Ethyl (2R)-4-i5-fluoro-2-oxo-4-r4-(2H-1.2.3-triazol-2-yl)phenvllpyridin1 (2H)-vl)--2-methvl-2-(methvlsulfonvl)butanoate

Pd(dppf)CI₂ (484 mg, 0.59 mmol) was added to a mixture of ethyl (2R)-4-(5-fluoro-4iodo-2-oxopyridin-1 (2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate, T2, (2.20 g, 4.94 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-1,2,3-triazole (2.01 g, 7.41 mmol), and potassium phosphate (3.95 g, 14.8 mmol) in 2methyltetrahydrofuran (200 mL) and deionized water (40 mL). The reaction was heated to 60 °C and was vigorously stirred at this température ovemight. The reaction was diluted with EtOAc (100 mL) and water (100 mL) and was filtered through a celite pad (~1 inch). The filter pad was washed with EtOAc (100 mL) and the filtrâtes were combined. The aqueous layer was separated and was extracted with EtOAc (2x100

K.Z mL). The combined organics were washed with brine (100 mL), dried (MgSO₄), filtered and concentrated. The crude material was purified via flash chromatography using a Varian SF25-40g column and an eluent of EtOAc in hexanes (30-100%) to afford the title compound as a yellow solid (1.54 g, 67.4%). MS (LCMS) m/z 463.0 (M+1). ¹H NMR (400 MHz, DMSO-7₆) δ ppm 1.23 (t, 3 H) 1.62 (s, 3 H) 2.18 - 2.32 (m, 1 H) 2.52 2.66 (m, 1 H) 3.16 (s, 3 H) 3.92 - 4.07 (m, 2 H) 4.08 - 4.24 (m, 2 H) 6.59 (d, 7=7.81 Hz, 1 H) 7.72 - 7.84 (m, 2 H) 8.10 (d, 7=6.63 Hz, 1 H) 8.12 - 8.17 (m, 2 H) 8.18 (s, 2 H).

Step C) (2R)-4~f5-Fluoro-2-oxo-4-r4-(2H-1.2.3-triazol-2-vDDhenvllDvridin-1(2H)-vll· 2-methvl-2-(methvlsulfonvl)butanoic acid

Potassium hydroxide (1.30 g, 23.2 mmol) was added to a solution of ethyl (2R)-4-{5fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1 (2H)-yl}-2-methyl-2(methylsulfonyl)butanoate (1.54 g, 3.33 mmol) in 2-methyltetrahydrofuran:water (2::1 42.5 mL) and the solution was stirred at rt overnight. Methanol (5 mL) was added and the reaction was heated to 60 °C. The reaction mixture was stirred at this température for 2 h. The reaction was concentrated and triturated in 3 M aq HCl. The solid was collected via filtration and washed with water (20 mL) and hexanes (20 mL). The solid was dried under vacuum to afford the title compound as a white solid (1.39 g, 96.1%). MS (LCMS) m/z 435.0 (M+1). ¹H NMR (400 MHz, DMSO-7₆) δ ppm 1.58 (s, 3 H) 2.13 2.30 (m, 0 H) 2.41 - 2.61 (m, 1 H) 3.17 (s, 3 H) 3.89-4.13 (m, 2 H) 6.59 (d, J=7.81 Hz, 1 H) 6.56 - 6.63 (m, 1 H) 7.79 (dd, 7=8.78, 1.76 Hz, 3 H) 8.09 (d, 7=6.83 Hz, 1 H) 8.12 8.17 (m, 2 H) 8.19 (s, 2 H).

Step D) (2R)-4-i5-Fluoro-2-oxo-4-r4-(2H-1.2.3-triazoi-2-yl)DhenvriDvridin-1(2H)-yl}2-methvl-2-(methvlsulfonvl)-N-(tetrahvdro-2H-pvran-2-vloxv)butanamide W-Methylmorpholine (540 pL, 4.9 mmol) was added to a solution of CDMT (750 mg, 4.27 mmol) and (2R)-4-(5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1 (2H)yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanoic acid (1.39 g, 3.20 mmol) in 2methyltetrahydrofuran (30 mL) and the reaction was stirred for 1 h at rt. 0-(Tetrahydro2H-pyran-2-yl)hydroxylamine (670 mg, 5.72 mmol) was added to the reaction and the reaction was stirred overnight at rt. The reaction was quenched with saturated aq NaHCO₃ (100 mL) and the aqueous layer was extracted with EtOAc (3x100 mL). The combined organics were washed with brine (100 mL), dried (MgSO₄), filtered and concentrated. The crude product was purified via flash chromatography using a Varian

SF25-40g column and eîuent of EtOAc in hexanes (30-100%) to afford the title compound as a white solid (1.53 g, 89.6%). MS (LCMS) m/z 532.2(M-1).

Step E) (2R)-4-ï5-Fluoro-2“OXO-4-r4-(2H-1,2,3-triazol-2-yl)DhenynDVridin-1 (2H)-vll· N-hydroxy-2-methvl-2-(methvlsulfonvl)butanamide

Pyridinium p-toluenesulfonate (360 mg, 0.50 mmol) was added to a solution of (2R)-4{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (1.53 g, 2.87 mmol) in éthanol (60 mL). The solution was heated to 70 °C and was stirred at this température for 3 h. The reaction was allowed to cool and was stirred at rt for three days. The solid was collected via filtration, washed with éthanol (20 mL) and hexanes (20 mL). The solid was dried under vacuum to afford the title compound as a white solid (1.05 g, 81.5%). MS (LCMS) m/z 450.0 (M+1), ¹H NMR (400 MHz, DMSO-d_e) δ ppm 1.58 (s, 3 H) 2.08 - 2.27 (m, 0 H) 2.38 - 2.59 (m, 1 H) 3.12 (s, 3 H) 3.72 - 3.90 (m, 1 H) 4.00 - 4.17 (m, 1 H) 6.62 (d, J=7.61 Hz, 1 H) 7.70 - 7.88 (m, 2 H) 8.08 (d, J=6.63 Hz, 1 H) 8.12 8.18 (m, 2 H) 8.19 (s, 2 H) 9.25 (d, J=1.95 Hz, 1 H) 11.09 (d, J=1.76 Hz, 1 H).

Example 27 (2R)-4-r5-FluorQ-4-(2-Îluoro-4-methoxvDhenvl)-2-oxoDvridin-1(2H)-yll-N-hydroxv-2methvl-2-(meÎhvlsulfonvl)butanamide

Step A) (2R)-4-[5-Fluoro-4-i2-fluoro-4-methoxvDhenvl)-2-oxoDyridin-1(2H)-vl1-2methvl-2-(methylsulfonyl)-N-(tetrahvdro-2H-Dvran-2-yloxv)butanamide

The title compound (1.5 g, 94%) was obtained from (2-fluoro-4-methoxyphenyl)boronic acid (737 mg, 4.34 mmol) and (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1 (2H)-yl)-2-methyl-2(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, T3, (1.6 g, 3.1 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-4(3-fluoro-4-methoxyphenyl)-2-oxopyridin-1 (2H)-yl]-2-methyl-2-(methylsulfonyl)-N(tetrahydro-2H-pyran-2-yloxy)butanamide, Example 19, Step A. MS (LCMS) m/z 513.3 (M+1).

Step B) (2R)-4-[5-Fluoro-4-(2-fluoro-4-methoxvDhenvl)-2-oxoDvridin-1 (2H)-vll-Nhydroxy-2-methyl-2-(methvlsulfonvÎ)butanamide

A solution of HCl (4 M in 1,4-dioxane, 4.4 mL, 17.5 mmol) was added to a solution of (2R)-4-[5-fluoro-4-(2-fluoro-4-methoxyphenyl)-2-oxopyridin-1 (2H)-yl]-2-methyl-2(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (1.5 g, 2.9 mmol) in 1,4dioxane (20 mL), DCM (20 mL), and water (5 mL) and the reaction was stirred for 20 min at rt. The réaction was concentrated under reduced pressure, isopropyl alcohol (10 mL) was added to the residue and the mixture was concentrated. Isopropyl alcohol (30 mL) was added to the residue and the solution was stirred overnight at rt to afford a precipitate. The precipitate was collected via filtration, washed with isopropyl alcohol, and dried under vacuum to afford the title compound as a light brown solid (725 mg, 58%) MS (LCMS) m/z 431.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.57 (s, 3 H) 2.07 - 2.25 (m, 1 H) 2.42 - 2.48 (m, 1 H) 3.11 (s, 3 H) 3.71 - 3.81 (m, 1 H) 3.83 (s, 3 H) 4.00 - 4.11 (m, 1 H) 6.44 (d, J=7.02 Hz, 1 H) 6.92 (dd, J=8.59, 2.54 Hz, 1 H) 7.00 (dd, J=12.39, 2.44 Hz, 1 H) 7.42 (t, J=8.49 Hz, 1 H) 8.03 (d, J=5.85 Hz, 1 H) 9.25 (br. s., 1 H) 11.10 (s, 1 H).

Example 28 (2R)-4-[5-Fluoro-4-(4-methoxyphenyn-2-oxopyridin-1 (2H)-yl1-N-hydroxy-2-methyl-2(methylsulfonvl)butanamide

Step A) (2R)-4-r5-Fluoro-4-(4-methoxvDhenvlÎ-2-oxoDvridin-1(2H)-vÎl-2-methvl-2(methvlsulfonvn-N-(tetrahvdro-2H-Dvran-2-vloxvlbutanamide

The title compound (1.90 g, 98.8%) was obtained as a yellow solid from (4methoxyphenyl)boronic acid (902 mg, 5.94 mmol) and (2R)-4-(5-fluoro-4-iodo-2oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2yloxyjbutanamide, T3, (2.0 g, 3.87 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2yloxy)butanamide, Example 19, Step A. MS (LCMS) m/z 495.4 (M-1).

Step B) (2R)-445-Fluoro-4-f4-methoxvDhenvlÎ-2-oxopvridin-1(2HÎ-vl1-N-hydroxv-266 methyl-2-(methylsulfonvl)butanamide

The title compound (651 mg, 41.3%) was obtained as a white solid from (2R)-4-[5fluoro-4-(4-methoxyphenyl)-2-oxopyridin-1 (2H)-yl]-2-methyl-2-(methylsulfonyl)-N(tetrahydro-2H-pyran-2-yloxy)butanamide (1.90 g, 3.83 mmol) using a procedure analogous to that described for the préparation of (2R)-4-{5-Îluoro-2-oxo-4-[4-(2H-1,2,3triazol-2-yl)phenyl]pyridin-1 (2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide Example 26, Step E. MS (LCMS) m/z 413.0 (M+1). ¹H NMR (400 MHz, DMSO-t/₆) δ ppm 1.57 (s, 3 H) 2.08 - 2.23 (m, 1 H) 2.41 - 2.48 (m, 1 H) 3.11 (s, 3 H) 3.72 - 3.80 (m, 1 H) 3.81 (s, 3 H) 3.97 - 4.13 (m, 1 H) 6.49 (d, J=7.81 Hz, 1 H) 6.95 - 7.15 (m, 2 H) 7.46 - 7.67 (m, 2 H) 7.99 (d, J=6.63 Hz, 1 H) 9.24 (s, 1 H) 11.11 (s, 1 H).

Example 29 (2R)-4-F5-Fluoro-4-(4-methvlphenyl)-2-oxopyridin-1(2H)-vl1-N-hydroxv-2-methvl-2(methylsulfonyl)butanamide

MeOjS^.

Step A) Ethyl (2R)-4-r5-fluoro-4-(4-methvlphenvlÎ-2-oxopyridin-1(2H)-yl1-2-methvl2-(methvlsulfonyl)butanoate

The title compound (484 mg) was obtained as a brown gum from (4methylphenyl)boronic acid (229 mg, 1.68 mmol) and ethyl (2R)-4-(5-fluoro-4-iodo-2oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate ,T2, (500 mg, 1.12 mmol) using a procedure analogous to that described for the préparation of ethyl (2R)-4-{5fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2(methylsulfonyl)butanoate, Example 27, Step B. MS (LCMS) m/z 410.1 (M+1).

Step B) (2R)-4-r5-Fluoro-4-(4-methvlphenyl)-2-oxopvridin-1(2H)-vl1-2-methvl-2(methylsulfonyl)butanoic acid

The title compound (294 mg, 65.2%) was obtained as a white solid from ethyl (2R)-4-[5-fluoro-4-(4-methylphenyl)-2-oxopyridin-1 (2H)-yl]-2-methyl-2(methylsulfonyl)butanoate (484 mg, 1.18 mmol) using a procedure analogous to that described for the préparation of (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2yl)phenyljpyridin-1 (2H)-yl}-2-methyl-2-(methylsulfonyl)butanoic acid, Example 26, Step

C. MS (LCMS) m/z 382.0 (M+1). ¹H NMR (400 MHz, DMSO-d_e) δ ppm 1.57 (s, 3 H)

2.14 - 2.25 (m, 0 H) 2.36 (s, 3 H) 2.43 - 2.54 (m, 1 H) 3.17 (s, 3 H) 3.89 - 4.07 (m, 2 H)

6.46 (d, 4=7.81 Hz, 1 H) 7.31 (d, 4=8.00 Hz, 2 H) 7.42 - 7.52 (m, 2 H) 8.03 (d, 4=6.83

Hz, 1 H).

Step C) (2R)-4-i5-Fluoro-4-(4-methvÎphenvl)-2-oxopyridin-1(2H)-vn-2-meÎhyl-2(methvlsulÎonvl)-N-(tetrahvdro-2H-pyran-2-yloxv)butanamide

The title compound (331 mg, 89.3%) was obtained as a white solid from (2R)-4-[5fluoro-4-(4-methylphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (294 mg, 0.77 mmol) using a procedure analogous to that described for the préparation of 2R)-4~[5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1 (2H)-yl)~ 2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, Example 26, Step D. MS (LCMS) m/z 479.3 (M-1).

Step D) (2R)-445-Fluoro-4-(4-methvlphenvl)-2-oxopvridin-1i2H)-yl1-N-hvdroxv-2methyl^-fmethylsulfonvDbutanamide

The title compound (96 mg, 34%) was obtained as a white solid from (2R)-4-[5-fluoro-4(4-methylphenyl)-2-oxopyridin-1 (2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2Hpyran-2-yloxy)butanamide (331 mg, 0.69 mmol) using a procedure analogous to that described for the préparation of 2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(meÎhylsulfonyl)butanamide, Example 26, Step E. MS (LCMS) m/z 397.0 (M+1). ¹H NMR (400 MHz, DMSO-4₆) δ ppm 1.58 (s, 3 H) 2.10 2.25 (m, 1 H) 2.37 (s, 3 H) 2.42 - 2.49 (m, 1 H) 3.12 (s, 3 H) 3.71 - 3.84 (m, 1 H) 4.00 4.12 (m, 1 H) 6.51 (d, 4=7.81 Hz, 1 H) 7.32 (d, 4=7.81 Hz, 2 H) 7.48 (dd, 4=8.20, 1.76 Hz, 2 H) 8.02 (d, 4=6.83 Hz, 1 H) 9.24 (d, 4=1.76 Hz, 1 H) 11.11 (d, 4=1.95 Hz, 1 H).

Example 30 (2R)-4-ί5-Fluoro-2-oxo-4-[4-ίtrifluoromethoxv)pheπvl1pvridin-1(2H)-vll·-N-hvdroxv-2methvl-2-(methvlsulfonvl)butanamide

NHOH x/

Step A) (2R)-4~i5-Fluoro-2-oxo-4-r4-(trifluoromeÎhoxv)ohenyllpyridin-1 (2Η)-νΙΤ2methvl-2-(methylsulfonvl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title comppund (69.7 mg, 49.1%) was obtained as a yellow-white solid from [4(trifluoromethoxy)phenyl]boronic acid (82.3 mg, 0.47 mmol) and (2R)-4-(5-fluoro-4-iodo2-oxopyridin-1 (2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2yloxy)butanamide, T3, (133 mg, 0.26 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2yloxy)butanamide, Example 20, Step A. MS (LCMS) m/z 551.1 (M-1).

Step B) (2R)-4-(5-Fluoro-2-oxo-4-[4-(trifluoromethoxv¹iphenvllPvridin-1 (2Η)-νΙΤ·Νhvdroxv-2-methvl-2-(methylsulfonvl)butanamide

The title compound (12.2 mg, 20.9%) was obtained as a white solid from (2R)-4-{5fluoro-2-oxO“4-[4-(trifluoromethoxy)phenyl]pyridin-1 (2H)-yl}-2-methyl-2-(methylsulfonyl)N-(tetrahydro-2H-pyran-2-yloxy)butanamide (68.9 mg, 0.13 mmol) using a procedure analogous to that described for the préparation of (2R)-4-(5-fluoro-2-oxo-4-[4-(2H-1,2,3triazol-2-yl)phenyl]pyridin-1 (2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, Example 26, Step E. MS (LCMS) m/z 467.0(M+1). ¹H NMR (400 MHz, DMSO-cf₆) δ ppm 1.57 (s, 3 H) 2.07 - 2.25 (m, 0 H) 2.39 - 2.55 (m, 1 H) 3.11 (s, 3 H) 3.72 - 3.86 (m, 1 H) 3.97 - 4.13 (m, 1 H) 6.58 (d, 1 H) 7.50 (d, J=8.00 Hz, 2 H) 7.65 - 7.77 (m, 2 H) 8.06 (d, J=6.44 Hz, 1 H) 9.23 (d, J=1.17 Hz, 1 H) 11.08 (s, 1 H).

Example 31 (2R)-4-[5-Fluoro-4-(4-fluoroDhenvl)-2-oxopyridin-1(2H)-vll-N-hydroxv-2-methyl-2(methvlsulfonvl)butanamide

NHOH

Step A) (2R)-4-f5-Fluoro-4-(4-fluorophenvl)-2-oxoovridin-1(2H)-vÎl-2-methvl-2(methvlsulfonvl)-N-(tetrahydro-2H-pvran-2-vloxv)butanamide

The title compound (67 mg, 54%) was obtained as a white solid from (4fluorophenyl)boronic acid (66.2 mg, 0.47 mmol) and (2R)-4-(5-fluoro-4-iodo-2oxopyridin-1 (2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-

yloxy)butanamide, T3, (133 mg, 0.26 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2yloxyjbutanamide, Example 19, Step A. MS (LCMS) m/z 483.1 (M-1).

Step B) (2R)-4-r5-Fluoro-4-(4-fluoroDhenyl)-2-oxoDyridin-1 (2H)-vll-N-hvdroxy-2methvl-2-(methvlsulfonvl)butanamide

The title compound (7.9 mg, 14%) was obtained as a white solid from (2R)-4-[5-fluoro-4(4-fluorophenyl)-2-oxopyridin-1 (2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2Hpyran-2-yloxy)butanamide (67 mg, 0.14 mmol) using a procedure analogous to that described for the préparation of (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2yl)phenyl]pyridin-1 (2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, Example 26, Step E. MS (LCMS) m/z 401.0 (M+1). ¹H NMR (400 MHz, DMSO-d_e) ô ppm 1.58 (s, 3 H) 2.10 - 2.24 (m, 1 H) 2.42 - 2.50 (m, 1 H) 3.12 (s, 3 H) 3.71 - 3.88 (m, 1 H) 3.99 - 4.14 (m, 1 H) 6.55 (d, J=7.61 Hz, 1 H) 7.25 - 7.45 (m, 2 H) 7.58 - 7.72 (m, 2 H) 8.05 (d, J=6.83 Hz, 1 H) 9.24 (s, 1 H) 11.10 (s, 1 H).

Example 32 (2R)-4-ί5-Fluoro-4-F4-ί6-methoxvpvridin-3-vlΐphenyll·2-oxopvridin-1(2H)-vll·N-hvdroxv2-methvl-2-(methylsulfonyl)butanamide

Step A) 2-Methoxv-5-f4-(4.4.5,5-tetramethvl-1,3_l2-dioxaborolan-2vDphenyllpyridine

The title compound (1.40 g) was obtained as a white solid from 5-(4-bromophenyl)-2methoxypyridine (1.0 g, 3.8 mmol) using a procedure analogous to that described for the préparation of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-1,2,3triazole, Example 26, Step A. MS (LCMS) m/z 312.1 (M+1).

Step B) (2R)-4-i5-Fluoro-4-[4-(6-methoxypyridin-3-vl)phenvÎl-2-oxopyridin-1(2H1νΙ>-2-ωθΐήνΙ-2-^θΐΚνΐ3υΙίοηνύ-Ν-(ΐθΐΓ3ήνάΐΌ-2Η-ρνΓ3η-2vloxy)butanamide

The title compound (273 mg, 61.4%) was obtained as a yellow solid from 2-methoxy-5[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyridine (362 mg, 1.16 mmol) and (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro2H-pyran-2-yloxy)butanamide, T3, (400 mg, 0.78 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2yloxy)butanamide, Example 19, Step A. MS (LCMS) m/z 574.0 (M+1).

Step C) (2R)-445-Fluoro-4-[4-(6-methoxvpyridin-3-yl)phenvn-2-oxoovridin-1(2H)yl}-N-hvdroxy-2-methyl-2-(methvlsulfonvl)butanamide

The title compound (156 mg, 67%) was obtained as a white solid from (2R)-4-{5-fiuoro4-[4-(6-methoxypyridin-3-yl)phenyl]-2-oxopyridin-1 (2H)-yl}-2-methyl-2-(methylsulfonyl)N-(tetrahydro-2H-pyran-2-yloxy)butanamide (273 mg, 0.48 mmol) using a procedure analogous to that described for the préparation of (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3triazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, Example 26, Step E. MS (LCMS) m/z 490.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.58 (s, 3 H) 2.09 - 2.27 (m, 0 H) 2.43 - 2.57 (m, 1 H) 3.12 (s, 3 H) 3.73 - 3.86 (m, 1 H) 3.91 (s, 3 H) 4.00-4.14 (m, 1 H) 6.59 (d, J=7.61 Hz, 1 H) 6.94 (d, J=8.59 Hz, 1 H) 7.60 - 7.73 (m, 2 H) 7.75 - 7.86 (m, 2 H) 7.98 - 8.19 (m, 2 H) 8.57 (d, J=2.54 Hz, 1 H) 9.25 (br. S., 1 H) 11.10 (s, 1 H).

Example 33 (2Ην4-ί4-Γ4-(ΡΐΑυοΓθΠΊθΐΙιοχν)ρΐΊθηνΠ-5-ίΙυοΓθ-2-οχορνΓ'^ΐη-1(2Η)-νΙ>-Ν-ΐΊνόΓθχν-2methvl^-fmethvIsulfonvDbutanamide

NHOH

Step A)

(2R)-4-i4-[4-(Difluoromethoxv)phenvll-5-fluoro-2-oxopvridin-1 (2H)-vl}-2- methyl-2-(methvlsulfonvl)-N-(tetrahvdro-2H-pvran-2-vloxv)butanamide

x/

The title compound (69.7 mg, 49.1%) was obtained as a yellow solid from 2-[4(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (82.3 mg, 0.47 mmol) and (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N(tetrahydro-2H-pyran-2-yloxy)butanamide, T3, (133 mg, 0.26 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-4-(3-fluoro-4methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2Hpyran-2-yloxy)butanamide, Example 19, Step A. MS (LCMS) m/z 531.2 (M-1).

Step B) (2R)-4-f4-r4-(Difluoromethoxy)phenvl1-5-fluoro-2-oxoovridin-1(2H)-yl}-Nhydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (9.0 mg, 18%) was obtained as a white solid from (2R)-4-{4-[4(difluoromethoxy)phenyl]-5-fluoro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N(tetrahydro-2H-pyran-2-yloxy)butanamide (58.0 mg, 0.11 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-2-oxo-4-[4-(2H-1,2,3trrazol-2-yl)phenyl]pyridin-1 (2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, Example 26, Step E. MS (LCMS) m/z 449.0 (M+1). ¹H NMR (400 MHz, DMSO-d_e) δ ppm 1.58 (s, 3 H) 2.09 - 2.26 (m, 1 H) 2.40 - 2.48 (m, 1 H) 3.12 (s, 3 H) 3.71 - 3.86 (m, 1 H) 3.98-4.14 (m, 1 H) 6.55 (d, 1 H) 7.13-7.57 (m, 3 H) 7.61 -7.80 (m, 2 H) 8.05 (d, J=6.63 Hz, 1 H) 9.24 (d, 7=1.76 Hz, 1 H) 11.10 (d, 7=1.56 Hz, 1 H).

Example 34 (2R)-4-Î5-Fluoro-4-(4-methoxv-3-methvlphenvl)-2-oxopvridin-1(2H)-vll-N-hvdrexy-2methvl-2-(methylsulfonyl)butanamide

NHOH

Step A) (2RÏ-445-Fluoro-4-(4-methoxv-3-methvlphenvl)-2-oxopyridin-1(2H)-vl1-2methvl-2-(methylsulfonvl)-N-(tetrahydro-2H-pvran-2-vloxv)butanamide

The title compound (332.1 mg, 65.2%) was obtained as a yellow solid from (4-methoxy3-methylphenyl)boronic acid (280 mg, 1.69 mmol) and (2R)-4-(5-fluoro-4-iodo-2oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2yloxy)butanamide, T3, (500 mg, 0.97 mmol) using a procedure analogous to that v/ described for the préparation of (2R)-4-[5-fiuoro-4-(3-fluoro-4-methoxyphenyl)-2oxopyridin-1 (2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2yloxyjbutanamide, Example 19, Step A, MS (LCMS) m/z 511.0 (M+1).

Step B) (2R)-4-r5-Fluoro-4-(4-methoxy-3-methylDhenyn-2-oxoDvridin-1(2H)-vl]-Nhvdroxv-2-methvl-2-(methvlsulfonvl)butanamide

The title compound (46 mg, 17%) was obtained as a white solid from (2R)-4-[5-fluoro-4(4-methoxy-3-methylphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N(tetrahydro-2H-pyran-2-yloxy)butanamide (322 mg, 0.63 mmol) using a procedure analogous to that described for the préparation of (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3triazol-2-yl)phenyl]pyridin-1 (2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, Example 26, Step E. MS (LCMS) m/z 427.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.57 (s, 3 H) 2.08 - 2.25 (m, 4 H) 2.38 - 2.49 (m, 1 H) 3.11 (s, 3 H) 3.70 - 3.81 (m, 1 H) 3.84 (s, 3 H) 3.97 - 4.11 (m, 1 H) 6.48 (d, 1 H) 7.05 (d, J=8.39 Hz, 1 H) 7.28 - 7.50 (m, 2 H) 7.98 (d, J=6.63 Hz, 1 H) 9.24 (br. S., 1 H) 11.11 (s, 1 H).

Examole 35 (2R)-4-(4-Γ4-(difluoromethoxy)-3-fluoroDhenvll-5-fluoro-2-oxoDyridin-1(2H)-yll·Nhydroxv-2-methyl-2-(methylsulfonvnbutanamide

Step A) (2R)-4-(4-r4-(DifluoromethoxyÎ-3-fluoroDhenvl1-5-fluoro-2-oxoDvridin1 (2H)-vn-2-methvl-2-(methylsulfonyl)-N-(tetrahvdro-2H-Dvran-2vloxvlbutanamide

The title compound (227 mg, 42.6%) was obtained as a yellow-white solid from 2-[4(difluoromethoxy)-3-fluorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (630 mg, 2.19 mmol) and (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1 (2H)-yl)-2-methyl-2-(methylsulfonyl)-N(tetrahydro-2H-pyran-2-yloxy)butanamide, T3, (500 mg, 0.97 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-4-(3-fluoro-4methoxyphenyl)-2-oxopyridin-1 (2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2Hpyran-2-yloxy)butanamide, Example 19, Step A. MS (LCMS) m/z 549.3 (M-1).

Step B) (2R)-4-{4-r4-(Difluoromethoxy)-3-fluoroDhenyn-5-fluoro-2-oxopvridin1 (2H)-vlÎ-N-hydroxy-2-methvl-2-(rneÎhylsulfonvl)butanamide

The title compound (92 mg, 62%) was obtained as a white solid from (2R)-4-{4-[4(difluoromethoxy)-3-fluorophenyl]-5-fluoro-2-oxopyridin-1 (2H)-yl}-2-methyl-2(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (227 mg, 0.41 mmol) using a procedure analogous to that described for the préparation of (2R)-4-{5“fluoro-2oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2(methylsulfonyl)butanamide, Example 26, Step E. MS (LCMS) m/z 467.0 (M+1). ¹H NMR (400 MHz, DMSO-cf₆) δ ppm 1.57 (s, 3 H) 2.08 - 2.22 (m, 1 H) 2.40 - 2.48 (m, 1 H) 3.11 (s, 3 H) 3.70 - 3.86 (m, 1 H) 3.97 - 4.14 (m, 1 H) 6.61 (d, 1 H) 7.09 - 7.38 (m, 1 H) 7.42 - 7.57 (m, 2 H) 7.69 (d, /=11.12 Hz, 1 H) 8.07 (d, /=6.63 Hz, 1 H) 9.24 (br. S., 1 H) 11.08 (s, 1 H).

Example 36 (2R)-4-Î5-Fluoro-4-r3-fluoro-4-(2H-1.2.3-triazol-2-yl)DhenyH-2-oxopvridin-1 (2H)-vll-N hvdroxv-2-methyl-2-(methylsulfonvl)butanamide

MeO₂S.

Step A) (1 E,2E)-Ethanedial bis[(4-bromo-2-fluorophenvl)hvdrazonel (4-Bromo-3-fluorophenyl)hydrazine-hydrochloride (5.0 g, 24.3 mmol) was added to a mixture of EtOAc (60 mL) and 3 N aq NaOH (60 mL) and the mixture was stirred until ail solids went into solution. The organic layer was separated and the aqueous layer was extracted with EtOAc (2x60 mL). The combined organics were washed with brine (60 mL), dried (MgSO₄), filtered and concentrated to afford an orange solid (3.27 g, 15.9 mmol). The solid was suspended in toluene (25 mL). Oxalaldéhyde (40% aq solution, 912 uL, 7.92 mmol) was added dropwise to the solution and the reaction was stirred overnight at rt. The precipitate was collected via filtration and washed with toluene (25 mL) and hexanes (50 mL). The solid was dried under vacuum to afford the title compound as a yellow solid (2.61 g, 78.1%). MS (LCMS) m/z 431.1 (M-1).

Step B)

2-(4-Bromo-2-fluorophenvl)-2H-1,2.3-triazole

Copper (II) trifluoromethanesulfonate (218 mg, 0.60 mmol) was added to a slurry of (1 E,2E)-ethanedial bis[(4-bromo-2-fluorophenyl)hydrazone] (2.61 g, 6.04 mmol) in toluene (25 mL). The reaction was heated to reflux and stirred at this température overnight. The réaction was allowed to cool and was filtered through celite, and the filter pad was washed with EtOAc (100 mL). The combined filtrâtes were washed with 1 N aq HCl (3x100 mL), water (100 mL), and brine (100 mL) and then dried (MgSO4), filtered and concentrated. The crude product was purified via flash chromatography using a Varian SF25-40g column and an eluent of EtOAc in hexanes (0-50%) to afford the title compound as a yellow solid (1.08 g, 73.9%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.44 (ddd, 1 H) 7.47-7.54 (m, 1 H) 7.76 (t, 1 H) 7.90 (s, 2 H).

Step C) 2-(2-Fluoro-4-(4,4.5.5-tetramethvl-1.3.2-dioxaborolan-2-vl)Dhenvl1-2H-

1,2,3-triazole

The title compound (1.54 g) was obtained as a yellow solid from 2-(4-bromo-2fluorophenyl)-2H-1,2,3-triazole (1.08 g, 4.82 mmol) using a procedure analogous to that described for the préparation of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl]-2H-1,2,3-triazole, Example 26, Step A. MS (LCMS) m/z 290.1 (M+1).

Step D) fëRM-ÎS-Fluoro^-fS-fluoro^-tëH-I^.S-triazol^-yDDhenvIl^-oxoDyridin1 (2H)-vlL2-methvl-2-(methvlsulÎonvl)-N-(tetrahvdro-2H-Dvran-2vloxv)butanamide

The title compound (275 mg, 51.5%) was obtained as a yellow solid from 2-[2-fluoro-4(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenyl]-2H-1,2,3-triazole (420 mg, 1.45 mmol) and (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1 (2H)-yl)-2-methyl-2-(methylsulfonyl)-N(tetrahydro-2H-pyran-2-yloxy)butanamide, T3, (500 mg, 0.97 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-4-(3-fluoro-4methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2Hpyran-2-yloxy)butanamide, Example 19, Step A. MS (LCMS) m/z 550.3 (M-1 ).

Step E) (2R)-4-Î5-Fluoro-4-(3-fluoro-4-(2H-1,2,3-triazol-2-yl)Dhenyn-2-oxoDvridin1 (2H)-yn-N-hvdroxy-2-methyl-2-(methylsulfonvl)butanamide

The title compound (133 mg, 57%) was obtained as a white solid from (2R)-4-(5-fluoro4-[3-fluoro-4-(2H-1,2,3-triazol-2-yl)phenyl]-2-oxopyridin-1 (2H)-yl}-2-methyl-2(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-y1oxy)butanamide (275 mg, 0.50 mmol)

V through a procedure analogous to that described for the préparation of (2R)-4-(5-fluoro2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyndin-1 (2H)-yl}-N-hydroxy-2-methyl-2(methylsulfonyl)butanamide, Example 26, Step E. MS (LCMS) m/z468.0 (M+1). ¹H NMR (400 MHz, DMSO-de) δ ppm 1.58 (s, 3 H) 2.10-2.25 (m, 0 H) 2.43-2.56 (m, 1 H) 3.12 (s, 3 H) 3.74-3.89 (m, 1 H) 4.00-4.15 (m, 1 H) 6.70 (d, J=7.61 Hz, 1 H) 7.60 - 7.66 (m, 1 H) 7.75 - 7.86 (m, 1 H) 8.00 (t, J=8.20 Hz, 1 H) 8.10 (d, J=6.63 Hz, 1 H) 8.23 (s, 2 H) 9.24 (br. S., 1 H) 11.08 (s, 1 H).

Examole 37 (2R)-4-f5-Fluoro-4-r3-methvl-4-(2H-1.2,3-triazol-2-vl)phenvll-2-oxopyridin-1 (2H)-yl}-N hvdroxv-2-meÎhyl-2-(methvlsulfonvl)butanamide

Step A) (1 E,2E)-Ethanedial bisK4-bromo-2-meÎhvlphenyl)hydrazone1

The title compound (1.45 g, 87.9%) was obtained as a yellow solid from (4-bromo-2methylphenyl)hydrazine-hydrochloride (2.00 g, 8.42 mmol) and oxalaldéhyde (40% aq solution, 450 uL, 3.9 mmol) through a procedure analogous to that described for the préparation of (1 E,2E)-ethanedial bis[(4-bromo-2-fluorophenyl)hydrazone], Example 36, Step A. MS (LCMS) m/z 425.0 (M+1). ¹H NMR (400 MHz, DMSO-de) δ ppm 2.20 (s, 6 H) 7.09 - 7.33 (m, 6 H) 7.95 (s, 2 H) 9.73 (s, 2 H).

Step B) 2-(4-Bromo-2-methvlohenvl)-2H-1.2.3-triazole

The title compound (608 g, 59.0%) was obtained as a yellow solid from (1 E,2E)ethanedial bis[(4-bromo-2-methylphenyl)hydrazone (1.45 g, 3.42 mmol) through a procedure analogous to that described for the préparation of 2-(4-bromo-2fluorophenyl)-2H-1,2,3-triazole, Example 36, Step B. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.38 (s, 3 H) 7.44 - 7.48 (m, 2 H) 7.50 - 7.53 (m, 1 H) 7.85 (s, 2 H).

Step C) 2-f2-Methyl-4-(4,4,5,5-tetramethvl-1.3,2-dioxaborolan-2-vl)phenvl1-2H-

1,2,3-triazole

The title compound (688 mg, 82.3%) was obtained as an orange solid from 2-(4-bromo2-methylphenyl)-2H-1,2,3-triazole (698 mg, 2.93 mmol) through a procedure analogous to that described for the préparation of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl]-2H-1,2,3-triazole, Example 26, Step A. ¹H NMR (400 MHz, CHLOROFORMtf) δ ppm 1.36 - 1.41 (m, 12 H) 2.42 (s, 3 H) 7.61 (d, J=8.00 Hz, 1 H) 7.76 (d, J=7.81 Hz, 1 H) 7.80 (S, 1 H) 7.85 (s, 2 H).

Step D) (2R)-4-Î5-Fluoro-4-[3-methvl-4-(2H-1,2,3-triazol-2-yl)phenvH-2-oxopvridin1(2H)-yl>-2-methvl-2-(methvlsulfonvl)-N-(tetrahvdro-2H-pvran-2yloxv)butanamide

The title compound (630 mg, 71.5%) was obtained as a yellow solid from 2-[2-methyl-4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-1,2,3-triazole (688 mg, 2.41 mmol) and (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1 (2H)-yl)-2-methyl-2-(methylsulfonyl)-N(tetrahydro-2H-pyran-2-yloxy)butanamide, T3, (830 mg, 1.61 mmol) through a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-4-(3fluoro-4-methoxyphenyl)-2-oxopyridin-1 (2H)-yl]-2-methyl-2-(methylsulfonyl)-N(tetrahydro-2H-pyran-2-yloxy)butanamide, Example 19, Step A. MS (LCMS) m/z 546.2(M-1).

Step E) (2R)-4-i5-Fluoro-4-Î3-methyl-4-(2H-1.2.3-triazol-2-vl)ohenvl1-2-oxopyridin1 (2Η)-νΙ>-Ν-Ι^Γθχν-2-Γη6ίήνΙ-2-(|·ϊΐ6ίΐΊνΐ3υΙΐοηνΙ^υΐ3η3ηΤ^θ

The title compound (253 mg, 47.5%) was obtained as a white solid from (2R)-4-{5fluoro-4-[3-methyl-4-(2H-1,2,3-triazol·2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (630 mg, 1.15 mmol) through a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2(methylsulfonyl)butanamide, Example 26, Step E. MS (LCMS) m/z 464.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.58 (s, 3 H) 2.11 - 2.26 (m, 1 H) 2.39 (s, 3 H) 3.11 (s, 3 H) 3.74 - 3.87 (m, 1 H) 3.99 - 4.16 (m, 1 H) 6.64 (d, J=7.61 Hz, 1 H) 7.60 (d, J=8.00 Hz, 1 H) 7.63 - 7.77 (m, 2 H) 8.08 (d, J=6.63 Hz, 1 H) 8.16 (s, 2 H) 9.24 (br. s., 1 H) 11.09 (s, 1 H).

Example 38 (2R)-4-(3,5-Difluoro-2-oxo-4-phenvlpvridin-1 (2H)-yl)-N-hydroxy-2-methyl-2(methvlsulfonvl)butanamide

J

Step A) 3,5-Difluoro-4-iodopyridin-2(1H)-one

2,3_I5-Trifluoro-4-iodopyridine (6.03 g, 23.3 mmol) was suspended in 6 M aq HCl (250 mL). The mixture was heated to reflux and was stirred at this température overnight. The reaction was concentrated to dryness to afford the title compound as an orange solid (4.14 g, 69.2%). MS (LCMS) m/z 257.9 (M+1).

Step B) Ethyl (2R)-4-(3,5-difluoro-4-iodo-2-oxopvridin-1 (2H)-vl)-2-methvl-2(methvlsulfonyl)butanoate

Césium carbonate (1.90 g, 5.84 mmol) was added to a solution of the 3,5-difluoro-4iodopyridin-2(1 H)-one (1.0 g, 3.9 mmol) and ethyl (2R)-4-bromo-2-methyl-2(methylsulfonyl)butanoate, T1, (1.45 g, 5.06 mmol) in tetrahydrofuran:t-butanol (1:1,50 mL). The resulting suspension was heated to reflux and was stirred at this température for 72 h. The reaction was filtered through celite, and the filter pad was washed with EtOAc (3x50 mL). The combined filtrâtes were concentrated and the crude product was purified via flash chromatography on an Analogix SF15-24g column using an eluent of EtOAc in hexanes (0-50%) to afford the title compound as a yellow solid (575.6 mg, 32%). MS (LCMS) m/z 463.9(M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.23 (s, 3 H) 1.58 (s, 3 H) 2.20 (dt, 7=13.90, 7.00 Hz, 1 H) 2.52 - 2.62 (m, 1 H) 3.14 (s, 3 H) 4.00 (t, 7=7.61 Hz, 2 H) 4.05 - 4.22 (m, 2 H) 7.94 (dd, 7=4.20, 2.05 Hz, 1 H).

Step C) Ethyl (2R)-4-(3,5-difluoro-2-oxo-4-phenylpyridin-1(2H)-vl)-2-methvl-2(methylsulfonvl)butanoate

The title compound (110 mg, 63%) was obtained as a white solid from phenylboronic acid (98.8 mg, 0.81 mmol) and ethyl (2R)-4-(3,5-difluoro-4-iodo-2-oxopyridin-1 (2H)-yl)2-methyl-2-(methylsulfonyl)butanoate (250 mg, 0.54 mmol) using a procedure analogous to that described for the préparation of ethyl (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-

1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoate, Example 26, Step B. MS (LCMS) m/z 414.0 (M+1). ¹H NMR (400 MHz, CHLOROFORM-7) δ ppm 1.33 - 1.46 (m, 3 H) 1.78 (s, 3 H) 2.44 - 2.65 (m, 2 H) 3.14 (s, 3 H) 3.98 - 4.16 (m, 1 H) 4.25 - 4.43 (m, 3 H) 7.23 (dd, J=5.07, 2.15 Hz, 1 H) 7.40 7.61 (m, 5 H).

Step D) (2R)-4-(3,5-Difluoro-2-oxo-4-phenylpyridin-1 (2H)-yl)-2-methyl-2(methvlsulfonyl)butanoic acid

The title compound (91 mg, 79.2%) was obtained as a white solid from ethyl (2R)-4(3,5-difluoro-2-oxo-4-phenylpyridin-1 (2H)-yl)-2-methyl-2-(methylsuifonyl)butanoate (110 mg, 0.27 mmol) using a procedure analogous to that described for the préparation of (2R)-4~(5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1 (2H)-yl}-2-methyl-2(methylsulfonyl)butanoic acid, Example 26, Step C. MS (LCMS) m/z 386.0 (M+1).

Step E) (2R)-4-(3,5-Difluoro-2-oxo-4-phenylovridin-1(2H)-vl)-2-methyl-2(methvlsulfonvl)-N-(tetrahvdro-2H-pvran-2-yloxv)butanamide

The title compound (75.9 mg, 66%) was obtained as an off-white solid from (2R)-4-(3,5difluoro-2-oxo-4-phenylpyridin-1 (2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (91 mg, 0.36 mmol) using a procedure analogous to that described for the préparation of 2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1 (2H)-yl}-2-methyl-2(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, Example 26, Step D. MS (LCMS) m/z 483.2 (M+1).

Step F) (2R)-4-(3,5-Difluoro-2-oxo-4-phenylpyridin-1 (2HÎ-yl)-N~hvdroxv-2-meÎhvl2-(methyisulfonv1)butanamide

The title compound (13.9 mg, 22%) was obtained as a white solid from (2R)-4-(3,5difluoro-2-oxo-4-phenylpyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2Hpyran-2-yloxy)butanamide (75 mg, 0.16 mmol) using a procedure analogous tothat described for the préparation of (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide Example 26, Step E. MS (LCMS) m/z 401.0 (M+1). ¹H NMR (400 MHz, DMSO-de) δ ppm 1.59 (s, 3 H) 2.11-2.22 (m, 1 H) 2.52-2.62 (m, 1 H) 3.10 (s, 3 H) 3.79-3.99 (m, 1 H) 4.03 -4.20 (m, 1 H) 7.40 - 7.64 (m, 5 H) 7.98 (dd, J=5.85, 1.95 Hz, 1 H) 9.24 (br. S., 1 H) 11.01 (s, 1 H).

Example 39 (2R)-4-(5-Fluoro-3-methoxv-2-oxo-4-phenvlpyridin-1 (2H)-vl)-N-hvdroxv-2-methvl-2(methylsulfonyl)butanamide x/

ΝΗΟΗ

Step A) (2R)-4-(5-Fluoro-3-methoxv-2-oxo-4-DhenylDvridin-1 (2H)-vl)-2-methvl-2(methylsulfonyl)butanoic acid

Potassium hydroxîde (100 mg, 1.78 mmol) was added to a solution of ethyl (2R)-4-(3,5difluoro-2-oxo-4-phenylpyridin-1 (2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate (77 mg, 0.19 mmol) in tetrahydrofuran:methanol:water (2:2:1 10 mL). The solution was heated to 50 °C and stirred at this température for 4 h. The reaction was concentrated and the residue was dissolved in 1 N aq NaOH (50 mL). The aqueous layer was washed with EtOAc (3x50 mL) and acidified to a pH of 3 using concentrated HCl. The solid was collected via filtration and was washed with water (30 mL) and hexanes (30 mL) to afford the title compound as a white solid (70 mg, 95%). MS (LCMS) m/z 398.0(M+1). ¹H NMR (400 MHz, METHANOL-^) δ ppm 1.69 -1.79 (m, 3 H) 2.30 - 2.46 (m, 1 H) 2.55 - 2.72 (m, 1 H) 3.18 (s, 3 H) 3.66 (s, 3 H) 4.08 - 4.22 (m, 1 H) 4.23 - 4.38 (m, 1 H)

7.39 - 7.51 (m, 5 H) 7.60 (d, 1 H).

Step B) (2R)-4-(5-Fluoro-3-methoxv-2-oxo-4-DhenylDvridin-1 (2H)-vl)-2-methvl-2(methvlsulfonvl)-N-(tetrahvdro-2H-Dvran-2-yloxv)butanamide

The title compound (52 mg, 83%) was obtained as an off-white solid from (2R)-4-(5fluoro-3-methoxy-2-oxo-4-phenylpyridin-1 (2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (50 mg, 0.13 mmol) using a procedure analogous to that described for the préparation of 2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2_t3-triazol-2-yl)phenyl]pyridin-1 (2H)-y)}2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, Example 26, Step D. MS (LCMS) m/z 497.0 (M+1).

Step C) (2R)-4-(5-Fluoro-3-methoxv-2-oxo-4-DhenvlDvridin-1(2H)-vl)-N-hydroxy-2methyl-2-(methvlsulfonyl)butanamide

The title compound (20.2 mg, 48%) was obtained as an off-white solid from (2R)-4-(5fluoro-3-methoxy-2-oxo-4-phenylpyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N(tetrahydro-2H-pyran-2-yloxy)butanamide (75 mg, 0.16 mmol) using a procedure analogous to that described for the préparation of (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3triazol-2-yl)phenyl]pyridin-1 (2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,

Example 26, Step E. MS (LCMS) m/z 413.0 (M+1). ¹H NMR (400 MHz, METHANOLd₄) δ ppm 1.72 (s, 3 H) 2.30 - 2.50 (m, 1 H) 2.55 - 2.78 (m, 1 H) 3.10 (s, 3 H) 3.68 (s, 3

H) 3.95 - 4.06 (m, 1 H) 4.21 - 4.37 (m, 1 H) 7.37 - 7.55 (m, 5 H) 7.61 (d, 1 H).

Example 40 (2R)-4-(5-Fluoro-3-hvdroxv-2-oxo-4-phenvlpyridin-1(2H)-vl)-N-hvdroxv-2-meÎhvl-2(methylsulfonvl)butanamide

NHOH

Step A) (2R)-4-(5-Fluoro-3-hvdroxv-2-oxo-4-phenvlpyridin-1 (2H)-vl)-N-hvdroxy-2methvl-2-(methylsulfonvl)butanamide

Boron tribromide (760 pL, 0.76 mmol, 1.0 M in dichloromethane) was added to a solution of (2R)-4-(5-fluoro-3-methoxy-2-oxo-4-phenylpyridin-1 (2H)-yl)-N-hydroxy-2methyl-2-(methylsulfonyl)butanamide (156 mg, 0.378 mmol) in DCM (16.0 mL) at 0 °C. The reaction was allowed to warm to rt and stirred overnight. The reaction mixture was concentrated to afford a brown solid. The crude product was purified via prepratory HPLC to afford the title compound as a yellow solid (25.4 mg, 16.9%). MS (LCMS) m/z 399.0 (M+1). ¹H NMR (400 MHz, DMSO-cfe) δ ppm 1.59 (s, 3 H) 2.11 - 2.25 (m, 1 H) 3.07 (s, 1 H) 3.13 (s, 2 H) 3.70 - 3.88 (m, 1 H) 4.02 - 4.26 (m, 1 H) 7.11 (d, J=7.81 Hz, 1 H) 7.37 - 7.65 (m, 5 H).

Example 41 (2R)-4-f5-Fiuoro-4-(4-isoxazol-3-ylphenvl)-2-oxopvridin-1(2H)-vn-N-hydroxy-2-methvl-2(methylsulfonvl)butanamide

NHOH

Step A) 3-(4-(4,4,5,5-Tetramethvl-1,3,2-dioxaborolan-2-yl)phenvl)isoxazole

The title compound (730 mg, 67.0%) was obtained as a white solid from 3-(4bromophenyl)isoxazole (900 mg, 4.02 mmol) using a procedure analogous to that described for the préparation of 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl]-2H-1,2,3-triazole, Example 26, Step A. MS (APCI) m/z 272.1 (M+1). ¹H

NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36-1.41 (m, 12 H) 2.42 (s, 3 H) 7.61 (d, J=8.00 Hz, 1 H) 7.76 (d, J=7.81 Hz, 1 H) 7.80 (s, 1 H) 7.85 (s, 2 H). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35 (s, 12 H) 6.66 - 6.70 (m, 1 H) 7.83 (s, 2 H) 7.88 (s, 2 H) 8.42-8.48 (m, 1 H).

Step B) (2R)-4-f5-Fluoro-4-(4-isoxazol-3-ylphenvl)-2-oxODvridin-1(2HÎ-vll-2-methvl2-(methvlsulfonvl)-N-(tetrahvdro-2H-Dvran-2-vloxy)butanamide

The title compound (655 mg, 63.4%) was obtained as a colorless oil from 3-(4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazole (525 mg, 1.94 mmol) and (2R)-4(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H15 pyran-2-yloxy)butanamide, T3, (1.00 g, 1.94 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2yloxy)butanamide, Example 19, Step A. MS (APCI) m/z 532.3 (M-1). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.53 -1.97 (m, 9 H) 2.31 - 2.47 (m, 1 H) 2.47 - 2.60 (m,

1 H) 3.19 (d, J=2.54 Hz, 3 H) 3.53 - 3.74 (m, 1 H) 4.00 (br. s., 1 H) 4.12 (s, 1 H) 4.27 -

4.40 (m, 1 H) 5.15 (d, J=14.24 Hz, 1 H) 6.63 - 6.75 (m, 2 H) 7.42 (d, J=5.46 Hz, 1 H) 7.62 (d, J=8.00 Hz, 2 H) 7.92 (d, J=8.59 Hz, 2 H) 8.49 (d, J=1.56 Hz, 1 H) 11.85 (d, J=17.76Hz, 1 H).

Step C) (2Rl-4-r5-Fluoro-4-(4-isoxazol-3-vlDhenvl)-2-oxoDvridin-1(2H)-yll-Nhvdroxy-2-methyl-2-(methvlsulfonvl)butanamide

A solution of 1.0 M aq HCl (15 mL) was added slowly to a solution of (2R)-4-[5-fluoro-4(4-isoxazol-3-ylphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro2H-pyran-2-yloxy)butanamide (655 mg, 1.23 mmol) in 1,4-dioxane (30 mL) at rt. The reaction was allowed to stir at rt overnight. The reaction was concentrated to a crude material. Water (30 mL) was added to the crude material and the mixture was boiled for 5 minutes. The mixture was allowed to cool to rt and the solid that formed was collected via filtration and dried under high vacuum to afford the title compound as a light yellow solid (314 mg, 56.9%). MS (APCI) m/z 450.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.55 (s, 3 H) 2.10 - 2.21 (m, 1 H) 2.42 - 2.49 (m, 1 H) 3.09 (s, 3 H) 3.66 - 3.85 (m,

H) 3.96 - 4.09 (m, 1 H) 6.59 (d, J=7.61 Hz, 1 H) 7.21 (d, J=1.56 Hz, 1 H) 7.71 (dd,

J=8.39, 1.76 Hz, 2 H) 8.00 (d, J=8.39 Hz, 2 H) 8.04 (d, J=6.44 Hz, 1 H) 9.03 (d, J=1.56

Hz, 1 H) 9.16 - 9.28 (m, 1 H) 11.06 (s, 1 H).

Example 42 (2R)-445-Fluoro-4-r4-(1.3-oxazol-2-yl)Dhenvl1-2-oxoDvridin-1(2H)-vl}-N-hydroxv-2methvl-2-(methylsulfonvl)butanamide

NHOH

Step A) 2-(4-(4,4,5,5-Tetramethvl-1.3,2-dioxaborolan-2-yl)Dhenvl1-1.3-oxazole

The title compound (240 mg, 34.3%) was obtained as a white solid from 2-(4iodophenyl)-1,3-oxazole (700 mg, 2.58 mmol) using a procedure analogous to that described for the préparation of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl]-2H-1,2,3-triazole, Example 26, Step A. MS (APCI) m/z 272.2 (M+1). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35 (s, 12 H) 7.23 - 7.24 (m, 1 H) 7.69 7.73 (m, 1 H) 7.86 - 7.91 (m, 2 H) 7.98 - 8.05 (m, 2 H).

Step B) (2R)-445- Fluoro-4-(4-( 1, 3-oxazol-2-vl)Dhenvl1-2-oxopvridin-1 (2Η)-νΙΤ·2methyl-2-(methylsulfonvl)-N-(tetrahvdro-2H-pvran-2-yloxy)butanamide The title compound (145 mg, 30.7%) was obtained as a colorless oil from 2-(4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-oxazole (240 mg, 0.89 mmol) and (2R)4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2Hpyran-2-yloxy)butanamide, T3, (435 mg, 0.84 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2yloxy)butanamide, Example 19, Step A. MS (APCI) m/z 532.5 (M-1). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.52- 1.98 (m, 9 H) 2.35 - 2.47 (m, 1 H) 2.48 - 2.60 (m, 1 H) 3.20 (d, J=2.93 Hz, 3 H) 3.56 - 3.71 (m, 1 H) 3.96 - 4.07 (m, 1 H) 4.12 - 4.22 (m, 1 H) 4.32 - 4.46 (m, 1 H) 5.12 - 5.23 (m, 1 H) 6.69 - 6.75 (m, 1 H) 7.27 (s, 1 H) 7.37 - 7.45 (m, 1 H) 7.63 (dd, J=8.39, 1.56 Hz, 2 H) 7.75 (s, 1 H) 8.14 (d, J=8.39 Hz, 2 H) 11.79 11.95 (m, 1 H).

Step C) (2R)-4-45-Fluoro-4-[4-(1 .a-oxazolAvIlDhenyll-AoxoDvridin-l (2Η)-νΙΪ-Νhvdroxv-2-methyl-2-(methylsulfonvl)butanamide

The title compound (31 mg, 25%) was obtained as a solid from (2R)-4-{5-fluoro-4-[4(1,3-oxazol-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N(tetrahydro-2H-pyran-2-yloxy)butanamide (145 mg, 0.27 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-4-(4-isoxazol-3ylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, Example 41, Step C. MS (APCI) m/z 450.2 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.55 (s, 3 H) 2.11 - 2.23 (m, 1 H) 2.39 - 2.47 (m, 1 H) 3.09 (s, 3 H) 3.61 - 3.84 (m, 1 H) 3.91 - 4.12 (m, 1 H) 6.58 (d, J=7.61 Hz, 1 H) 7.41 (s, 1 H) 7.72 (d, J=7.02 Hz, 2 H) 7.91 -8.12 (m, 3 H) 8.25 (s, 1 H) 9.12-9.29 (m, 1 H) 10.87 -11.17 (m, 1 H).

Example 43 (2R)-4-[5-Fluoro-4-(4-Îrideuteromethvlphenvh-2-oxopyridin-1(2H)-vll-N-hydroxv-2methvl-2-(methylsulfonvl)butanamide

Step A) (2R)-4-r5-Fluoro-4-(4-trideuteromethylphenvl)-2-oxopvridin-1(2H)-vl1-2meÎhvl-2-(methvlsulfonvl)-N-(tetrahvdro-2H-pvran-2-yloxy)butanamide

The title compound (216 mg, 76.9%) was obtained as a light orange oil from (4trideuteromethylphenyl)boronic acid (85 mg, 0.61 mmol) and (2R)-4-(5-fluoro-4-iodo-2oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2yloxy)butanamide,T3, (300 mg, 0.58 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2oxopyridin-1 (2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2yloxy)butanamide, Example 19, Step A. MS (APCI) m/z 482.4 (M-1). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.50 - 1.97 (m, 9 H) 2.32 - 2.44 (m, 1 H) 2.44 - 2.59 (m, 1 H) 3.17 (d, J=2.34 Hz, 3 H) 3.53 - 3.69 (m, 1 H) 4.00 (br. s., 1 H) 4.10 - 4.20 (m, 1 H)

4.31 (br. s., 1 H) 5.14 (d, J=14.44 Hz, 1 H) 6.65 (dd, J=7.22, 1.56 Hz, 1 H) 7.21 -7.28 (m, 2 H) 7.36 (d, J=5.27 Hz, 1 H) 7.38 - 7.44 (m, 2 H) 11.89 -12.06 (m, 1 H).

Step B) (2R)-4-[5-Fluoro-4-(4-trideuteromethvlDhenvn-2-oxoDvridin-1 (2H)-vl1-Nhydroxv-2-methvl-2-(methvlsulfonyl)butanamide

The title compound (62 mg, 35%) was obtained as a solid from (2R)-4-[5-fluoro-4-(4trideuteromethylphenyl)-2-oxopyridin-1(2H)-yl]-2-meÎhyl-2-(methylsulfonyl)-N(tetrahydro-2H-pyran-2-yloxy)butanamide (145 mg, 0.27 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-4-(4-isoxazol-3ylphenyl)-2-oxopyridin-1 (2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, Example 41, Step C. MS (APCI) m/z 400.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.54 (s, 3 H) 2.14 (br. s., 1 H) 2.47 (br. s., 1 H) 3.08 (s, 3 H) 3.75 (br. s., 1 H) 4.02 (br. s., 1 H) 6.47 (d, J=7.61 Hz, 1 H) 7.28 (d, J=8.00 Hz, 2 H) 7.44 (d, J=7.02 Hz, 2 H) 7.98 (d, J=6.63 Hz, 1 H) 9.21 (s, 1 H) 11.07 (s, 1 H).

Example 44 (2R)-4-[5-Fluoro-4-(4-trideuteromethoxvDhenvl)-2-oxopyridin-1 (2H)-vll-N-hydroxv-2methyl-2-(methvlsulfonyl)butanamide

Step A) (2R)-4-f5-Fluoro-4-(4-trideuteromethoxyphenvn-2-oxopyridin-1(2H)-yl1-2methyl-2-(methylsulfonvn-N-ftetrahvdro-2H-pyran-2-vloxv)butanamide

The title compound (216 mg, 76.9%) was obtained as a colorless oil from (4trideuteromethoxyphenyl)boronic acid (120 mg, 0.78 mmol) and (2R)-4-(5-fluoro-4-iodo2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2yloxy)butanamide, T3, (400 mg, 0.78 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2oxopyridin-1 (2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2yloxy)butanamide, Example 19, Step A. (122 mg, 31.5%). MS (APCI) m/z 498.3 (M-1). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.49 -1.98 (m, 9 H) 2.38 (dd, J=7.12, 3.80 Hz, 1 H) 2.44 - 2.61 (m, 1 H) 3.18 (d, J=2.54 Hz, 3 H) 3.65 (d, J=11.51 Hz, 1 H) 3.89-4.04 (m, 1 H) 4.11 -4.22 (m, 1 H) 4.24-4.38 (m, 1 H) 5.15 (d, J=14.63 Hz, 1 H)

6.64 (dd, J=7.41, 1.37 Hz, 1 H) 6.96 (d, J=8.78 Hz, 2 H) 7.35 (d, J=5.66 Hz, 1 H) 7.43 7.51 (m, 2 H) 12.02 (d, J=15.02 Hz, 1 H).

\Z

Step B) (2R)-4-i5-fluoro-4-(4-trideuteromethoxvohenvl)-2-oxopvridin-1 (2H)-vll-Nhvdroxv-2-methyl-2-(methvlsulfonvl)biJtariamide

The title compound (55 mg, 55%) was obtained as a solid from (2R)-4-[5-fluoro-4-(4trideuteromethoxyphenyl)-2-oxopyridin-1 (2H)-yl]-2-methyl-2-(methy1sulfonyl)-N(tetrahydro-2H-pyran-2-yloxy)butanamide (120 mg, 0.24 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-4-(4-isoxazol-3ylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide_fExample 41, Step C. MS (APCl) m/z 416.1 (M+1). ¹H NMR (400 MHz, DMSO-de) δ ppm 1.54 (s, 3 H) 2.14 (br. s., 1 H) 2.47 (br. s., 1 H) 3.08 (s, 3 H) 3.74 (br. s„ 1 H) 4.02 (br. s., 1 H) 6.46 (d, 4=7.81 Hz, 1 H) 7.02 (d, 4=8.39 Hz, 2 H) 7.51 (d, 4=7.41 Hz, 2 H) 7.96 (d, 4=6.63 Hz, 1 H) 9.20 (s, 1 H) 11.07 (s, 1 H).

Example 45 (2R)-4-f4-(4-Pentadeuteroethoxyphenvl)-5-fluoro-2-oxopyridin-1(2H)-yl1-N-hydroxy-2methvl-2-(methvlsulfonyl)butanamide

NHOH

Step A) (2R)-4-f4-i4-Pentadeuteroethoxvohenyl)-5-fluoro-2-oxopyridin-1(2H)-vll-2methvl-2-(methvlsulfonvl)-N-(tetrahvdro-2H-pyran-2-yloxv)butanamide

The title compound (184 mg 46.0%) was obtained as a colorless oil from (4pentadeuteroethoxyphenyl)boronic acid (132 mg, 0.78 mmol) and (2R)-4-(5-fluoro-4iodo-2-oxopyridin-1 (2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2yloxy)butanamide, T3, (400 mg, 0.78 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2oxopyridin-1 (2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2yloxy)butanamide, Example 19, Step A. MS (APCl) m/z 514.4 (M-1). ¹H NMR (400 MHz, CHLOROFORM-4) δ ppm 1.53 - 1.97 (m, 9 H) 2.39 (dt, 4=7.27, 3.68 Hz, 1 H) 2.45 - 2.60 (m, 1 H) 3.19 (d, 4=2.73 Hz, 3 H) 3.65 (d, 4=11.51 Hz, 1 H) 3.90 - 4.04 (m, 1 H) 4.16 (dd, 4=11.22, 2.44 Hz, 1 H) 4.24-4.38 (m, 1 H) 5.16 (d, 4=14.83 Hz, 1 H) 6.64 (dd, 4=7,42, 1.17 Hz, 1 H) 6.95 (d, 4=8.59 Hz, 2 H) 7.34 (d, 4=5.66 Hz, 1 H) 7.40 - 7.52 (m, 2 H) 12.03 (br. s., 1 H).

Step B) (2R)-4-i4-i'4-Pentadeuteroethoxvphenvl)-5-fluoro-2-oxoDvridin-1 (2H)-vll-Nhydroxv-2-methvl-2-(methvlsulfonyl)butanamide

The title compound (152 mg, 98.7%) was obtained as an off-white solid from (2R)-4-[4(4-pentadeuteroethoxyphenyl)-5’fluoro-2-oxopyridin-1 (2H)-yl]-2-methyl-2(methylsulfonyl)-N-(tetrahydro-2H-pyran’2-yloxy)butanamide (120 mg, 0.24 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-4-(4isoxazol-3“ylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2(methylsulfonyl)butanamide, Example 41, Step C. MS (APCI) m/z 432.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.54 (s, 3 H) 1.89 - 2.22 (m, 1 H) 2.32 - 2.47 (m, 1 H) 2.92 - 3.15 (m, 3 H) 3.57 - 3.80 (m, 1 H) 4.01 (br. s., 1 H) 6.45 (d, J=7.81 Hz, 1 H) 7.01 (d, J=8.78 Hz, 2 H) 7.50 (d, J=7.22 Hz, 2 H) 7.96 (d, J=6.83 Hz, 1 H) 9.21 (br. s., 1 H) 11.08 (s, 1 H).

Example 46 (2R)-4-i4-[4-(Cyclopropvloxy)phenvll-5-fluoro-2-oxopyridin-1 (2H)-vl}-N-hvdroxy-2methyl-2-(methvlsulfonvl)butanamide

NHOH

Step A) 2-r4-(Cyclopropyloxy)phenyll-4,4.5.5-tetramethvl-1,3.2-dioxaborolane

Pd(dppf)CI₂ (770 mg, 0.94 mmol) was added to a degassed suspension of 1-bromo-4(cyclopropyloxy)benzene (2.0 g, 9.39 mmol), potassium acetate (2.76 g, 28.12 mmol), and 4,4_l4^,,4'l5l5,5',5'-octamethyl-2,2^,-bi-1,3)2-dioxaborolane (2.62 g, 10.32 mmol) in anhydrous DMSO (20 mL). The réaction was heated to 80 °C and stirred at this température for 5 h. The réaction was allowed to cool to rt and diluted with water and diethyl ether. The organic phase was separated and the aqueous phase was extracted with diethyl ether. The organics were combined, dried (MgSO₄), filtered, and concentrated in vacuo. Hexanes were added to the residue and the resulting yellow solution was decanted from the brown residue. The yellow solution was concentrated, and the residue was purified via column chromatography using an eluent of 2% ethyl

acetate in hexanes to afford title compound as a colorless oil (878 mg, 36%). MS (LCMS) m/z 261.2 (M+1). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.74 - 0.83 (m, 4 H) 1.34 (s, 12 H) 3.73 - 3.82 (m, 1 H) 7.05 (d, 2 H) 7.75 (d, 2 H).

Step B) (2R)-4i4-r4-(Cvclopropvloxy)phenvl1-5-fluoro-2-oxopyridin-1 (2H)-vl>-2methvl-2-(methvlsulfonyD-N-ftetrahvdro-2H-Dvran-2-vloxv)butanamide The title compound (560 mg 55.3%) was obtained as a colorless oil from 2-[4(cyclopropyloxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (554 mg, 2.13 mmol) and (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N(tetrahydro-2H-pyran-2-yloxy)butanamide,T3, (1.0 g, 1.94 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-4-(3-fluoro-4methoxyphenyl)-2-oxopyridin-1 (2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2Hpyran-2-yloxy)butanamide, Example 19, Step A. MS (APCI) m/z 521.4 (M-1). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.57 - 0.82 (m, 4 H) 1.42 -1.91 (m, 9 H) 2.27 -

2.41 (m, 1 H) 2.41 - 2.58 (m, 1 H) 3.13 (s, 4 H) 3.45 - 3.64 (m, 1 H) 3.72 (dd, J=5.46, 2.93 Hz, 1 H) 3.80-3.98 (m, 1 H) 4.12 (d, J=10.93 Hz, 1 H) 4.17 - 4.31 (m, 1 H) 5.11 (d, J=13.85 Hz, 1 H) 6.59 (d, J=7.41 Hz, 1 H) 6.97 - 7.13 (m, 2 H) 7.36 (d, J=5.46 Hz, 1 H) 7.43 (d, J=8.59 Hz, 2 H) 11.82 -12.08 (m, 1 H).

Step B) (R)-4-(4-(4-Cvclopropoxvphenyl)-5-fluoro-2-oxopyridin-1(2H)-vn-Nhvdroxy-2-methyl-2-(methylsulfonvl)butanamide

The title compound (280 mg, 59.6%) was obtained as an off-white solid from (2R)-4-(4(4-cyclopropoxyphenyl)-5-fluoro-2-oxopyridin-1 (2H)-yl)-2-methyl-2-(methylsulfonyl)-N(tetrahydro-2H-pyran-2-yloxy)butanamide (560 mg, 1.07 mmol) using a procedure analogous to that described for the préparation of (R)-4-(5-fluoro-4-(4-(isoxazol-3yl)phenyl)-2-oxopyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, Example 41, Step C. MS (APCI) m/z 439.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) ^r“ ppm 0.55 - 0.69 (m, 2 H) 0.74 - 0.85 (m, 2 H) 1.54 (s, 3 H) 2.03 - 2.26 (m, 1 H) 2.33 -

2.46 (m, 1 H) 3.08 (s, 3 H) 3.64 - 3.80 (m, 1 H) 3.88 (dt, J=6.05, 3.02 Hz, 1 H) 3.94 4.10 (m, 1 H) 6.46 (d, J=7.81 Hz, 1 H) 7.02 - 7.23 (m, 2 H) 7.52 (dd, J=8.78, 1.95 Hz, 2 H) 7.97 (d, J=6.63 Hz, 1 H) 9.21 (s, 1 H) 11.08 (s, 1 H).

Example 47 (2R)-444-(2,2-Difluoro-1.3-benzodioxol-5-yl)-5-fluoro-2-oxopyridin-1 (2H)-vn-N-hvdroxv2-methyl2-(methylsulfonvl)butanamide

ΝΗΟΗ

Step A) (2R)-4-[4-(2.2-Difluoro-1.3-benzodioxol-5-vl)-5-fluoro-2-oxopyridin-1 (2H)vn-2-meÎhyl-2-(meÎhylsulfonvn-N-(tetrahvdro-2H-pyran-2vloxv)butanamide

The title compound (560 mg 55.3%) was obtained as a colorless oil from (2,2-difluoro-

1.3- benzodioxol-5-yl)boronic acid (129 mg, 0.639 mmol) and (2R)-4-(5-fluoro-4-iodo-2oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2yloxy)butanamide, T3, (300 g, 0.581 mmol) using a procedure analogous to that described for the préparation of (2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2oxopyridin-1(2H)-yl]-2~methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2yloxy)butanamide, Example 19, Step A. MS (LCMS) m/z 545.3 (M-1).

Step B) (2Η)-4-Γ4-(2,2-ΡίίΙυθΓθ-1,3·^6ηζοάιοχοΙ-5-νΙ)-54ΙυοΓθ-2-οχορνπάΐη-1(2Η)vl1-N-hvdroxy-2-methvl-2-(methvlsulfonvl)butanamide

Aqueous HCl (1.42 mL, 1.42 mmol) was added to a solution of (2R)-4-[4-(2,2-Difluoro-

1.3- benzodioxol-5-yl)-5-fluoro-2-oxopyridin-1 (2H)-yl]-2-methyl-2-(methylsulfonyl)-N(tetrahydro-2H-pyran-2-yloxy)butanamide (259 mg, 0.474 mmol) in éthanol (5 mL) and water (2 mL) and the reaction was stirred overnight at rt. The solid was collected via filtration, washed with water (5x3 mL) and dried under reduced pressure to afford the title compound (143 mg, 65.3%). ¹H NMR (400 MHz, DMSO-de) d ppm 1.58 (s, 3 H) 2.07 - 2.24 (m, 1 H) 2.36 - 2.49 (m, 1 H) 3.11 (s, 3 H) 3.68 - 3.86 (m, 1 H) 3.98 - 4.13 (m, 1 H) 6.58 (d, /=7.61 Hz, 1 H) 7.36 - 7.49 (m, 1 H) 7.55 (d, /=8.39 Hz, 1 H) 7.68 (s, 1 H) 8.06 (d, /=6.63 Hz, 1 H) 9.24 (br. s., 1 H) 11.08 (s, 1 H).

Example 48 (2R)-4-r5-Fluoro-2-oxo-4-(phenvlethvnvl)pyridin-1(2H)-vll-N-hvdroxy-2-methvl-2(methylsulfonvl)butanamide

Step A) Ethyl (2RM-f5-fluoro-2-oxo-4-(Dhenvlethvnvl)Dyridin-1 (2H)-yl]-2-methyl-2(methylsulfonvl)butanoate

A solution of ethyl (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1 (2H)-yl)-2-methyl-2(methylsulfonyl)butanoate (500 mg, 1.12 mmol) and diisopropylethylamine (6.0 mL, 30 mmol) in tetrahydrofuran (15 mL) was degassed with nitrogen. Pd(PPh₃)₄ (65.4 mg, 0.056) and copper iodide (21.8 mg, 0.112 mmol) were added to the solution, followed by phenylacetylene (150 uL, 1.4 mmol). The reaction was allowed to stir until complété via TLC. The reaction was diluted with EtOAc (100 mL) and washed with saturated aq NH₄CI (100 mL) and brine (100 mL), dried (MgSO₄), filtered, and concentrated. The crude residue was purified via flash chromatography using a Varian SF15-24g column and an eluent of EtOAc in hexanes (30-80%) to afford the title compound as a yellow solid (389 mg, 82.6 %). MS (LCMS) m/z 420.0 (M+1). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35 (t, 3 H) 1.75 (s, 3 H) 2.42 - 2.61 (m, 2 H) 3.11 (s, 3 H) 3.91 - 4.00 (m, 1 H) 4.19 - 4.27 (m, 1 H) 4.30 (q, J=7.02 Hz, 2 H) 6.72 (d, J=6.63 Hz, 1 H) 7.27 (t, J=2.34 Hz, 2 H) 7.35 - 7.44 (m, 2 H) 7.55 - 7.60 (m, 2 H).

Step B) (2R)-445-Fluoro-2-oxo-4-(DhenylethynyODvridin-1(2H)-vll-2-methyl-2(methylsulfonvllbutanoic acid

The title compound (195.1 mg, 72.1%) was obtained as a white solid from ethyl (2R)-4[5-fluoro-2-oxo-4-(phenylethynyl)pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoate (290 mg, 0.52 mmol) using a procedure analogous to that described for the préparation of ethyl (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-ΐΠ3ΖθΙ-2-γl)phenyl]pyridin-1 (2H)-yl}-2methyl-2-(methylsulfonyl)butanoate, Example 26, Step C. MS (LCMS) m/z 392.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.55 (s, 3 H) 2.10 - 2.24 (m, 0 H) 2.40 - 2.56 (m, 1 H) 3.16 (s, 3 H) 3.87 - 4.06 (m, 2 H) 6.65 (d, J=6.83 Hz, 1 H) 7.43 - 7.55 (m, 3 H) 7.57 -

7.65 (m, 2 H) 8.07 (d, J=5.46 Hz, 1 H).

Step C) (2R)-4-[5-Fluoro-2-oxo-4-(Dhenylethvnvl)Dvridin-1 (2H)-yl1-2-methyl-2(methylsulfonyl)-N-(tetrahydro-2H-Dvran-2-vloxv)butanamide

The title compound (232 mg, 95.0%) was obtained as a white solid from (2R)-4-[5fluoro-2-oxo-4-(phenylethynyl)89yridine-1 (2H)-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (195.1 mg, 0.50 mmol) using a procedure analogous to that described for the préparation of (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1 (2H)-yI}2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide Example 26,

Step D.

Step D) (2R)-4-r5-Fluoro-2-oxo-4-(phenvlethvnyl)90vridine-1 (2H)-vl1-N-hvdroxv-2methvl-2-(methylsulfonvl)butanamide

The title compound (124.4 mg, 64.7%) was obtained as a white solid from (2R)-4-[5fluoro-2-oxo-4-(phenylethynyl)90yridine-1 (2H)-yl]-2-methyl-2-(methylsulfonyl)-N(tetrahydro-2H-pyran-2-yloxy)butanamide (232 mg, 0.47 mmol) using a procedure analogous to that described for the préparation of (2R)-4-{5-Fluoro-2-oxo-4-[4-(2H-

1,2,3-triazol-2-yl)phenyl]pyridin-1 (2H)-yl}-N-hydroxy-2-methyl-2(methylsulfonyl)butanamide, Example 26, Step E. MS (LCMS) m/z 407.0 (M+1). ¹H NMR (400 MHz, DMSO-d_e) δ ppm 1.56 (s, 3 H) 2.04 - 2.21 (m, 1 H) 2.37 - 2.49 (m, 1 H) 3.10 (s, 3 H) 3.69-3.85 (m, 1 H) 3.92-4.12 (m, 1 H) 6.69 (d, 1 H) 7.39-7.57 (m, 3 H) 7.57 - 7.68 (m, 2 H) 8.05 (d, 7=5.46 Hz, 1 H) 9.22 (s, 1 H) 11.04 (s, 1 H).

Example 49 (2R)-4-(5-Fluoro-2-oxo-4-r3-(1.3-thiazol-2-vloxv)phenvllpvridin-1 (2Η)-νΙ)-Ν->~^Γθχν-2methyl-2-(methvlsulfonyl)butanamide

NHOH

Step A) 2-(3-lodophenoxv)-1,3-thiazole

Césium carbonate (4.52 g, 13.87 mmol) was added to 2-bromo-1,3-thiazole (1.90 g, 11.6 mmol) and 3-iodophenol (2.54 g, 11.5 mmol) in anhydrous DM F (30 mL). The reaction was heated to 135 °C and stirred at this température overnight. The reaction was allowed to cool, then was poured into water (100 mL), and extracted with EtOAc (3x100 mL). The combined organics were washed with brine (100 mL), dried (MgSO₄), filtered, and concentrated. The crude product was purified via flash chromatography using a Varian SF15-24g column and an eluent of EtOAc in hexanes (0-10%) to afford the title compound as a yellow oil (2.52 g, 71.8%). MS (LCMS) m/z 304.1 (M+1).

Step B) 243-(4,4,5.5-Tetramethvl-1.3.2-dioxaborolan-2-yl)Dhenoxvl-1,3-thiazole

The title compound (1.33 g) was prepared as a crude brown solid from 2-(3iodophenoxy)-1,3-thiazole (500 mg, 1.65 mmol) using a procedure analogous to that described for 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-tetrazole, Example 1, Step A. MS (LCMS) m/z 304.0 (M+1).

Step C) Ethyl (2R)-445-fluoro-2-oxo-4-r341.3-thiazol-2-yloxv)phenvllpyridin-1 (2H)vl}-2-methvl-2-(methvlsulfonyl)butanoate

The title compound (534 mg) was prepared as a crude brown oil from 2-(3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-1,3-thiazole (1.33 g, 4.39 mmol) and T2 (400 mg, 0.90 mmol) using a procedure analogous to that described for ethyl (2R)-4-(5f I uo ro -2-ΟΧΟ-4- (44(t ran s -4- (tetrahyd ro-2 H -py ran-2yloxy)cyclohexyl]methoxy}phenyl)pyridin-1 (2H)-yl]-2-methyl-2(methylsulfonyl)butanoate, Example 18, Step D. MS (LCMS) m/z 495.2 (M+1).

Step D) (2Ρ)-445-ΡΙυοΓθ-2-οχο-443-(1,3-ΐΐΊΪ3ΖθΙ-2-νΙοχν)ρΐΊθηνΙ1ρνπάΐη-1(2Η)-νΙ}-2methvl-2-(methvlsulfonvl)butanoic acid

The title compound (144 mg, 28.4%) was prepared as an off-white solid from ethyl (2R)4-{54luoro-2-oxo-4-[3-(1,3-thiazol-2-yloxy)phenyl]pyridin-1(2H)-yl}-2-methyl-2(methylsulfonyl)butanoate (538 mg, 1.09 mmol) using a procedure analogous tothat described for (2R)-4~(5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1 (2H)-y I}2-methyl-2-(methylsulfonyl)butanoic acid, Example 26, Step C. MS (LCMS) m/z 467.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.57 (s, 3 H) 2.12 - 2.27 (m, 1 H) 3.17 (s, 3 H) 3.85 - 4.11 (m, 2 H) 6.55 (d, J=7.61 Hz, 1 H) 7.24 - 7.35 (m, 2 H) 7.44 - 7.66 (m, 4 H) 8.07 (d, J=6.44 Hz, 1 H).

Step E) (2R)-445-Fluoro-2-oxo-4-r3-(1,3-thiazol-2-vloxv)DhenvllPvridin-1(2H)-yl}-2methyl-2-(methvlsulfonvl)-N-(tetrahvdro-2H-Dvran-2-yloxy)butanamide

The title compound (115 mg, 65.8%) was prepared as an off-white solid from (2R)-4-{5fluoro-2-oxo-4-[3-(1,3-thiazol-2-yloxy)phenyl]pyridin-1 (2H)-yl}-2-methyl-2(methylsulfonyl)butanoic acid (144 mg, 0.31 mmol) using a procedure analogous to that described for (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1 (2H)-yl}2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, Example 26, Step D. MS (LCMS) m/z 566.2 (M-1).

n/

Step F) f2R)-4-i5-fluoro-2-oxo-4-Î3-(1.3-thiazol-2-vloxv)phenvnpvridin-1 (2Ηΐ-νΙΕΝhvdroxy-2-meÎhvl-2-(methylsulfonvl)butanamide

The title compound (66.8 mg, 68.4%) was prepared as a white solid from (2R)-4-{5fluoro-2-oxo-4-[3-(1,3-thiazol-2-yloxy) phenyl] pyridin-1 (2H)-yl}-2-m ethyl-2(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (115 mg, 0.20 mmol) using a procedure analogous to that described for (2R)-4-(5-fluoro-2-oxo-4-[4-(2H-1,2,3triazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(meÎhylsulfonyl)butanamide, Example 26, Step E. MS (LCMS) m/z 482.2 (M+1). ¹H NMR (400 MHz, DMSO-tf_e) δ ppm 1.57 (s, 3 H) 2.09 - 2.23 (m, 1 H) 3.11 (s, 3 H) 3.70 - 3.87 (m, 1 H) 3.97 - 4.14 (m, 1 H) 6.58 (d, 7=7.61 Hz, 1 H) 7.25 - 7.35 (m, 2 H) 7.45 - 7.67 (m, 4 H) 8.06 (d, 7=6.44 Hz, 1 H) 9.23 (s, 1 H) 11.08 (s, 1 H).

BIOLOGICAL EXAMPLES

In order to assess the compounds biological activity, selected in vitro assays were conducted on selected compounds. One of the assays measured the compounds ability to disrupt the synthesis of lipopolysaccharide, LPS, which is a component of the outer membrane of Gram-negative bacteria. Disruption of this synthesis is léthal to the bacteria. The assay determined the compound’s ability to inhibit LpxC, which is the first enzyme in the biosynthetic pathway for LPS (measured as IC50). Additionally, MICs (minimal inhibitory concentrations) were determined for several bacteria. The spécifie protocols are described below:

A) ICsn assay, LoxC enzyme from P. aeruainosa (labeled as PA LpxC enzyme ICm):

IC50 détermination in the LpxC enzyme assay was carried out in a similar manner to that described by Malikzay et al in the 2006 Poster, Screening LpxC (UDP-3-O-(R-3hydroxymyristoyl)-GlcNAc deacetylase) using BioTrove RapidFire HTS Mass Spectrometry (aNew Lead Discovery and ^Inflammation and Infectious Disease, cStructural Chemistry, Schering-Plough Research Institute, Kenilworth, NJ 07033, (BioTrove, Inc. 12 Gill St., Suite 4000, Woburn, MA 01801). Briefly, Pseudomonas aeruginosa LpxC enzyme (0.1 nM) purified from E. co/i-overexpressing bacteria was incubated at 25 °C in a final volume of 50 ul containing 0.5 uM UDP-3-O-(R-3hydroxydecanoyl)-N-acetylglucosamine, 1 mg/mL BSA, and 50 mM sodium phosphate buffer, pH 8.0 in the presence and absence of inhibitor compound. At the end of 1 hour, 5 ul of 1 N HCl was added to stop the enzyme reaction, the plates were centrifuged, and then processed with the BioTrove Rapidfire HTMS Mass Spectrometry System. A noxZ enzyme control was used in calculating the IC50 values from the percent conversion values.

B) MIC déterminations: The in vitro antibacterial activity of compounds described in the Examples was evaluated by minimum inhibitory concentration (MIC) testing according to Clinical and Laboratory Standards Institute (CLSI). See: Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard-Eighth Edition. CLSI document M7-A8 [ISBN 1-56238-689-1]. Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2006; also Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing; Twentieth Informational Supplément. CLSI document M100-S20 [ISBN1-56238-716-2].CIinical and Laboratory Standards Institute.

The MIC détermination is a standard laboratory method for evaluating the antibacterial activity of a compound. The MIC represents the lowest drug concentration that inhibits visible growth of bacteria following ovemight incubation, ln order to détermine the MIC value, a range of drug concentrations (e.g. 0.06 pg/mL to 64 pg/mL) are incubated with a defined strain of bacteria. Typically, the drug concentration range is broken down into 2-fold incréments (e.g. 0.06 pg/mL , 0.12 pg/mL. 0.25 pg/mL, 0.50 pg/mL, 1.0 pg/mL, etc.) and the various drug concentrations are ail individually incubated ovemight with approximately the same number of bacteria. The MIC is then determined by visually inspecting the drug effect at each concentration, and identifying the lowest drug concentration that has inhibited bacterial growth as compared to the drug free control. Typically, bacteria continue to grow at drug concentrations lower than the MIC and don’t grow at concentrations at and above the MIC.

The MIC values described in Table 2 and 3 below were derived from assays wherein each test compound was evaluated in duplicate. ln cases where the duplicate values varied by 0 - 2-fold, the lower of the two values was reported below. Generally speaking, if the duplicate values varied by more than 2-fold, the assay was considered non-valid and was repeated until the variation between duplicate runs was £ 2-fold. ln line with the CLSI guidelines referred to above, both control organisms and reference compounds were utilized in each MIC assay to provide proper quality control. MIC values generated with these control organisms and reference compounds were required to fall within a defined range for the assay to be considered valid and be included herein. Those skilled in the art will recognize that MIC values can and do vary from

experiment to experiment. Generally speaking, it should be recognized that MIC values often vary +/- 2-fold from experiment to experiment. While a single MIC is reported for each compound and each microorganism, the reader should not conclude that each compound was only tested once. Several of the compounds were subjected to multiple tests. The data reported in Tables 2 and 3 is reflective of the compounds relative activity and different MICs may have been generated on these occasions in line with the guidelines described above.

The following bacterial strains were used in these MIC déterminations:

1) Pseudomonas aeruginosa UI-18: Wild-type, labeled as PA-7 in Tables 2 and 3;

2) Acinetobacter baumannii/haemolyticus: Multidrug-resistant clinical isolate labeled as AB-3167 in Tables 2 and 3;

3) Escherichia coli EC-1: VOGEL, mouse virulent labeled as EC-1 in Tables 2 and 3;

4) Klebsiella pneumoniae: Ciprofloxacin-resistant isolate, expresses extendedspectrum beta-lactamases (ESBL), clinical isolate, labeled as KP-3700 in Tables 2 and 3.

Table 2, below, shows the results that were obtained with the final products described in Examples 1 -47. If a particular table entry is left blank, then the data is not available at the current time.

Column 1 corresponds to the Example number, column 2 provides the IUPAC name, column 3 provides the results from the LpxC enzyme assay described above, and columns 4-7 provide the MIC data as described above.

Table 2

Example	IUPACNAME	PA:IC50 (μΜ)	AB3167 (pg/mL)	EC-1 (pg/mL)	KP3700 (M9/mL)	PA-7 (pg/mL)
1	(2 R) - 4 —(5-1 lu oro-2-oxo -4- [4- (2 Htetrazol-2-yl) pheny IJpyrid in -1 (2 H)yl}-N-hydroxy-2-mathyl-2(methylsu If onyl) butanam ide	0.00149	>64.0	>64.0	>64.0	32
2	(2R)-4-[5-fluoro-4-(2-fluoro-3methylphenyl)-2-oxopyridin-1(2H)yl]-N-hydroxy-2-methyl-2(methylsulfonyl)butanamide	0.000595	>64.0	0.25	1	0.25
3	(2R)-4-[4-(4-chlorophenyl)-5-fluoro- 2-oxopyridin-1(2H)-yl]-N-hydroxy-2methyl-2(methylsulfonyl)butanamide	0.000325	64	0.25	1	0.25
4	(2R)-4-[5-fluoro-4-(2-fluorophenyl)- 2-oxopyridin-1(2H)-yl]-N-hydroxy-2-	0.000717	>64.0	2	4	0.5

	methyl-2(methylsulfonyl)butanamide
5	(2R)-4-[4-(2,3-dihydro-1benzofuran-5-yl)-5-fluoro-2oxopyridin-1(2H)-yl]-N-hydroxy-2methyl-2(methylsulfonyl)butanamide	0.000822	>64.0	1	2	1
6	(2R)-4-[4-(3,4-difluorophenyl)-5fluoro-2-oxopyridin-1 (2H)-yl]-Nhydroxy-2- m ethyl-2(methylsu Ifonyl) butanam ide	0.000833	>64.0	1	2	0.5
7	(2R)-4-{5-fluoro-2-oxo-4-[4-(2,2,2trifluoroethoxy)phenyl]pyridin-1 (2H)yl}-N-hydroxy-2-methyl-2(methylsulfonyl)butanamide	0.000576	>64.0	0.25	2	1
8	(2R)-4-[4-{3,4-dihydro-2H-chromenè-y I) -5-f luoro-2-oxopyrid in-1 (2 H) -y ΟΝ - hyd roxy-2-methy I-2(methylsulfonyl)butanamide	0.000377	>64.0	0.5	2	1
19	(2R)-4-{5-f!uoro-4-[4- (methylthio)phenylJ-2-oxopyridin1 (2H)-yl}-N-hydroxy-2-methyl-2(methylsulfonyl)butanamide	0.00051	>64.0	0.25	1	0.5
10	(2R)-4-[4-(4-ethoxyphenyl)-5-fluoro- 2-oxopyridin-1(2H)-yl]-N-hydroxy-2methyl-2(methvlsu Ifonyl) butanam ide	0.000823	>64.0	0.25	1	1
11	(2R)-4-[5-fluoro-2-oxo-4-(4propylphenyl)pyridin-1 (2H)-yl]-Nhydroxy-2-methyl-2(methvlsulfonyl)butanamide	0.000482	>64.0	0.125	0.5	0.5
12	(2R) - 4-{5-f luoro-2-oxo-4- [4(pentafluoro-6Asulfanyl)phenyl]pyridin-1(2H)-yl}-Nhydroxy-2-methyl-2(methylsulfonyl)butanamide	0.00114	>64.0	4	16	4
13	(2R)-4-[5-fluoro-4-(3-methylphenyl)- 2-oxopyridin-1(2H)-yl]-N-hydroxy-2methyl-2(methylsulfonyl)butanamide	0.00105	>64.0	1	4	1
14	(2R)-4-[5-fluoro-4-(4-fluoro-3methylphenyl)-2-oxopyridin-1(2H)yl]-N-hydroxy-2-methyl-2(methylsulfonyl)butanamide	0.000758	>64.0	0.5	2	0.5
15	(2 R) -4-{5-f luoro-4-[4-(oxetan-3yloxy)phenyl]-2-oxopyrîdin-1(2H)yl}-N-hydroxy-2-methyl-2(methylsulfonyl)butanamide	0.00205	>64.0	16	32	16
16	(2R)-4-[4-(4-chloro-2-fluorophenyl)- 5-f Iuoro-2-oxopyrid in-1 (2H) -yl]-Nhydroxy-2-methyl-2{methylsulfonyl)butanamide	0.000336	>64.0	0.25	1	0.5
17	(2R)-4-[5-fluoro-4-(2-flUoro-3methoxyphenyl)-2-oxopyridin-1(2H)yl]-N-hydroxy-2-methyl-2(methylsu Ifonyl) butanam ide	0.0005	>64.0	0.5	1	1
18	(2R)-4-[5-fluoro-4-{4-[(trans-4hyd roxycycl ohexy I) m ethoxy] pheny I}2-oxopyridin-1(2H)-yl]-N-hydroxy-2methyl-2(methytsulfonyl)butanamide	0.000463	>64.0	0.125	2	1
19	(2R)-4-[5-fluoro-4-(3-fluoro-4-	0.000879	>64.0	2	4	1

	methoxyphenyl)-2-oxopyridin-1(2H)yl]-N-hydroxy-2-methyl-2(m ethylsu If onyl) butanam ide
20	(2R)-4-[5-fluoro-2-oxo-4-(4pyrimidin-2-ylphenyl)pyridin-1(2H)y I] - N-h yd roxy-2-m ethyl-2(m ethylsu Ifony I) b utan a mid e	0.000945	>64.0	0.125	0.5	1
21	(2R)-4-{5-fluoro-4-[4-(5methoxypyrimidin-2-yl)phenyl]-2oxopyrid i n-1 (2H) - y)}- N - hyd roxy-2m ethyl-2(methylsulfonyl)butanamide	0.000436	>64.0	0.125	0.5	1
22	(2R)-445-fluoro-4-[4-(4-methoxy2H-1,2,3-triazol-2-yl)phenyl]-2oxo py rid in-1 (2 H) -y l}-N-hydroxy-2methyl-2(methylsulfonyl)butanamide	0.000181	>64.0	£0.0600	0.125	0.5
23	(2R)-445-tluoro-4-[4-(4-methyl-2H- 1,2,3-triazol-2-yl)phenyl]-2oxopyridin-1(2H)-yl}-N-hydroxy-2methyl-2- (m ethylsu Ifo nyl) butan amide	0.000287	>64.0	0.06	0.125	0.5
24	(2R)-4-(5-fluoro-2-oxo-4-quinoxalin- 6-y Ipy rid i n-1 (2H) -y I) -N-hyd roxy-2methyl-2(methvlsulfonyl)butanam ide	0.00123	>64.0	4	8	4
25	(2R)-4-[5-fluoro-4-(3methoxyphenyl)-2-oxopyridln-1(2H)yl]-N-hydroxy-2-methyl-2(methylsulfonyl)butanamide	0.000412	>64.0	1	4	2
26	(2R)-4-f5-fluoro-2-oxo-4-[4-(2H- 1,2,3-triazol-2-yl) phenyl] pyridin1 (2H)-yl}-N-hydroxy-2-methyl-2(methylsulfonyl) butanam ide	0.0000743	>64.0	£0.0600	£0.0600	0.25
27	(2R)-4-[5-fluoro-4-(2-fluoro-4methoxyphenyi)-2-oxopyridin-1(2H)yl]-N-hydroxy-2-methyl-2(methylsulfonyl) butanam ide	0.0000498	>64.0	0.25	0.5	0.5
28	(2R)-4-[5-fluoro-4-(4methoxyphenyl)-2-oxopyridin-1(2H)yl]-N-hydroxy-2-methyl-2(methylsulfonyl)butanamîde	0.000564	>64.0	1	1	0.5
29	(2R)-4-[5-fluoro-4-(4-methylphenyl)- 2-oxopyridin-1(2H)-yl]-N-hydroxy-2methyl-2(methylsulfonyl)butanamide	0.000514	>64.0	0.5	1	0.5
30	(2 R) -4-{5-f luo ro-2-oxo-4- [4(trifluoromethoxy)phenyl]pyridin1 (2H)-yl}-N-hydroxy-2-methyl-2(methylsulfonyl)butanamide	0.000106	>64.0	0.25	2	0,5
31	(2R)-4-[5-fluoro-4-(4-fluorophenyl)- 2-oxopyrîdin-1(2H)-yl]-N'hydroxy-2m ethyl-2(methylsulfonyl)butanamide	0.000213	>64.0	1	4	0.5
32	(2R)-4-{5-fluoro-4-[4-(6methoxypyridin-3-yl)phenyl]-2oxopyridin-1(2H)-yl}-N-hydroxy-2methyl-2(methylsulfonyl)butanamide	0.0004	>64.0	£0.0600	1	1
33	(2R)-4-{4-[4- (difluoromethoxy)phenyl]-5-fluoro-2oxopy rid i n-1 (2H )-yl}-N - hyd roxy-2-	0.0000606	>64.0	0.5	2	0.5

	methyl-2(methylsulfonyl)butanamide
34	(2R)-4-[5-fiuoro-4-(4-methoxy-3methylphenyl)-2-oxopyridln-1(2H)yl]-N-hydroxy-2-methyl-2(methylsulfonyl)butanamide	0.000834	>64.0	0.25	2	0.5
35	(2R)-4-{4-[4-(difluoromethoxy)-3fluorophenyl]-5-fluoro-2-oxopyridin- 1 {2H)-yl}-N-hydroxy-2-methyl-2(methylsulfonyl)butanamide	0.000589	>64.0	1	2	0.5
36	(2R)-445-fluoro-4-[3-fluoro-4-(2H- 1,2,3-triazol-2-yl) phenyl]-2oxopyridin-1(2H)-yl}~N-hydroxy-2methyl-2(methylsulfonyl)butanamide	0.000398	>64.0	0.5	1	1
37	(2R)-445-fiuoro-4-(3-methyl-4-(2H- 1,2,3-triazol-2-yl)phenyl]-2oxopyridin-1(2H)-yl]~N-hydroxy-2methyl-2- (m ethylsu If onyl) buta nam ide		>64.0	0.5	1	1
38	(2R)-4-(3,5-difluoro-2-oxo-4phenylpyrldin-1(2H)-yl)-N-hydroxy2-methyl-2(methylsulfonyl)butanamida	0.00055	>64.0	1	2	0.5
39	(2R)-4-(5-fluoro-3-methoxy-2-oxo-4phenylpyridin-1(2H)-yl)-N-hydroxy2-methyl-2(methylsulfonyl)butanamide	0.00807	64	4	8	8
40	(2 R) -4- (5-fluoro-3 -h yd roxy-2-oxo-4ph e nyl pyrid in -1 (2 H) -yl)- N-hyd roxy2-methyl-2(methylsulfonyl) butanam ide	>0.100	64	16	32	16
41	(2R)-4-[5-fiuoro-4-(4-isoxazol-3ylphenyl)-2-oxopyridin-1(2H)-yl]-Nh ydroxy-2-m ethyl-2(methylsu If onyl) butanam ide	0.000237	16	0.5	0.25	0.5
42	(2R)-4-(5-fluoro-4-[4-(1,3-Oxazol-2yl)phenyl]-2-oxopyridin-1(2H)-yl}-Nhydroxy-2-methyl-2(methylsulfonyl)butanamide	0.000328	>64.0	0.25	0.25	1
43	(2R)-4-[5-fluoro-4-(4-methylphenyl)- 2-oxopyridin-1(2H)-yl]-N-hydroxy-2methyl-2(methylsulfonyl)butanamide-d 3	0.000653	>64.0	0.25	1	0.5
44	(2R)-4-[5-fluoro-4-(4methoxyph eny I) -2-oxo pyrid I n-1 (2 H) yl]-N-hydroxy-2-methyl-2(methylsulfonyl)butanamide-d 3	0.000664	>64.0	0.25	1	0.25
45	(2R)-4-[4-(4-ethoxyphenyl)-5-fluoro- 2-oxopyrid in -1 (2H)-y I] - N -hyd roxy-2methyl-2(methylsulfonyl)butanamide-d 5	0.000547	>64.0	0.125	0.5	0.5
46	(2R)-4-{4-[4- (cyclopropyloxy)phenyl]-5-fluoro-2oxo py rid in-1 (2 H) -y l}-N-hydroxy-2methyl-2(methylsulfonyl)butanamide	0.000229	>64.0	0.125	0.5	0.5
47	(2R)-4-[4-(2,2-difluoro-1,3benzodioxol-5-yl)-5-fluoro-2oxo pyrid in-1 (2 H) -y I]- N-hyd roxy-2methyl-2(methylsulfonyl)butanamide		>64.0	0.25	1	0.5

48	(2R)-4-[5-Îluoro-2OXO-4- (phenylethynyl)pyridîn-l (2H)-yl]-Nhydroxy-2-methyl-2(mathylsulfonyl)butanamide	0.000555	>64.0	0.06	0.25	0.5
49	(2R)-4-(5-Fluoro-2-oxo-4-[3-(1,3thiazol-2-yloxy)phenyl]pyridin-1(2H)yl}-N-hydroxy-2-methyl-2(methylsulfonyl)butanamlde	0.000758	>64	0.25	1	2

Examples 50 to 125

The compounds named below can be made following the general procedures outlined in Examples 1-49 above. Products are typically derived from a Suzuki-Miyaura cross coupling, as described above utilizing the appropriate starting materials, with optional deprotection of a terminal hydroxamic acid protecting group. Methods used to describe the synthesis of the precursors or coupling partners such as boronic acids or esters are known to those skilled in the art.

In Table 3 below, column 1 corresponds to the Example number, column 2 provides the IUPAC name, columns 3-6 provide in vitro biological data generated in the same manner as in Table 2, columns 7 and 8 provide the rétention times and mass spectra generated via LCMS, using the method described below. Ail data is not currently available for ail compounds, as indicated by a blank cell in Table 3.

The LCMS rétention times reported in column 7 were generated in the following manner:

Gradient:

0.05% TFA 95:5 to 5:95 Water:ACN

Flow rate: 1.3 mL/min

Column dimensions: Acquity UPLC BEH C18 1.7 pm 2.1x30 mm.

Runtime: 1.1 minutes

Table 3

Example Number	IUPACNAME	PA;IC50 (μΜ)	AB3167 (MS/mL)	EC-1 (pg/mL)	PA:UC12120 (pg/mL)	Rétention Time	Mass
50	4-[5-fluoro-2-oxo-4-(3-oxo-2,3dihydro-1 H-isoindol-5-yl)pyridin1 (2H)-yl]-N-hydroxy-2-methyl-2(methylsulfonyl)butanamide	0.0682	>64.0	>64.0	>64.0	0.42	438.1
51	4-[5-f!uoro-4-(1H-indazol-6-yl)- 2-oxopyridin-1 (2H)-yl]-Nhydroxy-2-methyl-2(methylsulfonyl)butanamide	0.0039	>64.0	>64.0	>64.0	0.49	423.1
52	2-fluoro-4-{5-fluoro-1 -[4(hydroxyamino)-3-methyl-3(methylsulfonyl)-4-oxobutyl]-2oxo-1,2-dihydropyridin-4-yl}-N-	0.0022	>64.0	64	32	0.45	458.1

	methylbenzamide
53	4-[5-ftuora-4-(4-hydraxyphenyl)- 2-oxopyridin-1 (2H)-yl]-Nhydroxy-2-methyl-2(methylsulfonyl)butanamide	0.0042	>64.0	>64.0	64	0.46	399
54	4-(4-(2,5-dimethoxyphenyl)-5f luoro-2-oxo pyri d in-1 (2 H) -y I] - Nhydroxy-2-methyl-2(methylsulfonyl)butanamide	>0.100	>64.0	>64.0	>64.0	0.58	443.1
55	4-(5,5'-difluoro-2'-oxo-3,4‘bipyridin-1'(2'H)-yl)-N-hydroxy2-methyl-2- (methylsu Ifonyl) butanam ide	0.0668	>64.0	>64.0	64
56	4-[4-(3-chloro-5-fluorophenyl)-5fluoro-2-oxopyridin-1(2H)-yl]-Nhydroxy-2-methyl-2- (methylsu Ifonyl) butanamide	0.0020	>64.0	8	2
57	4-[5-fluoro-4-(2-methyl-3-oxo- 2,3-dihydro-1H-isoindol-5-yi)-2oxopyrîdin-1 (2H)-yl]-N-hydroxy2-methyl-2- (methylsulfonyl)butanamide	0.0210	>64.0	>64.0	>64.0	0.46	452.1 I
58	4-[4-(4-cyano-3-fluorophenyl)-5fluoro-2-oxopyridin-1(2H)-yl]-Nhydroxy-2-methyl-2- (m ethylsu If ony I) butan am ide	0.0026	>64.0	32	8
59	4-[5-fluoro-4-{4- methoxyphenyl)-2-oxopyridin- 1 (2H)-yl]-N-hydroxy-2-methyl-2(methylsulfonyl) butanam ide	0.0010	>64.0	1	1
60	4-(4-(4-(1 -cyano-1methylethyl)phenyl]-5-fluoro-2oxopyridin-1 (2H)-yl}-N-hydroxy2-methyl-2- (methylsu Ifonyl) butanam ide	0.0039	>64.0	32	4	0.61	450.1
61	4-[4-(3-acetamidophenyl)-5fluoro-2-oxopyridin-1(2H)-yi]-Nhydroxy-2-methyl-2(methylsulfonyl) butanam ide	>0.100	>64.0	>64.0	>64.0	0.47	440.1
62	4-(4-(3,5-difluoro-4- methoxyphenyl)-5-fluoro-2oxopyridin-1 (2H)-yl]-N-hydroxy2-methy!-2- (methylsulfonyl) butanamide	0.0020	>64.0	4	2	0.62	449
62	4-[4-(3,5-difIuorophenyl)-5fluoro-2-oxopyridin-1 (2H)-yl]-Nhydroxy-2-methyl-2(methylsulfonyl) butanamide	0.0031	>64.0	8	1	0.61	419
64	4-[5-fluoro-4-(2-methyl-1 -oxo- 2,3-dihydro-1H-isoindol-5-yl)-2oxopyridin-1 (2H)-yl]-N-hydroxy2-methyl-2- (methylsu Ifonyl) butanam ide	0.0072	>64.0	>64.0	64	0.44	452.1
65	4-(5^,-fluoro-2'-oxo-3,4'-bipyridin- 1 ‘(2'H)-yl)-N-hydroxy-2-methyl· 2-(methylsulfonyl)butanamide	0.0823	>64.0	>64.0	32	0.31	384.1
66	4-[4-(4-chloro-2-fluorophenyl)-5fluoro-2-oxopyridin-1(2H)-yl]-Nhydroxy-2-methyl-2(methylsulfonyl) butanamide	0.0008	64	0.5	0.5
67	4-[5-fluoro-4-(4-fluoro-3- m ethoxyp henyl) -2-oxopyridin -	0.0045	64	16	4	0.59	431

100

	1 (2H)-yl]-N-hydroxy-2-methyl-2(methylsulfonyl)butanamide
68	4~{5-f luoro-1 -(4-(hydroxyamino)- 3-methyl-3-(methylsulfonyl)-4oxobutyl]-2-oxo-1,2dihydropyridin-4-yl}-N,Ndimethylbenzamide	0.0343	>64.0	>64.0	>64.0	0.46	454.1
69	4- (5 '-f lu oro-2-m eth oxy-2 ’-oxo3,4’-bipyridin-1’(2'H)-yl)-Nhydroxy-2-m eth y I-2(methylsulfonyl)butanamîde	0.0166	>64.0	64	8
70	-He-cyano-S'-fluoro^'-oxo-SA'bipyridin-1'(2’H)-yl)-N-hydroxy2-methyl-2(methylsulfonyl)butanamide	0.0333	>64.0	>64.0	64	0.47	409
71	4-[5-fluoro-4-(3-methyl-3Himidazo[4,5-b]pyridin-6-yl)-2oxopyridin-1 (2H)-yl]-N-hydroxy2-methyl-2- (methylsulfonyl)butanamide	>0.100	>64.0	>64.0	>64.0	0.37	438.1
72	4-(5-fluoro-4-furo[3,2-b]pyridin- 6-yl-2-oxopyridln-1 (2H)-yl)-Nhydroxy-2-methyl-2(methylsulfonyl)butanamlde	0.0348	>64.0	64	32	0.44	424
73	4-(3',5-difluoro-2-oxo-4,4'bipyridin-1(2H)-yl)-N-hydroxy-2methyl-2- (methylsulfonyl)butanamide	0.0083	>64.0	>64.0	8	0.43	402
74	4-[4-(4-cyano-3methoxyphenyl)-5-fluoro-2oxopyridin-1 (2H)-yl]-N-hydroxy2-methyl-2- (methylsulfonyl)butanamide	0.0059	>64.0	64	16
75	4-(5'-fluoro-5,6-dimethoxy-2'oxo-3,4^l-bipyridin-1^,(2'H)-yl)-Nhydroxy-2-methyl-2(methylsulfonyl)butanamide	0.0454	>64.0	>64.0	>64.0	0.51	444.1
76	4-[4-(4-ethoxyphenyl)-5-fluoro- 2-oxopyridin-1 (2H)-yl]-Nhydroxy-2-methyl-2(methvlsulfonyl)butanamide	0.0011	>64.0	0.25	0.5	0.63	427.1
77	4-{4-[4-(2-cyanoethyl)phenyl]-5fluoro-2-oxopyridin-1(2H)-yl}-Nhydroxy-2-methyl-2- (methylsu Ifonyl) butanam ide	0.0026	>64.0	32	4	0.54	436.1
78	4-(5-fluoro-2-oxo-4phenylpyridin-1 (2H)-yl)-Nhydroxy-2-methyl-2(methylsulfonyl)butanamide	0.0028	>64.0	4	1	0.57	383.1
79	4- [4-{4- [(dimethylamino)methyl]phenyl}- 5- fluoro-2-oxopyridin-1(2H)-yl]N-hydroxy-2-methyl-2(methylsulfonyl)butanamide	0.0359	>64.0	>64.0	16	0.37	440.1
80	4- (5’-f I uoro-6- hydroxy-2'-oxo3,4^,-bipyridin-1’(2'H)-yl)-Nhydroxy-2-methyl-2(methylsulfonyl)butanamide	>0.100	>64.0	>64.0	>64.0	0.35	400
81	4-[4-(4-acetamidophenyl)-5fluoro-2-oxopyridin-1(2H)-yl]-Nhydroxy-2-methyl-2(methylsu Ifonyl) butanamide	0.0243	>64.0	64	32	0.45	440.1 i

χΖ

101

82	4-[4-(3-cyanophenyl)-5-ftuoro-2oxopyridin-1 (2H)-yl]-N-hydroxy2-methyl-2- (methylsulfonyl)butanamide	0.0130	>64.0	64	8
83	4-(5,5'-difluoro-6-methyl-2'-oxo- 3,4'-bipyridin-1 '(2‘H)-yl)-Nhydroxy-2-methyl-2(methylsulfonyl)butanamide	0.0275	>64.0	>64.0	32	0.49	416.1
84	4-{5-fluoro-1 -[4-(hydroxyamino)- 3-methyl-3-(methylsulfonyl)-4oxobutyl]-2-oxo-1,2dihydropyridin-4-yl}-Nmethylbenzamide	0.0145	>64.0	>64.0	>64.0	0.43	440.1
85	4-[5'-fluoro-6-(hydroxymethyl)- 2'-oxo-3,4^,-bipyridin-1^,(2'H)-yl]N-hydroxy-2-methyl-2(methylsulfonyl) butanamide	>0.100	>64.0	>64.0	>64.0	0.32	414.1
86	4-[5-fluoro-4-(4-fluorophenyl)-2- oxopyridin-1 (2H)-yl]-N-hydroxy2-methyl-2- ( methylsulfonyl) butanamide	0.0017	>64.0	4	1
87	4-(5-fluoro-2-oxo-4-quinolin-3ylpyridin-1 (2H)-yl)-N-hydroxy-2methyl-2- (methylsulfonyl) butanamide	0.0061	>64.0	16	8	0.46	434.1
88	4-{5-fluoro-4-[4-(1- methoxyethyl)pheny1]-2oxopyridin-1 (2H)-yl}-N-hydroxy2-methyl-2- (methylsu Ifonyl) butanamide	0.0076	>64.0	16	4	0.59	441.1
89	4-(5'-fluoro-6-methoxy-2'-oxo- 3,4'-bipyridin-1 '(2'H)-yl)-Nhydroxy-2-methyl-2(m ethylsu Ifonyl) butanam ide	0.0031	>64.0	8	2
90	4-(5-chIoro-5'-fluoro-2'-oxo-2,4'bipyridin-T(2'H)-yl)-N-hydroxy2-methyl-2- (m ethylsu Ifonyl) butanam id e	0.0125	>64.0	64	16
91	4-{4-[4-(cyanomethyl)phenyl]-5fluoro-2-oxopyridin-1 (2H)-yl}-Nhydroxy-2-methyl-2(methylsulfonyl) butanamide	0.0023	>64.0	16	4	0.52	422.1
92	4-(2’-ethoxy'5-f luo γο-2-οχο-4 ,4'bipyridin-1(2H)-yl)-N-hydroxy-2methyl-2- (m ethylsu lfonyl)butanam ide	0.0057	>64.0	8	8	0.54	428.1
93	4-[5-fluoro-4-[3- (m ethoxymethy I) ph e ny I] -2oxopyridin-1 (2H)-yl}-N-hydroxy2-methyl-2- (methylsulfonyl)butanamide	0.0142	>64.0	32	8
94	4-[4-(2-cyanophenyl)-5-fluoro-2oxopyridin-1 (2H)-yl]-N-hydroxy2-methyl-2- (methylsulfonyl)butanamide	0.0323	32	8	32	0.52	408
95	4- [4-(4-ethoxy-3-fluorophenyl)> 5- fluoro-2-oxopyridin-1(2H)-yl]N-hydroxy-2-methyl-2(methylsulfonyl)butanamide	0.0012	64	1	2	0.63	445.1
96	4-[5-fluoro-4-(2-methylquinolin- 7-yl)-2-oxopyridin-1 (2H)-yi]-Nhydroxy-2-methyl-2-	0.0108	>64.0	16	32	0.39	448.1

102

	(methylsulfonyl)butanamide
97	4-[4-(2,4-drfluorophenyl)-5- f lu oro-2-oxopyrid In-1 (2 H) -y I] - Nhydroxy-2-methyl-2(methylsulfonyl) butanam ide	0.0012	>64.0	4	1	0.59	419
98	4-[4-(3,4-dimethoxyphenyl)-5fluoro-2-oxopyridin-1(2H)-yl]-Nhydroxy-2-methyl-2(methylsulfonyl)butanamide	0.0285	>64.0	64	32	0.53	443.1
99	4-(6-ethoxy-5'-fluoro-2'-oxo- 3,4'-bipyridin-T(2'H)-yl)-Nhydroxy-2-methyl-2(methylsulfonyl) butanam ide	0.0025	>64.0	2	2
100	4-[5-f!uoro-4-(3methoxyphenyl)-2-oxopyridln1 (2H)-yl]-N-hydroxy-2-methyl-2(methylsulfonyl)butanamide	0.0025	>64.0	4	2	0.58	413.1
101	4-(4-(4-cyan O-2methoxyphenyl)-5-fluoro-2oxopyridin-1 (2H)-yl]-N-hydroxy2-methyl-2- (methylsulfonyl)butanamide	0.0052	>64.0	64	8	0.55	438.1
102	4- [4-(4-ch!oro-3-cyanophenyl)- 5- fluoro-2-oxopyrîdin-1 (2H)-ylJN-hydroxy-2-methyl-2(methylsulfonyl)butanamide	0.0021	>64.0	4	4	0.6	442
103	4-[5-fluoro-4-(2-fluorophenyl)-2- oxopyridin-1 (2H)-yl]-N-hydroxy2-methyl-2- (methylsulfonyl)butanamide	0.0014	>64.0	4	0.5	0.57	401.1
104	4-(5'-fluoro-2-isopropoxy-2'-oxo- 3,4'-bipyridin-1^f(2'H)-yl)-Nhydroxy-2-methyl-2(methylsulfonyl)butanamide	>0.100	32	8	32
105	4-{5-fluoro-4-[4-fluoro-3- (hyd roxymethyl) ph eny l]-2oxopyridin-1 (2H)-yl}-N-hydroxy2-methyl-2- (methylsulfonyl)butanam ide		>64.0	>64.0	>64.0	0.49	431.1
106	4-[5-fluoro-2-oxo-4-(2-pyrrolidin- 1 -yl pyrim id i n-5-yl) pyrid in-1 (2H)yl]-N-hydroxy-2-methyl-2(methylsulfonyl)butanamide	0.0568	>64.0	32	64	0.5	454.1
107	4-[4-(4-chlorophenyl)-5-fluoro-2- oxopyridin-1 (2H)-yl]-N-hydroxy2-methyl-2- (methylsulfonyl)butanamide	0.0010	>64.0	1	0.25	0.64	417
108	4-[5-fluoro-2-oxo-4-(1 -oxo-2,3dihydro-1H-isoindol-5-yl)pyridin1 (2H)-yl]-N-hydroxy-2-methyl-2(m ethylsulfonyl) butan amide	0.0072	>64.0	>64.0	>64.0	0.4	438.1
109	4-[4-(4-chloro-3hydroxyphenyl)-5-fluoro-2oxopyridin-1 (2H)-yl]-N-hydroxy2-methyl-2- (methylsulfonyl) butanam ide	0.0073	>64.0	32	32	0.56	433
110	4-{5-fluoro-4-[2- (methoxymethyl)phenyl]-2oxopyridin-1 (2H)-yl}-N-hydroxy2-methyl-2- (methylsulfonyl)butanamide	>0.100	>64.0	>64.0	>64.0	0.56	427.1
111	4-[5-fluoro-4-(2-fluoro-3-	0,0030	>64.0	4	4	0.61	445.1

103

	methoxy-5-methylphenyl)-2oxopyridin-1 (2H)-yl]-N-hydroxy2-methyl-2- (methylsulfonyl)butanamide
112	4-[4-(3-ethoxyphenyl)-5-fluoro- 2-oxo pyrid in-1 (2H)-yl]-Nhydroxy-2-methyl-2(methylsulfonyl)butanamide	0.0031	>64.0	2	4
113	4-[5'-fluoro-2'-oxo-6(trifluoromethyO-SZ-bipyridin1 '(2'H)-yl]-N-hydroxy-2-methyl2-(methylsulfonyl)butanamide	0.0296	>64.0	>64.0	32	0.58	452
114	4- [4-(4-cyano-3-methylphenyl)- 5- fluoro-2-oxopyridin-1 (2H)-y!JN-hydroxy-2-methyl-2- (m ethylsu Ifonyl) butanam id e	0.0013	>64.0	4	2	0.57	422.1
115	4- {4-[2- (dimethylamino)pyrimidin-5-yl]- 5- fluoro-2-oxopyridin-1(2H)-yl}- N-hydroxy-2-methyl-2(methylsu Ifonyl) butanamide	0.0741	>64.0	32	32	0.48	428.1 I
116	4-[5-f luo ro-4-(3-f I uoroph e nyl) -2oxopyridin-1 (2H)-yl]-N-hydroxy2-methyl-2(methylsulfonyl)butanamide	0.0010	>64.0	4	1	0.58	401.1
117	4-(4-(2,3-difluorophenyl)-5fluoro-2-oxopyridin-1(2H)-yl]-Nhyd roxy-2-m ethyl-2(methylsulfonyl) butanamide	0.0008	>64.0	2	0.5	0.59	419.1
118	4-[5-fluoro-4-(2-fluoro-3methoxyphenyl)-2-oxopyridin1 (2H)-yl]-N-hydroxy-2-methyl-2(methylsulfonyl)butanamide	0.0007	>64.0	1	1	0.57	431.1
119	4-(4-(3-cyano-5methoxyphenyl)-5-ftuoro-2oxopyridin-1 (2H)-yl]-N-hydroxy2-methyl-2(methylsulfonyl)butanamide	0.0508	>64.0	>64.0	64	0.57	438.1
120	4- (4-(2,3-dihydro-1 -benzofuran- 5- yl)-5-fluoro-2-oxopyridin- 1 (2H)-yl]-N-hydroxy-2-methyl-2(m ethylsu Ifonyl) butanamide	0.0009	>64.0	2	1	0.57	425.1
121	4-[5-fluoro-2-oxo-4-(1 H-pyrazol- 3-yl)pyridin-1 (2H)-yl]-Nhydroxy-2-methyl-2(methylsulfonyl)butanamide		>64.0	>64.0	>64.0
122	4-{5-fluoro-4-(2-fluoro-3- (h y d roxym ethyl) ph e nyl]-2oxopyridin-1 (2H)-yl}-N-hydroxy2-methyl-2- (methylsulfonyl)butanamide	0.0024				0.46	431.1
123	4~{4-[3-(2-amino-2oxoethyl)phenyl]-5-fluoro-2oxopyridin-1 (2H)-yl}-N-hydroxy2-methyl-2- (m ethylsu Ifonyl) butanam i d e		>64.0	>64.0	>64.0	0.43	440.1
124	4-[4-(4-cyanophenyl)-5-fluora-2oxopyridin-1 (2H)-yl]-N-hydroxy2-methyl-2- (methylsulfonyl)butanamide	0.0034	>64.0	32	8	0.53	408
125	4-[5-fluoro-4-(2- methoxyphenyl)-2-oxopyridïn-	0.0129	>64.0	64	8	0.57	413.1

104

1 (2Η) -yl]-N-hydroxy-2-methyl-2(methylsulfonyl)butanamide

Claims

What is claimed is:

1. A compound of the formula:

E-

H or a pharmaceutically acceptable sait thereof, in which:

R¹ is represented by C_rC3 alkyl;

R² is represented by hydrogen or C1-C3 alkyl;

R³ is represented by hydrogen, halogen, hydroxy, cyano, C^Cgalkyl, C^Cgalkoxy, trifluoromethyl or trifluoromethoxy;

T is represented by ethynyl, optionally substituted (C₆-C₁₀)aryl or optionally substituted heteroaryl;

D is absent, or is represented by -(CH_a)_r-, -(CH₂)_n-O-(CH₂)_p-, or a bond;

r is represented by the integer 1,2, or 3;

n and p are each independently represented by the integer 0,1, or 2;

E is absent, or is represented by a substituent selected from the group consisting of:

i) (C₃.C_1o)cycloalkyl, optionally substituted;

ii) (C₆-C₁₀)aryl optionally substituted;

iii) heteroaryl, optionally substituted; and iv) heterocyclic, optionally substituted;

with the proviso that:

1) if E is absent, then D is also absent;
2) T is not represented by unsubstituted phenyl; when E and D both are absent, R³is hydrogen and R¹ and R² are each methyl.

106

2. A compound according to claim 1 in which R¹ and R² are each methyl.

3. A compound according to claims 1 or 2 in which R³ is hydrogen.

4. A compound according to claims 2 or 3 in which said compound is the Renantiomer, substantially pure.

5. A compound according to any of claims 1,2, 3 or 4 in which T is represented by phenyl which may be optionally substituted.

6. A compound according to any of claims 1,2, 3, 4 or 5 in which D and E are both absent.

7. A compound according to any of claims 1 -5 in which D is a bond.

8. A compound according to claim 7 in which E is represented by cyclohexyl, pyrimidinyl, triazolyl, pyridinyl, isoxazolyl, or cyclopropyl, any of which may be optionally substituted.

9. A compound of the formula la or a pharmaceutically acceptable sait thereof, in which;

R³ is represented by hydrogen, halogen, hydroxy, cyano, C^Cgalkyl, Cy C₃alkoxy, trifluoromethyl or trifluoromethoxy;

R^a is represented by one or more substituents selected from the group consisting of CrC₃alkyl, Ci-C₃ alkoxy, fluorine, chlorine, hydroxy, trifluoromethyl and trifluoromethoxy.

x/

107

10. (2R)-4-(5-Fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)pheny l]pyridin-1 (2H)-yl}-Nhydroxy-2-methyl-2-(methylsulfonyl)butanamide, or a pharmaceutically acceptable sait thereof.

11. (2R)-4-[5-Fluoro-4-(2-fluoro-4-methoxyphenyl)-2-oxopyridin-1 (2H)-yl]-N-hydroxy2-methyl-2-(methylsulfonyl)butanamide, or a pharmaceutically acceptable sait thereof.

10 12. A pharmaceutical composition comprising a compound according to any of daims 1-11 in admixture with at least one pharmaceutically acceptable excipient.

13. Use of a compound according to any of clairns 1-11 in the manufacture of a médicament for bacterial infections.