WO2011045703A2 - C-linked hydroxamic acid derivatives useful as antibacterial agents - Google Patents

C-linked hydroxamic acid derivatives useful as antibacterial agents Download PDF

Info

Publication number
WO2011045703A2
WO2011045703A2 PCT/IB2010/054463 IB2010054463W WO2011045703A2 WO 2011045703 A2 WO2011045703 A2 WO 2011045703A2 IB 2010054463 W IB2010054463 W IB 2010054463W WO 2011045703 A2 WO2011045703 A2 WO 2011045703A2
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
methylsulfonyl
butanamide
hydroxy
mmol
Prior art date
Application number
PCT/IB2010/054463
Other languages
French (fr)
Other versions
WO2011045703A3 (en
Inventor
Matthew Frank Brown
Anthony Marfat
Michael Joseph Melnick
Usa Reilly
Original Assignee
Pfizer Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Inc. filed Critical Pfizer Inc.
Priority to US13/501,776 priority Critical patent/US8853258B2/en
Priority to EP10818065A priority patent/EP2488489A2/en
Priority to CA2774250A priority patent/CA2774250C/en
Priority to JP2012533716A priority patent/JP5671545B2/en
Publication of WO2011045703A2 publication Critical patent/WO2011045703A2/en
Publication of WO2011045703A3 publication Critical patent/WO2011045703A3/en
Priority to US14/469,657 priority patent/US20140364398A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C07C317/48—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C317/50—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C07C317/46—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C07C317/48—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/64—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton
    • C07C323/65—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton containing sulfur atoms of sulfone or sulfoxide groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C07D233/36—One oxygen atom with hydrocarbon radicals, substituted by nitrogen atoms, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered

Definitions

  • This invention relates to novel hydroxamic acid derivatives that are useful for the treatment of bacterial infections, especially Gram-negative infections.
  • the invention also relates to methods of using such compounds in the treatment of bacterial infections in mammals, and to pharmaceutical compositions containing such compounds.
  • Acinetobacter baumannii is a major health problem, especially in the case of hospital- acquired infections.
  • antibiotic therapies which severely limits treatment options.
  • 33% of Pseudomonas aeruginosa infections from intensive care units were resistant to fluoroquinolones, while resistance to imipenem was 22% (CI D 42: 657-68, 2006).
  • MDR multi-drug resistant 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).
  • LPS lipopolysaccharide
  • the major lipid component of LPS is Lipid A, and inhibition of Lipid A biosynthesis is lethal 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 is the enzyme that catalyzes the first committed step in the Lipid A biosynthetic pathway, the removal of the N-acetyl group of UDP-3-0-(R-3-hydroxymyristoyl)-N-acetylglucosamine.
  • LpxC is a Zn 2+ - dependent enzyme that has no mammalian homologue, making it a good target for the development of novel antibiotics.
  • Several inhibitors of LpxC [UDP-3-0-(R-3- hydroxymyristoyl)-GlcNAc deacetylase] with low nM affinity have been reported (Biochemistry 45: 7940-48, 2006). Summary of the Invention
  • LpxC inhibitors A new class of LpxC inhibitors has been discovered. These compounds, or their pharmaceutical salts, can be represented by Formula I below:
  • R 1 is represented by C1-C3 alkyl
  • R 2 is represented by hydrogen or C1-C3 alkyl
  • X is represented CH 2 , O, NH, S or S0 2 ,
  • A is represented by phenyl or a 6-membered heteroaryl as depicted below:
  • R 3 is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxy, amino, (C 1 -C 6 )alkyl optionally substituted, (C 1 -C 6 )alkoxy optionally substituted, trifluoromethyl, and trifluoromethoxy;
  • L is absent, or is represented by S, SH, OH, -(CH 2 ) p -0-(CH 2 ) n -,
  • n is represented by an integer ranging from 0 to 3;
  • p is represented by an integer ranging from 0 to 3;
  • z is represented by an integer from 1 to 3;
  • D is absent, or is represented by a substituent selected from the group consisting of:
  • heteroaryl(C C 6 )alkyl in which the heteroaryl and alkyl moieties may each be optionally substituted
  • heterocyclic(C C 6 )alkyl in which the alkyl and heterocyclic moieties may each be optionally substituted;
  • T is absent, or is represented by -(CH 2 ) Z -, -(CH 2 )n-C(0)-(CH2) -,
  • G is absent, or is represented by a substituent selected from the group consisting of:
  • 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 animals.
  • the compounds of Formula I are useful for treating a variety of infections
  • Gram-negative infections including nosocomial pneumonia, 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), Helicobacter pylori (and relief of associated gastric complications such as peptic ulcer disease, gastric carcinogenesis, etc.), endocarditis, diabetic foot infections, osteomyelitis, and central nervous system infections.
  • the compounds will typically be admixed with at least one excipient and formulated into a pharmaceutical dosage form.
  • dosage forms include tablets, capsules, solutions/suspensions for injection, aerosols for inhalation and solutions/suspensions for oral ingestion.
  • - 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.
  • 6-membered heteroaryl refers to an aromatic 6 membered ring that may
  • Such rings include pyridyl, pyridazinyl, pyrimidinyl, and pryazinyl.
  • 6-membered heteroaryl refers to a 6-membered
  • heteroaryl ring as described above, in which up to 3 carbon atoms of any such ring may be substituted with a non-hydrogen substituent, each substituent is independently selected from the group consisting of halogen, nitro, cyano, hydroxy, amino, (C 1 -C 6 )alkyl optionally substituted, (C 1 -C 6 )alkoxy optionally substituted, trifluoromethyl, and trifluoromethoxy.
  • halogen refers to a chlorine, fluorine, iodine, or bromine atom.
  • C C 6 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.
  • C.,- C 6 alkoxy refers to a straight or branched chain alkoxy group containing from 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, isobutoxy, pentoxy, etc; which may be unsubstituted or optionally further substituted with halogen, hydroxy, thiol or amino.
  • C.,- C 6 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 6 hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, cyano, -0-R a , -SR a , and -NR a R b in which R a and R b are each independently represented by hydrogen or C-1-C6 alkyl.
  • (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.
  • cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and the like.
  • (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 1 -C 6 )alkyl optionally substituted, (C 1 -C 6 )alkoxy optionally substituted, trifluoromethyl, trifluromethoxy, phosphate, oxo, -S0 2 NR 4 , -(CH 2 ) m -N-C(0)-R 4 , -(CH 2 ) m -C(0)-N-R 4 , -C(0)-R 4 ,
  • (C 6 -C 10 )aryl means a cyclic, aromatic hydrocarbon containing from 6 to 10 carbon atoms. Examples of such aryl groups include phenyl, naphthyl, etc. k. "(C 6 -C 10 )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 1 -C 6 )alkyl optionally substituted, (C 1 -C 6 )alkoxy optionally substituted, trifluoromethyl, trifluromethoxy, phosphate, oxo, -S0 2 NR 4 , -(CH 2 ) m -N-C(0)-R 4 , -(CH 2 ) m -C(0)-N-R 4 , -C(0)-R 4 ,-
  • heteroaryl refers to an aromatic ring having one, or more, heteroatoms
  • oxygen selected from oxygen, nitrogen and sulfur. More specifically, it refers to a 5- or 6- membered 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.
  • 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.
  • heteroaryl ring systems include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, indolyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, benzofuran, tetrazole, isoquinolinyl, oxadiazolyl, thiadiazolyl, isothiazolyl, isoxazolyl, triazolyl, benzo[6]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 7-benzimidazolyl, or
  • heteroaryl 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, (C 1 -C 6 )alkyl optionally substituted, (C 1 -C 6 )alkoxy optionally substituted, trifluoromethyl, trifluromethoxy, phosphate, oxo, S0 2 NR 4 , -(CH 2 ) m -N-C(0)-R 4 , -(CH 2 ) m -C(0)-N-R 4 ,
  • 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;
  • the 5-membered ring has 0 to 1 double bonds
  • the 6- and 7-membered rings have 0 to 2 double bonds
  • the 8, 9, or 10 membered rings may have 0, 1 , 2, or 3 double bonds.
  • 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-1 H- isoindole, tetrahydro-oxazolyl, tetrahydro-oxazinyl, thiomorpholinyl,
  • 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 1 -C 6 )alkyl optionally substituted, (C 1 -C 6 )alkoxy optionally substituted, trifluoromethyl, trifluromethoxy, phosphate, oxo, S0 2 NR 4 , -(CH 2 ) m -N-C(0)-R 4 , -(CH 2 ) m -C(0)-N-R 4 , -C(0)-R 4 , - C(0)-0-R 4 , -SR 4 , -S0 2 R 4 and -NR 4 R 5 , in which m, R 4 and R 5 are as defined above.
  • 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-Ce) alkyl, if such substitution is chemically permissible.
  • 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.
  • patient refers to warm blooded animals such as, for example, guinea pigs, mice, rats, gerbils, cats, rabbits, dogs, monkeys, chimpanzees, and humans.
  • treat refers to the ability of the compounds to relieve, alleviate or slow the
  • pharmaceutically acceptable indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith,
  • isomer means “stereoisomer” and “geometric isomer” as defined below, “stereoisomer” means compounds that possess one or more chiral centers and each center may exist in the R or S configuration. Stereoisomers include all diastereomeric, enantiomeric and epimeric forms as well as racemates and mixtures thereof.
  • geometric isomer means compounds that may exist in cis, trans, anti,
  • the acids that may be used to prepare 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, isonicotinate, 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 , 1 '-methylene-bis-(2-hydroxy- 3-naphthoate
  • the invention also relates to base addition salts of the compounds of the invention.
  • the chemical bases that may be used as reagents to prepare
  • pharmaceutically acceptable base salts of those compounds of the compounds of the invention that are acidic in nature are those that form non-toxic base salts with such compounds.
  • non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine- (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.
  • suitable base salts include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • compositions of the formula (I) may exist as geometric isomers.
  • the compounds of the formula (I) may possess one or more asymmetric centers, thus existing as two, or more, stereoisomeric forms.
  • the present invention includes all the individual stereoisomers and geometric isomers of the compounds of formula (I) and mixtures thereof. Individual enantiomers can be obtained by chiral separation or using the relevant enantiomer in the synthesis.
  • the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
  • the compounds may also exist in one or more crystalline states, i.e. polymorphs, or they may exist as amorphous solids. All such forms are encompassed by the claims.
  • the invention also relates to prodrugs of the compounds of the invention.
  • prodrugs of the compounds of the invention may have little or no
  • prodrugs 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 derivatives 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 Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical
  • This invention also encompasses compounds of the invention containing protective groups.
  • 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, Plenum Press (1973) and “Protective Groups in Organic Synthesis", 3rd edition, T.W. Greene and P.G.M. Wuts, Wiley- Interscience (1999).
  • the present 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.
  • 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, 2 H, 3 H, C, 14 C, 1 ⁇ ⁇ , ⁇ ⁇ , ⁇ ⁇ , d1 P, -*P, *S, F, and *CI, respectively.
  • Compounds of the present 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 isotopically- labeled compounds of the present invention, for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • isotopically-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 isotopically-labeled reagent for a non-isotopically-labeled reagent.
  • This sulfonyl moiety will always be substituted with a lower alky moiety. Typically it will be methyl.
  • the carbon atom adjacent to the sulfonyl may optionally be
  • R 2 substituted, as represented by R 2 .
  • R 1 and R 2 will be methyl.
  • the linker represented by X will typically be methylene.
  • 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:
  • All of the compounds of Formula I contain either a phenyl ring or a 6-membered heteroaryl ring, as depicted by A. Either the phenyl ring or the heteroaryl ring may be optionally substituted as described above by the R 3 substituent.
  • R 3 may represent up to 4-non-hydrogen substituents when A is phenyl. When A is a 6-membered heteroaryl, R 3 may represent up to 3 non-hydrogen substituents. These substituents may be the same or different and are listed above.
  • A When A is heteroaryl, it will be connected to the rest of the molecule via carbon atoms as depicted above. When A is a heteroaryl, it will typically be pyridyl, pyrimidyl, or pyridazinyl.
  • pyridyl's examples include:
  • these pyridyl rings will be unsubstituted or mono-substituted with C-1-C6 lower alkyl optionally substituted, hydroxy or amino.
  • All of the compounds may also contain one of the substituents as defined by D.
  • D may be absent, along with T and G, and the tail of the molecule may be one of the ether or thioether moieties defined by L as discussed below.
  • D may be cycloalkyl, aryl, heteroaryl, or heterocyclic.
  • D may be (cycloalkyl)alkyl, (heteroaryl)alkyl, (aryl)alkyl, or heterocyclic(alkyl), etc. Any of theses ring systems may be optionally substituted with up to 4 non-hydrogen
  • substituents from the list specified above may be the same or different. Such substitution may occur wherever chemically permissible. For example, in a heterocyclic system, a nitrogen atom may be substituted with an alkyl moiety. In an aromatic system, substitution may only occur on a carbon atom.
  • D is (cycloalkyl)alkyl, (heteroaryl)alkyl, etc.
  • the alkyl moiety will be bonded to the phenyl or heteroaryl ring represented by A.
  • This alkylene moiety may be optionally substituted with up to 6- non-hydrogen atoms as described above. These substituents may be the same or different.
  • D will either be phenyl, or pyridyl. If D represents phenyl; then it will be unsubstituted, or substituted with halogen, amino, nitro, phosphate, or hydroxyl . If pyridyl, D will be typically be unsubstituted.
  • L is optional.
  • the moieties represented by A and D may be bonded to each other, or L may serve as a linker.
  • L may serve as the tail of the molecule, when D, T and G are absent. Most typically, L will be absent.
  • T is optional. It may serve as a linker between the rings that define D and G. Typically T will be absent.
  • G in the molecule is also optional. It may be absent.
  • R 1 is methyl
  • R 1 and R 2 are each methyl
  • R 1 and R 2 are each methyl and X is CH 2 ;
  • R 1 and R 2 are each methyl, X is CH 2 and A is phenyl or pyridyl;
  • R 1 and R 2 are each methyl, X is CH 2 and A is phenyl or pyridyl in which R 3 is hydrogen;
  • R 1 and R 2 are each methyl, X is CH 2, A and D are both optionally substituted phenyl, L, T and G are all absent; h) R 1 and R 2 are each methyl, X is CH 2 , L, T and G are each absent, A and D are each independently selected from the group consisting of optionally substituted pyridyl and optionally substituted phenyl, and;
  • R 1 and R 2 are each methyl, X is CH 2 , D, T and G are each absent, and L is present and as defined above.
  • the compounds of Formula I can be prepared by a variety of methods that are analogously known in the art.
  • the reactions schemes presented below illustrate one method for preparing these compounds. Others, including modifications thereof will be readily apparent to one skilled in the art.
  • Scheme A provides an overview of how to synthesize the compounds of Formula I in which X is CH 2 , as depicted.
  • X is CH 2
  • Reaction Scheme B For the generation of the phenyl or heteroaryl intermediate identified as structure 1 , see Reaction Scheme B.
  • Z will be represented by a suitable reactive group such as halogen, boronic acid or boronate ester, etc, depending upon the identity of D, T and G in the final product.
  • Y will typically be represented by a hydroxyl group or the protected sulfonyl- containing moiety as depicted.
  • "PG" is a protecting group such as a lower alkyl (as part of an ester) or a tetrahydropyranyl group (as part of a hydroxamate).
  • the final step in the synthesis is to incorporate the hydroxamic acid moiety into the molecule utilizing the methodologies depicted in Scheme 2 infra. As is readily apparent to one skilled in the art, the order in which the reactions are carried out is typically not critical. If desired, the hydroxamic acid moiety may be incorporated into the molecule and then the G-T-D-L moiety may be added. Further D, T or G may also be added separately. Such manipulations are readily apparent to one skilled in the art and can be carried out using standard techniques well known to medicinal chemists.
  • cycloalkylalkyl aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, cycloalkyl, or cycloalkyl alkyl (any of which may be optionally substituted).
  • One of the starting materials will be an appropriately substituted phenyl or heteroaryl moiety as described by structure 1 .
  • R 3 will typically be represented by the same substituent as is desired in the final product.
  • Z will be a halide, boronic acid, boronate ester or other appropriately reactive group.
  • Y will be hydroxyl or the protected sulfonyl-containing moiety as depicted above.
  • the other reactant, G-T-D-M 1 will be represented by the same moiety as desired in the final product except that it will be substituted by a halogen atom or metal such as magnesium, copper, or a boronate ester, etc. at the desired point of attachment to the aryl moiety "A".
  • the molecule may be assembled using any of a number of coupling reactions known in the art.
  • the Suzuki-Miyaura strategy may be used.
  • M 1 will be a boronic acid/ester and Z will be a halogen atom or a triflate (or vice versa).
  • Equivalent molar amounts of the reactants will be contacted in a solvent such as THF, dioxane, water, toluene, or an admixture thereof; in the presence of a transition metal catalyst such as palladium, or nickel (or resin bound catalyst) along with a base such as sodium carbonate, potassium carbonate, cesium fluoride or cesium carbonate.
  • the reactants will be heated by microwave or other conventional technique till completed. Once completed the desired product may be isolated and recovered from the reaction and further purified as is known in the art. Alternatively the crude may be used in Step 2 described below.
  • M 1 will be copper or nickel and Z will be a halogen.
  • Equivalent amounts of the reactants will be contacted in an aprotic solvent such as ether, DMF, or DME and the reactants are heated to reaction completion.
  • the desired product of structure 2 may be isolated and purified as is known in the art, or used as a crude mixture in the next step of the reaction.
  • Scheme 1 B is appropriate for the compounds in which L is present and a C-0 or C-S bond is desired (i.e. L is an ether or thioether linkage) between L and at least one of A or D.
  • a Willamson/Ullmann ether coupling, Mitsunobu or alkylation reaction may be utilized to produce these derivatives.
  • One of the starting materials will be an appropriately substituted phenyl or heteroaryl moiety as described by structure 1 .
  • R 3 will typically be represented by the same substituent as is desired in the final product.
  • Z will be halide, boronic acid, hydroxyl, etc. and Y will be hydroxyl or the protected sulfonyl moiety as depicted above.
  • G-T-D-L-M 2 will be represented by the same moiety as desired in the final product, except that it will be substituted by a hydroxyl function at the desired point of attachment to the aryl moiety ⁇ ". If a thioether is desired, G-T-D-L-M 2 will be an appropriately substituted disulfide moiety.
  • the Ullmann ether reaction can be carried out in the presence of copper salts. If a Williamson ether approach is used, then equivalent amounts of the reactants will be contacted in an aprotic solvent such as dioxane in the presence or absence of a phase transfer catalyst such as 18-crown-6. A base such as potassium hydroxide, sodium t- butoxide or sodium methoxide will typically be added as well. The reactants will be heated by microwave or other conventional technique to reaction completion.
  • the desired product of structure 2 may be isolated and purified as is known in the art, or used as a crude mixture in the next step of the reaction.
  • Scheme IC is appropriate for those compounds in which L is absent and a carbon-nitrogen bond is desired between the carbon of the heteroaryl moiety, "A", and a nitrogen atom of the D moiety.
  • This reaction will be used when D is any of heteroaryl or heterocyclic (either of which may be optionally substituted).
  • One of the starting materials will be an appropriately substituted phenyl or heteroaryl moiety as described by structure 1.
  • R 3 will typically be represented by the same substituent as is desired in the final product.
  • Z will be a boronic acid, boronate ester or other appropriately reactive group.
  • Y will be hydroxyl or the protected sulfonyl moiety as depicted above.
  • the other reactant, G-T-D will be represented by the same moiety as desired in the final product.
  • the carbon-nitrogen bond may be formed using a Buchwald-Hartwig cross- coupling or Ullmann strategy similar to that described above. Equivalent amounts of the reactants will be contacted in an aprotic solvent solvent such as ether,
  • Scheme 1 D is appropriate for compounds in which L is present and forms a carbon-carbon bond with A and D (if D is present).
  • One of the starting materials will be the derivative of structure 1 as described above in Scheme 1A in which R 3 will be represented by the same substituent as is desired in the final product and Y will be hydroxyl or the protected sulfonyl moiety depicted above.
  • Z will be halide, boronic acid, boronate ester, or other appropriately reactive group.
  • the other reactant, G-T-D-L' will be represented by the same moiety as desired in the final product except that it will be substituted by a halogen atom or metal such as magnesium, copper, or a boronate ester, at the desired point of attachment to the aryl moiety "A".
  • the coupling reaction of Scheme 1 D can be carried out using either the Suzuki-Miyaura strategy or the Ullmann coupling strategy described above in Scheme 1A.
  • the second step in the reaction is to incorporate the hydroxamic acid moiety into the molecule. This may be accomplished as depicted in Scheme 2 below:
  • the hydroxyl function depicted in structure 2 is converted into a leaving group.
  • G, T, D, L and R 3 will typically be represented by the same moiety as is desired in the final product.
  • the leaving group will be a halogen atom, such as iodine, but it may also be a tosylate or mesylate functional group. Methods of incorporating such leaving groups are well known to those skilled in the art.
  • the desired leaving group is iodine
  • the compound of structure 2 is placed in a solution of imidazole and contacted with a molar excess of both triphenylphosphine and iodine.
  • the reaction is typically carried out at reduced temperatures (i.e. 0° C) and allowed to proceed to completion.
  • the desired product of structure 3 may then be isolated and purified as is known in the art, or the crude product may be used in Step B.
  • Step B the leaving group is displaced with the protected alkylsulfonyl acetate or 2-alkylsulfonyl propionic ester as depicted in Scheme 2.
  • R 1 and R 2 will typically be represented by the same moiety as is desired in the final product. An ethyl ester moiety is depicted, but any standard ester group may be utilized.
  • the alkylation may be carried out as is known in the art.
  • equivalent amounts of the compound of structure 3 and the protected sulfonyl ester are contacted in an aprotic solvent such as
  • An excess of an inorganic base such as cesium carbonate, potassium carbonate or sodium hydride is added to the reaction.
  • the reaction may be run at room temperature or heated to accelerate completion.
  • the desired product of structure 4 may be isolated and purified as is known in the art.
  • Step C the protecting group of the carboxylic acid is removed generating the intermediate of structure 5.
  • 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.
  • Step D the hydroxamic acid moiety depicted is incorporated into the molecule. This can also be carried out as is known in the art. If desired, a protected
  • hydroxylamine may be used, followed by a subsequent deprotection reaction.
  • hydroxylamine may be directly incorporated.
  • the hydroxamic acid functionality is incorporated into the molecule using standard amidation reactions.
  • the compound of structure 5 may be contacted with an excess of oxalyl chloride in an aprotic solvent such as dichloromethane to allow formation of the corresponding acid chloride, followed by the addition of an excess of either the hydroxylamine or protected hydroxylamine. The reaction is then allowed to proceed to completion and the final product of Formula I or its corresponding protected
  • Scheme B depicted below teaches how to prepare the starting material described in Scheme A:
  • the penultimate starting material, structure 1 can be produced using techniques well known in the art. This material is produced from the carboxylic acid depicted as structure 6.
  • the ring will either be phenyl or heteroaryl depending upon the desired final product.
  • R 3 will also typically be represented by the same substituent as is desired in the final product.
  • Z will be a halogen or otherappropriately reactive group.
  • Such carboxylic acids may be purchased or produced as described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations by Richard C. Larock, 2 nd Edition, 2000, published by Wiley, John & Sons, Inc.
  • the reduction is typically carried out in an aprotic solvent such as
  • the carboxylic acid is contacted with an excess of a reducing agent such as borane, etc. at room temperature.
  • a reducing agent such as borane, etc. at room temperature.
  • the reaction is quenched with a weak base such as potassium carbonate, sodium carbonate, etc.
  • the resulting alcohol, structure 7, may be isolated and purified as known in the art or used as crude in the next step.
  • Step B a halogenation reaction is carried out in which the hydroxyl function is converted to a chlorine atom.
  • a chlorinating agent such as thionyl chloride or oxalyl chloride and with a catalytic amount of dimethylformamide (DMF).
  • DMF dimethylformamide
  • Step C a nitrile addition is carried out as depicted.
  • the product from Step B is contacted with an aprotic solvent such as dimethylformamide, etc.
  • An excess of sodium cyanide, or other cyanide source is typically added to the reaction mixture and the reaction is allowed to proceed to completion at room temperature.
  • the product, structure, 9, may be isolated and purified or used as crude product in the next step.
  • Step D The hydrolysis of Step D may be conducted by contacting structure 9 with an aqueous solution of a strong acid such as HCI, etc.
  • a strong acid such as HCI, etc.
  • the resulting carboxylic acid may be isolated and purified or used as crude product in Step E.
  • Step E the carbonyl is reduced generating the alcohol depicted as structure 1 .
  • This reduction may be carried out in the same manner as Step A immediately above.
  • the desired product may be isolated and purified as is known in the art.
  • reaction schemes depicted above for producing 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 specific compound, availability of reagents, etc.
  • the compounds may be used for the treatment or prevention of infectious disorders, especially those caused by susceptible and multi-drug resistant (MDR) Gram- negative bacteria.
  • 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 ( ⁇ - lactamase positive and negative), Helicobacter pylori, Klebsiella oxytoca, Klebsiella pneumoniae (including those encoding extended-spectrum ⁇ -lactamases (hereinafter "ESBLs”),
  • Enterobacteriaceae that express ESBLs KPCs, CTX-M, metallo-3-lactamases, and AmpC-type beta-lactamases that confer resistance to currently available
  • cephalosporins cephamycins, carbapenems, and beta-lactam/beta-lactamase inhibitor combinations, Mannheimia haemolyticus, Pasteurella spp., Proteus mirabilis,
  • Pseudomonas aeruginosa Pseudomonas spp.
  • Salmonella spp. Shigella spp.
  • Serratia marcescens Serratia marcescens
  • Treponema spp. Burkholderia cepacia
  • Vibrio spp. Yersinia spp.
  • Stenotrophomonas malophilia Pseudomonas aeruginosa
  • Serratia marcescens Serratia marcescens
  • Treponema spp. Burkholderia cepacia
  • Vibrio spp. Vibrio spp.
  • Yersinia spp. and Stenotrophomonas malophilia.
  • the Gram-negative bacteria are selected from the group consisting of Acinetobacter baumannii, Acinetobacter spp., Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae , Serratia marcescens, Pseudomonas aeruginosa and members of the Enterobacteriaceae and Pseudomonas that express ESBLs, KPCs, CTX-M, metallo- ⁇ - lactamases, and AmpC-type beta-lactamases that confer resistance to currently available cephalosporins, cephamycins, carbapenems, and beta-lactam/beta-lactamase inhibitor combinations.
  • infections examples 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.
  • the compounds can be used to treat Helicobacter 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 recurrence and rebleeding, reduced risk of gastric cancer, etc.
  • H. pylori and its impact on gastrointestinal illness may be found at: www.informahealthcare.com, Expert Opin. Drug Saf. (2008) 7(3).
  • 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 decide the total daily dosage of the compound. The specific
  • therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
  • the total daily dose will typically range from about 0.1 mg/kg/day to about 5000mg/kg/day in single or in divided doses.
  • dosages for humans will range from about 10 mg to about 3000 mg per day, in a single or multiple doses.
  • Parenteral administrations include injections to generate a systemic effect or injections directly into to the afflicted area. Examples of parenteral administrations are
  • Topical administrations include the treatment of areas readily accessibly 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 other lower intestinal tract.
  • Transmucosal administration includes nasal aerosol or inhalation applications.
  • compositions can be formulated for administration by any route known in the art, such as subdermal, by-inhalation, oral, topical or parenteral.
  • the compositions may be in any form known in the art, including but not limited to tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • topical formulations of the present invention can be presented as, for instance, ointments, creams or lotions, ophthalmic ointments/drops and otic drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients, etc.
  • Such topical formulations may also contain conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present, for example, from about 1 % up to about 98% of the formulation.
  • Tablets and capsules for oral administration may be in unit dose presentation 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 magnesium stearate, 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 will known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying 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.
  • suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or
  • fluid unit dosage forms are prepared utilizing the compound and a sterile 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.
  • the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
  • agents such as a local anesthetic preservative and buffering agents can be dissolved in the vehicle.
  • 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.
  • Parenteral 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 sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions may contain, for example, from about 0.1 % by weight, to about
  • compositions comprise dosage units
  • each unit will contain, for example, from about 5-500 mg of the active ingredient.
  • 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.
  • the compounds of the invention may be administered in combination with one or more additional anti-bacterial agents ("the additional active agent").
  • the additional active agent may be for simultaneous, separate or sequential use.
  • Mass spectrometry data is reported from either liquid chromatography-mass spectrometry (LCMS) or atmospheric pressure chemical ionization (APCI). Chemical shifts for nuclear magnetic resonance (NMR) data are expressed in parts per million (ppm, ⁇ ) 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), or a 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 temperature refers to 20-25°C.
  • reaction conditions length of reaction and temperature
  • reaction conditions may vary.
  • 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 eluants/gradients were chosen to provide appropriate R f S or retention times.
  • Pd(dppf)CI 2 bis(diphenylphosphino)ferrocenepalladium(ll) chloride
  • Pd tetrakis Tetrakis(triphenylphosphine)palladium(0)
  • TPP triphenyl phosphine
  • TPPO triphenyl phosphine oxide
  • LiHMDS lithium hexamethyldisilazide/ lithium bis(trimethylsilyl)amide
  • Step 1
  • Triethylamine (5.49 g, 54.3 mmol) and 1 H-benzo[d][1 ,2,3]triazol-1 -ol (7.5 g, 49 mmol) were added to a solution of the (+/-)-4-(4-bromophenyl)-2-methyl-2- (methylsulfonyl)butanoic acid (9.1 g, 27.1 mmol) in dichloromethane (100 mL).
  • Oxalyl chloride (4.50 mL, 50 mmol) was added to a solution of 4-(4- bromophenyl)-2-methyl-2-(methylsulfonyl)butanoic acid (II) (14.69 g, 43.82 mmol) in DCM (300 mL) under nitrogen at ambient temperature, followed by DMF (340 ul). The reaction was stirred until effervescence ceased and then was allowed to stir for 1 hour. O-TMS-hydroxylamine (16.0 mL, 130 mmol) was added via syringe and the suspension was stirred for 1 hour.
  • the title compound (3.69 g, 60.4 %) was prepared from (+/-)-2-methyl-2- (methylsulfonyl)-4-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]butanoic acid (4.86 g, 12.7 mmol) and 0-tetrahydro-2H-pyran-2yl-hydroxylamine (2.1 g, 18.0 mmol) by a procedure analogous to that described for (+/-)-4-(4-bromophenyl)-2-methyl-2- (methylsulfon
  • the title compound (10.5 g, 93 %) was prepared from ethyl (2R)-4-(4- bromophenyl)-2-methyl-2-(methylsulfonyl)butanoate, (10.0 g, 27.5 mmol) and bis(pinacolato)diborane (7.69 g, 30.3 mmol) by a procedure analogous to that described for (+/-)-ethyl 2-methyl-2-(methylsulfonyl)-4-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)phenyl]butanoate as described in Preparation 3 step A.
  • Step F 4-Bromo-1-(2-iodo-ethyl)-2-methyl-benzene
  • Step G 4-(4-Bromo-2-methyl-phenyl)-2-methanesulfonyl-2-methyl-butyric acid ethyl ester
  • Step H 4-(4-Bromo-2-methylphenyl)-2-methyl-2-(methylsulfonyl)butanoic acid
  • the reaction mixture was diluted with 20 ml. of dichloromethane and 60 ml. of water.
  • the aqueous layer was extracted with dichloromethane (2x 40 ml_).
  • the organics were combined, dried over magnesium sulfate, filtered and concentrated onto silica gel.
  • Silica chromatography (30% ethyl acetate 70% heptane for 10 minutes, then 30% ethyl acetate 70% heptane to 60% ethyl acetate 40% heptane for 40 minutes) afforded the title compound as a white solid (2.1 1 g, 50.1 %).
  • Step J 2-Methyl-4-(3-methylbiphenyl-4-yl)-2-(methylsulfonyl)-N-(tetrahvdro-2H-pyran-2- yloxy)butanamide
  • Step K N-hvdroxy-2-methyl-4-(3-methylbiphenyl-4-yl)-2(methylsulfonyl)butanamide
  • Step B 4-Bromo-2-fluoro-phenyl-acetic acid
  • Step D 4-Bromo-1 -(2-iodo-ethyl)-2-fluoro-benzene
  • Step E 4-(4-Bromo-2-fluoro-phenyl)-2-methanesulfonyl-2-methyl-butyric acid ethyl ester
  • the title compound was synthesized according to the general procedure of Preparation # 2, Step 2, except that 4-bromo-1-(2-iodo-ethyl)-2-fluoro-benzene was used instead of 1-bromo-4-(2-iodoethyl)benzene and the reaction conducted at 40°C to furnish the title compound as a white solid 2.2g, (33%).
  • Step H 4-(3-Fluorobiphenyl-4-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahvdro-2H-pyran- 2-yloxy)butanamide
  • Step I 4-(3-Fluorobiphenyl-4-yl)-N-hvdroxy-2-methyl-2-(methylsulfonyl)butanamide
  • Step B Ethyl 4-(6-bromopyridin-3-yl)-2-(methylsulfonyl)butanoate
  • Step C Ethyl 4-(6-bromopyridin-3-yl)-2-methyl-2-(methylsulfonyl)butanoate
  • Step F N-Hvdroxy-2-methyl-2-(methylsulfonyl)-4-(6-phenylpyridin-3-yl)butanamide
  • Step B Ethyl 4-(5-bromopyridin-2-yl)-2-methyl-2-(methylsulfonyl)butanoate
  • Step D 4-(5-Bromopyridin-2-yl)-N-hvdroxy-2-methyl-2-(methylsulfonyl)butanamide
  • Step E N-Hvdroxy-2-methyl-2-(methylsulfonyl)-4-(5-phenylpyridin-2-yl)butanamide
  • the title compound (2 mg, 1 %) was prepared from 4-(5-bromopyridin-2-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)butanamide (151 mg, 0.43 mmol) and
  • Step A (+/-V2-Methyl-2-(methylsulfonylV4-(4'-nitrobiDhenyl-4-ylVN-(tetrahvdro-2H- pyran-2-yloxy)butanamide
  • Step B (+/-)-N-Hvdroxy-2-methyl-2-(methylsulfonyl)-4-(4'-nitrobiphenyl-4-yl)butanamide
  • Step A Ethyl (2R)-4-(4'-hvdroxybiphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanoate
  • Step B Ethyl (2R)-4- ⁇ 4'-r(di-tert-butoxyphosphoryl)oxylbiphenyl-4-yl)-2-methyl-2- (methylsulfonyl)butanoate
  • Step C (2RV4- ⁇ 4'-r(Di-tert-butoxyDhosDhorvnoxylbiDhenyl-4-yl -2-methyl-2- (methylsulfonyl)butanoic acid
  • Step D Di-tert-butyl 4'-f(3RV3-methyl-3-(methylsulfonvn-4-oxo-4-r(tetrahvdro-2H- PVran-2-yloxy)aminolbutyl)biphenyl-4-yl phosphate
  • Step E 4'-[(3R)-4-(Hvdroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyllbiphenyl-4-yl dihvdroqen phosphate
  • Step A (2R -Biphenyl-4-yl-2-methyl-2-(methylsulfonvn-N-(tetrahvdro-2H-pyran-2- yloxy)butanamide
  • Trisdibenzylidine dipalladium (0.19 g, 0.21 mmol) was added to a mixture of potassium carbonate (1.45 g, 10.5 mmol, 5.0 equiv), (2R)-2-methyl-2-(methylsulfonyl)- N-(tetrahydro-2H-pyran-2-yloxy)-4-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]butanamide, which may be prepared as in Preparation 8C (1.0 g, 2.1 mmol) and bromobenzene (0.26 mL, 2.5 mmol) in 1 ,2-dimethoxyethane-methanol (8.0 mL, 1 :1 ).
  • Step B Preparation of (2R)-4-Biphenyl-4-yl-N-hvdroxy-2-methyl-2- (methylsulfonyl)butanamide
  • Step A ⁇ 4-[4-Ethoxy-3-methyl-3-(methylsulfonyl)-4-oxobutyllphenyl ⁇ boronic acid
  • Step B Ethyl 2-methyl-2-(methylsulfonyl)-4-(4-phenoxyphenyl)butanoate
  • Step D 2-Methyl-2-(methylsulfonyl)-4-(4-phenoxyphenyl)-N-(tetrahydro-2H-pyran-2- yloxy)butanamide
  • Step E N-Hvdroxy-2-methyl-2-(methylsulfonyl)-4-(4-phenoxyphenyl)butanamide
  • Step A Ethyl 2-methyl-2-(methylsulfonyl)-4-[4-(1 H-pyrazol-1-yl)phenyllbutanoate
  • Step B 2-Methyl-2-(methylsulfonyl)-4-r4-(1 H-pyrazol-1 -yl)phenyllbutanoic acid
  • Step C 2-Methyl-2-(methylsulfonvn-4-r4-(1 H-pyrazol-1 -vnphenyll-N-(tetrahvdro-2H- pyran-2-yloxy)butanamide
  • Step D N-hvdroxy-2-methyl-2-(methylsulfonyl)-4-[4-(1 H-pyrazol-1-yl)phenyllbutanamide
  • Step A Ethyl 2-methyl-2-(methylsulfonyl)-4-r4-(phenylthio)phenyllbutanoate
  • Step B 2-Methyl-2-(methylsulfonyl)-4-r4-(phenylthio)phenyll-butanoic acid
  • Step C 2-Methyl-2-(methylsulfonylV4-r4-(phenylthio)phenyll-N-(tetrahvdro-2H-pyran-2- yloxy)butanamide
  • Step D N-hvdroxy-2-methyl-2-(methylsulfonyl)-4-[4-(phenylthio)phenyllbutanamide
  • 2-methyl-2-(methylsulfonyl)-4-[4-(phenylthio)phenyl]-N- (tetrahydro-2H-pyran-2-yloxy)butanamide (268.4 mg, 0.579 mmol) in methylene chloride (3 mL) at ambient temperature was added HCI (4M in 1 ,4-dioxane, 4.34 mL, 17.4 mmol) and the resulting solution was stirred at RT for 5 minutes.
  • Methanol 500 uL was added followed by silica gel and the mixture was concentrated to dryness.
  • the crude material was purified via silica gel chromatography eluting with methylene
  • Step B 4-(4-Cvclohept-1-en-1-ylphenyl)-N-r(1 -methoxypentyl)oxyl-2-methyl-2- (methylsulfonyl)butanamide
  • Step C 4-(4-Cvclohept-1-en-1-ylphenyl)-N-hvdroxy-2-methyl-2- (methylsulfonyl)butanamide
  • Step A N- (5SV3-r4-(5.5-dimethyl-1.3.2-dioxaborinan-2-vn-3-fluoroDhenyll-2-oxo-1.3- oxazolidin-5-yl ⁇ methyl)acetamide
  • Step B (2RV4-f4'-r(5RV5-(acetamidomethvn-2-oxo-1 ,3-oxazolidin-3-yll-2'- fluorobiphenyl-4-yl ⁇ -2-methyl-2-(methylsulfonyl)-N-(tetrahvdro-2H-pyran-2- yloxy)butanamide
  • Step C (2R)-4- ⁇ 4'-r(5R)-5-(acetamidomethyl)-2-oxo-1 ,3-oxazolidin-3-yll-2'- fluorobiphenyl-4-yl ⁇ -N-hvdroxy-2-methyl-2-(methylsulfonyl)butanamide
  • Step B Ethyl 4-[4-(benzyloxy)phenyll-2-(methylsulfonyl)butanoate
  • Step E (+/-)-Ethyl 4-[4-(cvclopentyloxy)phenyll-2-methyl-2-(methylsulfonyl)butanoate Diethyl azodicarboxylate (40%, 220 uL, 0.48 mmol) was added to a solution of cyclopentanol (30.2 uL, 0.333 mmol), triphenylphosphine (120 mg. 0.456 mmol), and (+/-)-ethyl 4-(4-hydroxyphenyl)-2-methyl-2-(methylsulfonyl)butanoate (120 mg, 0.40 mmol) in THF (3 mL) at 0°C under nitrogen.
  • Step F (+/-)-4-r4-(Cvclopentyloxy)phenyll-2-methyl-2-(methylsulfonyl)butanoic acid (+/-)-Ethyl 4-[4-(cyclopentyloxy)phenyl]-2-methyl-2-(methylsulfonyl)butanoate was converted to the title compound following the procedure described in Preparation 2, Step 3, for preparation of (ll). The title compound was obtained as a white solid (90 mg, 98%). LC-MS m/z 339.1 (M+1 ).
  • Step G (+/-)-4-r4-(Cvclopentyloxy)phenyll-N-hvdroxy-2-methyl-2- (methylsulfonyl)butanamide
  • (+/-)-4-[4-(Cyclopentyloxy)phenyl]-2-methyl-2-(methylsulfonyl)butanoic acid was converted to the title compound following the procedure described in Preparation 2, Step 5, for the preparation of (IV)
  • the title compound was obtained as a white solid (69 mg, 74%).
  • Step A (+/-)-Ethyl 2-methyl-2-(methylsulfonyl)-4-r4-(pyridin-2- ylmethoxy)phenyllbutanoate
  • Step B (+/-)-2-Methyl-2-(methylsulfonyl)-4-[4-(pyridin-2-ylmethoxy)phenyllbutanoic acid (+/-)-Ethyl 2-methyl-2-(methylsulfonyl)-4-[4-(pyridin-2-ylmethoxy) phenyl] butanoate was converted to the title compound following the general procedure described in Preparation 2, Step 3, for preparation of (II). The reaction was
  • Step C of (+/-)-N-Hvdroxy-2-methyl-2-(methylsulfonyl)-4-r4-(pyridin-2- ylmethoxy)phenyllbutanamide
  • (+/-)-2-Methyl-2-(methylsulfonyl)-4-[4-(pyridin-2-ylmethoxy)phenyl] butanoic acid was converted to the title compound following the general procedure described in Preparation 2, Step 5, for the preparation of (IV).
  • the title compound was obtained as a white solid (44 mg, 17%).
  • Step A (+/-)-Ethyl 4-r4-(2-cvclopropylethoxy)phenyll-2-methyl-2- (methylsulfonyl)butanoate
  • Example 15 (125 mg, 0.416 mmol) in THF (3 ml.) at 0°C under nitrogen. The reaction was allowed to warm to RT and stirred overnight, thendiluted with water (30 ml.) and extracted with ethyl acetate (3x30 ml_). The combined organics were dried (MgS0 4 ), filtered, and concentrated in vacuo. The crude product was purified via flash chromatography using an Analogix SF10-8g column and an eluant of 20% ethyl acetate in heptane to afford the title compound as a white solid (84 mg, 66%). LC-MS m/z
  • Step B (+/-)-4-r4-(2-Cvclopropylethoxy)phenyll-2-methyl-2-(methylsulfonyl)butanoic acid
  • (+/-)-Ethyl 4-[4-(2-cyclopropylethoxy)phenyl]-2-methyl-2- (methylsulfonyl)butanoate was converted to the title compound following the general procedure described in Preparation 2, Step 3, for preparation of (II). The title compound was obtained as a white solid (80 mg, 100%).
  • (+/-)-4-[4-(2-Cyclopropylethoxy)phenyl]-2-methyl-2-(methylsulfonyl)butanoic acid was converted to the title compound following the general procedure described in Preparation 2, Step 5, for the preparation of (IV).
  • the crude material was purified using preparatory HPLC to afford the title compound as a white solid (44 mg, 17%).
  • Step A 4'-Fluoro-4-(2-iodoethyl)-3-methoxybiphenyl
  • Step B (+/-) Ethyl 4-(4'-fluoro-3-methoxybiphenyl-4-yl)-2-methyl-2- (methylsulfonyl)butanoate
  • Step C (+/-)-4-(4'-Fluoro-3-methoxybiphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanoic acid
  • (+/-)-4-(4'-Fluoro-3-methoxybiphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanoic acid was converted to the title compound following the general procedure of step 4,
  • Step E (+/-)-4-(4'-Fluoro-3-methoxybiphenyl-4-yl)-N-hvdroxy-2-methyl-2- (methylsulfonyl)butanamide
  • (+/-)-4-(4'-Fluoro-3-methoxybiphenyl-4-yl)-2-methyl-2-(methylsulfonyl)-N- (tetrahydro-2H-pyran-2-yloxy)butanamide was converted to the title compound following the general procedure outlined for (+/-)-4-(4-bromophenyl)-N-hydroxy-2- methyl-2-(methylsulfonyl)butanamide as described in Preparation 2, Step 5.
  • the title compound was obtained as a white solid (364 mg, 69%) LC-MS m/z 396.5 (M+1 ).
  • Step A (+/-)-4-(4'-Fluoro-3-hvdroxybiphenyl-4-yl)-N-hvdroxy-2-methyl-2- (methylsulfonyl)butanamide
  • Step A 4'-Fluoro-4-(2-iodoethyl)-2-methoxybiphenyl
  • Step B Ethyl 4-(4'-fluoro-2-methoxybiphenyl-4-yl)-2-(methylsulfonyl)butanoate
  • Step C 4-(4'-Fluoro-2-methoxybiphenyl-4-yl)-N-hvdroxy-2-methyl-2- (methylsulfonyl)butanamide
  • Lithium hydroxide (44.7mg, 1.06mmol) was added to a stirred solution of ethyl 4- (4'-fluoro-2-methoxybiphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanoate (435mg,
  • TMSO-hydroxylamine (287uL, 2.38mmol) was added to the solution after five minutes resulting in the formation of a white solid.
  • the reaction mixture was allowed to stir for an additional 60 minutes before methanol (10mL) was added.
  • the white solids were taken up in EtOAc (100mL) and washed with water (75mL).
  • the aqueous phase was extracted with EtOAc, (40mL).
  • the combined organics were dried over Na 2 S0 4 , filtered and concentrated in vacuo to furnish a pale yellow solid.
  • the crude material was purified by chromatography on silica gel (100% dichloromethane to 97:3 DCM: MeOH) to yield the title compound as an off white solid (1 10mg, 35.3%).
  • Step A 4-(4'-Fluoro-2-hvdroxybiphenyl-4-yl)-N-hvdroxy-2-methyl-2- (methylsulfonyl)butanamide
  • Step A Tert-Butyl r4-(2-hvdroxyethyl)phenyl1carbamate
  • Triethylamine (30 mL, 220 mmol) was added to a solution of 2-(4- aminophenyl)ethanol (26.62 g, 194 mmol) in 1 ,4-dioxane (200 mL) followed by the addition of di-tert-butyl dicarbonate (50 g, 230 mmol). The reaction was stirred overnight at room temperature under nitrogen. The reaction was concentrated, dissolved in ethyl acetate (500 mL), washed with water (3x100 mL) and brine (100 mL), dried (MgS0 4 ), filtered and concentrated in vacuo to afford a crude white solid.
  • Step B tert-Butyl [4-(2-iodoethyl)phenyllcarbamate
  • tert-Butyl [4-(2-hydroxyethyl)phenyl]carbamate (6.45 g, 27.18 mmol) in dichloromethane (20 mL) was added drop-wise to a solution of imidazole (2.04 g, 30.0 mmol), triphenylphosphine (8.60 g, 32.8 mmol), and iodine (8.28 g, 32.6 mmol) in dichloromethane (80 mL) at 0°C.
  • the reaction was allowed to warm to rt and was stirred overnight at room temperature.
  • the reaction was cooled to 0°C and quenched with water (100 mL).
  • Step C (+/-)-Ethyl 4- ⁇ 4-r(tert-butoxycarbonyl)aminolphenyl ⁇ -2-methyl-2- (methylsulfonyl)butanoate
  • Trifluoroacetic acid 50 mL, 650 mmol was added to a solution of (+/-)-ethyl 4- ⁇ 4- [(tert-butoxycarbonyl)amino]phenyl ⁇ -2-methyl-2-(methylsulfonyl)butanoate (6.47 g, 16.2 mmol) in dicholoromethane (100 mL) at 0°C.
  • the reaction was allowed to warm to room temperature and was stirred for 2 hours. The reaction was then concentrated; the residue was dissolved in 1 N aqueous HCI (100 mL) and washed with ethyl acetate (3x100 mL). The organic layers were discarded.
  • the aqueous layer was made basic with 1 N aqueous NaOH, and extracted with ethyl acetate (3x100 mL). The combined organics were washed with water (100 mL), brine (100 mL), dried (MgS0 4 ), filtered, and concentrated in vacuo to afford a crude orange oil.
  • the crude product was purified via flash chromatography using an Analogix SF40-150g column and an eluant of ethyl acetate in heptane (1 :1 ) to afford the title compound as a yellow oil (3.52 g, 72.6%).
  • Step F (+/-)-Ethyl 4-r4-(2H-indazol-2-yl)phenyll-2-methyl-2-(methylsulfonyl)butanoate
  • (+/-)-Ethyl-2-methyl-2-(methylsulfonyl)-4-(4- ⁇ [(1 E)-(2-nitrophenyl)methylene] amino ⁇ phenyl) butanoate (912 mg, 2.1 1 mmol) was added to a solution of triethyl phosphite (10mL) and the solution was refluxed overnight at 160°C under nitrogen. The reaction was concentrated in vacuo and the residue was dissolved in ethyl acetate (50mL) and washed with water (3x 50mL). The organic layer was dried (MgS0 4 ), filtered and concentrated in vacuo. The crude product was purified via flash
  • Step G (+/-)-4-r4-(2H-lndazol-2-yl)phenyll-2-methyl-2-(methylsulfonyl)butanoic acid (+/-)-Ethyl 4-[4-(2H-indazol-2-yl)phenyl]-2-methyl-2-(methylsulfonyl)butanoate was converted to the title compound following the general procedure described in Step 3, Preparation 2, for the formation of compound (II) using potassium hydroxide in place of lithium hydroxide.
  • Step H (+/-)-4-r4-(2H-indazol-2-yl)phenyll-2-methyl-2-(methylsulfonyl)-N-(tetrahvdro- 2H-pyran-2-yloxy)butanamide
  • (+/-)-4-[4-(2H-lndazol-2-yl)phenyl]-2-methyl-2-(methylsulfonyl)butanoic acid was converted to the title compound following the general procedure described in step 4 of Preparation 2, for the preparation of compound (III) using N,N- diisopropylethylamine in place of triethylamine.
  • the title compound was obtained as a white solid (437 mg, 87.6%) LC-MS m/z 472.7(M+1 ).
  • Step I (+/-)-N-hvdroxy-4-r4-(2H-indazol-2-yl)phenyll-2-methyl-2-(methylsulfonyl) butanamide
  • (+/.)-4-[4-(2H-indazol-2-yl)phenyl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H- pyran-2-yloxy)butanamide was converted to the title compound following an analogous procedure as described for the preparation of Example 1 1 , Step D.
  • the title compound was obtained as a white solid (232 mg, 64.6%) LC-MS m/z 388.5 (M+1 ).
  • Step A (2R)-2-Methyl-2-(methylsulfonyl)-N-(tetrahvdro-2H-pyran-2-yloxy)-4-r4'- (tetrahvdro-2H-pyran-2-yloxy)biphenyl-4-yllbutanamide
  • Step B (2R)-N-Hvdroxy-4-(4'-hvdroxybiphenyl-4-yl)-2-methyl-2-(methylsulfonyl) butanamide
  • Step B 4-Fluoro-4'-(2-iodoethyl)biphenyl
  • Step D 4-(4'-Fluorobiphenyl-4-yl)-2-(methylsulfonyl)butanoic acid
  • Step E 4-(4'-Fluorobiphenyl-4-yl)-N-hvdroxy-2-(methylsulfonyl)butanamide
  • Step C Ethyl 2-methyl-2-(methylsulfonyl)-4-r4-(phenoxymethyl)phenyllbutanoate
  • Step D 2-Methyl-2-(methylsulfonyl)-4-r4-(phenoxymethyl)phenyllbutanoic acid
  • Step E N-hvdroxy-2-methyl-2-(methylsulfonyl)-4-r4-(phenoxymethyl)phenyllbutanamide
  • LPS lipopolysaccharide
  • IC50 determination 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-3-0-(R-3- hydroxymyristoyl)-GlcNAc deacetylase) using BioTrove RapidFire HTS Mass
  • co//-overexpressing bacteria was incubated at 25°C in a final volume of 50 ul containing 0.5 uM UDP-3-0-(R-3- hydroxydecanoyl)-N-acetylglucosamine, 1 mg/mL BSA, and 50mM sodium phosphate buffer, pH 8.0 in the presence and absence of inhibitor compound.
  • 50 ul containing 0.5 uM UDP-3-0-(R-3- hydroxydecanoyl)-N-acetylglucosamine, 1 mg/mL BSA, and 50mM sodium phosphate buffer, pH 8.0 in the presence and absence of inhibitor compound.
  • 5ul of 1 N HCI was added to stop the enzyme reaction; the plates were centrifuged, and then processed with the BioTrove Rapidfire HTMS Mass Spectrometry System.
  • a no- enzyme control was used in calculating the IC50 values from the percent conversion values.
  • Pseudomonas aeruginosa UI-18 Wild-type, labeled as PA-7 in Tables 1 , 2 and 3;
  • Acinetobacter baumanii/haemolyticus Multidrug-resistant clinical isolate labeled as AB-3167 in Tables 1 , 2 and 3;
  • Escherichia coli EC-1 VOGEL, mouse virulent labeled as EC-1 in Tables 1 , 2 and 3;
  • Klebsiella pneumoniae Ciprofloxacin-resistant isolate, expresses extended- spectrum beta-lactamases (ESBL), clinical isolate, labeled as KP-3700 in Tables 1, 2, and 3.
  • Example 9 0.00032 32 0.125 4 2
  • Example 19 0.00343 >64 8 32 16
  • Example 20 > 64 1 8 16
  • Table 2 lists these compounds by name, provides characterization data such as liquid chromatography-mass spectrometry and retention times. Table 2 also provides selected biological data using the same protocols as described above for Examples 1 -25.
  • R 1 and R 2 are methyl, X is CH 2 , A is unsubstituted phenyl, L is absent, D forms an aryl or heteroaryl ring, and both G and T may be absent or present and are as defined above in Formula I.
  • (+/-)-4-(4- Bromophenyl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (1 OOmg, 0.266mmol (1 eq)
  • an appropriately substituted boronic derivative i.e. a G-T-D moiety corresponding to the desired final product, (( 0.404mmol) (1.5eq)) into a 2-5ml_ microwave vial followed by the addition of a catalytic amount of Palladium (II) EnCat catalyst (approx 10mol%), potassium carbonate (1 ml_ of 0.123M in water (-3 eq) and 1 ml.
  • column 2 provides the lUPAC name; column's 3-7 provide in-vitro biological data, column 8 reports the mass spectrometry data generated via LCMS and column 9 reports LCMS retention times.
  • the in-vitro data in column's 3-7 was generated in the same manner as that described in Table I above.
  • the LCMS retention times (LCMS-RT) reported in column 9 were generated in the following manner:
  • Solvent B 0.06%NH4OH (in acetonitrile)
  • Run time 4 minutes LCMS data and retention times were not available for all compounds. This could be due to errors in computation, inability to locate data, errors in methodology,

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pyrane Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Hydrogenated Pyridines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
  • Quinoline Compounds (AREA)
  • Furan Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

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

Description

C-LINKED HYDROXAMIC ACID DERIVATIVES USEFUL AS ANTIBACTERIAL
AGENTS Field of the Invention
This invention relates to novel hydroxamic acid derivatives that are useful for the treatment of bacterial infections, especially Gram-negative infections. The invention also relates to methods of using such compounds in the treatment of bacterial infections in mammals, and to pharmaceutical compositions containing such compounds.
Background of the Invention
Infection by Gram-negative bacteria such as Pseudomonas aeruginosa,
Extended Spectrum β-lactamase producing (ESBL) Enterobacteriaceae, and
Acinetobacter baumannii is a major health problem, especially in the case of hospital- acquired infections. In addition, there is an increasing level of resistance to current antibiotic therapies, which severely limits treatment options. For example, in 2002, 33% of Pseudomonas aeruginosa infections from intensive care units were resistant to fluoroquinolones, while resistance to imipenem was 22% (CI D 42: 657-68, 2006). In addition, multi-drug resistant (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 lethal 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 is the enzyme that catalyzes the first committed step in the Lipid A biosynthetic pathway, the removal of the N-acetyl group of UDP-3-0-(R-3-hydroxymyristoyl)-N-acetylglucosamine. LpxC is a Zn2+ - dependent enzyme that has no mammalian homologue, making it a good target for the development of novel antibiotics. Several inhibitors of LpxC [UDP-3-0-(R-3- hydroxymyristoyl)-GlcNAc deacetylase] with low nM affinity have been reported (Biochemistry 45: 7940-48, 2006). Summary of the Invention
A new class of LpxC inhibitors has been discovered. These compounds, or their pharmaceutical salts, can be represented by Formula I below:
Figure imgf000003_0001
in which
R1 is represented by C1-C3 alkyl;
R2 is represented by hydrogen or C1-C3 alkyl;
X is represented CH2, O, NH, S or S02,
A is represented by phenyl or a 6-membered heteroaryl as depicted below:
Figure imgf000003_0002
R3 is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxy, amino, (C1-C6)alkyl optionally substituted, (C1-C6)alkoxy optionally substituted, trifluoromethyl, and trifluoromethoxy;
L is absent, or is represented by S, SH, OH, -(CH2)p-0-(CH2)n-,
-(CH2)p-0-(CH2)z-0-(CH2)n-, S-(CH2)Z, or (CH2)Z-S;
n is represented by an integer ranging from 0 to 3;
p is represented by an integer ranging from 0 to 3;
z is represented by an integer from 1 to 3;
D is absent, or is represented by a substituent selected from the group consisting of:
i) (C3_C10)cycloalkyl, optionally substituted,
ii) (C3-C10)cycloalkyl (C1-C6)alkyl, in which the alkyl and cycloalkyl moieties may each be optionally substituted,
iii)(C6-C10)aryl optionally substituted, iv) (C6-C10)aryl (C1-C6)alkyl, in which the alkyl and aryl moieties may each be optionally substituted,
v) heteroaryl, optionally substituted,
vi) heteroaryl(C C6)alkyl, in which the heteroaryl and alkyl moieties may each be optionally substituted,
vii) heterocyclic, optionally substituted, and;
viii) heterocyclic(C C6)alkyl, in which the alkyl and heterocyclic moieties may each be optionally substituted;
T is absent, or is represented by -(CH2)Z-, -(CH2)n-C(0)-(CH2) -,
0-(CH2)z-, -(CH2)z-0-, or -0-(CH2)p-C(0)-(CH2)n-;
G 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:
a) at least one of D or L must be present b) if D is absent, then Tand G are also absent.
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 animals.
The compounds of Formula I are useful for treating a variety of infections;
especially Gram-negative infections including nosocomial pneumonia, 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), Helicobacter pylori (and relief of associated gastric complications such as peptic ulcer disease, gastric carcinogenesis, etc.), endocarditis, diabetic foot 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, aerosols for inhalation 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.
Definitions 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-|- 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. "6-membered heteroaryl" refers to an aromatic 6 membered ring that may
contain 1 , 2, 3, or 4 nitrogen atoms Examples of such rings include pyridyl, pyridazinyl, pyrimidinyl, and pryazinyl.
c. "optionally substituted 6-membered heteroaryl" refers to a 6-membered
heteroaryl ring, as described above, in which up to 3 carbon atoms of any such ring may be substituted with a non-hydrogen substituent, each substituent is independently selected from the group consisting of halogen, nitro, cyano, hydroxy, amino, (C1-C6)alkyl optionally substituted, (C1-C6)alkoxy optionally substituted, trifluoromethyl, and trifluoromethoxy.
d. "halogen" refers to a chlorine, fluorine, iodine, or bromine atom.
e. "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.
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, n- butoxy, isobutoxy, pentoxy, etc; which may be unsubstituted or optionally further substituted with halogen, hydroxy, thiol or amino.
g. "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 6 hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, cyano, -0-Ra, -SRa, and -NRaRb in which Ra and Rb are each independently represented by hydrogen or C-1-C6 alkyl. h. "(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.
i. "(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, (C1-C6)alkyl optionally substituted, (C1-C6)alkoxy optionally substituted, trifluoromethyl, trifluromethoxy, phosphate, oxo, -S02NR4, -(CH2)m-N-C(0)-R4, -(CH2)m-C(0)-N-R4, -C(0)-R4,
-C(0)-0-R4, -SR4, -S02R4 and -NR4R5, in which R4 and R5 are each
independently represented by hydrogen or C1-C6 alkyl, which may be optionally substituted as defined above, and m is 0-4.
j. "(C6-C10)aryl" means a cyclic, aromatic hydrocarbon containing from 6 to 10 carbon atoms. Examples of such aryl groups include phenyl, naphthyl, etc. k. "(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, (C1-C6)alkyl optionally substituted, (C1-C6)alkoxy optionally substituted, trifluoromethyl, trifluromethoxy, phosphate, oxo, -S02NR4, -(CH2)m-N-C(0)-R4, -(CH2)m-C(0)-N-R4, -C(0)-R4,-
C(0)-0-R4, -SR4, -S02R4 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.
I. "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 6- membered 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. 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, imidazolyl, oxazolyl, indolyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, benzofuran, tetrazole, isoquinolinyl, oxadiazolyl, thiadiazolyl, isothiazolyl, isoxazolyl, triazolyl, benzo[6]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 7-benzimidazolyl, or
benzothiazolyl.
"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-C6)alkyl optionally substituted, (C1-C6)alkoxy optionally substituted, trifluoromethyl, trifluromethoxy, phosphate, oxo, S02NR4, -(CH2)m-N-C(0)-R4, -(CH2)m-C(0)-N-R4,
-C(0)-R4, -C(0)-0-R4, -SR4, -S02R4 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,
"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;
1 sulfur atom; 1 nitrogen and 1 sulfur atom; 1 nitrogen and 1 oxygen atom;
2 oxygen atoms in non-adjacent positions; 1 oxygen and 1 sulfur atom in non- adjacent 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 have 0 to 2 double bonds, and the 8, 9, or 10 membered rings may have 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-1 H- isoindole, tetrahydro-oxazolyl, tetrahydro-oxazinyl, thiomorpholinyl,
tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl,
octahydrobenzimidazolyl, and octahydrobenzothiazolyl.
"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, (C1-C6)alkyl optionally substituted, (C1-C6)alkoxy optionally substituted, trifluoromethyl, trifluromethoxy, phosphate, oxo, S02NR4, -(CH2)m-N-C(0)-R4, -(CH2)m-C(0)-N-R4, -C(0)-R4, - C(0)-0-R4, -SR4, -S02R4 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 nitrogen atom within such a heterocyclic ring may optionally be substituted with (Ci-Ce) alkyl, if such substitution is chemically permissible.
p. "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.
q. "patient" refers to warm blooded animals such as, for example, guinea pigs, mice, rats, gerbils, cats, rabbits, dogs, monkeys, chimpanzees, and humans. r. "treat" refers to the ability of the compounds to relieve, alleviate or slow the
progression of the patient's bacterial infection (or condition) or any tissue damage associated with the disease.
s. "pharmaceutically acceptable" indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith,
"isomer" means "stereoisomer" and "geometric isomer" as defined below, "stereoisomer" means compounds that possess one or more chiral centers and each center may exist in the R or S configuration. Stereoisomers include all diastereomeric, enantiomeric and epimeric forms as well as racemates and mixtures thereof.
u. "geometric isomer" means compounds that may exist in cis, trans, anti, entgegen
(E), and zusammen (Z) forms as well as mixtures thereof,
v. Compounds of "Formula I", "formula I" and "compounds of the invention" are being used interchangeably thru-out the application and should be treated as synonyms. The phrase "pharmaceutically acceptable salt(s)", as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of the present invention. The compounds of the present 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 prepare 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, isonicotinate, 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 , 1 '-methylene-bis-(2-hydroxy- 3-naphthoate)] salts. The compounds of the present 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 prepare
pharmaceutically acceptable base salts of those compounds of the compounds of the invention that are acidic in nature 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 metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine- (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, magnesium, 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, Selection, 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 geometric isomers. The compounds of the formula (I) may possess one or more asymmetric centers, thus existing as two, or more, stereoisomeric forms. The present invention includes all the individual stereoisomers and geometric isomers of the compounds of formula (I) and mixtures thereof. Individual enantiomers can be obtained by chiral separation or using the relevant enantiomer in the synthesis.
In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention. The compounds may also exist in one or more crystalline states, i.e. polymorphs, or they may exist as amorphous solids. All such forms are encompassed by the claims.
The invention also relates to prodrugs of the compounds of the invention. Thus certain derivatives of compounds of the invention which may have 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 derivatives 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 Series (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, Plenum Press (1973) and "Protective Groups in Organic Synthesis", 3rd edition, T.W. Greene and P.G.M. Wuts, Wiley- Interscience (1999).
The present 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, C, 14C, 1ΰΝ, ηΌ, ηΌ, d1P, -*P, *S, F, and *CI, respectively. Compounds of the present 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 isotopically- labeled compounds of the present 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 preparation 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. Isotopically-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 isotopically-labeled reagent for a non-isotopically-labeled reagent.
All of the compounds of Formula I contain a sulfonyl moiety as depicted below:
Figure imgf000011_0001
This sulfonyl moiety will always be substituted with a lower alky 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. The linker represented by X will typically be methylene.
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:
Figure imgf000012_0001
All of the compounds of Formula I contain either a phenyl ring or a 6-membered heteroaryl ring, as depicted by A. Either the phenyl ring or the heteroaryl ring may be optionally substituted as described above by the R3 substituent. R3 may represent up to 4-non-hydrogen substituents when A is phenyl. When A is a 6-membered heteroaryl, R3 may represent up to 3 non-hydrogen substituents. These substituents may be the same or different and are listed above.
When A is heteroaryl, it will be connected to the rest of the molecule via carbon atoms as depicted above. When A is a heteroaryl, it will typically be pyridyl, pyrimidyl, or pyridazinyl.
Examples of such pyridyl's include:
Figure imgf000012_0002
Figure imgf000012_0003
Typically these pyridyl rings will be unsubstituted or mono-substituted with C-1-C6 lower alkyl optionally substituted, hydroxy or amino.
All of the compounds may also contain one of the substituents as defined by D. Alternatively, D may be absent, along with T and G, and the tail of the molecule may be one of the ether or thioether moieties defined by L as discussed below.
D, if present, may be cycloalkyl, aryl, heteroaryl, or heterocyclic. Alternatively, D may be (cycloalkyl)alkyl, (heteroaryl)alkyl, (aryl)alkyl, or heterocyclic(alkyl), etc. Any of theses ring systems may be optionally substituted with up to 4 non-hydrogen
substituents from the list specified above. These substituents may be the same or different. Such substitution may occur wherever chemically permissible. For example, in a heterocyclic system, a nitrogen atom may be substituted with an alkyl moiety. In an aromatic system, substitution may only occur on a carbon atom.
If D is (cycloalkyl)alkyl, (heteroaryl)alkyl, etc., the alkyl moiety will be bonded to the phenyl or heteroaryl ring represented by A. This alkylene moiety may be optionally substituted with up to 6- non-hydrogen atoms as described above. These substituents may be the same or different.
Typically, D will either be phenyl, or pyridyl. If D represents phenyl; then it will be unsubstituted, or substituted with halogen, amino, nitro, phosphate, or hydroxyl . If pyridyl, D will be typically be unsubstituted.
The presence of L is optional. The moieties represented by A and D may be bonded to each other, or L may serve as a linker. Alternatively, L may serve as the tail of the molecule, when D, T and G are absent. Most typically, L will be absent.
The presence of T is optional. It may serve as a linker between the rings that define D and G. Typically T will be absent.
The presence of G in the molecule is also optional. It may be absent.
Alternatively, it may be represented by a heteroaryl moiety, a heterocyclic moiety, (C3- C-10) cycloalkyl, or (C6-C-10) aryl. Any of these moieties may be unsubstituted or optionally substituted. They may be substituted with up to 4-non-hydrogen substituents. These substituents may be the same or different. Such substitution may occur wherever chemically permissible. Typically, G will be absent.
More specific embodiments of the invention include compounds of Formula I in which:
a) R1 is methyl;
b) R1 and R2 are each methyl;
c) X is CH2;
d) R1 and R2 are each methyl and X is CH2;
e) R1 and R2 are each methyl, X is CH2 and A is phenyl or pyridyl;
f) R1 and R2 are each methyl, X is CH2 and A is phenyl or pyridyl in which R3 is hydrogen;
g) R1 and R2 are each methyl, X is CH2, A and D are both optionally substituted phenyl, L, T and G are all absent; h) R1 and R2 are each methyl, X is CH2, L, T and G are each absent, A and D are each independently selected from the group consisting of optionally substituted pyridyl and optionally substituted phenyl, and;
i) R1 and R2 are each methyl, X is CH2, D, T and G are each absent, and L is present and as defined above.
Synthesis
The compounds of Formula I can be prepared by a variety of methods that are analogously known in the art. The reactions schemes presented below illustrate one method for preparing these compounds. Others, including modifications thereof will be readily apparent to one skilled in the art.
Scheme A provides an overview of how to synthesize the compounds of Formula I in which X is CH2, as depicted. For the generation of the phenyl or heteroaryl intermediate identified as structure 1 , see Reaction Scheme B. In the compound of structure 1 , Z will be represented by a suitable reactive group such as halogen, boronic acid or boronate ester, etc, depending upon the identity of D, T and G in the final product. Y will typically be represented by a hydroxyl group or the protected sulfonyl- containing moiety as depicted. "PG" is a protecting group such as a lower alkyl (as part of an ester) or a tetrahydropyranyl group (as part of a hydroxamate).
Scheme A )-0-PG
)-NH-OPG
Scheme 1A D
L absent
D and A linked
C-C bond
G-T-D-M1
Figure imgf000015_0001
1
Figure imgf000015_0002
As depicted in Scheme A, the next step in the synthesis will depend upon the identity of D,T, G, and L in the final product. Four alternative reactions are depicted. If L is absent and the goal is to form a carbon-carbon bond then Scheme 1A should be chosen. This is appropriate for compounds in which D is aryl, arylalkyi, cycloalkyi, cycloalkylalkyl, C-linked heteroaryl, etc.
If L forms an ether or thioether with at least one of D or A, then Scheme 1 B should be chosen. If L is absent and D is a heteroaryl or heterocyclic moiety and the bond will be with the heteroatom (i.e. C-N), then Scheme 1 C should be chosen. Finally, if L is present and forms a carbon-carbon bond with both A and D (if present), then Scheme 1 D should be utilized. The specifics of these reactions are discussed infra.
The final step in the synthesis is to incorporate the hydroxamic acid moiety into the molecule utilizing the methodologies depicted in Scheme 2 infra. As is readily apparent to one skilled in the art, the order in which the reactions are carried out is typically not critical. If desired, the hydroxamic acid moiety may be incorporated into the molecule and then the G-T-D-L moiety may be added. Further D, T or G may also be added separately. Such manipulations are readily apparent to one skilled in the art and can be carried out using standard techniques well known to medicinal chemists.
Scheme 1 A is appropriate for the compounds in which L is absent and a C-C bond is desired. Thus this reaction will be used when D is any of cycloalkyl,
cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, cycloalkyl, or cycloalkyl alkyl (any of which may be optionally substituted).
One of the starting materials will be an appropriately substituted phenyl or heteroaryl moiety as described by structure 1 . R3 will typically be represented by the same substituent as is desired in the final product. Z will be a halide, boronic acid, boronate ester or other appropriately reactive group. Y will be hydroxyl or the protected sulfonyl-containing moiety as depicted above. The other reactant, G-T-D-M1, will be represented by the same moiety as desired in the final product except that it will be substituted by a halogen atom or metal such as magnesium, copper, or a boronate ester, etc. at the desired point of attachment to the aryl moiety "A".
The molecule may be assembled using any of a number of coupling reactions known in the art. For example, the Suzuki-Miyaura strategy may be used. In such a reaction M1 will be a boronic acid/ester and Z will be a halogen atom or a triflate (or vice versa). Equivalent molar amounts of the reactants will be contacted in a solvent such as THF, dioxane, water, toluene, or an admixture thereof; in the presence of a transition metal catalyst such as palladium, or nickel (or resin bound catalyst) along with a base such as sodium carbonate, potassium carbonate, cesium fluoride or cesium carbonate. The reactants will be heated by microwave or other conventional technique till completed. Once completed the desired product may be isolated and recovered from the reaction and further purified as is known in the art. Alternatively the crude may be used in Step 2 described below.
Alternatively an Ullmann coupling strategy may be used. In such a reaction M1 will be copper or nickel and Z will be a halogen. Equivalent amounts of the reactants will be contacted in an aprotic solvent such as ether, DMF, or DME and the reactants are heated to reaction completion. The desired product of structure 2 may be isolated and purified as is known in the art, or used as a crude mixture in the next step of the reaction.
Scheme 1 B is appropriate for the compounds in which L is present and a C-0 or C-S bond is desired (i.e. L is an ether or thioether linkage) between L and at least one of A or D. A Willamson/Ullmann ether coupling, Mitsunobu or alkylation reaction may be utilized to produce these derivatives. One of the starting materials will be an appropriately substituted phenyl or heteroaryl moiety as described by structure 1 . R3 will typically be represented by the same substituent as is desired in the final product. Z will be halide, boronic acid, hydroxyl, etc. and Y will be hydroxyl or the protected sulfonyl moiety as depicted above. The other reactant, G-T-D-L-M2, will be represented by the same moiety as desired in the final product, except that it will be substituted by a hydroxyl function at the desired point of attachment to the aryl moiety Ά". If a thioether is desired, G-T-D-L-M2 will be an appropriately substituted disulfide moiety.
The Ullmann ether reaction can be carried out in the presence of copper salts. If a Williamson ether approach is used, then equivalent amounts of the reactants will be contacted in an aprotic solvent such as dioxane in the presence or absence of a phase transfer catalyst such as 18-crown-6. A base such as potassium hydroxide, sodium t- butoxide or sodium methoxide will typically be added as well. The reactants will be heated by microwave or other conventional technique to reaction completion. The desired product of structure 2 may be isolated and purified as is known in the art, or used as a crude mixture in the next step of the reaction.
Scheme IC is appropriate for those compounds in which L is absent and a carbon-nitrogen bond is desired between the carbon of the heteroaryl moiety, "A", and a nitrogen atom of the D moiety. This reaction will be used when D is any of heteroaryl or heterocyclic (either of which may be optionally substituted). One of the starting materials will be an appropriately substituted phenyl or heteroaryl moiety as described by structure 1. R3 will typically be represented by the same substituent as is desired in the final product. Z will be a boronic acid, boronate ester or other appropriately reactive group. Y will be hydroxyl or the protected sulfonyl moiety as depicted above. The other reactant, G-T-D, will be represented by the same moiety as desired in the final product.
The carbon-nitrogen bond may be formed using a Buchwald-Hartwig cross- coupling or Ullmann strategy similar to that described above. Equivalent amounts of the reactants will be contacted in an aprotic solvent solvent such as ether,
dimethylformamide, or dimethyoxyethane in the presence of a source of copper, such as copper acetate, and a base such as pyridine or catalyst such as a palladium complex. The reaction will be allowed to proceed to completion and the desired product of structure 2 may be isolated and purified as is known in the art, or used as crude in the next step of the reaction.
Scheme 1 D is appropriate for compounds in which L is present and forms a carbon-carbon bond with A and D (if D is present). One of the starting materials will be the derivative of structure 1 as described above in Scheme 1A in which R3 will be represented by the same substituent as is desired in the final product and Y will be hydroxyl or the protected sulfonyl moiety depicted above. Z will be halide, boronic acid, boronate ester, or other appropriately reactive group. The other reactant, G-T-D-L', will be represented by the same moiety as desired in the final product except that it will be substituted by a halogen atom or metal such as magnesium, copper, or a boronate ester, at the desired point of attachment to the aryl moiety "A". The coupling reaction of Scheme 1 D can be carried out using either the Suzuki-Miyaura strategy or the Ullmann coupling strategy described above in Scheme 1A.
As noted in Reaction Scheme A, the second step in the reaction is to incorporate the hydroxamic acid moiety into the molecule. This may be accomplished as depicted in Scheme 2 below:
Scheme 2
Figure imgf000019_0001
Step C
Hydrolysis
Figure imgf000019_0002
Step D Η2Ν-ΟΡ'
Amidation and P'= H or Protecting Group
tional Deprotection ψ
Figure imgf000019_0003
In the initial step, the hydroxyl function depicted in structure 2 is converted into a leaving group. In structure 2, G, T, D, L and R3 will typically be represented by the same moiety as is desired in the final product. Typically, the leaving group will be a halogen atom, such as iodine, but it may also be a tosylate or mesylate functional group. Methods of incorporating such leaving groups are well known to those skilled in the art. For example, if the desired leaving group is iodine, then the compound of structure 2 is placed in a solution of imidazole and contacted with a molar excess of both triphenylphosphine and iodine. The reaction is typically carried out at reduced temperatures (i.e. 0° C) and allowed to proceed to completion. The desired product of structure 3 may then be isolated and purified as is known in the art, or the crude product may be used in Step B.
In Step B, the leaving group is displaced with the protected alkylsulfonyl acetate or 2-alkylsulfonyl propionic ester as depicted in Scheme 2. R1 and R2 will typically be represented by the same moiety as is desired in the final product. An ethyl ester moiety is depicted, but any standard ester group may be utilized. The alkylation may be carried out as is known in the art. Typically equivalent amounts of the compound of structure 3 and the protected sulfonyl ester are contacted in an aprotic solvent such as
dimethylformamide, tetrahydrofuran, etc. An excess of an inorganic base such as cesium carbonate, potassium carbonate or sodium hydride is added to the reaction. The reaction may be run at room temperature or heated to accelerate completion. The desired product of structure 4 may be isolated and purified as is known in the art.
Alternatively the crude product may be used in Step C.
In Step C, the protecting group of the carboxylic acid is removed generating the intermediate of structure 5. 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.
In Step D, the hydroxamic acid moiety depicted is incorporated into the molecule. This can also be carried out as is known in the art. If desired, a protected
hydroxylamine may be used, followed by a subsequent deprotection reaction.
Alternatively hydroxylamine may be directly incorporated. In either case the hydroxamic acid functionality is incorporated into the molecule using standard amidation reactions. For example, the compound of structure 5 may be contacted with an excess of oxalyl chloride in an aprotic solvent such as dichloromethane to allow formation of the corresponding acid chloride, followed by the addition of an excess of either the hydroxylamine or protected hydroxylamine. The reaction is then allowed to proceed to completion and the final product of Formula I or its corresponding protected
intermediate is isolated from the reaction medium and purified as is known in the art. As mentioned above, any deprotection, if required, may be carried out as is known in the art.
Scheme B depicted below teaches how to prepare the starting material described in Scheme A:
Figure imgf000021_0001
The penultimate starting material, structure 1 , can be produced using techniques well known in the art. This material is produced from the carboxylic acid depicted as structure 6. The ring will either be phenyl or heteroaryl depending upon the desired final product. R3 will also typically be represented by the same substituent as is desired in the final product. Z will be a halogen or otherappropriately reactive group. Such carboxylic acids may be purchased or produced as described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations by Richard C. Larock, 2nd Edition, 2000, published by Wiley, John & Sons, Inc.
The reduction is typically carried out in an aprotic solvent such as
tetrahydrofuran, etc. The carboxylic acid is contacted with an excess of a reducing agent such as borane, etc. at room temperature. The reaction is quenched with a weak base such as potassium carbonate, sodium carbonate, etc. The resulting alcohol, structure 7, may be isolated and purified as known in the art or used as crude in the next step.
In Step B, a halogenation reaction is carried out in which the hydroxyl function is converted to a chlorine atom. This may be accomplished by contacting the alcohol of structure 7 with a chlorinating agent such as thionyl chloride or oxalyl chloride and with a catalytic amount of dimethylformamide (DMF). The reaction will typically be carried out at ambient to reflux temperature and the resulting product, structure 8, may be recovered and isolated as is known or used as crude in Step C.
In Step C, a nitrile addition is carried out as depicted. The product from Step B is contacted with an aprotic solvent such as dimethylformamide, etc. An excess of sodium cyanide, or other cyanide source, is typically added to the reaction mixture and the reaction is allowed to proceed to completion at room temperature. The product, structure, 9, may be isolated and purified or used as crude product in the next step.
The hydrolysis of Step D may be conducted by contacting structure 9 with an aqueous solution of a strong acid such as HCI, etc. The resulting carboxylic acid may be isolated and purified or used as crude product in Step E.
In Step E, the carbonyl is reduced generating the alcohol depicted as structure 1 . This reduction may be carried out in the same manner as Step A immediately above. The desired product may be isolated and purified as is known in the art.
The reaction schemes depicted above for producing 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 specific compound, availability of reagents, etc.
Medical and Veterinary Uses
The compounds may be used for the treatment or prevention of infectious disorders, especially those caused by susceptible and multi-drug resistant (MDR) Gram- negative 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 (β- lactamase positive and negative), Helicobacter pylori, Klebsiella oxytoca, Klebsiella pneumoniae (including those encoding extended-spectrum β-lactamases (hereinafter "ESBLs"), Legionella pneumophila, Moraxella catarrhalis (P-lactamase positive and negative), Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitidis, Proteus vulgaris, Porphyromonas spp., Prevotella spp., members of the
Enterobacteriaceae that express ESBLs KPCs, CTX-M, metallo-3-lactamases, and AmpC-type beta-lactamases that confer resistance to currently available
cephalosporins, cephamycins, carbapenems, and beta-lactam/beta-lactamase inhibitor combinations, 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 malophilia.
In a more specific embodiment, the Gram-negative bacteria are selected from the group consisting of Acinetobacter baumannii, Acinetobacter spp., Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae , Serratia marcescens, Pseudomonas aeruginosa and members of the Enterobacteriaceae and Pseudomonas that express ESBLs, KPCs, CTX-M, metallo-β- lactamases, and AmpC-type beta-lactamases that confer resistance 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 Helicobacter 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 recurrence 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 decide the total daily dosage of the compound. The specific
therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. As a general guideline however, the total daily dose will typically range from about 0.1 mg/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, parenteral, topical, rectal, transmucosal, and intestinal, can be used to administer the compounds. Parenteral administrations include injections to generate a systemic effect or injections directly into to the afflicted area. Examples of parenteral administrations are
subcutaneous, intravenous, intramuscular, intradermal, intrathecal, and intraocular, intranasal, intravetricular injections or infusions techniques. Topical administrations include the treatment of areas readily accessibly 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 other lower intestinal tract. Transmucosal administration includes nasal aerosol 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 parenteral. The compositions may be in any form known in the art, including but not limited to tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
The topical formulations of the present invention can be presented as, for instance, ointments, creams or lotions, ophthalmic ointments/drops and otic drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients, etc. Such topical formulations may also contain conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present, for example, from about 1 % up to about 98% of the formulation.
Tablets and capsules for oral administration may be in unit dose presentation 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 magnesium stearate, 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 will known in normal pharmaceutical practice.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying 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 parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile 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. Parenteral 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 sterile 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
60% 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 5-500 mg of the active ingredient. 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 anti-bacterial 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 preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations. In the following examples molecules with a single chiral center, unless otherwise noted, exist as a racemic mixture. Those molecules 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 atmosphere (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 resonance (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), or a 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 temperature refers to 20-25°C.
For syntheses referencing procedures in other Examples, reaction conditions (length of reaction and temperature) 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 eluants/gradients were chosen to provide appropriate RfS or retention times.
In the discussion above and in the examples below, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.
aqueous
broad multiplet
ferf-butoxycarbonyl
broad doublet
broad singlet
1 , 1 '-carbonyldiimidazole
doublet
doublet of doublets
doublet of quartets
doublet of triplets
dimethylformamide
dimethylacetamide
dimethylaminopyridine
dimethyl sulfoxide
equivalents
grams
hours
high pressure liquid chromatography
leaving group
multiplet
molar
mole percent
maximum
milliequivalent milligram
milliliter
millimeter
millimol
quartet
singlet
triplet
tert-butyldimethylsilyl
trifluoroacetic acid
tetrahydrofuran
thin layer chromatography
preparative thin layer chromatography microliter
normality
methanol
dichloromethane
hydrochloric acid
acetonitrile
mass spectrometry
room temperature
ethyl acetate
ethoxy
acetate
1 -methyl-2-pyrrolidinone
microliter
coupling constant
nuclear magnetic resonance megahertz
hertz
mass to charge ratio
minutes
precipitate
benzyloxycarbonyl
1 ,3-dicyclohexylcarbodiimide PyBop = benzotriazole-1 -yl-oxy-trispyrrolidinophosphonium
hexafluorophosphate
Pd(dppf)CI2 = bis(diphenylphosphino)ferrocenepalladium(ll) chloride
Pd(dppf)CI2 DCM complex
Pd tetrakis = Tetrakis(triphenylphosphine)palladium(0)
Pd (II) EnCat = Pd (II) EnCat™BINAP 30
LDA = lithium diisopropylamide
mCPBA = meta-chloroperbenzoic acid
TMS = trimethyl silyl
TPP = triphenyl phosphine
TPPO = triphenyl phosphine oxide
DME = dimethyl ether
I PA = isopropanol
Et20 = diethyl ether
LiHMDS = lithium hexamethyldisilazide/ lithium bis(trimethylsilyl)amide
9-BBN = 9-Borabicyclo[3.3.1]nonane
sat. = saturated
PREPARATION OF STARTING MATERIALS
Preparation 1
Ethyl 2-(methylsulfonyl)propanoate
Figure imgf000029_0001
Sodium methyl sulfinate (103 g, 937 mmol) was combined with the ethyl 2- chloropropionate (109 g, 892 mmol) in ethanol (350 mL) in a 500 mL one neck round bottom flask. The reaction was warmed to 77°C for 20 hours and then allowed to cool to room temperature. Solids were removed by filtration through celite, and the filter pad was washed with ethanol and the combined filtrates were concentrated. 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%). 1 H 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). Preparation 2
(+/-)-4-(4-Bromophenyl)-N-hvdroxy-2-me
Scheme 1
Figure imgf000030_0001
Step 1 :
1 -Bromo-4-(2-iodoethyl)benzene
A solution of 2-(4-bromophenyl)ethanol (40.0 g, 0.199 mol) in dichloromethane (10 mL) was added dropwise to a solution of imidazole (22.4 mg, 0.329 mmol), triphenylphosphine (66.5 g, 0.254 mol), and iodine (65.0 g, 0.26 mol) in
dichloromethane (50 mL) at 0°C. When the addition was complete it was warmed to rt. After 1 hour the reaction was filtered through celite, the filtrate was washed with saturated aqueous sodium thiosufate (2x100 mL), brine (100 mL), dried over MgS04, filtered and concentrated in vacuo. Purification by flash column chromatography on silica gel (heptane/ethyl acetate 4: 1 ) afforded the title compound as a yellow-white solid (59.09 g, 60%). 1 HNMR (400 MHz, CHLOROFORM-d) δ ppm 3.14 (t, J=7.69 Hz, 2 H) 3.33 (t, J=7.69 Hz, 2 H) 7.08 (d, J=7.89 Hz, 2 H) 7.45 (d, J=8.31 Hz, 2 H)
Step 2:
(+/-)-Ethyl 4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)butanoate (I)
A suspension of 1-bromo-4-(2-iodo-ethyl)-benzene (25.0 g, 80 mmol) and (+/-)-2- methanesulfonyl-propionic acid ethyl ester (15.9 g, 88.4 mmol) in DMF (100 mL) with solid CS2CO3 (52.4 g, 161 mmol) was stirred overnight at room temperature. After 16 hours the reaction was poured into water (500 mL). The resulting suspension was stirred for 2 h. The mixture was extracted with diethylether (2X). The organic layers were combined and washed with water then brine, dried (Na2S04) and concentrated in vacuo. Purification by flash column chromatography on silica gel (hexanes/ethyl acetate 9:1 - 8:2) afforded the title compound as a white solid (21.0 g, 72%). 1 HNMR (400 MHz, CHLOROFORM-d) δ ppm 1.35 (t, J=7.22 Hz, 3 H) 1.70 (s, 3 H) 2.14 - 2.24 (m, 1 H) 2.42 - 2.55 (m, 2 H) 2.68 - 2.78 (m, 1 H) 3.04 (s, 3 H) 4.25 - 4.31 (m, 2 H) 7.07 (d, J=8.20 Hz, 2 H) 7.43 (d, J=8.20 Hz, 2 H)
Step 3:
(+/-)-4-(4-Bromophenyl)-2-methyl-2-(methylsulfonyl)butanoic acid (II)
Lithium hydroxide (3.29 g, 78.5 mmol) was added to a stirred solution of (+/-)- ethyl 4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)butanoate (9.50 g, 78.5 mmol) in THF:MeOH:water (2:2:1 , 225 mL) at 0° C. The reaction was warmed to room temperature as the ice bath expired. After 18 hours the reaction was acidified to pH 4 with 1 N HCI (aq) and extracted with ethyl acetate (2x). The organic layers were combined, dried (Na2S04) and concentrated in vacuo to give a white solid (8.5 g, 97%). LCMS m/z 333.1 (M-1 ). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.53 (s, 3 H) 1.95 - 2.05 (m, 1 H) 2.30 - 2.48 (m, 2 H) 2.67 - 2.79 (m, 1 H) 3.10 (s, 3 H) 3.26 (br. s., 1 H) 7.17 - 7.24 (m, 2 H) 7.43 - 7.52 (m, 2 H). Step 4:
(+/-)-4-(4-Bromophenyl)-2-methyl-2-(methylsulfonyl)-N-(tetrahvdro-2H-pyran-2- yloxy)butanamide (II I) (a mixture of diastereomers)
Triethylamine (5.49 g, 54.3 mmol) and 1 H-benzo[d][1 ,2,3]triazol-1 -ol (7.5 g, 49 mmol) were added to a solution of the (+/-)-4-(4-bromophenyl)-2-methyl-2- (methylsulfonyl)butanoic acid (9.1 g, 27.1 mmol) in dichloromethane (100 mL). After 10 minutes 0-tetrahydro-2H-pyran-2yl-hydroxylamine (4.6 g, 39 mmol) was added followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1 ,3-diamine hydrochloride (EDCI) (7.2 g, 38 mmol). After 12 h the reaction was quenched by the addition of saturated aqueous NaHC03. The layers were separated and the organic layer was dried (Na2S04), filtered and concentrated in vacuo. Purification by flash column chromatography on silica gel (hexanes / ethyl acetate 7:3 - 6:4) afforded the title compound as a white solid (9.0 g, 76 %). LCMS m/z 434.1 (M+1 ) 1 H NMR (400 MHz, DMSO-de) δ ppm 1 .54 (d, J=3.90 Hz, 6 H) 1.69 (br. s., 3 H) 1.78 - 2.06 (m, 1 H) 2.27 - 2.55 (m, 2 H) 2.59 - 2.72 (m, 1 H) 3.03 (d, J=6.64 Hz, 3 H) 3.50 (d, J=1 1.32 Hz, 1 H) 3.95 - 4.22 (m, 1 H) 4.97 (d, J=9.37 Hz, 1 H) 7.22 (dd, J=8.39, 4.49 Hz, 2 H) 7.49 (d, J=8.20 Hz, 2 H) 1 1.36 (br. s., 1 H)
Step 5:
(+/-)-4-(4-Bromophenyl)-N-hvdroxy-2-met (IV)
Oxalyl chloride (4.50 mL, 50 mmol) was added to a solution of 4-(4- bromophenyl)-2-methyl-2-(methylsulfonyl)butanoic acid (II) (14.69 g, 43.82 mmol) in DCM (300 mL) under nitrogen at ambient temperature, followed by DMF (340 ul). The reaction was stirred until effervescence ceased and then was allowed to stir for 1 hour. O-TMS-hydroxylamine (16.0 mL, 130 mmol) was added via syringe and the suspension was stirred for 1 hour. The reaction was quenched with methanol (60 mL), stirred for 1 hour and concentrated in vacuo to afford a yellow-white solid. The solid was triturated in DCM (200 mL) overnight. The solid was collected by filtration, washed with 1 :1 DCM:heptane (2x100mL), and dried under vacuum to afford the title compound as a white solid (14.85 g, 96.76%). LC-MS m/z 350.0 (M+1 ). 1 H NMR (500 MHz,
METHANOL-d4) δ ppm 1.64 (s, 3 H) 2.00 - 2.10 (m, 1 H) 2.44 - 2.58 (m, 2 H) 2.61 - 2.77 (m, 1 H) 3.04 (s, 3 H) 7.18 (d, J=8.29 Hz, 2 H) 7.44 (d, J=8.29 Hz, 2 H).
Preparation 3
(+/-)-2-Methyl-2-(methylsulfonyl)-N-(tetrahvdro-2H-pyran-2-yloxy)-4-r4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllbutanamide (VII)
Scheme 2
Figure imgf000032_0001
Step A:
(+/-VEthyl 2-methyl-2-(methylsulfonvn-4-r4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- vDphenyllbutanoate (V)
General procedure for pinacol boronate ester formation
A solution of (+/-)-ethyl 4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)butanoate
(12.50 g, 34.41 mmol), bis(pinacolato)diborane (10.5 g, 41.3 mmol), potassium acetate (16.9 g, 172 mmol) and Pd(dppf)CI2 (2.81 g, 3.44 mmol) in 1 ,4-dioxane (150 ml.) was heated to reflux. After 12 hours the reaction was diluted with dichloromethane and filtered through celite. The filtrate was concentrated in vacuo and subjected to purification by flash column chromatography on silica gel (hexanes/ethyl acetate 8:2-
1 :1 ) to give the title compound as a tan solid (10.0 g, 71 %). APCI m/z 41 1.3 (M+1 ). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (t, J=7.03 Hz, 3 H) 1.28 (s, 12 H) 1.57 (s, 3 H) 1.97 - 2.1 1 (m, 1 H) 2.35 - 2.48 (m, 2 H) 2.69 - 2.84 (m, 1 H) 3.1 1 (s, 3 H) 4.12 - 4.27 (m, 2 H) 7.25 (d, J=8.01 Hz, 2 H) 7.61 (d, J=8.20 Hz, 2 H). Step B:
(+/-)-2-Methyl-2-(methylsulfonyl)-4-r4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- vDphenyllbutanoic acid (VI)
The title compound (5.47 g, 100%) was prepared from (+/-)-ethyl 2-methyl-2- (methylsulfonyl)-4-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]butanoate (5.2 g, 12.7 mmol) and lithium hydroxide (2.13 g, 50.8 mmol) by a procedure analogous to that described for (+/-)-4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)butanoic acid (II/ Step 3-Preparation Number 2). LCMS m/z 381.6 (M-1 ). 1 H NMR (400 MHz,
CHLOROFORM-d) δ ppm 1 .36 (s, 12 H) 1.75 (s, 3 H) 2.19 - 2.30 (m, 1 H) 2.44 - 2.55 (m, 1 H) 2.56 - 2.67 (m, 1 H) 2.76 - 2.87 (m, 1 H) 3.09 (s, 3 H) 7.23 (d, J=8.01 Hz, 2 H) 7.76 (d, J=8.20 Hz, 2 H).
Step C:
(+/-V2-Methyl-2-(methylsulfonvn-N-(tetrahvdro-2H-pyran-2-yloxy')-4-r4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllbutanamide (VII) (mixture of diastereomers) The title compound (3.69 g, 60.4 %) was prepared from (+/-)-2-methyl-2- (methylsulfonyl)-4-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]butanoic acid (4.86 g, 12.7 mmol) and 0-tetrahydro-2H-pyran-2yl-hydroxylamine (2.1 g, 18.0 mmol) by a procedure analogous to that described for (+/-)-4-(4-bromophenyl)-2-methyl-2- (methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (III/ Step 4- Preparation Number 2). LCMS m/z 480.3 (M-1 ). Preparation 4
2-(5-Bromopyridin-2-yl)ethanol
Figure imgf000034_0001
6 5 Preparation of 2:
3-Bromopyridine-N-oxide
To a solution of 3-bromopyridine (1 , 250.0 g, 1 .58 mol) in DCM (3500 mL) was added a solution of NaHC03 (358.9 g, 4.27 mol) in H20 (4270 mL). The biphasic system was cooled to 0°C and mCPBA (70-75% with H20, 780.0 g, 3.16 mol) was added in portions. The mixture was allowed to warm up to room temperature and was stirred overnight. The layers were separated and the aqueous phase was extracted with DCM (2x 2000 mL). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo, but this led to an insignificant isolation of desired material. The aqueous phase was re-extracted with CHC (2x 1000 mL), yielding 50 g of the desired product. The remaining material was suspended in H20 (1000 mL) and stirred for 30 min. The solids were filtered and the aqueous phase re-extracted with CHCI3 (3x 500 mL). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo which gave a further 46.2 g. Combined yield of desired 96.2 g of compound 2 (0.55 mol, 35%). 1 H-NMR (CDCI3, 300 MHz): δ ppm 7.17 (t, 1 H, ArH), 7.42 (d, 1 H, ArH), 8.16 (d, 1 H, ArH), 8.38 (s, 1 H, ArH).
Preparation of 3: 5-(5-Bromopyridin-2(1 H)-ylidene)-2,2-dimethyl-1 ,3-dioxane-4,6-dione (Two identical batches were performed) Two solutions of Meldrum's acid (30.32 g, 210.3 mmol) in Ac20 (210 mL) were cooled to 0°C. 3-Bromopyridine-N-oxide (36.6 g, 210.3 mmol) was added drop-wise to each, keeping the reaction temperatures below 5°C. The two reaction mixtures were allowed to warm up to room temperature and stirred overnight. The batches were combined and filtered. The remaining solid (4) was washed with hot chloroform (50- 55°C). The filtrate was concentrated in vacuo. The residue was crystallized from methanol to give the desired product (3) (29.63 g, 23%). 1 H-NMR (CDCI3, 300 MHz): δ 1.61 (s, 6H, 2x CH3), 8.23 (d, 1 H, ArH), 8.54 (d, ArH), 8.65 (d, 1 H, ArH). Preparation of 5:
2-(5-Bromopyridin-2-yl)acetic acid
A solution of 5-(5-bromopyridin-2(1 H)-ylidene)-2,2-dimethyl-1 ,3-dioxane-4,6- dione (3) (40.0 g, 133.3 mmol) in HCI (30%, 400 mL) was heated gently to reflux, and was refluxed for 2h. The solvent was removed in vacuo and the residue (29.75 g) was used in the next step without further purification. 1 H-NMR (CDCI3, 300 MHz): δ 3.79 (s,
2H, CH2), 7.41 (d, 1 H, ArH), 8.08 (dd, 1 H, ArH), 8.66 (d, 1 H, ArH).
Preparation of 6:
2-(5-Bromopyridin-2-yl)ethanol
Under N2, a solution of 2-(5-bromopyridin-2-yl)acetic acid (5, 29.75 g) in THF (450 mL) was cooled to 0°C. Borane THF complex (1 M in THF, 413.2 mL, 413.2 mmol) was added dropwise, keeping the reaction temperature below 5°C. The mixture was allowed to warm to room temperature and stir for 4h. The mixture was cooled to 0°C and saturated aqueous K2C03 solution (500 mL) and H20 (500 mL) were added slowly. The mixture was extracted with EtOAc (3x 500 mL). The combined organic layers were washed with brine (500 mL), dried over Na2S04 and filtered. The solvent was removed in vacuo and the residue was purified by column chromatography (silica,
Heptane/EtOAc 3:7) yielding compound 6 (10.9 g, 53.9 mmol, 40% over 2 steps). 1 H- NMR (CDCI3, 300 MHz): δ 3.00 (t, 2H, CH2), 3.64 (bs, 1 H, OH), 4.03 (t, 2H, CH2), 7.10 (d, 1 H, ArH), 7.76 (dd, 1 H, ArH), 8.59 (d, 1 H, ArH). Preparation 5
2-(4'-Fluoro-3-methoxy-biphenyl-4-yl)-ethanol
Figure imgf000036_0001
Preparation of 8:
4-Bromo-2-methoxy-1 -vinyl-benzene
To a suspension of Ph3PCH2Br (140 g, 0.384 mol) in anhydrous toluene (11) was added LiHMDS (350 mL, 0.35 mol) at 0°C. After the addition, the mixture was stirred at room temperature for 1 hr, then cooled to 0°C, and a solution of compound 7 (62 g, 0.288 mol) in anhydrous toluene (800 mL) was added dropwise. The mixture was stirred at room temperature overnight. TLC (petroleum ether/ethyl acetate 10/1 ) showed the reaction was complete. The mixture was cooled to 0°C and NH4CI (500 mL) was added. The mixture was extracted with ethyl acetate (2x 300 mL), and the combined organic layers were washed with brine (3x 100 mLI), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to give crude product(96 g), which was purified via column chromatography on silica gel (petroleum ether) to give compound 8 (42 g, 68.3%) as an oil. Preparation of 9:
2-(4-Bromo-2-methoxy-phenyl Methanol
To a solution of compound 8 (37 g, 0.174 mol) in anhydrous THF (400 mL) was added dropwise 9-BBN (418 mL, 0.209 mol) at 0°C under N2. After the addition, the reaction mixture was stirred at room temperature overnight. TLC (petroleum ether/ethyl acetate 5/1 ) indicated the reaction was complete. The mixture was cooled to 0°C and methanol (300 mL) was added, followed by the addition of 2 M NaOH solution (35 g, in 440 mL of H20) and H2O2 (185 ml_, 30% in water). The reaction mixture was then stirred at room temperature for 2 h. The mixture was concentrated in vacuo and the residue was suspended in water (200 mL) and extracted with diethyl ether (300 ml_x3). The combined organic layers were washed with brine (200 mL), filtered and the filtrate was concentrated in vacuo to give crude product (32 g), which was purified via column chromatography on silica gel (petroleum ether/ethyl acetate from 20/1 to 4/1 ) to give compound 9 (26.5 g, 66.1%) as a white solid.
Preparation of 10:
2-(4'-Fluoro-3-methoxy-biphenyl-4-yl)-ethanol
A mixture of compound 9 (15 g, 64.9 mmol), 4-fluorophenyl boronic acid (10.9 g, 77.9 mmol), Pd(Ph3P)4 (2 g) and Na2C03 (27.5 g, in 130 mL water) in DME (150 mL) was heated to reflux and stirred overnight. TLC (petroleum ether/ethyl acetate 3/1 ) indicated the reaction was complete. The mixture was cooled to room temperature and extracted with ethyl acetate (100 mLx3). The combined organic layers were washed with brine (50 mL), dried over Na2S04, filtered and the filtrate was concentrated in vacuo to give crude product (26 g), which was purified via column chromatography on silica gel (petroleum ether/ethyl acetate from 10/1 to 4/1 ) to give compound 10 (12.5 g, 78.1 %) as a white solid.
Preparation 6
Resolution of I: (+/-)-ethyl 4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)butanoate to
generate individual enantiomers la and lb
Figure imgf000037_0001
The title compounds were isolated via chiral chromatography with a packing material of Chiralcel OJ and a mobile phase of 68/32/0.1 heptane/ ethanol/ phosphoric acid. Both isomers were isolated separately. They were evaporated to low volume, water was added, and the solids that crashed out were filtered and dried. The desired (2R) enantiomer 1 a was determined to have an optical rotation in DMSO [a]58925 3 = +19.18°.
Preparation 7
A) Resolution of II: 2-methyl-2-methylsulfonyl-4-(4-bromophenyl)butanoic acid
Figure imgf000038_0001
Ila
A mixture of (+/-)-4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)butanoic acid (17.3 g, 51.6 mmol) and (-) ephedrine (8.5 g 51.6 mmol) was dissolved in a mixture of IPA (175 mL) and water (2.5 mL) by the application of some heat. The clear solution was diluted with the same amount of solvents and seeded. Crystallization started rapidly and more IPA (50 mL) and water (1 mL) were added. Crystallization was allowed to proceed over 2 daysand the solid was isolated. This afforded 12.45 g of the ephedrine salt of Ila (48%) with an ee of 74%. Recrystallization of this material from IPA-water (200 mL + 3 mL) afforded 10 g of the salt with an ee of 97.4%. This was triturated with IPA (200 mL) to afford 9.5 g (36%) of the salt with an ee of 99+%. Liberation of the salt with 1 N HCI followes by EtOAc extraction afforded 5.7 g of acid Ila.
Figure imgf000038_0002
(I lia)
B) Preparation of Ilia: (2R)-4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)-N- (tetrahvdro-2H-pyran-2-yloxy)butanamide (mixture of diastereomers) The title compound (10.0 g, 77 %) was prepared from (2R)-4-(4-bromophenyl)-2- methyl-2-(methylsulfonyl)butanoic acid (I la)(10.0 g, 29.8 mmol) and 0-tetrahydro-2H- pyran-2yl-hydroxylamine (5.0 g, 43 mmol) by a procedure analogous to that described for (+/-)-4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2- yloxy)butanamide as in Preparation 2 Step 4. LCMS m/z 434.1 (M-1 ).
Pre aration 8
Figure imgf000039_0001
A) Preparation of Va: ethyl (2R)-2-methyl-2-(methylsulfonyl)-4-r4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyllbutanoate
The title compound (10.5 g, 93 %) was prepared from ethyl (2R)-4-(4- bromophenyl)-2-methyl-2-(methylsulfonyl)butanoate, (10.0 g, 27.5 mmol) and bis(pinacolato)diborane (7.69 g, 30.3 mmol) by a procedure analogous to that described for (+/-)-ethyl 2-methyl-2-(methylsulfonyl)-4-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)phenyl]butanoate as described in Preparation 3 step A.
1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.32 (t, J=7.32, 3 H) 1 .32 (s, 12 H) 1.69 (s, 3 H) 2.14 - 2.24 (m, 1 H) 2.42 - 2.56 (m, 2 H) 2.71 - 2.81 (m, 1 H) 2.99 - 3.05 (m, 3 H) 4.23 - 4.30 (m, 2 H) 7.18 (d, J=8.01 Hz, 2 H) 7.73 (d, J=8.01 Hz, 2 H)
Figure imgf000039_0002
B) Preparation of Via: (2R)-2-methyl-2-(methylsulfonyl)-4-r4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyllbutanoic acid
The title compound (7.4 g, 76 %) was prepared from ethyl (2R)-2-methyl-2- (methylsulfonyl)-4-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]butanoate (10.5 g, 25.6 mmol) and lithium hydroxide (4.3 g, 102 mmol) by a procedure analogous to that described for (+/-)-4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)butanoic acid as in Preparation 3 step B. LCMS m/z 381.6 (M-1 ).
1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35 (s, 12 H) 1.72 (s, 3 H) 2.21 (td, J=12.83, 5.17 Hz, 1 H) 2.39 - 2.54 (m, 1 H) 2.61 (td, J=12.83, 4.39 Hz, 1 H) 2.71 - 2.90 (m, 1 H) 3.08 (s, 3 H) 4.36 (br. s., 1 H) 7.21 (d, J=7.81 Hz, 2 H) 7.75 (d, J=8.00 Hz, 2 H)
Figure imgf000040_0001
Vila
C) Preparation of Vila: (2R)-2-methyl-2-(methylsulfonyl)-N-(tetrahvdro-2H-pyran-2- yloxy)-4-r4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllbutanamide (mixture of diastereomers)
The title compound (7.2 g, 77 %) was prepared from (2R)-2-methyl-2- (methylsulfonyl)-4-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]butanoic acid (7.4 g, 19.3 mmol) and 0-tetrahydro-2H-pyran-2yl-hydroxylamine (3.3 g, 28 mmol) by a procedure analogous to that described for (+/-)-4-(4-bromophenyl)-2-methyl-2- (methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide as in Preparation 3 step C. LCMS m/z 480.8 (M-1 ).
Example 1
N-Hvdroxy-2-methy -4-(3-methylbiphenyl-4-yl)-2(methylsulfonyl)butanamide
Figure imgf000040_0002
Step A: (4-Bromo-2-methyl-phenyl)-methanol
4-Bromo-2-methylbenzoic acid (100 g, 460 mmol) was dissolved in THF (300 ml_), and cooled in an ice-bath to 0°C. Borane (1 M in THF, 500 ml_, 1.1 eq.) was added dropwise over a period of 30 minutes, while keeping the temperature below 20°C. After complete addition, the reaction mixture was stirred for 1 hour at room temperature, and was then carefully added to saturated aq. K2CO3 (250 mL). The obtained suspension was diluted with H20 (500 mL). The THF layer was separated, and concentrated under reduced pressure. The aqueous layer was extracted with EtOAc (3 x 300 mL). The residue from the concentrated THF layer was dissolved in the combined organic layer, which was washed with brine. The organic layer was dried (Na2S04), filtered, and concentrated in vacuo yielding the title compound (62 g, 308 mmol, 67%) with acceptable purity according to 1 H NMR as a yellow oil. 1 H NMR (CDCI3, 300 MHz) δ ppm 2.31 (s, 3H); 4.63 (s, 2H); 7.22 (d, 1 H); 7.33 (s, 2H)
Step B: 4-Bromo-1-chloromethyl-2-methyl-benzene
(4-Bromo-2-methyl-phenyl)-methanol (40.0 g, 199 mmol) was added to thionyl chloride (106.6 g, 0.896 mole, 65.3 mL) .The mixture was heated to reflux, for 1.5 hours. After cooling to room temperature the mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (300 mL) and added carefully to saturated aqueous NaHC03 (500 mL). The EtOAc layer was separated, and the aqueous layer was extracted with EtOAc (250 mL). The combined organic layers were dried (Na2S04), filtered and concentrated in vacuo yielding the title compound (34.19 g, 157 mmol, 79 %) as a slightly colored oil that solidified to a white solid upon standing.1 H NMR (CDCI3, 300 MHz) δ ppm 2.38 (s, 3H); 4.57 (s, 2H); 7.12 (d, 1 H); 7.28 (s, 1 H); 7.55 (d, 1 H)
Step C: (4-Bromo-2-methylphenyl)acetonitrile
4-Bromo-1-chloromethyl-2-methyl-benzene (63 g, 287 mmol) was dissolved in DMF (180 mL). NaCN (15.5 g, 316 mmol, 1.1 eq.) was added in 1 portion, and the reaction was stirred at room temperature overnight under a N2 atmosphere. The mixture was concentrated under reduced pressure, and the residue was taken into a mixture of sat. aq. NH4CI (300 mL) and EtOAc (300 mL). The bi-phase solution was diluted with H20 (200 mL). The EtOAc layer was separated, and the aqueous layer was re-extracted with EtOAc (2x 200 mL). The combined organic layers were washed with brine (3x 300 mL), dried (Na2S04), filtered, and concentrated under reduced pressure, yielding the title compound (58.8 g, 280 mmol, 98%) with acceptable purity as a brown oil, which solidified to a brown solid on standing.1 H-NMR (CDCI3, 300 MHz) δ ppm 2.34 (s, 3H); 3.63 (s, 2H); 7.26 (t, 1 H); 7.38 (d, 2H). Step D: (4-Bromo-2-methylphenyl)acetic acid
To (4-Bromo-2-methylphenyl)acetonitrile (58.8 g, 280 mmol) was added 30% aq. HCI (500 mL). The suspension was refluxed for 18 hours. After cooling to room temperature, the solids were collected by filtration, and the filtrate was extracted with CH2CI2 (750 mL). The solids were dissolved in the organic layer, which was washed with brine, dried (Na2S04), filtered and concentrated under reduced pressure, yielding the title acid (59 g, 258 mmol, 92%) as a brownish solid. 1 H-NMR (CDCI3, 300 MHz) δ ppm 2.32 (s, 3H); 3.64 (s, 2H); 7.09 (d, 1 H); 7.31 (d, 1 H); 7.36 (s, 1 H)
Step E: 2-(4-Bromo-2-methylphenyl)ethanol
(4-Bromo-2-methylphenyl)acetic acid (59 g, 258 mmol) was dissolved in THF (100 mL), and cooled in an ice-bath to 0°C. Borane (1 M in THF, 310 mL, 1.2 eq) was added dropwise. During the addition the temperature rose slowly to 20°C. After complete addition, the ice-bath was removed and stirring was continued for 2 hours. The reaction mixture was poured into sat. aq. K2CO3 (300 mL), and the obtained suspension was diluted with H20 (500 mL). The THF layer was separated and concentrated under reduced pressure. The aqueous layer was extracted with EtOAc (2x 250 mL, 1x 100 mL). The residue from the concentrated THF layer was dissolved in the combined organic layer, which was washed with brine. The organic layer was dried (Na2S04), filtered, and concentrated under reduced pressure, yielding the crude product (54.6 g) as a brown oil. The crude product was purified by column chromatography (S1O2, 2 Lof 30% EtOAc in heptanes, Rf = 0.3). Desired fractions were combined and concentrated under reduced pressure, yielding the title compound as a yellow oil (31.6 g, 144 mmol, 56%). 1 H-NMR (CDCI3, 300 MHz) δ ppm 2.3 (s, 3H); 2.68 (t, 2 H); 2.82 (t, 2H); 7.07 (d, 1 H); 7.30 (d, 2H).
Step F: 4-Bromo-1-(2-iodo-ethyl)-2-methyl-benzene
To a 250mL flask in an ice bath was added triphenyl phosphine (6.17g,
22.8mmol), imidazole (1 .6g, 22.8mmol) and 100mL of anhydrous dichloromethane.
Once dissolved, iodine (5.79g, 22.8mmol) was added. The reaction was then stirred for about 30 minutes (ppt formed). The 2-(4-bromo-2-methylphenyl)ethanol (3.93g, 18.3mmol)was added in batches and the flask was rinsed with the remaining DCM (22mL) which was also added to the reaction mixture. The reaction was warmed to room temperature and was stirred overnight. The reaction mixture was filtered through a small pad of celite and washed with DCM (100ml_). The filtrate was washed with saturated aqueous sodium thiosulfate (200ml_) and brine 200ml_. The organics were concentrated in vacuo to furnish a white solid (triphenyphosphine oxide + desired product). The material was triturated with heptanes for 5-10 mins then filtered to remove the majority of the triphenylphosphine oxide The filtrate was concentrated in vacuo to furnish a total of 5.86g (98.8%) of the title compound as a clear oil that solidified upon standing. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.30 (s, 3 H) 3.04 - 3.20 (m, 2 H) 3.21 - 3.39 (m, 2 H) 7.02 (d, J=8.20 Hz, 1 H) 7.23 - 7.29 (m, 1 H) 7.30 - 7.38 (m, 1 H).
Step G: 4-(4-Bromo-2-methyl-phenyl)-2-methanesulfonyl-2-methyl-butyric acid ethyl ester
The title compound was synthesized according to the general procedure
Preparation #2, Step 2, except that 4-bromo-1-(2-iodo-ethyl)-2-methyl-benzene was used instead of 1-bromo-4-(2-iodoethyl)benzene and the reaction was conducted at 40°C to yield: 2.2g (33%). 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1 .37 (t, J=7.22 Hz, 3 H) 1.73 (s, 3 H) 2.09 (td, 1 H) 2.30 (s, 3 H) 2.33 - 2.43 (m, 1 H) 2.49 (td, J=12.88, 4.29 Hz, 1 H) 2.70 (td, J=12.59, 4.88 Hz, 1 H) 3.01 - 3.07 (m, 3 H) 4.32 (q, J=7.03 Hz, 2 H) 7.00 (d, J=8.20 Hz, 1 H) 7.27 (s, 1 H) 7.31 (s, 1 H).
Step H: 4-(4-Bromo-2-methylphenyl)-2-methyl-2-(methylsulfonyl)butanoic acid
The title compound was synthesized according to the general procedure of Preparation Number 2, Step 3, for the preparation of (II) except that 4-(4-bromo-2- methyl-phenyl)-2-methanesulfonyl-2-methyl-butyric acid ethyl ester was used instead of (+/-)-ethyl 4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)butanoate and that the lithium hydroxide was dissolve in water prior to addition. Yield: 3.25g(81.2%).
LC-MS m/z 349.0(M-1 ) 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1 .77 (s, 3 H) 2.09 - 2.20 (m, 1 H) 2.30 (s, 3 H) 2.39 (td, J=12.88, 4.29 Hz, 1 H) 2.58 (td, J=12.98, 4.49 Hz, 1 H) 2.68 - 2.81 (m, 1 H) 3.10 (s, 3 H) 7.01 (d, J=8.20 Hz, 1 H) 7.29 (d, J=2.34 Hz, 1 H) 7.31 (s, 1 H). Step I: 4-(4-Bromo-2-methylphenyl)-2-methyl-2-(methylsulfonyl)-N-(tetrahvdro-2H- pyran-2-yloxy)butanamide
4-(4-Bromo-2-methylphenyl)-2-methyl-2-(methylsulfonyl)butanoic acid (3.28 g, 9.39 mmol), 0-tetrahydro-2H-pyran-2-yl-hydroxylamine (2.19 g, 18. 7 mmol), 1 -hydroxy benzotriazole monohydrate (3.68 g, 24 mmol), triethylamine (3.35 ml_, 24 mmol) and (3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.59 g, 18.7 mmol) were combined followed by the addition 60 ml. of dichloromethane. The reaction was allowed to stir at room temperature overnight. The reaction mixture was diluted with 20 ml. of dichloromethane and 60 ml. of water. The aqueous layer was extracted with dichloromethane (2x 40 ml_). The organics were combined, dried over magnesium sulfate, filtered and concentrated onto silica gel. Silica chromatography (30% ethyl acetate 70% heptane for 10 minutes, then 30% ethyl acetate 70% heptane to 60% ethyl acetate 40% heptane for 40 minutes) afforded the title compound as a white solid (2.1 1 g, 50.1 %).
LC-MS m/z 448.2(M-1 )
Step J: 2-Methyl-4-(3-methylbiphenyl-4-yl)-2-(methylsulfonyl)-N-(tetrahvdro-2H-pyran-2- yloxy)butanamide
4-(4-Bromo-2-methylphenyl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran- 2-yloxy)butanamide (250 mg, 0.558 mmol), phenyl boronic acid (102 mg, 0.837 mmol), sodium carbonate (181 mg, 1 .71 mmol), Pd (II) EnCat (144 mg, 0.056 mmol, 0.39 mmol/g loading) were combined in a 2-5ml_ microwave vial followed by the addition of 2 ml. of dioxane, and 2 ml. of water. The reaction was irradiated in a microwave at 120°C for 40 minutes, followed by neutralization through the addition of 5 ml. of aqueous 4N HCI and the mixture was extracted with ethyl acetate (3x15 ml_). The organics were combined, dried over magnesium sulfate, filtered and concentrated onto silica gel. Silica chromatography (30% ethyl acetate 70% heptane for 10 minutes, then 30% ethyl acetate 70% heptane to 60% ethyl acetate 40% heptane for 40 minutes) afforded the title compound as a white solid (170 mg, 68%).LC-MS m/z 444.2(M-1 )
Step K: N-hvdroxy-2-methyl-4-(3-methylbiphenyl-4-yl)-2(methylsulfonyl)butanamide
2-Methyl-4-(3-methylbiphenyl-4-yl)-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2- yloxy)butanamide (170 mg, 0.382 mmol) was dissolved in 5 ml. of dichloromethane at ambient temperature. To this was added a 4M HCI solution in dioxane (2.86 ml_, 1 1.5 mmol) and the reaction was stirred at ambient temperature for 5 minutes. 0.5 ml. of methanol was then added followed by silica gel and the mixture was concentrated to dryness. Silica chromatography (100% dichloromethane to 96% DCM 4% MeOH over 60 minutes) yielded product that contained impurities and was further triturated with a solution of 4:1 heptane:isopropanol afforded the title compound as a white solid (8 mg, 6%).
1 H NMR (400 MHz, METHANOL-d4) δ ppm 1.69 (br. s., 3 H) 2.01 - 2.28 (m, 1 H) 2.17 - 2.31 (m, 1 H) 2.39 (br. s., 3 H) 2.55 (br. s., 3 H) 2.75 (br. s., 1 H) 3.04 (br. s., 3 H) 7.22 (br. s., 1 H) 7.29 (br. s., 2 H) 7.40 (br. s., 3 H) 7.56 (br. s., 2 H)
Example 2
4-(3-Fluorobiphenyl-4-yl)-N-hvdroxy-2-methyl-2-(methylsulfonyl)butanamide
Figure imgf000045_0001
Step A: (4-Bromo-2-fluoro-phenyl)-acetonitrile
2-Fluoro-4-bromo-chloromethylbenzene (25.0 g, 1 12 mmol) and NaCN (6.32 g, 129 mmol) were dissolved in DMF (70 ml.) and the solution was stirred under a N2 atmosphere for 18 hrs at ambient temperature. The solution was poured into water (300 ml_), and was extracted with EtOAc (1x 1 L, 4x 300 ml_). The combined organic layers were dried (Na2S04), filtered and concentrated under reduced pressure, yielding the title compound (22.5 g, 105 mmol, 93%) as a yellow oil that contained some traces of DMF. 1 H-NMR (CDCI3, 300 MHz) : 3.75 (s, 2H); 7.20-7.4 (m, 3H)
Step B: 4-Bromo-2-fluoro-phenyl-acetic acid
(4-Bromo-2-fluoro-phenyl)-acetonitrile (41.4 g, 174 mmol) (21.2 g, 99.1 mmol) was suspended in 30% aq. HCI (200 ml.) and heated to reflux for 20 hours. After cooling to room temperature, the solids were collected by filtration, washed with water and allowed to dry in open air. The solids were azeotroped with toluene under reduced pressure to remove the final traces of water, yielding the title compound as a solid (21 .7 g, 89 mmol, 94%).1 H-NMR (CD3OD, 300 MHz): 3.68 (s, 2H); 7.20-7.4 (m, 3H)
Step C: 2-(4-Bromo-2-fluoro-phenyl)-ethanol
4-Bromo-2-fluoro-phenyl-acetic acid (36 g, 154 mmol) (40.6 g, 174 mmol) was dissolved in THF (100 ml_), and cooled to 0°C in an ice-bath. Borane (1 M in THF, 200 ml_, 1 .2 eq) was then added dropwise. During the addition, the temperature rose slowly to 27°C. After complete addition the ice-bath was removed and the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was added carefully to saturated aqueous K2CO3 (300 ml_), and the obtained suspension was diluted with H20 (500 ml_). The THF layer was separated and concentrated under reduced pressure. The aqueous layer was extracted with EtOAc (2x 100 ml_). The residue from the concentrated THF layer was dissolved into the combined organic layers, which was washed with brine. The organic layer was dried (Na2S04), filtered, and concentrated under reduced pressure, yielding crude material (35.6 g) as a yellow oil, which solidified to a white solid upon standing. The crude material was purified by column
chromatography (Si02; 1750 ml_, 0 - 5% MeOH in CH2CI2), yielding the title compound as a white solid (31.5 g, 144 mmol, 82%).1 H-NMR (CDCI3, 300 MHz): 1.50 (s, 1 H); 2.95 (t, 2H); 3.92 (t, 2H); 7.18 (t, 1 H); 7,28 (m, 1 H)
Step D: 4-Bromo-1 -(2-iodo-ethyl)-2-fluoro-benzene
The title compound was synthesized according to the same general procedure described for the synthesis of 4-bromo-1-(2-iodo-ethyl)-2-methyl-benzene in Preparation #2, Step 1 , except that 2-(4-bromo-2-fluoro-phenyl)-ethanol was used instead of 2-(4- bromo-2-methylphenyl)ethanol to yield the title compound as a clear oil (5.75g, 95.7%) 1 H NMR (400 MHz, CHLOROFORM-d)5 ppm 3.13 - 3.24 (m, 2 H) 3.26 - 3.44 (m, 2 H) 7.06 - 7.14 (m, 1 H) 7.21 - 7.24 (m, 1 H) 7.26 - 7.31 (m, 1 H)
Step E: 4-(4-Bromo-2-fluoro-phenyl)-2-methanesulfonyl-2-methyl-butyric acid ethyl ester
The title compound was synthesized according to the general procedure of Preparation # 2, Step 2, except that 4-bromo-1-(2-iodo-ethyl)-2-fluoro-benzene was used instead of 1-bromo-4-(2-iodoethyl)benzene and the reaction conducted at 40°C to furnish the title compound as a white solid 2.2g, (33%). 1 H NMR (400 MHz, CHLOROFORM-d)5 ppm 1.35 (t, J=7.03 Hz, 3 H) 1.72 (s, 3 H) 2.19 (td, 1 H) 2.38 - 2.48 (m, 1 H) 2.52 - 2.61 (m, 1 H) 2.72 - 2.86 (m, 1 H) 3.05 (s, 3 H) 4.28 (q, J=7.16 Hz, 2 H) 7.08 (t, J=8.00 Hz, 1 H) 7.19 - 7.25 (m, 1 H) 7.25 - 7.34 (m, 1 H). Step F: 4-(4-Bromo-2-fluoro-phenyl)-2-methanesulfonyl-2-methyl-butyric acid
The title compound was synthesized according to the general procedure of Preparation 2, Step 3, for the preparation of (II) except that 4-(4-bromo-2-fluoro-phenyl)- 2-methanesulfonyl-2-methyl-butyric acid ethyl ester was used instead of (+/-)-ethyl 4-(4- bromophenyl)-2-methyl-2-(methylsulfonyl)butanoate and that lithium hydroxide was dissolve in water prior to addition to yield as a white solid: 1.96g, (96.2%). 1 H NMR
(400 MHz, CHLOROFORM-d)5 ppm 1.76 (s, 3 H) 2.23 (td, 1 H) 2.47 (td, J=12.59, 4.88 Hz, 1 H) 2.63 (td, J=12.88, 4.68 Hz, 1 H) 2.84 (td, J=12.49, 5.07 Hz, 1 H) 3.1 1 (s, 3 H) 7.10 (t, J=8.20 Hz, 1 H) 7.20 - 7.23 (m, 1 H) 7.25 - 7.34 (m, 1 H) Step G: 4-(4-Bromo-2-fluorophenyl)-2-methyl-2-(methylsulfonyl)-N-(tetrahvdro-2H- pyran-2-yloxy)butanamide
4-(4-Bromo-2-fluoro-phenyl)-2-methanesulfonyl-2-methyl-butyric acid (1.96 g, 5.55 mmol), 0-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.910 g, 7.77 mmol), 1 -hydroxy benzotriazole monohydrate (1.53 g, 9.99 mmol), triethylamine (1.39 mL, 9.99 mmol) and 1 , (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.49 g, 7.77 mmol) were combined followed by the addition 60 mL of dichloromethane. The reaction was allowed to stir at room temperature overnight, was then diluted with 20 mL of dichloromethane and 60 mL of water. The aqueous layer was re-extracted with DCM (2x40 mL). The organics were combined, dried over magnesium sulfate, filtered and concentrated onto silica gel. Silica chromatography (40% ethyl acetate 60% heptane to 40% ethyl acetate 60% heptane to 80% ethyl acetate 20% heptane for 60 minutes) afforded the title compound as a white foam 2.0g, (79.9%). LC-MS m/z 452.1 (M-1 )
Step H: 4-(3-Fluorobiphenyl-4-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahvdro-2H-pyran- 2-yloxy)butanamide
4-(4-Bromo-2 -fluorophenyl )-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran- 2-yloxy)butanamide (250 mg, 0.558 mmol), phenyl boronic acid (91 mg, 0.747 mmol), sodium carbonate (216 mg, 2.04 mmol),and Pd (II) EnCat (144 mg, 0.056 mmol, 0.39 mmol/g loading) were combined in a 2-5mL microwave vial followed by the addition of 2 mL of dioxane, and 2 mL of water. The reaction was irradiated in a microwave at 120°C for 40 minutes, followed by neutralization through the addition of 5 mL of 4 N HCI in water and extracted with ethyl acetate (3x15 mL). The organics were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the title compound as a crude brown solid (206.7mg, 67%). LC-MS m/z 448.3 (M-1 )
Step I: 4-(3-Fluorobiphenyl-4-yl)-N-hvdroxy-2-methyl-2-(methylsulfonyl)butanamide
4-(3-Fluorobiphenyl-4-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2- yloxy)butanamide (170 mg, 0.382 mmol) was dissolved in 5 mL of dichloromethane at ambient temperature. To this solution was added 4M HCI (2.86 mL, 1 1.5 mmol) in dioxane and the solution was stirred at ambient temperature for 5 minutes. The reaction was quenched by the addition of 0.5 mL of methanol. After stirring for an additional 5 minutes, the reaction was concentrated in vacuo. Purification was performed using Shimadzu prep HPLC to provide the title compound (24.4mg, 14.5%) LC-MS m/z 366.5 (M+1 ) 1 H NMR (400 MHz, METHANOL-d4) δ ppm 1.68 (s, 3 H) 2.06 - 2.16 (m, 1 H) 2.53 - 2.59 (m, 1 H) 2.60 - 2.67 (m, 1 H) 2.79 - 2.89 (m, 1 H) 3.06 (s, 3 H) 7.30 - 7.33 (m, 1 H) 7.31 - 7.33 (m, 1 H) 7.34 - 7.37 (m, 1 H) 7.38 (d, J=3.12 Hz, 1 H) 7.40 - 7.42 (m, 1 H) 7.43 - 7.46 (m, 2 H) 7.58 - 7.64 (m, 2 H)
Example 3
N-Hvdroxy-2-meth -2-(methylsulfonyl)-4-(6-phenylpyridin-3-yl)butanamide
Figure imgf000048_0001
Step A: 2-Bromo-5-(2-iodoethyl)pyridine
A solution of 2-(6-bromopyridin-3-yl)ethanol (2.0 g, 9.9 mmol, 1 .0 equiv) in dichloromethane (31 mL) was added dropwise to a solution of imidazole (0.91 g, 13.4 mmol, 1.4 equiv), triphenylphosphine (3.3 g, 12.4 mmol, 1.3 equiv), and iodine (3.1 g, 12.4 mmol, 1.3 equiv) in dichloromethane (31 mL) at room temperature. After stirring for 6 h, the reaction was filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (15% ethyl acetate in heptane) to provide the title compound as a white solid (2.83 g, 92%). MS (LCMS) m/z 312.0 (M+1 ). 1 H NMR (400 MHz, METHANOL-d4) δ ppm 3.15 (t, J=7.03 Hz, 2 H) 3.43 (t, J=7.03 Hz, 2 H) 7.54 (d, J=7.81 Hz, 1 H) 7.61 (dd, J=8.20, 2.73 Hz, 1 H) 8.22 (d, J=2.34 Hz, 1 H).
Step B: Ethyl 4-(6-bromopyridin-3-yl)-2-(methylsulfonyl)butanoate
A solution of ethyl(methylsulfonyl)acetate (1090 mg, 6.6 mmol, 1.0 equiv) in DMF (1 1 mL) was added dropwise to a mixture of 60% sodium hydride in mineral oil (315 mg, 7.9 mmol, 1.2 equiv) in DMF (1 1 mL) at 0°C. The reaction was warmed to room temperature and allowed to stir for 40 min. The reaction was cooled to 0°C and a solution of 2-bromo-5-(2-iodoethyl)pyridine (2560 mg, 8.2 mmol, 1 .3 equiv) in DMF (1 1 mL) was added dropwise, and the reaction was allowed to stir for 3 days. Saturated aqueous ammonium chloride solution (30 mL) was added, and the mixture was extracted with ethyl acetate (3 x 70 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (7:3 heptane/ethyl acetate) to provide the title compound as a white solid (1628 mg, 71 %). MS (LCMS) m/z 352.1 (M+1 ). 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 - 1.35 (m, 3 H) 2.30 - 2.44 (m, 2 H) 2.62 - 2.78 (m, 2 H) 3.00 (s, 3 H) 3.71 (dd, J=9.37, 4.68 Hz, 1 H) 4.21 - 4.35 (m, 2 H) 7.36 - 7.46 (m, 2 H) 8.19 (d, J=1.56 Hz, 1 H).
Step C: Ethyl 4-(6-bromopyridin-3-yl)-2-methyl-2-(methylsulfonyl)butanoate
A solution of methyl iodide (633 uL, 10.2 mmol, 2.2 equiv), potassium carbonate (895 mg, 6.5 mmol, 1.4 equiv), and ethyl 4-(6-bromopyridin-3-yl)-2- (methylsulfonyl)butanoate (1620 mg, 4.6 mmol, 1.0 equiv) in DMF (15 mL) was allowed to stir at room temperature overnight. The reaction was diluted with 0.5 M hydrochloric acid (220 mL) and was extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with water (170 mL) and sodium thiosulfate (170 mL, 10% aq. solution), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (7:3 heptane/ethyl acetate) to provide the title compound as a white solid (1 107 mg, 66%). MS (LCMS) m/z 364.1 (M+1 ). 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (t, J=7.22 Hz, 3 H) 1.69 (s, 3 H) 2.12 - 2.23 (m, 1 H) 2.39 - 2.59 (m, 2 H) 2.69 - 2.79 (m, 1 H) 3.02 (s, 3 H) 4.27 (qd, J=7.16, 2.73 Hz, 2 H) 7.35 - 7.43 (m, 2 H) 8.20 (d, J=1.95 Hz, 1 H). Step D: 4-(6-Bromopyridin-3-yl)-2-methyl-2-(methylsulfonyl)butanoic acid
A solution of lithium hydroxide (357 mg, 8.5 mmol, 4.0 equiv) and ethyl 4-(6- bromopyridin-3-yl)-2-methyl-2-(methylsulfonyl)butanoate (775 mg, 2.1 mmol, 1. 0 equiv) in 1 :1 :1 tetrahydrofuran-methanol-water (3 mL) was allowed to stir at room temperature for 2 h. The reaction was diluted with water (150 mL), acidified (to pH = 2) with 0.5 M hydrochloric acid, and then was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound (716 mg, 98%). MS (LCMS) m/z 334.1 (M-1 ). 1 H NMR (400 MHz,
CHLOROFORM-d) δ ppm 1 .56 (s, 3 H) 2.03 (td, J=12.78, 5.27 Hz, 1 H) 2.31 (td, J=12.68, 4.68 Hz, 1 H) 2.51 (td, J=12.98, 4.49 Hz, 1 H) 2.59 - 2.70 (m, 1 H) 2.96 (s, 3 H) 7.30 - 7.39 (m, 2 H) 8.07 (d, J=1.56 Hz, 1 H). Step E: 4-(6-Bromopyridin-3-yl)-N-hvdroxy-2-methyl-2-(methylsulfonyl)butanamide
DMF (1.6 uL, 0.02 mmol, 0.01 equiv) was added to a solution of oxalyl chloride (1.0 mL, 2.07 mmol, 1.0 equiv) and 4-(6-bromopyridin-3-yl)-2-methyl-2- (methylsulfonyl)butanoic acid (695 mg, 2.07 mmol, 1.0 equiv) in dichloromethane (20 mL) at room temperature. After 10 min (gas evolution subsided), O- (trimethylsilyl)hydroxylamine (843 uL, 6.2 mmol, 3.0 equiv) was added and the reaction was allowed to stir overnight. Methanol (8.8 mL) was added, and the reaction was allowed stir for an additional hour. The reaction was diluted with water (80 mL), and the resulting mixture was extracted with ethyl acetate (2 x 65 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound as a white powder (666 mg, 92%). MS (LCMS) m/z 353.0 (M+1 ).
Step F: N-Hvdroxy-2-methyl-2-(methylsulfonyl)-4-(6-phenylpyridin-3-yl)butanamide
A solution of tetrakis(triphenylphosphine)palladium (0) (59 mg, 0.023 mmol, 0.1 equiv), sodium bicarbonate (45 mg, 0.73 mmol, 3.2 equiv), phenylboronic acid (42 mg, 0.35 mmol, 1.5 equiv), and 4-(6-bromopyridin-3-yl)-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide (81 mg, 0.23 mmol, 1 .0 equiv) in 1 :1 DMF-water (2 mL) was heated at 130°C for 1 h. The reaction was diluted with 0.5 M hydrochloric acid (10 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layers (from the acidic extraction) were discarded. The aqueous phase was basified (to pH = 8) with a saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate (3 x 15 ml_). The combined organic layers (from the second basic extraction) were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (1 :0 - 9: 1
dichloromethane/methanol) to provide the title compound (29 mg, 36%). LCMS m/z 349.2 (M+1 ). 1 H NMR (400 MHz, CD3OD) δ 1 .69 (s, 3H), 2.13 (m, 1 H), 2.55-2.65 (m, 2H), 2.83 (m, 1 H), 3.06 (s, 3H), 7.40-7.50 (m, 3H), 7.78-7.83 (m, 2H), 7.89-7.92 (m, 2H), 8.50 (br s, 1 H).
Example 4
N-Hvdroxy-2-meth -2-(methylsulfonyl)-4-(5-phenylpyridin-2-yl)butanamide
Figure imgf000051_0001
Step A: 5-Bromo-2-(2-iodoethyl)pyridine
The title compound (3571 mg, 77%) was prepared from 2-(5-bromopyridin-2- yl)ethanol (Compound 6, Preparation 4) (3.0 g, 14.9 mmol) by a procedure analogous to that described for the preparation of 2-bromo-5-(2-iodoethyl)pyridine in Preparation 2, Step L MS (LCMS) m/z 312.0 (M+1 ). 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.24 - 3.36 (m, 2 H) 3.41 - 3.56 (m, 2 H) 7.06 (d, J=8.20 Hz, 1 H) 7.74 (dd, J=8.20, 2.34 Hz, 1 H) 8.60 (d, J=2.34 Hz, 1 H).
Step B: Ethyl 4-(5-bromopyridin-2-yl)-2-methyl-2-(methylsulfonyl)butanoate
The title compound (2030 mg, 49%) was prepared from 5-bromo-2-(2- iodoethyl)pyridine (3571 mg, 1 1.5 mmol) and (+/-)-2-ethanesulfonyl-propionic acid ethyl ester (2270 mg, 12.6 mmol) by a procedure analogous to that described for the preparation of compound (I) from Preparation 2, Step 2, i.e. (+/-)-ethyl 4-(4- bromophenyl)-2-methyl-2-(methylsulfonyl)butanoate. MS (LCMS) m/z 364.0 (M+1 ). 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1 .31 (t, J=7.03 Hz, 3 H) 1.68 (s, 3 H) 2.28 - 2.39 (m, 1 H) 2.54 - 2.76 (m, 2 H) 2.83 - 2.95 (m, 1 H) 3.05 (s, 3 H) 4.24 (q, J=7.29 Hz, 2 H) 7.05 (d, J=8.59 Hz, 1 H) 7.71 (dd, J=8.20, 2.34 Hz, 1 H) 8.56 (d, J=1.95 Hz, 1 H). Step C: 4-(5-Bromopyridin-2-yl)-2-methyl-2-(methylsulfonyl)butanoic acid
The title compound (1740 mg, 93%) was prepared from ethyl 4-(5-bromopyridin- 2-yl)-2-methyl-2-(methylsulfonyl)butanoate (2025 mg, 5.6 mmol) by a procedure analogous to that described for the preparation of compound (II) 4-(6-bromophenyl-3- yl)-2-methyl-2-(methylsulfonyl)butanoic acid, Preparation 2, step 3. MS (LCMS) m/z 336.1 (M+1 ). 1 H NMR (400 MHz, METHANOL-d4) δ ppm 1 .63 (s, 3 H) 2.25 (ddd, J=13.27, 1 1.71 , 5.07 Hz, 1 H) 2.58 (ddd, J=13.27, 1 1.32, 5.07 Hz, 1 H) 2.70 - 2.81 (m, 1 H) 2.88 - 2.99 (m, 1 H) 3.10 (s, 3 H) 7.27 (d, J=8.20 Hz, 1 H) 7.86 - 7.92 (m, 1 H) 8.53 (d, J=1 .95 Hz, 1 H).
Step D: 4-(5-Bromopyridin-2-yl)-N-hvdroxy-2-methyl-2-(methylsulfonyl)butanamide
The title compound (454 mg, 25%) was prepared from 4-(5-bromopyridin-2-yl)-2- methyl-2-(methylsulfonyl)butanoic acid (1740 mg, 5.2 mmol) and O- (trimethylsilyl)hydroxylamine (1810 mg, 15.5 mmol) by a procedure analogous to that described for the preparation of compound (IV) 4-(6-Bromophenyl-3-yl)-N-hydroxy-2- methyl-2-(methylsulfonyl)butanamide from Preparation 2, Step 5. MS (LCMS) m/z 351.0 (M+1 ). 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.70 (s, 3 H) 2.17 - 2.38 (m, 1 H) 2.52 - 2.68 (m, 1 H) 2.70 - 2.85 (m, 1 H) 2.85 - 2.96 (m, 1 H) 3.00 (s, 3 H) 7.09 (d, J=8.20 Hz, 1 H) 7.76 (dd, J=8.20, 2.34 Hz, 1 H) 8.58 (d, J=2.34 Hz, 1 H).
Step E: N-Hvdroxy-2-methyl-2-(methylsulfonyl)-4-(5-phenylpyridin-2-yl)butanamide The title compound (2 mg, 1 %) was prepared from 4-(5-bromopyridin-2-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)butanamide (151 mg, 0.43 mmol) and
phenylboronic acid (79 mg, 0.65 mmol) by a procedure analogous to that described in Step F of Example 3. LCMS m/z 349.4 (M+1 ). 1 H NMR (400 MHz, CD3OD) δ 1.68 (s, 3H), 2.25 (m, 1 H), 2.66-2.82 (m, 2H), 2.95 (m, 1 H), 3.08 (s, 3H), 7.38-7.51 (m, 4H), 7.63-7.66 (m, 2H), 8.02 (dd, J=8.1 , 2.3 Hz, 1 H), 8.71 (dd, J=2.4, 0.8 Hz, 1 H). Example 5
Synthesis of (+/-)-N-hvdroxy-2-methyl-2-(methylsulfonyl)-4-(4'-nitrobiphenyl-4- tanamide
Figure imgf000053_0001
Step A: (+/-V2-Methyl-2-(methylsulfonylV4-(4'-nitrobiDhenyl-4-ylVN-(tetrahvdro-2H- pyran-2-yloxy)butanamide
Water (1.0 ml.) was added to a solution of (+/-)-4-(4-bromophenyl)-2-methyl-2- (methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (0.35 g, 0.806 mmol), which may be prepared as in Preparation 2, Step 4, in 1 ,4-dioxane (5.0 ml_). (4- nitrophenyl)boronic acid (209 mg, 1.01 mmol), cesium fluoride (0.49 mg, 3.22 mmol) and tetrakis(triphenylphosphine)palladium (0.094 g, 0.810 mmol) were added and the solution was heated to 90°C. After 4 hours the reaction was concentrated in vacuo and the resulting residue was triturated with ethyl acetate. The suspension was filtered through celite. The filtrate was washed with brine, dried (Na2S04), and concentrated in vacuo. Purification on Biotage flash 40S (hexanes/ethyl 6:4 - 1 :1 ) afforded the title compound as a yellow solid (700 mg, 50 %). LCMS m/z 475.2 (M-1 ).
Step B: (+/-)-N-Hvdroxy-2-methyl-2-(methylsulfonyl)-4-(4'-nitrobiphenyl-4-yl)butanamide
A solution of HCI in dioxane (4.0 M, 10 ml.) was added to a solution of (+/-)-2- methyl-2-(methylsulfonyl)-4-(4'-nitrobiphenyl-4-yl)-N-(tetrahydro-2H-pyran-2- yloxy)butanamide (700 mg, 1 .47 mmol) in DCM (5 ml.) at 0°C. The reaction was warmed to room temperature as the ice bath expired. After 4 hours the reaction was concentrated. Purification on silica by flash column chromatography (DCM/MeOH 99:1 - 95:5) afforded the title compound as a yellow solid (500 mg, 87 %).LCMS m/z 391 .1 (M-1 ).1 H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (s, 3 H) 1.87 - 2.01 (m, 1 H) 2.35 - 2.59 (m, 2 H) 2.64 - 2.80 (m, 1 H) 3.05 (s, 3 H) 7.41 (d, J=8.20 Hz, 2 H) 7.74 (d, J=8.59 Hz, 2 H) 7.88 - 8.06 (m, 2 H) 8.22 - 8.39 (m, 2 H) 9.23 (br. s., 1 H) 10.98 (s, 1 H) Example 6
4'-[(3R)-4-(Hvdroxyamino)-3-methyl-3-(m
dihydrogen phosphate
Figure imgf000054_0001
Step A: Ethyl (2R)-4-(4'-hvdroxybiphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanoate
A mixture of palladium (II) EnCat (0.1 equiv), potassium carbonate (3.0 equiv), 4- iodophenol and ethyl (2R)-2-methyl-2-(methylsulfonyl)-4-[4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]butanoate, which may be prepared as in Preparation 8A, was heated to 80 °C in 10:1 1 ,4-dioxane-water to provide the title compound (54%) after purification by flash chromatography on silica gel. MS (LCMS) m/z 399.5 (M+Na). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (t, J=7.13 Hz, 3 H) 1.72 (s, 3 H) 2.18 - 2.28 (m, 1 H) 2.47 - 2.58 (m, 2 H) 2.72 - 2.84 (m, 1 H) 3.04 (s, 3 H) 4.22 - 4.31 (m, 2 H) 4.91 (s, 1 H) 6.85 - 6.92 (m, 2 H) 7.17 - 7.24 (m, 2 H) 7.40 - 7.51 (m, 4 H).
Step B: Ethyl (2R)-4-{4'-r(di-tert-butoxyphosphoryl)oxylbiphenyl-4-yl)-2-methyl-2- (methylsulfonyl)butanoate
A solution of 1 H-tetrazole (2.37 g, 33.9 mmol, 3.0 equiv), di-tert-butyl-N,N- diisopropylphosphoramidite (7.42 mL, 22.6 mmol, 2.0 equiv), and ethyl (2R)-4-(4 - hydroxybiphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanoate (4.25 g, 1 1.3 mmol, 1.0 equiv) in tetrahydrofuran (1 13 mL) was allowed to stir overnight at room temperature. A solution of saturated sodium sulfite (330 mL) was added, and the mixture was extracted with dichloromethane (3 x 440 mL). The combined organic layers were washed with water (3 x 330 mL), brine (3 x 330 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (50% ethyl acetate in heptane) to provide a colorless oil (5.84 g, 91 %). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1 .33 (t, J=7.13 Hz, 3 H) 1.50 - 1.52 (m, 18 H) 1 .71 (s, 3 H) 2.17 - 2.30 (m, 1 H) 2.46 - 2.61 (m, 2 H) 2.72 - 2.85 (m, 1 H) 3.04 (s, 3 H) 4.26 (qd, J=7.13, 1.27 Hz, 2 H) 7.21 - 7.28 (m, 4 H) 7.45 - 7.53 (m, 4 H).
Step C: (2RV4-{4'-r(Di-tert-butoxyDhosDhorvnoxylbiDhenyl-4-yl -2-methyl-2- (methylsulfonyl)butanoic acid
The title compound (4.44 g, 81 %) was prepared from ethyl (2R)-4-{4'-[(di-tert- butoxyphosphoryl)oxy]biphenyl-4-yl}-2-methyl-2-(methylsulfonyl)butanoate (5.8 g, 10.2 mmol) by following a procedure analogous to that described for the preparation of 4-(6- bromopyridin-3-yl)-2-methyl-2-(methylsulfonyl)butanoic acid ( i.e. Example 3, Step D). MS (LCMS) m/z 539.5 (M-1 ). 1H N MR (400 MHz, CHLOROFORM-d) δ ppm 1.53 - 1.57 (m, 18 H) 1.69 (s, 3 H) 2.09 - 2.18 (m, 1 H) 2.38 - 2.53 (m, 2 H) 2.62 - 2.73 (m, 1 H) 3.05 (s, 3 H) 7.10 (d, J=8.20 Hz, 2 H) 7.25 - 7.37 (m, 4 H) 7.45 - 7.51 (m, 2 H).
Step D: Di-tert-butyl 4'-f(3RV3-methyl-3-(methylsulfonvn-4-oxo-4-r(tetrahvdro-2H- PVran-2-yloxy)aminolbutyl)biphenyl-4-yl phosphate
A solution of triethylamine (2.0 ml_, 15 mmol, 1 .8 equiv), 1-hydroxyl benzotriazole monohydrate (2.3 g, 15 mmol, 1.8 equiv), (2R)-4-{4'-[(di-tert- butoxyphosphoryl)oxy]biphenyl-4-yl}-2-methyl-2-(methylsulfonyl)butanoic acid (4.4 g, 8.2 mmol, 1.0 equiv), 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (1 .4 g, 12 mmol, 1.4 equiv), and N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI) (2.2 g, 1 1 mmol, 1.4 equiv) in dichloromethane (205 ml.) was allowed to stir at room temperature for 1 day. The reaction was diluted with water (600 ml.) and
dichloromethane (600 ml_), the aqueous phase was separated and extracted with dichloromethane (2 x 300 ml_). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (60% ethyl acetate in heptane) to provide the title compound (3.29 g, 63%). MS (LCMS) m/z 638.8 (M-1 ).
Step E: 4'-[(3R)-4-(Hvdroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyllbiphenyl-4-yl dihvdroqen phosphate
The title compound (2.03 mg, 89%) was prepared from di-tert-butyl 4'-{(3R)-3- methyl-3-(methylsulfonyl)-4-oxo-4-[(tetrahydro-2H-pyran-2-yloxy)amino]butyl}biphenyl- 4-yl phosphate (3.29 g, 5.1 mmol) by following a procedure analogous to that described for Preparation 2, Step 5, compound (IV). LCMS m/z 442.5 (M-1 ). 1 H NMR (400 MHz, CD3OD) δ 1 .66 (s, 3H), 2.09 (m, 1 H), 2.52- 2.63 (m, 2H), 2.75 (m, 1 H), 3.05 (s, 3H), 7.27 (dd, J=8.9, 1.3 Hz, 2H), 7.31 (d, J=8.3 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H), 7.58 (br d, J=8.7 Hz, 2H).
Example 7
(2R)-4-Biphenyl-4-yl-N-hvdroxy-2-methyl-2-(methylsulfonyl)butanamide
Figure imgf000056_0001
Step A: (2R -Biphenyl-4-yl-2-methyl-2-(methylsulfonvn-N-(tetrahvdro-2H-pyran-2- yloxy)butanamide
Trisdibenzylidine dipalladium (0.19 g, 0.21 mmol) was added to a mixture of potassium carbonate (1.45 g, 10.5 mmol, 5.0 equiv), (2R)-2-methyl-2-(methylsulfonyl)- N-(tetrahydro-2H-pyran-2-yloxy)-4-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]butanamide, which may be prepared as in Preparation 8C (1.0 g, 2.1 mmol) and bromobenzene (0.26 mL, 2.5 mmol) in 1 ,2-dimethoxyethane-methanol (8.0 mL, 1 :1 ). The reaction was heated to 80 °C and allowed to stir overnight. The reaction was diluted with ethyl acetate (60 mL), filtered through a pad of Celite, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (heptane/ethyl acetate system) to provide the title compound as a tan gum-like material (72 mg, 8%). MS (LCMS) m/z 430.8 (M-1 ).
Step B: Preparation of (2R)-4-Biphenyl-4-yl-N-hvdroxy-2-methyl-2- (methylsulfonyl)butanamide
A solution of hydrochloric acid (4.2 mL, 4.0 M in 1 ,4-dioxane) was added to {2R)- 4-biphenyl-4-yl-2-methyl-2-(methylsulfonyl)-/\/-(tetrahydro-2H-pyran-2-yloxy)butanamide (72 mg, 0.17 mmol). The reaction was allowed to stir at room temperature for 15 min, then anhydrous methanol (10 mL) was added. After 1 h, the reaction was concentrated under reduced pressure to provide a residue that was triturated with diethyl ether (35 mL). The ether was decanted off and the residual solvent was removed under reduced pressure to provide the title compound as an off-white solid (32 mg, 55%). LCMS m/z 348.2 (M+1 ). 1H NMR (400 MHz, CDCI3) δ 1.62 (s, 3H), 2.09 (m, 1 H), 2.45-2.56 (m, 2H), 2.65 (m, 1 H), 2.96 (s, 3H), 7.21 (d, J=8.3 Hz, 2H), 7.25-7.29 (m, 1 H), 7.34-7.39 (m, 2H), 7.46 (d, J=8.3 Hz, 2H), 7.49-7.52 (m, 2H).
Example 8
N-Hvdroxy-4-(2'-hvdrox biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanam
Figure imgf000057_0001
Step A:
To a flask containing 2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2- yloxy)-4-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]butanamide prepared as in Preparation Number 3 (150 mg, 0.312 mmol) was added 2-iodophenol (89.3 mg, 0.406 mmol), cesium fluoride (190 mg, 1.25 mmol), water (500 uL) and 1 ,4-dioxane (3 mL). To this mixture was added Palladium tetrakis (54.3 mg, 0.047 mmol) and the mixture was heated to 1 15°C with stirring overnight. The mixture was diluted with ethyl acetate and water. The phases were separated and the crude organic extract was concentrated in vacuo to dryness. The crude material was purified via silica gel chromatography eluting with ethyl acetate/heptanes to afford 4-(2'-hydroxybiphenyl-4- yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide as solid. 19.6 mg LCMS: (M-1 ) 446.3.
Step B:
4-(2'-Hydroxybiphenyl-4-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran- 2-yloxy)butanamide (19.6 mg, 0.044 mmol) was dissolved in methylene chloride (1 mL) at ambient temperature. To this solution was added HCI (4M in 1 ,4-dioxane, 0.33 mL, 1.32 mmol) and the solution was stirred at RT for 5 minutes. Methanol (100 uL) was added followed by silica gel and the mixture was concentrated to dryness. The crude material was purified via silica gel chromatography and eluted with methylene chloride/methanol to afford N-hydroxy-4-(2'-hydroxybiphenyl-4-yl)-2-methyl-2- (methylsulfonyl)butanamide as a solid. 6.5 mg
LCMS: (M-1 ) 362.2. Example 9
N-Hvdroxy-4-{4'-r3-(hvdroxymethyl)isoxazol-5-yllbiphenyl-4-yl}-2-methyl-2- (methylsulfonyl)butanamide
Figure imgf000058_0001
To flask containing 2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)-
4-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]butanamide, which may be prepared as in Preparation 3, (100 mg, 0.208 mmol) was added [5-(4-Bromo-phenyl)- isoxazol-3-yl]-methanol (58.2 mg, 0.229 mmol), cesium fluoride (126 mg, 0.832 mmol), water (200 uL) and 1 ,4-dioxane (2 ml_). To this mixture was added Palladium tetrakis (35.8 mg, 0.031 mmol) and the mixture was heated to 1 15°C with stirring for 3 hours.
The mixture was diluted with ethyl acetate and washed with aqueous HCI (0.1 N). The phases were separated and the crude organic extract was concentrated to dryness. The crude material was purified via silica gel chromatography eluting with ethyl acetate/heptanes to afford N-hydroxy-4-{4'-[3-hhydroxymethyl)isoxazol-5-yl]biphenyl-4- yl}-2-methyl-2-(methylsulfonyl)butanamide as a solid 21 mg.
LCMS: (M+1 ) 445.2. 1H NMR (CD3OD) 7.87 (2H, d, J=8.71 Hz), 7.73 (2H, d, J=8.29 Hz), 7.61 (2H, d, J=8.29 Hz), 7.34 (2H, d, J=7.88 Hz) 6.80 (1 H, s), 4.67(2H, s), 3.03 (3H, s), 2.79-2.71 (1 H, m), 2.62-2.52 (2H, m), 2.12-2.04 (1 H, m), 1.65 (3H, s) ppm.
Example 10
N-Hvdroxy-2-methyl-2-(methylsulfonyl)-4-(4-phenoxyphenyl)butanamide
Figure imgf000059_0001
Step A: {4-[4-Ethoxy-3-methyl-3-(methylsulfonyl)-4-oxobutyllphenyl}boronic acid
To a solution of ethyl 2-methyl-2-(methylsulfonyl)-4-[4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]butanoate, which may be prepared as in Preparation Number 3, Step A, (4.75 g, 11 .5 mmol) in acetone (90 mL) was added ammonium acetate (0.1 M in water, 232 mL, 23.2 mmol) and sodium periodate (7.43 g, 34.7 mmol). The mixture was stirred at ambient temperature overnight. The mixture was diluted with 1 N HCI aq. and extracted with ether 2x. The combined organic extracts were dried over
magnesium sulfate, filtered and concentrated in vacuo to give {4-[4-ethoxy-3-methyl-3- (methylsulfonyl)-4-oxobutyl]phenyl}boronic acid as an orange oil 3.44 g. LCMS: (M+1 ) 329.2
Step B: Ethyl 2-methyl-2-(methylsulfonyl)-4-(4-phenoxyphenyl)butanoate
To a solution of {4-[4-ethoxy-3-methyl-3-(methylsulfonyl)-4- oxobutyl]phenyl}boronic acid (599 mg, 1.83 mmol) in methylene chloride (3 mL) was added phenol (86 mg, 0.91 mmol), pyridine (148 uL, 1 .83 mmol) and copper (II) acetate (157 mg, 0.866 mmol). The mixture was stirred at ambient temperature under open atmosphere for 2 days. Silica gel was added and the mixture was concentrated to dryness and purified via silica gel chromatography eluting with ethyl acetate/heptanes to afford ethyl 2-methyl-2-(methylsulfonyl)-4-(4-phenoxyphenyl)butanoate as an oil. 312 mg. LCMS: (M+1 ) 377.2
Step C: 2-Methyl-2-(methylsulfonyl)-4-(4-phenoxyphenyl)butanoic acid
To a solution of ethyl 2-methyl-2-(methylsulfonyl)-4-(4-phenoxyphenyl)butanoate (312 mg, 0.829 mmol) in tetrahyrofuran/methanol (4:1 , 10 mL) was added a solution of lithium hydroxide monohydrate in water (1.66 M, 3.32 mmol). The mixture was stirred at ambient temperature overnight. The mixture was diluted with aqueous HCI (1 N in water) and extracted with ether 2x. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to dryness to afford 2- methyl-2-(methylsulfonyl)-4-(4-phenoxyphenyl)butanoic acid as an oil. 285 mg. LCMS: (M-1 ) 347.3
Step D: 2-Methyl-2-(methylsulfonyl)-4-(4-phenoxyphenyl)-N-(tetrahydro-2H-pyran-2- yloxy)butanamide
To a solution of 2-methyl-2-(methylsulfonyl)-4-(4-phenoxyphenyl)butanoic acid (285 mg, 0.818 mmol) in methylene chloride (8.18 mL) at ambient temperature was added 1 ,(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (220 mg, 1.1 mmol), 1-hydroxy benzotriazole monohydrate (230 mg, 1 .5 mmol), triethylamine (0.2 mL, 1 .4 mmol) and 0-tetrahydro-2H-pyran-2-yl-hydroxylamine (140 mg, 1.2 mmol). The resulting mixture was stirred at ambient temperature overnight. The mixture was diluted with methylene chloride and water. The phases were separated and the aqueous layer extracted with methylene chloride two times. The organic extracts were combined and dried over magnesium sulfate, filtered and concentrated in vacuo to a crude residue. The crude residue was purified via silica gel chromatography eluting with methylene chloride and methanol. The fractions containing the desired product were combined and concentrated in vacuo to afford 2-methyl-2-(methylsulfonyl)-4-(4-phenoxyphenyl)-N- (tetrahydro-2H-pyran-2-yloxy)butanamide as a solid. 247.2 mg
LCMS: (M-1 ) 446.3
Step E: N-Hvdroxy-2-methyl-2-(methylsulfonyl)-4-(4-phenoxyphenyl)butanamide
2-Methyl-2-(methylsulfonyl)-4-(4-phenoxyphenyl)-N-(tetrahydro-2H-pyran-2- yloxy)butanamide (247.2 mg, .552 mmol) was dissolved in methylene chloride (10 mL) at ambient temperature. To this solution was added HCI (4M in 1 ,4-dioxane, 4.14 mL, 16.6 mmol) and the solution was stirred at RT for 5 minutes. Methanol (500 uL) was added followed by silica gel and the mixture was concentrated to dryness. The crude material was purified via silica gel chromatography eluting with methylene
chloride/methanol to afford N-hydroxy-2-methyl-2-(methylsulfonyl)-4-(4- phenoxyphenyl)butanamide as a solid. 94.4 mg. LCMS: (M-1 ) 362.3 Example 11
N-Hvdroxy-2-methyl-2-(methylsulfonyl)-4-r4-(1 H-pyrazol-1-yl)phenyllbutanamid
Figure imgf000061_0001
Step A: Ethyl 2-methyl-2-(methylsulfonyl)-4-[4-(1 H-pyrazol-1-yl)phenyllbutanoate
To a solution of {4-[4-ethoxy-3-methyl-3-(methylsulfonyl)-4- oxobutyl]phenyl}boronic acid which may be prepared as in Example 10, Step, A (597 mg, 1 .82 mmol) in methylene chloride (3 mL) was added pyrazole (62 mg, 0.91 mmol), pyridine (147 uL, 1.82 mmol) and copper (II) acetate (157 mg, 0.866 mmol). The mixture was stirred at ambient temperature under an open atmosphere for 2 days. Silica gel was added, the mixture was concentrated to dryness and purified via silica gel chromatography eluting with ethyl acetate/heptanes to afford ethyl 2-methyl-2- (methylsulfonyl)-4-[4-(1 H-pyrazol-1 -yl)phenyl]butanoate as an oil. 316.9 mg. LCMS: (M+1 ) 351.2.
Step B: 2-Methyl-2-(methylsulfonyl)-4-r4-(1 H-pyrazol-1 -yl)phenyllbutanoic acid
To a solution of ethyl 2-methyl-2-(methylsulfonyl)-4-[4-(1 H-pyrazol-1 - yl)phenyl]butanoate (316 mg, 0.902 mmol) in tetrahyrofuran/methanol (4:1 , 10 mL) was added a solution of lithium hydroxide monohydrate in water (1.8 M, 3.61 mmol). The mixture was stirred at ambient temperature overnight. The mixture was diluted with aqueous 1 N HCI and extracted with ether 2x. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to dryness to afford 2-methyl-2-(methylsulfonyl)-4-[4-(1 H-pyrazol-1 -yl)phenyl]butanoic acid as an oil. 286 mg. LCMS: (M-1 ) 321.3.
Step C: 2-Methyl-2-(methylsulfonvn-4-r4-(1 H-pyrazol-1 -vnphenyll-N-(tetrahvdro-2H- pyran-2-yloxy)butanamide
To a solution of 2-Methyl-2-(methylsulfonyl)-4-[4-(1 H-pyrazol-1 - yl)phenyl]butanoic acid (286 mg, 0.887 mmol) in methylene chloride (8.87 ambient temperature was added 1 ,(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (240 mg, 1.2 mmol), 1 -hydroxy benzotriazole monohydrate (240 mg, 1.6 mmol), triethyl amine (220 uL, 1.6 mmol) and 0-tetrahydro-2H-pyran-2-yl-hydroxylamine (150 mg, 1.3 mmol). The resulting mixture was stirred at ambient temperature overnight. The mixture was diluted with methylene chloride and water. The phases were separated and the aqueous layer was extracted with methylene chloride two times. The organic extracts were combined and dried over magnesium sulfate, filtered and concentrated in vacuo to a crude residue. The crude residue was purified via silica gel chromatography eluting with methylene chloride and methanol. The fractions containing desired product were combined and concentrated in vacuo to afford 2- methyl-2-(methylsulfonyl)-4-[4-(1 H-pyrazol-1-yl)phenyl]-N-(tetrahydro-2H-pyran-2- yloxy)butanamide as a solid. 302.9 mg. LCMS: (M-1 ) 420.3.
Step D: N-hvdroxy-2-methyl-2-(methylsulfonyl)-4-[4-(1 H-pyrazol-1-yl)phenyllbutanamide
2-Methyl-2-(methylsulfonyl)-4-[4-(1 H-pyrazol-1 -yl)phenyl]-N-(tetrahydro-2H- pyran-2-yloxy)butanamide (302.9 mg, 0.719 mmol) was dissolved in methylene chloride (10 ml.) at ambient temperature. To this solution was added HCI (4M in 1 ,4-dioxane, 5.39 ml_, 21.6 mmol) and the solution was stirred at RT for 5 minutes. Methanol (500 uL) was added followed by silica gel and the mixture was concentrated to dryness. The crude material was purified via silica gel chromatography eluting with methylene chloride/methanol to afford N-hydroxy-2-methyl-2-(methylsulfonyl)-4-[4-(1 H-pyrazol-1- yl)phenyl]butanamide as a solid. 67.8 mg. LCMS: (M-1 ) 336.3 1H NMR (CD3OD) 8.16 (1 H, d, J=2.54 Hz), 7.69 (1 H, d, J=1.17 Hz), 7.64 (2H, d, J=8.59), 7.36 (2H, d, J=8.40) 6.50 (1 H, t), 3.03 (3H, s), 2.80-2.72 (1 H, m), 2.61-2.52 (2H, m), 2.1 1-2.03 (1 H, m), 1.65 (3H, s) ppm.
Example 12
N-Hvdroxy-2-methyl-2-(methylsulfonyl)-4-r4-(phenylthio)phenyllbutanamide
Figure imgf000062_0001
Step A: Ethyl 2-methyl-2-(methylsulfonyl)-4-r4-(phenylthio)phenyllbutanoate
To a solution of {4-[4-ethoxy-3-methyl-3-(methylsulfonyl)-4- oxobutyl]phenyl}boronic acid which may be prepared by the method described in Example 10, Step A, (600 mg, 1.83 mmol) in DMSO/water (2:1 , 10 mL) at ambient temperature was added phenyl disulfide (200 mg, 0.914 mmol), [2,2']Bipyridinyl (7.20 mg, 0.046 mmol), and copper (I) iodide. The mixture was heated to 100°C and stirred for 2 days. The mixture was allowed to cool to ambient temperature, diluted with diethyl ether and washed with water 3x. Silica gel was added to the organic extracts and the mixture was concentrated to dryness. The crude material was purified via silica gel chromatography eluting with ethyl acetate/heptanes to afford ethyl 2-methyl-2-
(methylsulfonyl)-4-[4-(phenylthio)phenyl]butanoate as an oil. 348.6 mg LCMS: (M+1 ) 393.2.
Step B: 2-Methyl-2-(methylsulfonyl)-4-r4-(phenylthio)phenyll-butanoic acid
To a solution of ethyl 2-methyl-2-(methylsulfonyl)-4-[4-
(phenylthio)phenyl]butanoate (348.6 mg, 0.887 mmol) in tetrahydrofuran/methanol (4:1 , 10 mL) was added a solution of lithium hydroxide monohydrate in water (1 .78 M, 3.55 mmol). The mixture was stirred at ambient temperature overnight. The mixture was diluted with aqueous HCI (1 N in water) and extracted with diethyl ether 2x. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to dryness to afford 2-methyl-2-(methylsulfonyl)-4-[4- (phenylthio)phenyl]-butanoic acid as a solid. 323 mg. LCMS: (M-1 ) 363.3.
Step C: 2-Methyl-2-(methylsulfonylV4-r4-(phenylthio)phenyll-N-(tetrahvdro-2H-pyran-2- yloxy)butanamide
To a solution of 2-methyl-2-(methylsulfonyl)-4-[4-(phenylthio)phenyl]-butanoic acid (315.7 mg, 0.866 mmol) in methylene chloride (8.66 mL) at ambient temperature was added 1 ,(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (230 mg, 1.2 mmol), 1-hydroxy benzotriazole monohydrate (240 mg, 1.6 mmol), triethyl amine (210 uL, 1.5 mmol) and 0-tetrahydro-2H-pyran-2-yl-hydroxylamine (150 mg, 1.3 mmol). The resulting mixture was stirred at ambient temperature overnight. The mixture was diluted with methylene chloride and water. The phases were separated and the aqueous layer was extracted with methylene chloride two times. The organic extracts were combined and dried over magnesium sulfate, filtered and concentrated to a crude residue. The crude residue was purified via silica gel chromatography eluting with methylene chloride and methanol. The fractions containing the desired product were combined and concentrated to afford 2-methyl-2-(methylsulfonyl)-4-[4-(phenylthio)phenyl]-N- (tetrahydro-2H-pyran-2-yloxy)butanamide as a solid. 268.4 mg. LCMS: (M-1 ) 462.2. Step D: N-hvdroxy-2-methyl-2-(methylsulfonyl)-4-[4-(phenylthio)phenyllbutanamide To a solution of 2-methyl-2-(methylsulfonyl)-4-[4-(phenylthio)phenyl]-N- (tetrahydro-2H-pyran-2-yloxy)butanamide (268.4 mg, 0.579 mmol) in methylene chloride (3 mL) at ambient temperature was added HCI (4M in 1 ,4-dioxane, 4.34 mL, 17.4 mmol) and the resulting solution was stirred at RT for 5 minutes. Methanol (500 uL) was added followed by silica gel and the mixture was concentrated to dryness. The crude material was purified via silica gel chromatography eluting with methylene
chloride/methanol to afford N-hydroxy-2-methyl-2-(methylsulfonyl)-4-[4- (phenylthio)phenyl]butanamide as a solid. 7.8 mg. LCMS: (M+1 ) 380.1. Example 13
4-(4-Cvclohept-1 -en-1 -ylphenyl)-N-hvdroxy-2-methyl-2-(methylsulfonyl)butanamide
Figure imgf000064_0001
Step A: Cvclohept-1-en-1-yl trifluoromethanesulfonate
To a solution of LDA (1 .8 M in THF, 12.5 mL, 22.5 mmol) in tetrahydrofuran (70 mL) at -78°C was added a solution of cycloheptanone (2.2 g, 19.6 mmol) in
tetrahydrofuran (10 mL). The mixture was stirred at -78°C for 45 minutes. To this solution was added 1 , 1 , 1-trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]
methanesulfonamide (7.7 g, 21 .5 mmol) in tetrahydrofuran (30 mL). The mixture was allowed to warm to ambient temperature and was stirred overnight. The mixture was diluted with diethyl ether and washed with aqueous HCI (1 N in water) and water successively. The organic extracts were dried over magnesium sulfate, filtered and concentrated to a crude residue. The residue was dissolved in heptanes and passed through a pad of silica gel eluting with heptanes. The eluant was concentrated to dryness to afford cyclohept-1-en-1 -yl trifluoromethanesulfonate as acolorless oil. 2.87 g 1H NMR (CDCI3) 5.86 (1 H, t), 2.51-2.49 (2H, m), 2.16-2.12 (2H, m), 1.74-1.59 (6H, m) ppm 19F NMR (CDCI3) -74.41 (3F, s) ppm.
Step B: 4-(4-Cvclohept-1-en-1-ylphenyl)-N-r(1 -methoxypentyl)oxyl-2-methyl-2- (methylsulfonyl)butanamide
To flask containing 2-methanesulfonyl-2-methyl-N-(tetrahydro-pyran-2-yloxy)-4- [4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-phenyl]-butyramide which may be prepared by the method described in Preparation 3 (800 mg, 01.66 mmol) was added cyclohept-1-en-1-yl trifluoromethanesulfonate (812 mg, 3.32 mmol), sodium carbonate (528 mg, 4.99 mmol), water (500 uL) and 1 ,4-dioxane (4 ml_). To this mixture was added pd tetrakis (288 mg, 0.249 mmol) and the mixture was heated to 50°C with stirring overnight. The mixture was diluted with ethyl acetate and washed with water 2x. The phases were separated, silica gel was added to the organic extracts and the mixture was concentrated to dryness. The crude material was purified via silica gel chromatography eluting with ethyl acetate/heptanes to afford 4-(4-cyclohept-1 -en-1 - ylphenyl)-N-[(1-methoxypentyl)oxy]-2-methyl-2-(methylsulfonyl)butanamide as a solid 205 mg. LCMS: (M+1 ) 448.3.
Step C: 4-(4-Cvclohept-1-en-1-ylphenyl)-N-hvdroxy-2-methyl-2- (methylsulfonyl)butanamide
4-(4-Cyclohept-1-en-1 -ylphenyl)-N-[(1-methoxypentyl)oxy]-2-methyl-2- (methylsulfonyl)butanamide (205 mg, 0.36 mmol) was dissolved in methylene chloride (4 ml.) at ambient temperature. To this solution was added HCI (4M in 1 ,4-dioxane, 1.82 ml_, 7.30 mmol) and the solution was stirred at rt for 20 minutes. Methanol (500 uL) was added followed by silica gel and the mixture was concentrated to dryness. The crude material was purified via silica gel chromatography eluting with methylene chloride/methanol to afford 4-(4-cyclohept-1-en-1-ylphenyl)-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide as a solid. 91.5 mg. LCMS: (M+1 ) 366.2. Example 14
(2RV4-f4'-r(5R)-5-(Acetamidomethvn-2-oxo-1 ,3-oxazolidin-3-yll-2'-fluorobiphenyl-4-yl>-
N-hvdroxy-2-methyl-2-(methylsulfonyl)butanamide
Figure imgf000066_0001
Step A: N- (5SV3-r4-(5.5-dimethyl-1.3.2-dioxaborinan-2-vn-3-fluoroDhenyll-2-oxo-1.3- oxazolidin-5-yl}methyl)acetamide
N-{[(5S)-3-(4-bromo-3-fluorophenyl)-2-oxo-1 ,3-oxazolidin-5- yl]methyl}acetamide (500mg, 1 .51 mmmol) was weighed into a 20ml_ vial, followed by the addition of bis(neopentyl glycolato) diboron (619mg, 1.81 mmol), potassium acetate (593mg, 6.04mmol) and [1 , 1'-bis-(diphenylphosphino)ferrocene]-dichloropalladium (II) dcm complex (1 16mg, 0.151 mmol). The reaction mixture was purged with vacuum and backfilled with nitrogen three times. To this was added N,N dimethyl formamide(10ml_). The reaction was heated at 100°C for 72 hours, cooled to ambient temperature,filtered through celite (~1 inch), and the celite was washed with additional ethyl acetate
(100ml_). The combined organics were then concentrated in vacuo. The residue was dissolved in ethyl acetate (100ml_) and organic phase was washed with water (25ml_). The aqueous layer was extracted with additional ethyl acetate (100ml_). The combined organics were then washed with brine (2x50ml_), dried (MgS04), filtered, and
concentrated in vacuo. The crude material was purified by chromatography on silica gel (gradient: 80:20 hexanes:ethyl acetate) to afford the title compound as a light red solid (274mg, 50%). MS (APCI) m/z 604.3 (M+1 ) 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1 .04 (s, 6 H) 2.01 - 2.04 (m, 3 H) 3.56 - 3.68 (m, 2 H) 3.69 - 3.78 (m, 2 H) 3.80 (s, 3 H) 4.07 (t, J=8.98 Hz, 1 H) 4.73 - 4.85 (m, 1 H) 6.03 (br. s., 1 H) 7.20 (dd, J=8.20, 2.15 Hz, 1 H) 7.37 (dd, J=11 .91 , 2.15 Hz, 1 H) 7.73 (dd, J=8.20, 7.23 Hz, 1 H).
Step B: (2RV4-f4'-r(5RV5-(acetamidomethvn-2-oxo-1 ,3-oxazolidin-3-yll-2'- fluorobiphenyl-4-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahvdro-2H-pyran-2- yloxy)butanamide
Palladium (II) EnCat (230mg, 0.07mmol) was added to a mixture of potassium carbonate (207mg, 1.5mmol), N-({(5S)-3-[4-(5,5-dimethyl-1 ,3,2-dioxaborinan-2-yl)-3- fluorophenyl]-2-oxo-1 ,3-oxazolidin-5-yl}methyl)acetamide (234mg, 0.644mmol), and Ilia (2R)-4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2- yloxy)butanamide which was prepared as in Preparation 7 (200mg, 0.46mmol) in dioxane:water (6mL, 5: 1 ) in a 20mL sealed vial. The vial was heated overnight at 90°C. The reaction was cooled to ambient temperature, filtered through celite and the filtrate was washed with ethyl acetate (30ml_) and methanol (15ml_). The combined
organicswere concentrated in vacuo and purified by chromatography on silica gel (gradient: 80:20 heptanes:ethyl acetate to 0:100 heptanes:ethyl acetate, followed by ethyl acetate:methanol 90:10) to furnish the title compound as a light brown gum. Yield 50mg, 18% theoretical yield. LCMS m/z 604.3 (M-1 )
Step C: (2R)-4-{4'-r(5R)-5-(acetamidomethyl)-2-oxo-1 ,3-oxazolidin-3-yll-2'- fluorobiphenyl-4-yl}-N-hvdroxy-2-methyl-2-(methylsulfonyl)butanamide
HCI (4.0 M in 1 ,4-dioxane, 1.0 ml.) was added to a solution of (2R)-4-{4'-[(5R)-5- (acetamidomethyl)-2-oxo-1 ,3-oxazolidin-3-yl]-2'-fluorobiphenyl-4-yl}-2-methyl-2- (methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (50mg, 0.083 mmol) in 1 ,4 dioxane/dichloromethane/water (1 :1 :1 , 3 ml_). After 15 minutes reaction was
concentrated to give a white solid. The solid was triturated with a mixture of diethyl ether/2-propanol (10: 1 , 10 ml.) for 2 hours. The title compound was collected as a white solid (16 mg, 37%) by filtration. LCMS m/z 522.6 (M+1 ) 1 H NMR (400 MHz, DMSO-de) δ ppm 1 .55 (s, 3 H) 1.84 (s, 3 H) 1.88 - 1.98 (m, 1 H) 2.37 - 2.48 (m, 1 H) 2.63 - 2.76 (m, 2 H) 3.05 (s, 3 H) 3.43 (t, J=5.47 Hz, 2 H) 3.78 (dd, J=9.28, 6.35 Hz, 1 H) 4.17 (t, J=8.98 Hz, 1 H) 4.70 - 4.82 (m, 1 H) 7.34 (d, J=8.20 Hz, 2 H) 7.40 (dd, J=8.49, 2.25 Hz, 1 H) 7.45 - 7.51 (m, 2 H) 7.51 - 7.62 (m, 2 H) 8.26 (t, J=5.86 Hz, 1 H).
Example 15
(+/-)-4-[4-(Cvclopentyloxy)phenyll-N-hvdroxy-2-methyl-2-(methylsulfonyl)butanamide
Figure imgf000067_0001
Step A: 1-(Benzyloxy)-4-(2-iodoethyl)benzene
2-[4-(Benzyloxy)phenyl]ethanol was converted to the title compound following the general procedure outlined for 1-bromo-4-(2-iodoethyl)benzene in Preparation 2, step 1. The title compound was obtained as a white solid (34.32 g, 93%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.13 (t, J=8.01 Hz, 2 H) 3.33 (t, J=7.61 Hz, 2 H) 5.07 (s, 2 H) 6.94 (d, J=8.59 Hz, 2 H) 7.12 (d, J=8.40 Hz, 2 H) 7.31 - 7.47 (m, 5 H).
Step B: Ethyl 4-[4-(benzyloxy)phenyll-2-(methylsulfonyl)butanoate
Sodium hydride (1 .80 g, 45 mmol, 60% in mineral oil) was added in three portions to a solution of ethyl (methylsulfonyl)acetate (6.70 g, 40.3 mmol) in DMF (200 mL) at 0°C. The reaction was allowed to warm to room temperature and stirred for 1 hour. 1-(Benzyloxy)-4-(2-iodoethyl)benzene was added to the solution and the reaction was stirred overnight at rt. The reaction was quenched with 1 N aqueous HCI (200 mL) and extracted with ethyl acetate (3x 100 mL). The combined organics were dried (MgS04), filtered and concentrated in vacuo. Chromatography on a Biotage 40L column using 1 :4 ethyl acetate in heptane afforded the title compound as a white solid (13.13 g, 86.5%). LC-MS m/z 375.2(M-1 ). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1 .34 (t, J=7.03 Hz, 3 H) 2.31 - 2.47 (m, 2 H) 2.55 - 2.68 (m, 1 H) 2.70 - 2.80 (m, 1 H) 3.00 (s, 3 H) 3.66 - 3.80 (m, 1 H) 4.18 - 4.38 (m, 2 H) 5.06 (s, 2 H) 6.92 (d, J=8.59 Hz, 2 H) 7.09 (d, J=8.59 Hz, 2 H) 7.31 - 7.47 (m, 5 H).
Step C: (+/-)-Ethyl 4-r4-(benzyloxy)phenyll-2-methyl-2-(methylsulfonyl)butanoate
Cesium carbonate (9.30 g, 28.5 mmol) was added to ethyl 4-[4- (benzyloxy)phenyl]-2-(methylsulfonyl)butanoate (8.86 g, 23.5 mmol) in DMF (100 mL) and stirred for 30 minutes, lodomethane was added to the reaction followed by stirring overnight at room temperature. The reaction mixture was poured into 1 N aqueous HCI (100 mL) and extracted with EtOAc (3x100 mL). The combined organics were washed with saturated aqueous sodium thiosulfate (100 mL) then dried (MgS04), filtered and concentrated in vacuo to afford a crude solid. The crude product was purified via silica gel chromatography using an eluant of ethyl acetate in heptane (10- 100%) to afford the title compound as a white solid (8.35 g, 90.9%). LC-MS m/z 391.2(M+1 ). Step D: (+/-)-Ethyl 4-(4-hvdroxyphenyl)-2-methyl-2-(methylsulfonyl)butanoate
Pearlman's catalyst (Pd(OH)2/C, 1 .19 g, 8.48 mmol) was added to a solution of (+/-)-Ethyl 4-[4-(benzyloxy)phenyl]-2-methyl-2-(methylsulfonyl)butanoate (4.73 g, 12.1 mmol) and cylcohexene (12.3 mL, 121 mmol) in ethanol (50 mL). The mixture was refluxed overnight. The reaction was filtered through celite (~1 inch), washed with ethanol (100 mL) and ethyl acetate (200 mL), and the combined filtrates were concentrated in vacuo. The crude product was purified via column chromatography using an Analogiz SF15-40g column and eluting with 500 mL 1 :9 EtOAc:Heptane, and 1 L 1 :1 EtOAc:Heptane to afford the title compound as a clear liquid (3.44g, 94.6%) LC- MS m/z 301.1 (M+1 ). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (t, J=7.13 Hz, 3 H) 1.70 (s, 3 H) 2.10 - 2.24 (m, 1 H) 2.37 - 2.53 (m, 2 H) 2.62 - 2.78 (m, 1 H) 3.04 (s, 3 H) 4.26 (q, J=7.03 Hz, 2 H) 5.77 - 6.01 (m, 1 H) 6.77 (d, J=8.59 Hz, 2 H) 7.01 (d, J=8.59 Hz, 2 H).
Step E: (+/-)-Ethyl 4-[4-(cvclopentyloxy)phenyll-2-methyl-2-(methylsulfonyl)butanoate Diethyl azodicarboxylate (40%, 220 uL, 0.48 mmol) was added to a solution of cyclopentanol (30.2 uL, 0.333 mmol), triphenylphosphine (120 mg. 0.456 mmol), and (+/-)-ethyl 4-(4-hydroxyphenyl)-2-methyl-2-(methylsulfonyl)butanoate (120 mg, 0.40 mmol) in THF (3 mL) at 0°C under nitrogen. The reaction was allowed to warm to rt and was stirred overnight. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (3x 30 mL). The combined organics were dried (MgS04), filtered, and concentrated in vacuo. The crude product was purified via column chromatography using an Analogiz SF10-8 g using EtOAc in Heptane (10-50%) to afford the title compound as a clear oil (100 mg, 67.8%). LC-MS m/z 369.4 (M+1 ).
Step F: (+/-)-4-r4-(Cvclopentyloxy)phenyll-2-methyl-2-(methylsulfonyl)butanoic acid (+/-)-Ethyl 4-[4-(cyclopentyloxy)phenyl]-2-methyl-2-(methylsulfonyl)butanoate was converted to the title compound following the procedure described in Preparation 2, Step 3, for preparation of (ll).The title compound was obtained as a white solid (90 mg, 98%). LC-MS m/z 339.1 (M+1 ). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.58 - 1.66 (m, 2 H) 1.74 (s, 3 H) 1.76 - 1.96 (m, 6 H) 2.15 - 2.28 (m, 1 H) 2.38 - 2.62 (m, 2 H) 2.65 - 2.81 (m, 1 H) 3.08 (s, 3 H) 4.66 - 4.79 (m, 1 H) 6.81 (d, J=8.79 Hz, 2 H) 7.09 (d, J=8.79 Hz, 2 H).
Step G: (+/-)-4-r4-(Cvclopentyloxy)phenyll-N-hvdroxy-2-methyl-2- (methylsulfonyl)butanamide
(+/-)-4-[4-(Cyclopentyloxy)phenyl]-2-methyl-2-(methylsulfonyl)butanoic acid was converted to the title compound following the procedure described in Preparation 2, Step 5, for the preparation of (IV) The title compound was obtained as a white solid (69 mg, 74%). LC-MS m/z 356.2. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1 .55 - 1.69 (m, 5 H) 1.70 - 1.85 (m, 4 H) 1.85 - 1.96 (m, 2 H) 2.01 (s, 1 H) 2.40 - 2.57 (m, 2 H) 2.58 - 2.69 (m, 1 H) 3.04 (s, 3 H) 4.74 (none, 1 H) 6.80 (d, J=8.59 Hz, 2 H) 7.1 1 (d, J=8.59 Hz, 2 H). Example 16
(+/-)-N-Hvdroxy-2-methyl-2-(methylsulfonyl)-4-r4-(pyridin-2- ylmethoxy)phenyl1butanamide
Figure imgf000070_0001
Step A: (+/-)-Ethyl 2-methyl-2-(methylsulfonyl)-4-r4-(pyridin-2- ylmethoxy)phenyllbutanoate
2-(Bromomethyl)pyridine (215 mg, mmol) was added to a suspension of cesium carbonate (485 mg, 1.49 mmol) and 4-(4-hydroxyphenyl)-2-methyl-2- (methylsulfonyl)butanoate, prepared as described in Example 15 step D (215 mg, mmol) in DMF in a 50 ml. round bottom flask under N2. The reaction was stirred overnight at rt, then diluted with 1 N aqueous NaOH (30 ml.) and extracted with ethyl acetate (3x 30ml_). The combined organics were dried (MgS04), filtered, and concentrate in vacuo. The crude product was purified via flash chromatography using an Analogix SF10-4g column and ethyl acetate in heptane (50-100%) to afford the title compound as a yellow solid (161 mg, 58%). LC-MS m/z 392.3.
Step B: (+/-)-2-Methyl-2-(methylsulfonyl)-4-[4-(pyridin-2-ylmethoxy)phenyllbutanoic acid (+/-)-Ethyl 2-methyl-2-(methylsulfonyl)-4-[4-(pyridin-2-ylmethoxy) phenyl] butanoate was converted to the title compound following the general procedure described in Preparation 2, Step 3, for preparation of (II). The reaction was
concentrated in vacuo to afford the title compound as a white solid containing salts (270 mg, >100%) which was used directly in the next reaction. LC-MS m/z 364.1. 1H NMR (400 MHz, DMSO-de) δ ppm 1.50 (s, 3 H) 1 .89 - 2.03 (m, 1 H) 2.27 - 2.43 (m, 2 H) 2.60 - 2.74 (m, 2 H) 3.08 (s, 3 H) 5.16 (s, 2 H) 7.14 (d, J=8.59 Hz, 2 H) 7.33 - 7.41 (m, 1 H) 7.53 (d, J=7.81 Hz, 1 H) 7.80 - 7.95 (m, 2 H) 8.59 (d, J=5.07 Hz, 1 H).
Step C: of (+/-)-N-Hvdroxy-2-methyl-2-(methylsulfonyl)-4-r4-(pyridin-2- ylmethoxy)phenyllbutanamide
(+/-)-2-Methyl-2-(methylsulfonyl)-4-[4-(pyridin-2-ylmethoxy)phenyl] butanoic acid was converted to the title compound following the general procedure described in Preparation 2, Step 5, for the preparation of (IV). The title compound was obtained as a white solid (44 mg, 17%). LC-MS m/z 379.2. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1 .62 (s, 3 H) 1.94 - 2.08 (m, 1 H) 2.37 - 2.56 (m, 2 H) 2.58 - 2.72 (m, 1 H) 3.02 (s, 3 H) 5.15 (none, 2 H) 6.93 (d, J=8.79 Hz, 2 H) 7.15 (d, J=8.59 Hz, 2 H) 7.30 - 7.41 (m, 1 H) 7.58 (d, J=8.01 Hz, 1 H) 7.80 - 7.93 (m, 1 H) 8.51 - 8.54 (m, 1 H).
Example 17
(+/-)-4-[4-(2-Cvclopropylethoxy)phenyll-N-hvdroxy-2-methyl-2-
(methylsulfonyl)butanamide
Figure imgf000071_0001
Step A: (+/-)-Ethyl 4-r4-(2-cvclopropylethoxy)phenyll-2-methyl-2- (methylsulfonyl)butanoate
1 , 1 '-(Azodicarbonyl)-dipiperidine (125 mg, 0.495 mmol) was added to a solution of cyclohexanol (30 mg, 0.35 mmol), tri-n-butylphosphine (12 uL), and (+/-)-ethyl 4-(4- hydroxyphenyl)-2-methyl-2-(methylsulfonyl)butanoate prepared as described in
Example 15, Step D, (125 mg, 0.416 mmol) in THF (3 ml.) at 0°C under nitrogen. The reaction was allowed to warm to RT and stirred overnight, thendiluted with water (30 ml.) and extracted with ethyl acetate (3x30 ml_). The combined organics were dried (MgS04), filtered, and concentrated in vacuo. The crude product was purified via flash chromatography using an Analogix SF10-8g column and an eluant of 20% ethyl acetate in heptane to afford the title compound as a white solid (84 mg, 66%). LC-MS m/z
369.2. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.08 - 0.16 (m, 2 H) 0.44 - 0.54 (m, 2 H) 0.77 - 0.92 (m, 1 H) 1.34 (t, J=7.03 Hz, 3 H) 1.61 - 1.79 (m, 5 H) 2.09 - 2.28 (m, 1 H) 2.39 - 2.55 (m, 2 H) 2.63 - 2.82 (m, 1 H) 3.04 (s, 3 H) 4.02 (t, J=6.64 Hz, 2 H) 4.22 - 4.33 (m, 2 H) 6.85 (d, J=8.79 Hz, 2 H) 7.09 (d, J=8.79 Hz, 2 H).
Step B: (+/-)-4-r4-(2-Cvclopropylethoxy)phenyll-2-methyl-2-(methylsulfonyl)butanoic acid
(+/-)-Ethyl 4-[4-(2-cyclopropylethoxy)phenyl]-2-methyl-2- (methylsulfonyl)butanoate was converted to the title compound following the general procedure described in Preparation 2, Step 3, for preparation of (II). The title compound was obtained as a white solid (80 mg, 100%). LC-MS m/z 369.2. Step C: of (+/-)-4-r4-(2-Cvclopropylethoxy)phenyll-N-hvdroxy-2-methyl-2- (methylsulfonyl)butanamide
(+/-)-4-[4-(2-Cyclopropylethoxy)phenyl]-2-methyl-2-(methylsulfonyl)butanoic acid was converted to the title compound following the general procedure described in Preparation 2, Step 5, for the preparation of (IV). The crude material was purified using preparatory HPLC to afford the title compound as a white solid (44 mg, 17%). LC-MS m/z 356.2. 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.06 - 0.23 (m, 2 H) 0.40 - 0.55 (m, 2 H) 0.79 - 0.97 (m, 1 H) 1.55 - 1.73 (m, 5 H) 1 .92 - 2.09 (m, 1 H) 2.36 - 2.57 (m, 2 H) 2.57 - 2.74 (m, 1 H) 3.03 (s, 3 H) 4.01 (t, J=6.64 Hz, 2 H) 6.84 (d, J=8.59 Hz, 2 H) 7.13 (d, J=8.98 Hz, 2 H).
Example 18
(+/-)-4-(4'-Fluoro-3-methoxybiphenyl-4-yl)-N-hvdroxy-2-methyl-2-
(methylsulfonyl)butanamide
Figure imgf000072_0001
Step A: 4'-Fluoro-4-(2-iodoethyl)-3-methoxybiphenyl
2-(4'-Fluoro-3-methoxybiphenyl-4-yl)ethanol (product of Preparation 5) was converted to the title compound following the general procedure in Preparation 2, Step 1. The title compound was obtained as a white solid (1.38 g, 92.6%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.23 (t, J=8.00 Hz, 2 H) 3.40 (t, J=7.61 Hz, 2 H) 3.90 (s, 3 H) 7.00 (s, 1 H) 7.04 - 7.22 (m, 4 H) 7.50 - 7.58 (m, 2 H).
Step B: (+/-) Ethyl 4-(4'-fluoro-3-methoxybiphenyl-4-yl)-2-methyl-2- (methylsulfonyl)butanoate
Cesium carbonate (2.90 g, 8.90 mmol) was added to a solution of 4'-fluoro-4-(2- iodoethyl)-3-methoxybiphenyl (1.38 g, 3.87 mmol) and ethyl 2-(methylsulfonyl) propanoate (770 mg, 4.27 mmol) in DMF (5 mL). The reaction was stirred overnight at room temperature under nitrogen. The reaction was diluted with water (60 mL) and extracted with ethyl acetate (3x60 mL). The combined organics were dried (MgS04), filtered and concentrated in vacuo to afford a clear oil. The crude oil was purified via flash chromatography using an Analogix SF25-40g column and eluting with ethyl acetate in heptane (0-30%) to afford the title compound as a white solid (1.48 g, 93.6%). LC-MS m/z 409.5(M+1 ). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1 .35 (t, J=7.02 Hz, 3 H) 1.75 (s, 3 H) 2.12 - 2.30 (m, 1 H) 2.38 - 2.61 (m, 2 H) 2.79 - 2.94 (m, 1 H) 3.07 (s, 3 H) 3.90 (s, 3 H) 4.21 - 4.33 (m, 4 H) 7.00 (d, J=1.56 Hz, 1 H) 7.07 (dd, J=7.61 , 1.76 Hz, 1 H) 7.10 - 7.20 (m, 3 H) 7.49 - 7.56 (m, 2 H).
Step C: (+/-)-4-(4'-Fluoro-3-methoxybiphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanoic acid
(+/-) Ethyl 4-(4'-fluoro-3-methoxybiphenyl-4-yl)-2-methyl-2- (methylsulfonyl)butanoate was converted to the title compound following the general procedure of Step 3, Preparation 2, for the formation of compound (II) using potassium hydroxide in place of lithium hydroxide.
The title compound was obtained as a white solid (670 mg, 95.9%). LC-MS m/z
379.5(M-1 ). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.78 (s, 3 H) 2.22 - 2.35 (m, 1 H) 2.37 - 2.51 (m, 1 H) 2.54 - 2.66 (m, 1 H) 2.83 - 2.95 (m, 2 H) 3.1 1 (s, 3 H) 3.90 (s, 3 H). Step D: (+/-)-4-(4'-Fluoro-3-methoxybiphenyl-4-yl)-2-methyl-2-(methylsulfonyl)-N-
(tetrahvdro-2H-pyran-2-yloxy)butanamide
(+/-)-4-(4'-Fluoro-3-methoxybiphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanoic acid was converted to the title compound following the general procedure of step 4,
Preparation 2, for the formation of compound (III) using Ν,Ν-diisopropylethylamine in place of triethylamine. The title compound was obtained as a white solid (647 mg,
76.6%) LC-MS m/z 478.6(M-1 ).
Step E: (+/-)-4-(4'-Fluoro-3-methoxybiphenyl-4-yl)-N-hvdroxy-2-methyl-2- (methylsulfonyl)butanamide
(+/-)-4-(4'-Fluoro-3-methoxybiphenyl-4-yl)-2-methyl-2-(methylsulfonyl)-N- (tetrahydro-2H-pyran-2-yloxy)butanamide was converted to the title compound following the general procedure outlined for (+/-)-4-(4-bromophenyl)-N-hydroxy-2- methyl-2-(methylsulfonyl)butanamide as described in Preparation 2, Step 5. The title compound was obtained as a white solid (364 mg, 69%) LC-MS m/z 396.5 (M+1 ). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1 .65 (s, 3 H) 2.00 - 2.16 (m, 1 H) 2.38 - 2.60 (m, 2 H) 2.72 - 2.89 (m, 1 H) 3.05 (s, 3 H) 3.91 (s, 3 H) 7.07 - 7.25 (m, 5 H) 7.55 - 7.65 (m, 2 H).
Example 19
(+/-)-4-(4'-Fluoro-3-hvdroxybiphenyl-4-yl)-N-hvdroxy-2-methyl-2- (methylsulfonyl)butanamide
Figure imgf000074_0001
Step A: (+/-)-4-(4'-Fluoro-3-hvdroxybiphenyl-4-yl)-N-hvdroxy-2-methyl-2- (methylsulfonyl)butanamide
Boron tribromide (750 ul, 0.75 mmol, 1.0 M in dichloromethane) was added to a solution of (+/-)-4-(4'-fluoro-3-methoxybiphenyl-4-yl)-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide prepared as in Example 18 (154 mg, 0.389 mmol) in dichloromethane (10 mL) at 0°C. The reaction was allowed to warm to rt and stirred until complete, then was diluted with water (60 mL) and extracted with ethyl acetate (3x 60mL). The combined organics were dried (MgS04), filtered and concentrated in vacuo. The solid was dissolved in 1 N aqueous NaOH (60mL), washed with ethyl acetate (3x 80mL), acidified using 1 N aqueous HCI, and extracted with ethyl acetate (3x 100mL). The combined organics were dried (MgS04), filtered, and concentrated in vacuo to afford the title compound as an off-white solid (25.4 mg, 17.1 %). LC-MS m/z 382.5(M+1 ). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.68 (s, 3 H) 2.12 - 2.23 (m, 1 H) 2.41 - 2.55 (m, 2 H) 2.74 - 2.90 (m, 1 H) 3.07 (s, 3 H) 6.97 - 7.03 (m, 2 H) 7.10 - 7.20 (m, 3 H) 7.53 - 7.60 (m, 2 H).
Example 20
4-(4'-Fluoro-2-methoxybiphenyl-4-yl)-N-hvdroxy-2-methyl-2-(methylsulfonyl)butanamide
Figure imgf000074_0002
Step A: 4'-Fluoro-4-(2-iodoethyl)-2-methoxybiphenyl
The title compound (549mg, 74.5%) was prepared from 2-(4'-fluoro-2- methoxybiphenyl-4-yl)ethanol (which may be made as described in Preparation Number 5) following the general procedure described in Preparation 2, Step 1 for 1 -bromo-4-(2- iodoethyl)benzene. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.1 1 (t, J=8.00 Hz, 2 H) 3.33 (t, J=7.81 Hz, 2 H) 3.90 (s, 3 H) 6.66 - 6.73 (m, 4 H) 6.87 (d, J=8.59 Hz, 2 H) 7.27 (s, 1 H).
Step B: Ethyl 4-(4'-fluoro-2-methoxybiphenyl-4-yl)-2-(methylsulfonyl)butanoate
The title compound (450mg, 1 15%) containing minor solvent impurities was prepared as described in Preparation 2, Step 2, for the formation of compound (I) except that 4'-fluoro-4-(2-iodoethyl)-2-methoxybiphenyl was used. 1 H NMR (400 MHz, METHANOL-d4) δ ppm 2.33 - 2.51 (m, 3 H) 2.71 - 2.91 (m, 3 H) 3.07 (s, 3 H) 3.83 (s, 3 H) 3.97 - 4.06 (m, 1 H) 4.16 - 4.33 (m, 3 H) 6.90 - 6.94 (m, 1 H) 6.98 (s, 1 H) 7.27 (d, J=7.42 Hz, 1 H) 7.64 - 7.70 (m, 2 H) 7.70 - 7.75 (m, 2 H).
Step C: 4-(4'-Fluoro-2-methoxybiphenyl-4-yl)-N-hvdroxy-2-methyl-2- (methylsulfonyl)butanamide
Lithium hydroxide (44.7mg, 1.06mmol) was added to a stirred solution of ethyl 4- (4'-fluoro-2-methoxybiphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanoate (435mg,
1.06mmol) in THF:MeOH:Water (2:2:1 , 10mL) at 0° C. The reaction was warmed to room temperature as the ice bath expired. After 18 hours the reaction was acidified to pH 4 with 1 N HCI (aq) and extracted with ethyl acetate (2x). The organic layers were combined, dried (Na2S04) and concentrated in vacuo to give a white solid (300mg). The solid obtained was taken up in DCM (15mL) at ambient temperature under a nitrogen atmosphere. To this solution was added oxalyl chloride (72uL, 0.797mmol) followed by 1 drop of DMF. Immediate effervescence occurred. TMSO-hydroxylamine (287uL, 2.38mmol) was added to the solution after five minutes resulting in the formation of a white solid. The reaction mixture was allowed to stir for an additional 60 minutes before methanol (10mL) was added. The white solids were taken up in EtOAc (100mL) and washed with water (75mL). The aqueous phase was extracted with EtOAc, (40mL). The combined organics were dried over Na2S04, filtered and concentrated in vacuo to furnish a pale yellow solid. The crude material was purified by chromatography on silica gel (100% dichloromethane to 97:3 DCM: MeOH) to yield the title compound as an off white solid (1 10mg, 35.3%). MS (LC/MS) m/z 396.2 (M+1 ).1 H NMR (400 MHz, METHANOL-d4) δ ppm 1 .67 (s, 3 H) 2.04 - 2.17 (m, 1 H) 2.48 - 2.66 (m, 2 H) 2.70 - 2.83 (m, 1 H) 3.05 (s, 3 H) 3.80 (s, 3 H) 6.89 (dd, J=7.81 , 1 .56 Hz, 1 H) 6.95 (s, 1 H) 7.01 - 7.12 (m, 2 H) 7.19 (d, J=7.42 Hz, 1 H) 7.41 - 7.50 (m, 2 H).
Example 21
4-(4'-Fluoro-2-hvdroxybiphenyl-4-yl)-N-hvdroxy-2-methyl-2-(methylsulfonyl)bu
Figure imgf000076_0001
Step A: 4-(4'-Fluoro-2-hvdroxybiphenyl-4-yl)-N-hvdroxy-2-methyl-2- (methylsulfonyl)butanamide
To a solution of the product of Example 20 (82mg, 0.21 mmol) in dichloromethane (2.0ml_) under external ice cooling and a nitrogen atmosphere was added a 1.0M solution of boron tribromide in dichloromethane (0.42ml_, 0.42mmol). The reaction mixture formed a precipitate after several minutes and was stirred for two hours under ice cooling. The reaction mixture was quenched with water 50ml_ and extracted with ethyl acetate (100ml_). The organics were washed with brine 80ml_, dried over Na2S04, filtered and concentrated in vacuo to furnish 80mg of a clear oil. The residue was treated with approx 2:1 Et20:IPA (6ml_) to attempt a trituration. However, the material was soluble; therefore, an equal portion of heptanes was added and the solution was concentrated in vacuo to 3-4 mL and a fine precipitate formed. An additional 1-2ml_ of heptanes were added then the mixture was left to triturate overnight. The solids were collected via filtration to furnish the title compound as a white solid (69mg, 87%). MS (LC/MS) m/z 382.3 (M+1 ).
Example 22
(+/-)-N-hvdroxy-4-[4-(2H-indazol-2- l)phenyll-2-methyl-2-(methylsulfonyl)butanamide
Figure imgf000076_0002
Step A: Tert-Butyl r4-(2-hvdroxyethyl)phenyl1carbamate
Triethylamine (30 mL, 220 mmol) was added to a solution of 2-(4- aminophenyl)ethanol (26.62 g, 194 mmol) in 1 ,4-dioxane (200 mL) followed by the addition of di-tert-butyl dicarbonate (50 g, 230 mmol). The reaction was stirred overnight at room temperature under nitrogen. The reaction was concentrated, dissolved in ethyl acetate (500 mL), washed with water (3x100 mL) and brine (100 mL), dried (MgS04), filtered and concentrated in vacuo to afford a crude white solid. A portion of the crude white solid (10.64 g) was purified via flash chromatography using an Analogix SF40-150g column and an eluant of ethyl acetate in heptane (30-60%) to afford the title compound as a white solid (6.45 g). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.52 (s, 9 H) 2.72 - 2.83 (m, 2 H) 3.68 - 3.77 (m, 2 H) 7.05 - 7.24 (m, 2 H) 7.25 - 7.44 (m, 2 H).
Step B: tert-Butyl [4-(2-iodoethyl)phenyllcarbamate
tert-Butyl [4-(2-hydroxyethyl)phenyl]carbamate (6.45 g, 27.18 mmol) in dichloromethane (20 mL) was added drop-wise to a solution of imidazole (2.04 g, 30.0 mmol), triphenylphosphine (8.60 g, 32.8 mmol), and iodine (8.28 g, 32.6 mmol) in dichloromethane (80 mL) at 0°C. The reaction was allowed to warm to rt and was stirred overnight at room temperature. The reaction was cooled to 0°C and quenched with water (100 mL). The organic layer was separated, washed with saturated aqueous sodium thiosulfate (100 mL), water (100 mL), and brine (100 mL). The organics were dried (MgS04), filtered, and concentrated in vacuo. The crude product was purified via flash chromatography using an Analogix SF40-150g column eluting with 30% EtOAc in heptane to afford the title compound as a white solid (8.16 g, 86.5%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.52 (s, 9 H) 3.13 (t, J=8.00 Hz, 2 H) 3.27 - 3.35 (m, 2 H) 7.12 (d, J=8.59 Hz, 2 H) 7.32 (d, J=8.59 Hz, 2 H).
Step C: (+/-)-Ethyl 4-{4-r(tert-butoxycarbonyl)aminolphenyl}-2-methyl-2- (methylsulfonyl)butanoate
tert-Butyl [4-(2-iodoethyl)phenyl]carbamate was converted to the title compound following the general procedure described in Step 2, of Preparation 2, for the formation of compound (I). The title compound was afforded as a white solid (6.47 g, 75.8%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1 .36 (t, J=7.22 Hz, 3 H) 1.54 (s, 9 H) 1.71 (s, 3 H) 2.13 - 2.25 (m, 1 H) 2.40 - 2.54 (m, 2 H) 2.64 - 2.79 (m, 1 H) 3.05 (s, 3 H) 4.25 - 4.32 (m, 2 H) 7.1 1 (m, J=8.39 Hz, 2 H) 7.29 (d, J=8.59 Hz, 2 H). Step D: (+/-) -Ethyl 4-(4-aminophenyl)-2-methyl-2-(methylsulfonyl)butanoate
Trifluoroacetic acid (50 mL, 650 mmol) was added to a solution of (+/-)-ethyl 4-{4- [(tert-butoxycarbonyl)amino]phenyl}-2-methyl-2-(methylsulfonyl)butanoate (6.47 g, 16.2 mmol) in dicholoromethane (100 mL) at 0°C. The reaction was allowed to warm to room temperature and was stirred for 2 hours. The reaction was then concentrated; the residue was dissolved in 1 N aqueous HCI (100 mL) and washed with ethyl acetate (3x100 mL). The organic layers were discarded. The aqueous layer was made basic with 1 N aqueous NaOH, and extracted with ethyl acetate (3x100 mL). The combined organics were washed with water (100 mL), brine (100 mL), dried (MgS04), filtered, and concentrated in vacuo to afford a crude orange oil. The crude product was purified via flash chromatography using an Analogix SF40-150g column and an eluant of ethyl acetate in heptane (1 :1 ) to afford the title compound as a yellow oil (3.52 g, 72.6%). LC-MS m/z 300.5(M+1 ). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1 .55 (t, J=7.13 Hz, 3 H) 1.88 (s, 3 H) 2.24 - 2.39 (m, 1 H) 2.56 - 2.77 (m, 2 H) 2.84 - 2.98 (m, 1 H) 3.31 (s, 3 H) 4.42 - 4.49 (m, 2 H) 6.91 (d, J=8.40 Hz, 2 H) 7.19 (d, J=8.40 Hz, 2 H).
Step E: (+/-VEthyl 2-methyl-2-(methylsulfonylV4-(4-{rn EH2-nitrophenvn
methylenelamino}phenyl)butanoate
A solution of 2-nitrobenzaldehyde (555 mg, 3.67 mmol) and (+/-)-ethyl 4-(4- aminophenyl)-2-methyl-2-(methylsulfonyl)butanoate (1.10 g 3.67 mmol) was stirred at reflux in ethanol for 2 hours. The reaction was concentrated in vacuo to afford a crude orange oil. The crude product was purified via flash chromatography using an Analogix SF25-40g column and eluted with ethyl acetate in heptane (20-50%) to afford the title compound as a yellow oil (1.31 g, 82.4%). LC-MS m/z 433.6 (M+1 ). 1H NMR (400
MHz, CHLOROFORM-d) δ ppm 1.37 (t, J=7.12 Hz, 3 H) 1.53 (s, 3 H) 2.18 - 2.32 (m, 1 H) 2.48 - 2.65 (m, 2 H) 2.76 - 2.89 (m, 1 H) 3.07 (s, 3 H) 4.27 - 4.33 (m, 1 H) 7.13 - 7.40 (m, 4 H) 7.60 - 7.68 (m, 1 H) 7.75 (t, J=7.42 Hz, 1 H) 8.05 - 8.13 (m, 1 H) 8.27 - 8.36 (m, 1 H) 8.95 (s, 1 H).
Step F: (+/-)-Ethyl 4-r4-(2H-indazol-2-yl)phenyll-2-methyl-2-(methylsulfonyl)butanoate
(+/-)-Ethyl-2-methyl-2-(methylsulfonyl)-4-(4-{[(1 E)-(2-nitrophenyl)methylene] amino}phenyl) butanoate (912 mg, 2.1 1 mmol) was added to a solution of triethyl phosphite (10mL) and the solution was refluxed overnight at 160°C under nitrogen. The reaction was concentrated in vacuo and the residue was dissolved in ethyl acetate (50mL) and washed with water (3x 50mL). The organic layer was dried (MgS04), filtered and concentrated in vacuo. The crude product was purified via flash
chromatography using an Analogix SF15-24g column and an eluant of 30% ethyl acetate in heptane to afford the title compound as a yellowish-white solid coded (499.5 mg, 56.7%). LC-MS m/z 401.5 (M+1 ). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.37 (t, J=7.03 Hz, 3 H) 1.57 (s, 3 H) 2.20 - 2.35 (m, 1 H) 2.47 - 2.69 (m, 2 H) 2.78 - 2.92 (m, 1 H) 3.05 - 3.10 (m, 3 H) 4.24 - 4.40 (m, 2 H) 7.08 - 7.17 (m, 1 H) 7.31 - 7.40 (m, 3 H) 7.69 - 7.75 (m, 1 H) 7.76 - 7.82 (m, 1 H) 7.83 - 7.89 (m, 2 H) 8.41 (d, J=0.98 Hz, 1 H). Step G: (+/-)-4-r4-(2H-lndazol-2-yl)phenyll-2-methyl-2-(methylsulfonyl)butanoic acid (+/-)-Ethyl 4-[4-(2H-indazol-2-yl)phenyl]-2-methyl-2-(methylsulfonyl)butanoate was converted to the title compound following the general procedure described in Step 3, Preparation 2, for the formation of compound (II) using potassium hydroxide in place of lithium hydroxide.
The title compound was obtained as a white solid (379 mg, 84.9%). LC-MS m/z
373.5 (M+1 ). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (s, 0 H) 2.02 - 2.16 (m, 0 H) 2.40 - 2.60 (m, 2 H) 2.79 - 2.92 (m, 1 H) 3.14 (s, 3 H) 7.07 - 7.15 (m, 1 H) 7.28 - 7.36 (m, 1 H) 7.46 (d, J=8.59 Hz, 2 H) 7.68 - 7.81 (m, 2 H) 8.03 (d, J=8.59 Hz, 2 H) 9.08 (d, J=0.78 Hz, 1 H).
Step H: (+/-)-4-r4-(2H-indazol-2-yl)phenyll-2-methyl-2-(methylsulfonyl)-N-(tetrahvdro- 2H-pyran-2-yloxy)butanamide
(+/-)-4-[4-(2H-lndazol-2-yl)phenyl]-2-methyl-2-(methylsulfonyl)butanoic acid was converted to the title compound following the general procedure described in step 4 of Preparation 2, for the preparation of compound (III) using N,N- diisopropylethylamine in place of triethylamine. The title compound was obtained as a white solid (437 mg, 87.6%) LC-MS m/z 472.7(M+1 ).
Step I: (+/-)-N-hvdroxy-4-r4-(2H-indazol-2-yl)phenyll-2-methyl-2-(methylsulfonyl) butanamide
(+/.)-4-[4-(2H-indazol-2-yl)phenyl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H- pyran-2-yloxy)butanamide was converted to the title compound following an analogous procedure as described for the preparation of Example 1 1 , Step D. The title compound was obtained as a white solid (232 mg, 64.6%) LC-MS m/z 388.5 (M+1 ). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.69 (s, 3 H) 2.06 - 2.21 (m, 1 H) 2.54 - 2.69 (m, 2 H) 2.76 - 2.91 (m, 1 H) 3.07 (s, 3 H) 7.10 - 7.18 (m, 1 H) 7.32 - 7.39 (m, 1 H) 7.48 (d, J=8.79 Hz, 2 H) 7.67 - 7.72 (m, 1 H) 7.74 - 7.81 (m, 1 H) 7.90 (d, J=8.79 Hz, 2 H) 8.75 (d, J=0.98
Hz, 1 H).
Example 23
(2R)-N-hvdroxy-4-(4'-hvdroxybiphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanam
Figure imgf000080_0001
Step A: (2R)-2-Methyl-2-(methylsulfonyl)-N-(tetrahvdro-2H-pyran-2-yloxy)-4-r4'- (tetrahvdro-2H-pyran-2-yloxy)biphenyl-4-yllbutanamide
Palladium (II) EnCat (575mg, 0.22mmol) was added to a mixture of potassium carbonate (892mg, 3.1 mmol), (2R)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran- 2-yloxy)-4-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]butanamide (1 .01 g, 2.1 mmol), ( i.e. compound Vila, which was prepared as in Preparation 8) and 2-(4- bromophenoxy)tetrahydro-2H-pyran (819mg, 3.18 mmol) in dioxane:water (20mL, 1 :1 ) in a 50ml_ flask and the reaction was heated at 90°C overnight. The reaction was filtered and the resin was washed with ethyl acetate (50ml_) and water (50ml_). The organic layer was separated and aqueous layer extracted with ethyl acetate (2x
100ml_). The combined organics were washed with saturated aqueous sodium bicarbonate (100ml_), dried (MgS04), filtered and concentrated in vacuo to furnish the crude product. The material was dissolved in a minimum amount of DCM and loaded onto an Analogix SF25-40g column and eluted with 100% heptane (500ml_) followed by increasing EtOAc in heptane 20%-30%-50% over 500ml_ volumes. The title compound was obtained as a white solid (830 mg, 74.4%) LC-MS m/z 530.8 (M-1 ).
Step B: (2R)-N-Hvdroxy-4-(4'-hvdroxybiphenyl-4-yl)-2-methyl-2-(methylsulfonyl) butanamide
(2R)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)-4-[4'- (tetrahydro-2H-pyran-2-yloxy)biphenyl-4-yl]butanamide was converted to the title compound following the method described for the preparation of Example 1 1 , step D. The title compound was obtained as an off-white solid (522.3 mg, 63.2%). LC-MS m/z 386.5 (M+Na+1 ). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55 (s, 3 H) 1.82 - 1.99 (m, 1 H) 2.29 - 2.47 (m, 2 H) 2.59 - 2.72 (m, 1 H) 3.04 (s, 3 H) 6.83 (d, 2 H) 7.26 (d, J=8.20 Hz, 2 H) 7.39 - 7.59 (m, 4 H).
Example 24
4-(4'-Fluorobiphen -4-yl)-N-hvdroxy-2-(methylsulfonyl)butanamide
Figure imgf000081_0001
Step A: 2-(4'-Fluorobiphenyl-4-yl)ethanol
To a 2-5ml_ microwave vial was added 2-(4-bromophenyl)ethanol (603 mg, 3.0mmol), (4-fluorophenyl)boronic acid (462 mg, 3.3 mmol), sodium carbonate (973mg, 9.0mmol), palladium acetate (33.7mg, 0.15mmol),1 ,4 dioxane (4.5ml_) and water (4.5ml_). The mixture was irradiated in a CEN microwave at 120°C for 10 minutes. The reaction mixture was biphasic upon reaction completion. The reaction mixture was extracted into ethyl acetate (2x150ml_) dried over Na2S04 then filtered through a pad of celite. The organics were concentrated in vacuo and the crude material was purified by chromatography on silica gel (gradient: 70:30 heptanes: EtOAc). Isolated material still contained 2-(4-bromophenyl)ethanol, therefore, the material was triturated in heptanes to furnish the title compound as a white solid. (430mg, 45%).
1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.84 (t, J=6.44 Hz, 1 H) 2.93 (t, J=6.44 Hz, 1 H) 3.86 (t, J=6.44 Hz, 1 H) 3.92 (t, J=6.65 Hz, 1 H) 7.07 - 7.19 (m, 3 H) 7.32 (d, J=7.89 Hz, 1 H) 7.45 (d, J=8.31 Hz, 1 H) 7.48 - 7.58 (m, 3 H)
Step B: 4-Fluoro-4'-(2-iodoethyl)biphenyl
The title compound (650mg, 100%) was prepared following the general procedure of step 1 , Preparation 2, outlined for 1-bromo-4-(2-iodoethyl)benzene except that 2-(4'-fluorobiphenyl-4-yl)ethanol (430mg, 1.99mmol) was used in place of 2-(4- bromophenyl)ethanol. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.23 (t, J=7.69 Hz, 2 H) 3.39 (t, J=7.69 Hz, 2 H) 7.13 (t, J=8.72 Hz, 2 H) 7.24 - 7.30 (m, 2 H) 7.48 - 7.58 (m, 4 H). Step C: Ethyl 4-(4'-fluorobiphenyl-4-yl)-2-(methylsulfonyl)butanoate
A mixture of ethyl(methylsulphonyl) acetate (330 mg, 1.99 mmol) in 4 mL of DMF was treated with sodium hydride (88 mg, 60% dispersion in mineral oil, 2.19 mmol), until effervescence ceased in an ice bath under nitrogen. To this was added 4-fluoro-4'-(2- iodoethyl)biphenyl (650 mg, 1.99 mmol) as a solid and the residual material was dissolved by the addition of DMF (2 mL). The mixture was warmed to room
temperature, then heated at 50°C for 2 hours. The mixture was then cooled to room temperature, poured into 60 mL of 0.5N aqueous HCI and extracted 2x60 mL with ethyl acetate. The organic phase was dried over sodium sulfate filtered and concentrated in vacuo to yield a light yellow oil with some white solid particulates. The crude yield was 840 mg. The material was purified by flash chromatography on a 40 mm flash column using 120 g silica gel eluting with 0-50% ethyl acetate/heptane. This afforded the title compound as an oil (510 mg, 70.2%). MS (LC/MS) m/z 365.2 (M+1 ).
1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1 .29 - 1.42 (m, 3 H) 2.33 - 2.55 (m, 2 H) 2.64 - 2.78 (m, 1 H) 2.78 - 2.91 (m, 1 H) 3.01 (s, 3 H) 3.79 (dd, J=10.39, 4.15 Hz, 1 H) 4.17 - 4.40 (m, 2 H) 7.09 - 7.17 (m, 2 H) 7.25 (d, J=7.89 Hz, 2 H) 7.47 - 7.57 (m, 4 H).
Step D: 4-(4'-Fluorobiphenyl-4-yl)-2-(methylsulfonyl)butanoic acid
To a solution of ethyl 4-(4'-fluorobiphenyl-4-yl)-2-(methylsulfonyl)butanoate in THF (2.2 mL) and methanol (0.6 mL) was added a solution of lithium hydroxide in water (37 mg, 1.54 mmol, 0.6 mL water) and stirred at room temperature for 30 minutes. The mixture was diluted with water (30 mL) and washed with Et20 50 mL. The organic layer was discarded. The aqueous layer was acidified with 0.5N HCI and the white suspension was re-extracted with Et20. The ether extract was washed with brine 50mL, dried over Na2S04, filtered and concentrated in vacuo to afford the title compound as a white solid (1 13 mg, 87.5%) MS (LC/MS) m/z 335.1 (M-1 )
1 H NMR (400 MHz, METHANOL-d4) δ ppm 2.31 - 2.41 (m, 2 H) 2.68 - 2.79 (m, 1 H) 2.82 - 2.92 (m, 1 H) 3.08 (s, 3 H) 3.89 - 3.96 (m, 1 H) 7.15 (t, J=8.72 Hz, 2 H) 7.31 (d, J=7.89 Hz, 2 H) 7.54 (d, J=8.31 Hz, 2 H) 7.58 - 7.64 (m, 2 H).
Step E: 4-(4'-Fluorobiphenyl-4-yl)-N-hvdroxy-2-(methylsulfonyl)butanamide
To a solution of 4-(4'-fluorobiphenyl-4-yl)-2-(methylsulfonyl)butanoic acid (1 13 mg, 0.336 mmol) in dichloromethane (1.8 mL) at ambient temperature under a nitrogen atmosphere was added a solution of oxalyl chloride (319 uL, 0.638 mmol) in dichloromethane (1.8 mL) followed by 1 drop of DMF. Immediate effervescence occurred. TMSO-hydroxylamine (89 ul, 0.739 mmol) was added to the solution after 5 minutes resulting in the formation of a white solid. 1 mL of MeOH was added to the reaction and the mixture was concentrated to dryness. The white solids were taken up in EtOAc (100 mL) and washed with water (75 mL). The aqueous phase was extracted with EtOAc (40 mL). The combined organics were dried over Na2S04, filtered and concentrated in vacuo to furnish an off white solid. This material was triturated with diethyl ether overnight. The solid was collected via filtration and was washed with additional diethyl ether to furnish the title compound as a white solid (77 mg, 65%) MS (LC/MS) m/z 352.1 (M+1 ).
Example 25
N-Hvdroxy-2-methyl-2-(methylsulfonyl)-4-r4-(phenoxymethyl)phenyllbutanamide
Figure imgf000083_0001
Step A: 2-r4-(Phenoxymethyl)phenyllethanol
To a flask containing [4-(phenoxymethyl)phenyl]acetic acid (1 .0g, 4.13 mmol), in THF (20 mL) under external ice cooling was added a 1.0M sol of LiAIH4 in THF (8.3 mL, 8.3 mmol) (effervescence noted). The reaction mixture was stirred for three hours under ice cooling, then allowed to stir at room temperature for 48 hours. The reaction mixture was quenched with water (4.1 mL) and 1 N NaOH (24 mL) then extracted into EtOAc (200mL). The organic layer was washed with brine (150 mL). The organics were dried over Na2S04, filtered and concentrated in vacuo to furnish 1.64 g of the title compound as a white solid (174%), containing aluminum salt impurities. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.90 (t, J=6.64 Hz, 2 H) 3.88 (t, J=6.44 Hz, 2 H) 5.05 (s, 2 H) 6.93 - 7.02 (m, 3 H) 7.22 - 7.36 (m, 4 H) 7.40 (d, J=8.20 Hz, 2 H).
Step B: 1-(2-lodoethyl)-4-(phenoxymethyl)benzene
2-[4-(Phenoxymethyl)phenyl]ethanol was converted to the title compound (960 mg, 68.7%) following the general procedure of Step 1 , outlined in Preparation 2. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.13 - 3.23 (m, 2 H) 3.31 - 3.39 (m, 2 H) 5.05 (s, 2 H) 6.95 - 7.01 (m, 3 H) 7.23 (d, J=8.20 Hz, 2 H) 7.28 - 7.36 (m, 2 H) 7.41 (d, J=8.20 Hz, 2 H).
Step C: Ethyl 2-methyl-2-(methylsulfonyl)-4-r4-(phenoxymethyl)phenyllbutanoate
1-(2-lodoethyl)-4-(phenoxymethyl)benzene (960mg, 2.84mmol) and ethyl 2-
(methylsulfonyl)propanoate (512mg, 2.84mmol) were converted to the title compound (1.17g, 106%) containing minor solvent impurities following the general procedure of step 2 in Preparation 2 for the formation of compound (I). 1 H NMR (400 MHz,
CHLOROFORM-d) δ ppm 1 .22 - 1.31 (m, 3 H) 1.68 - 1.75 (m, 3 H) 2.16 - 2.27 (m, 1 H) 2.45 - 2.59 (m, 2 H) 2.69 - 2.85 (m, 1 H) 2.89 (s, 3 H) 4.21 - 4.33 (m, 2 H) 5.01 - 5.09 (m, 2 H) 6.94 - 7.01 (m, 2 H) 7.21 (d, J=8.20 Hz, 1 H) 7.26 - 7.33 (m, 4 H) 7.36 - 7.46 (m, 2 H).
Step D: 2-Methyl-2-(methylsulfonyl)-4-r4-(phenoxymethyl)phenyllbutanoic acid
The title compound (247 mg, 24%) was prepared from ethyl 2-methyl-2- (methylsulfonyl)-4-[4-(phenoxymethyl)phenyl]butanoate (1.1 g, 2.8 mmol) following the general procedure of step 3, from Preparation 2, for the formation of compound (II). MS (LC/MS) m/z 361 .2 (M-1 ).1 H NMR (400 MHz, METHANOL-d4) δ ppm 1.62 - 1.69 (m, 3 H) 2.06 - 2.18 (m, 1 H) 2.42 - 2.65 (m, 2 H) 2.74 - 2.86 (m, 1 H) 3.10 (s, 3 H) 5.04 (s, 2 H) 6.91 (t, J=7.42 Hz, 1 H) 6.97 (d, J=7.81 Hz, 2 H) 7.22 - 7.29 (m, 4 H) 7.37 (d, J=8.20 Hz, 2 H).
Step E: N-hvdroxy-2-methyl-2-(methylsulfonyl)-4-r4-(phenoxymethyl)phenyllbutanamide
2-Methyl-2-(methylsulfonyl)-4-[4-(phenoxymethyl)phenyl]butanoic acid (245 mg, 0.676 mmol) was converted to the title compound (249 mg, 97.6%) following the method described for 4-(4'-fluorobiphenyl-4-yl)-N-hydroxy-2-(methylsulfonyl)butanamide in Step D, of Example H . MS (LC/MS) m/z 378.1 (M+1 ).
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 lethal 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 specific protocols are described below:
A) ICgn assay, LpxC enzyme from P. aeruginosa (labled as PA LpxC enzyme IC½):
IC50 determination 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-3-0-(R-3- hydroxymyristoyl)-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//-overexpressing bacteria was incubated at 25°C in a final volume of 50 ul containing 0.5 uM UDP-3-0-(R-3- hydroxydecanoyl)-N-acetylglucosamine, 1 mg/mL BSA, and 50mM sodium phosphate buffer, pH 8.0 in the presence and absence of inhibitor compound. At the end of 1 hour, 5ul of 1 N HCI was added to stop the enzyme reaction; the plates were centrifuged, and then processed with the BioTrove Rapidfire HTMS Mass Spectrometry System. A no- enzyme control was used in calculating the IC50 values from the percent conversion values.
B) MIC determinations: 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, formerly NCCLS) guidelines. See: Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved
Standard-Seventh Edition. CLSI document M7-A7 [ISBN 1-56238-587-9]. 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; Eighteenth
Informational Supplement. CLSI document M100-S18 [ISBN1-56238-653-0]. Clinical and Laboratory Standards Institute.
The following bacterial strains were used in these MIC determinations:
1 ) Pseudomonas aeruginosa UI-18: Wild-type, labeled as PA-7 in Tables 1 , 2 and 3;
2) Acinetobacter baumanii/haemolyticus: Multidrug-resistant clinical isolate labeled as AB-3167 in Tables 1 , 2 and 3;
3) Escherichia coli EC-1 : VOGEL, mouse virulent labeled as EC-1 in Tables 1 , 2 and 3; 4) Klebsiella pneumoniae: Ciprofloxacin-resistant isolate, expresses extended- spectrum beta-lactamases (ESBL), clinical isolate, labeled as KP-3700 in Tables 1, 2, and 3.
The following results were obtained with the final products described in Examples 1-25:
TABLE 1
Example Number PA LpxC AB-3167 EC-1: KP-3700 PA-7
enzyeme
IC50 uM
Example 1 0.00168 16 2 8 4
Example 2 0.00026 16 1 4 1
Example 3 >64 16 >64 16
Example 4 >64 16 >64 8
Example 5 0.00012 32 0.5 1 0.5
Example 6 0.0881 >64 >64 >64 >64
Example 7 0.00031 16 0.5 2 0.5
and
0.00047
Example 8 >64 >64 >64 8 Example 9 0.00032 32 0.125 4 2
Example 10 32 16 32 8
Example 11 >64 >64 >64 16
Example 12 0.0119 8 8 32 8
Example 13 0.00029 0.5 2 4 1
Example 14 0.00148 >64 16 >64 32
Example 15 32 16 >64 4
Example 16 0.00501 >64 >64 >64 16
Example 17 0.00136 32 32 >64 8
Example 18 0.00063 16 4 16 4
Example 19 0.00343 >64 8 32 16 Example 20 > 64 1 8 16
Example 21 0.0154 > 64 16 > 64 16
Example 22 > 64 4 8 4
Example 23 0.00018 > 64 4 8 2
Example 24 32 32 32 1
Example 25 0.00238 16 4 16 8
Examples 26 - 234
In addition to the Examples above, a number of compounds were generated via combinatorial chemistry. Table 2 below lists these compounds by name, provides characterization data such as liquid chromatography-mass spectrometry and retention times. Table 2 also provides selected biological data using the same protocols as described above for Examples 1 -25.
The compounds described below in Table 2 form a subset of those described by Formula I. In all of these compounds R1 and R2 are methyl, X is CH2, A is unsubstituted phenyl, L is absent, D forms an aryl or heteroaryl ring, and both G and T may be absent or present and are as defined above in Formula I.
These compounds were generally produced in the following manner. (+/-)-4-(4- Bromophenyl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (1 OOmg, 0.266mmol (1 eq)), which may be produced as in Preparation 2, was combined with an appropriately substituted boronic derivative, i.e. a G-T-D moiety corresponding to the desired final product, (( 0.404mmol) (1.5eq)) into a 2-5ml_ microwave vial followed by the addition of a catalytic amount of Palladium (II) EnCat catalyst (approx 10mol%), potassium carbonate (1 ml_ of 0.123M in water (-3 eq) and 1 ml. of dioxane. The microwave vial was sealed and irradiated at 120°C for 40 minutes. The reaction was filtered through a thin pad of celite and rinsed with ethyl acetate (2-5ml_). The solvents removed via Genevac, followed by a DMSO dilution (approx 100mg/ml_) and transferred to a 96 well plate for purification. The material was purified via reverse phase HPLC methods and purity determined by HPLC with a corresponding retention time HPLC Method: (UPLC 0.05% TFA 95% 5% to 5% 95% Water Acetonitrile). A few of the compounds below in Table 2 were produced individually, not by combinatorial methods, but the teachings above could be used to generate the compound.
In Table 2 below, column 2 provides the lUPAC name; column's 3-7 provide in-vitro biological data, column 8 reports the mass spectrometry data generated via LCMS and column 9 reports LCMS retention times. The in-vitro data in column's 3-7 was generated in the same manner as that described in Table I above. The LCMS retention times (LCMS-RT) reported in column 9 were generated in the following manner:
1 ) Acidic-labelled as "a in column 9
Gradients:
0.05% TFA 95_5 to 5_95 Water_ACN
Flow rate: 1.3mL/min
Column dimensions: Acquity UPLC BEH C18 1.7μηι 2.1x30mm.
Run time: 1.1 minutes
2) Basic- labelled as "b in column 9
Gradients:
Solvent A: 0.06%NH4OH (in water)
Solvent B: 0.06%NH4OH (in acetonitrile)
Time (min) %A %B
0 95 5
0.4 95 5
3.2 5 95
3.5 5 95
4.0 95 5
Flow rate: 2mL/min
Column dimensions: Not currently available
Run time: 4 minutes LCMS data and retention times were not available for all compounds. This could be due to errors in computation, inability to locate data, errors in methodology,
machinery failure etc. ("na" in column's 8 or 9 means that such data is not available).
TABLE 2
Example lUPACNAME PA LpxC AB- EC-1 KP- PA-7 LCMS LCMS Number enzyeme 3167 MIC 3700 MIC ELSD -RT
IC50 uM MIC MIC
26 4-biphenyl-4-yl-N-hydroxy-2-methyl-2- 4 4 8 1 100 na
(methylsulfonyl)butanamide
27 4-(4'-fluorobiphenyl-4-yl)-N-hydroxy-2-methyl-2- 8 2 4 1 73 1.65°
(methylsulfonyl)butanamide
28 4-(4'-cyanobiphenyl-4-yl)-N-hydroxy-2- >64 32 >64 2 100 1.27 °
(methylsulfonyl)butanamide
29 4-(4'-cyanobiphenyl-4-yl)-N-hydroxy-2-methyl-2- >64 1 2 1 100 1.32 °
(methylsulfonyl)butanamide
30 (2R)-4-(4'-fluorobiphenyl-4-yl)-N-hydroxy-2- 32 8 16 1 100 1.37D
(methylsulfonyl)butanamide
31 (2S)-4-(4'-fluorobiphenyl-4-yl)-N-hydroxy-2- >64 16 >64 2 100 1.37D
(methylsulfonyl)butanamide
32 4-(4-bromophenyl)-N-hydroxy-2-methyl-2- >64 32 >64 32 100 0.36a
(methylsulfonyl)butanamide
33 4-(3',4'-dimethoxybiphenyl-4-yl)-N-hydroxy-2- >64 16 32 16 100 0.42a methyl-2-(methylsulfonyl)butanamide
34 N-hydroxy-4-[4'-(2-hydroxyethyl)biphenyl-4-yl]- 0.000331 >64 4 8 4 100 0.35a
2-methyl-2-(methylsulfonyl)butanamide
35 4-{4-[6-(dimethylamino)pyridin-3-yl]phenyl}-N- >64 4 16 32 100 0.27a hydroxy-2-methyl-2-(methylsulfonyl)butanamide
36 4-biphenyl-4-yl-N-hydroxy-2- 32 16 16 2 na na
(methylsulfonyl)butanamide
37 4-{4-[6-(dimethylamino)-5-methylpyridin-3- >64 16 >64 16 na na yl]phenyl}-N-hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
38 4-(2',5'-difluorobiphenyl-4-yl)-N-hydroxy-2- 0.000752 16 2 32 1 100 0.44a methyl-2-(methylsulfonyl)butanamide
39 N-hydroxy-2-methyl-2-(methylsulfonyl)-4-[4-(2- >64 4 32 >64 94 0.32a morpholin-4-ylpyrimidin-5-yl)phenyl]butanamide
40 N-hydroxy-2-methyl-2-(methylsulfonyl)-4-[4'- na 16 0.5 2 2 na na
(methylthio)biphenyl-4-yllbutanamide
41 4-(2'-fluoro-6'-methoxybiphenyl-4-yl)-N-hydroxy- >64 16 >64 8 100 0.45a
2-methyl-2-(methylsulfonyl)butanamide
42 4-(3'-fluorobiphenyl-4-yl)-N-hydroxy-2-methyl-2- 0.000335 >64 2 4 0.5 na na
(methylsulfonyl)butanamide
43 N-hydroxy-4-(3'-isopropylbiphenyl-4-yl)-2- 4 4 16 8 100 0.53a methyl-2-(methylsulfonyl)butanamide
44 4-(4'-chlorobiphenyl-4-yl)-N-hydroxy-2-methyl- 6.69E-05 16 0.5 1 0.5 na na
2-(methylsulfonyl)butanamide
45 4-(4'-cyano-3'-fluorobiphenyl-4-yl)-N-hydroxy-2- >64 0.5 4 1 100 0.41a methyl-2-(methylsulfonyl)butanamide
46 N-hydroxy-2-methyl-2-(methylsulfonyl)-4-[4-(4- >64 2 4 2 na na methyl-2-thienyl)phenyllbutanamide
47 N-hydroxy-4-[4'-(3-hydroxypropyl)biphenyl-4-yl]- 0.000132 >64 0.5 2 1 100 0.37a
2-methyl-2-(methylsulfonyl)butanamide
48 4-(2',5'-dimethoxybiphenyl-4-yl)-N-hydroxy-2- 16 16 >64 >64 100 0.43a methyl-2-(methylsulfonyl)butanamide
49 N-hydroxy-4-(4'-isopropoxybiphenyl-4-yl)-2- 8 2 4 4 97 0.46a methyl-2-(methylsulfonyl)butanamide
50 4-(2'-fluorobiphenyl-4-yl)-N-hydroxy-2-methyl-2- 0.000731 16 2 8 0.5 95 1.45D
(methylsulfonyl)butanamide
51 N-hydroxy-4-(4'-hydroxybiphenyl-4-yl)-2-methyl- 0.000922 >64 16 16 2 100 0.33a
2-(methylsulfonyl)butanamide
52 4-(3',5'-dimethylbiphenyl-4-yl)-N-hydroxy-2- 8 2 4 2 100 0.47a methyl-2-(metnylsulfonyl)butanamide
53 4-(2',4'-difluorobiphenyl-4-yl)-N-hydroxy-2- 8 1 4 0.5 na na methyl-2-(methylsulfonyl)butanamide 4-(2',6'-difluorobiphenyl-4-yl)-N-hydroxy-2- 16 4 16 1 100 0.45a methyl-2-(methylsulfonyl)butanamide
N-hydroxy-4-(4'-methoxybiphenyl-4-yl)-2- 16 0.5 2 0.5 na na methyl-2-(methylsulfonyl)butanamide
N-hydroxy-2-methyl-2-(methylsulfonyl)-4-[3'- 0.000417 8 2 4 2 100 0.47a (methylthio)biphenyl-4-yllbutanamide
N-hydroxy-4-[4-(1 H-indol-5-yl)phenyl]-2-methyl- 0.000295 8 0.5 8 0.5 100 0.38a 2-(methylsulfonyl)butanamide
N-hydroxy-2-methyl-4-(2'-methylbiphenyl-4-yl)- 32 8 32 4 100 1.52° 2-(methylsulfonyl)butanamide
4-(2',3'-dichlorobiphenyl-4-yl)-N-hydroxy-2- 0.000213 2 0.5 2 2 100 0.52a methyl-2-(methylsulfonyl)butanamide
N-hydroxy-4-(4'-methoxy-2'-methylbiphenyl-4- >64 4 16 4 na na yl)-2-metnyl-2-(methylsulfonyl)butanamide
N-hydroxy-2-methyl-2-(methylsulfonyl)-4-(4- >64 >64 >64 16 100 0.21a pyridin-3-ylphenyl)butanamide
4-(2',3'-difluorobiphenyl-4-yl)-N-hydroxy-2- 0.000185 16 0.5 16 0.25 100 0.45a methyl-2-(methylsulfonyl)butanamide
N-hydroxy-4-(4'-isobutylbiphenyl-4-yl)-2-methyl- 0.000356 8 2 4 16 85 1.83d 2-(methylsulfonyl)butanamide
4-(3'-cyanobiphenyl-4-yl)-N-hydroxy-2-methyl-2- 0.000739 >64 4 8 2 100 0.4a (methylsulfonyl)butanamide
4-(2',4'-dimethoxybiphenyl-4-yl)-N-hydroxy-2- 32 1 2 2 na 0.41a methyl-2-(methylsulfonyl)butanamide
4-(3'-fluoro-4'-methoxybiphenyl-4-yl)-N-hydroxy- 16 1 8 1 99 0.44a 2-methyl-2-(methylsulfonyl)butanamide
N-hydroxy-4-(4'-methoxy-3'-methylbiphenyl-4- >64 4 8 16 100 0.25a yl)-2-methyl-2-(methylsulfonyl)butanamide
N-hydroxy-2-methyl-4-{4'- >64 32 32 4 100 0.33a
[(methylamino)sulfonyl]biphenyl-4-yl}-2-
(methylsulfonyl)butanamide
4-(2'-ethylbiphenyl-4-yl)-N-hydroxy-2-methyl-2- >64 16 >64 16 100 0.5a (methylsulfonyl)butanamide
4-(2',4'-dichlorobiphenyl-4-yl)-N-hydroxy-2- 32 1 2 1 100 0.52a methyl-2-(methylsulfonyl)butanamide
N-hydroxy-4-[4'-(1-methoxyethyl)biphenyl-4-yl]- 32 4 16 4 100 0.44a 2-methyl-2-(methylsulfonyl)butanamide
N-hydroxy-4-[4-(6-methoxypyridin-3-yl)phenyl]- >64 8 32 4 100 0.35a 2-methyl-2-(methylsulfonyl)butanamide
4-(2',5'-dimethylbiphenyl-4-yl)-N-hydroxy-2- 4 16 >64 32 100 0.5a methyl-2-(methylsulfonyl)butanamide
4-[4-(2,3-dihydro-1-benzofuran-5-yl)phenyl]-N- 16 1 4 1 100 0.42a hydroxy-2-methyl-2-(methylsulfonyl)butanamide
4-(3',4'-difluorobiphenyl-4-yl)-N-hydroxy-2- 8 1 4 0.5 100 0.46a methyl-2-(methylsulfonyl)butanamide
N-hydroxy-4-[4-(2-methoxypyridin-3-yl)phenyl]- >64 32 >64 16 100 0.38a 2-methyl-2-(methylsulfonyl)butanamide
N-hydroxy-2-methyl-2-(methylsulfonyl)-4-[4-(3- 0.000991 >64 8 16 2 100 0.42a thienyl)phenyl]butanamide
4-(2',3'-dimethylbiphenyl-4-yl)-N-hydroxy-2- 0.000444 >64 2 16 2 100 0.49a methyl-2-(methylsulfonyl)butanamide
N-hydroxy-2-methyl-2-(methylsulfonyl)-4-[4'- >64 32 >64 4 100 0.33a (methylsulfonyl)biphenyl-4-yllbutanamide
N-hydroxy-2-methyl-2-(methylsulfonyl)-4-(4- >64 8 32 8 100 0.38a pyrimidin-5-ylphenyl)butanamide
4-(2'-chlorobiphenyl-4-yl)-N-hydroxy-2-methyl- 0.000448 32 2 8 1 100 0.46a 2-(methylsulfonyl)butanamide
4-[4-(5-cyano-2-thienyl)phenyl]-N-hydroxy-2- 8 0.5 2 0.5 100 0.41a methyl-2-(methylsulfonyl)butanamide
4-(3',4'-dimethylbiphenyl-4-yl)-N-hydroxy-2- 0.000242 8 1 4 2 100 0.5a methyl-2-(methylsulfonyl)butanamide
N-hydroxy-4-[3'-(hydroxymethyl)biphenyl-4-yl]- >64 >64 >64 16 94 0.34a 2-methyl-2-(methylsulfonyl)butanamide
4'-[4-(hydroxyamino)-3-methyl-3- >64 32 >64 16 100 0.31a
(methylsulfonyl)-4-oxobutyl]-N-methylbiphenyl-
4-carboxamide 86 N-hydroxy-4-[4-(6-methoxy-2-methylpyridin-3- >64 8 32 4 100 0.31a yl)phenyl]-2-methyl-2-
(methylsulfonyl)butanamide
87 N-hydroxy- 2-methyl-4-(3'-methylbiphenyl-4-yl)- 8 2 4 1 100 0.47a
2-(methylsulfonyl)butanamide
88 4-(3'-chlorobiphenyl-4-yl)-N-hydroxy-2-methyl- 0.000364 4 1 4 1 100 0.48a
2-(methylsulfonyl)butanamide
89 4-(2'-fluoro-3'-methoxybiphenyl-4-yl)-N-hydroxy- 16 0.5 1 0.5 100 0.42a
2-methyl-2-(methylsulfonyl)butanamide
90 4-(5'-chloro-2'-fluorobiphenyl-4-yl)-N-hydroxy-2- 8 8 8 8 na na methyl-2-(methylsulfonyl)butanamide
91 4- (4'-cyano-2'-methyl bi phenyl-4-yl )- N-hydroxy- 0.000266 16 2 8 2 100 0.43a
2-methyl-2-(methylsulfonyl)butanamide
92 N-hydroxy- 2-methyl-4-[4'-(1 -methyl- 1 H- >64 16 32 32 100 0.26a imidazol-2-yl)biphenyl-4-yl]-2-
(methylsulfonyl)butanamide
93 4-[4-(6-cyanopyridin-3-yl)phenyl]-N-hydroxy-2- >64 16 32 4 100 0.35a methyl-2-(methylsulfonyl)butanamide
94 N-hydroxy- 2-methyl-2-(methylsulfonyl)-4-[2'- >64 32 >64 32 100 0.46a
(methylthio)biphenyl-4-yllbutanamide
95 4-[4-(3-furyl)phenyl]-N-hydroxy-2-methyl-2- >64 16 16 4 100 0.38a
(methylsulfonyl)butanamide
96 4'-[4-(hydroxyamino)-3-methyl-3- >64 >64 >64 8 100 0.28a
(methylsulfonyl)-4-oxobutyl]biphenyl-4- carboxamide
97 4-(3',5'-difluorobiphenyl-4-yl)-N-hydroxy-2- 8 2 4 1 100 0.46a methyl-2-(methylsulfonyl)butanamide
98 4-(4'-fluoro-2'-methylbiphenyl-4-yl)- N-hydroxy- 2- 0.00123 32 4 16 2 100 0.47a methyl-2-(methylsulfonyl)butanamide
99 N-hydroxy-2-methyl-4-[4-(5-methyl-2- >64 16 32 8 100 0.38a furyl)phenyll-2-(methylsulfonyl)butanamide
100 N-hydroxy-4-(2'-methoxybiphenyl-4-yl)-2- >64 32 >64 8 100 0.43a methyl-2-(methylsulfonyl)butanamide
101 N-hydroxy-2-methyl-4-[4-( 1 -methyl- 1 H-pyrazol- >64 32 32 8 100 0.38a 4-yl)phenyl]-2-(methylsulfonyl)butanamide
102 N-hydroxy-4-(4'-isopropylbiphenyl-4-yl)-2- 4 2 8 4 100 0.53a methyl-2-(methylsulfonyl)butanamide
103 4-[4-(2-furyl)phenyl]-N-hydroxy-2-methyl-2- 32 8 16 4 93 0.38a (methylsulfonyl)butanamide
104 4-(3'-chloro-4'-fluorobiphenyl-4-yl)-N-hydroxy-2- 0.000127 2 0.5 2 1 100 0.49a methyl-2-(methylsulfonyl)butanamide
105 4-(2'-cyanobiphenyl-4-yl)-N-hydroxy-2-methyl-2- >64 8 32 16 100 0.4a (methylsulfonyl)butanamide
106 4-[4'-(cyanomethyl)biphenyl-4-yl]-N-hydroxy-2- >64 2 8 1 100 0.37a methyl-2-(methylsulfonyl)butanamide
107 (2R)-4-(4'-cyanobiphenyl-4-yl)-N-hydroxy-2- 0.000134 16 0.25 1 0.25 na na methyl-2-(methylsulfonyl)butanamide
108 4-(4'-acetylbiphenyl-4-yl)-N-hydroxy-2-methyl-2- 0.000176 32 0.5 2 0.5 100 0.4a (methylsulfonyl)butanamide
109 4- (4'-cyano-3'-methyl bi phenyl-4-yl )- N-hydroxy- 0.000144 32 0.5 2 2 100 1.47D 2-methyl-2-(methylsulfonyl)butanamide
110 (2R)-4-(4'-fluorobiphenyl-4-yl)-N-hydroxy-2- 8 2 4 0.25 100 0.44a methyl-2-(methylsulfonyl)butanamide
111 4-[4'-(aminomethyl)biphenyl-4-yl]-N-hydroxy-2- >64 >64 >64 32 100 0.25a methyl-2-(methylsulfonyl)butanamide
112 N-hydroxy-4-[4'-(hydroxymethyl)biphenyl-4-yl]- >64 >64 >64 4 57 0.32a 2-methyl-2-(methylsulfonyl)butanamide
113 N-hydroxy-4-[4'-(2-hydroxyethoxy)biphenyl-4- 0.000148 >64 2 8 1 100 0.33a yll-2-methyl-2-(methylsulfonyl)butanamide
114 4-[4'-(2-aminoethyl)biphenyl-4-yl]-N-hydroxy-2- >64 >64 >64 16 100 0.26a methyl-2-(methylsulfonyl)butanamide
115 N-hydroxy-4-[4'-(3-hydroxypropoxy)biphenyl-4- 0.000388 >64 0.5 2 2 100
yll-2-methyl-2-(methylsulfonyl)butanamide 1.3b
116 4-[4'-(2-aminoethoxy)biphenyl-4-yl]-N-hydroxy- >64 >64 >64 4 100 0.26a 2-methyl-2-(methylsulfonyl)butanamide
117 4-[4'-(3-aminopropoxy)biphenyl-4-yl]-N-hydroxy- >64 >64 >64 8 100 0.28a 2-methyl-2-(methylsulfonyl)butanamide 118 4-[4'-(4-aminobutoxy)biphenyl-4-yl]-N-hydroxy- >64 32 >64 16 100 0.3a 2-methyl-2-(methylsulfonyl)butanamide
119 4-[6-(4-fluorophenyl)pyridin-3-yl]-N-hydroxy-2- >64 16 >64 8 100 0.26a methyl-2-(methylsulfonyl)butanamide
120 N-hydroxy-4-[6-(4-methoxyphenyl)pyridin-3-yl]- >64 4 16 8 100 0.25a 2-methyl-2-(methylsulfonyl)butanamide
121 N-hydroxy-2-methyl-2-(methylsulfonyl)-4-{6-[4- >64 1 4 4 100 0.29a (methylthio)phenyllpyridin-3-yl}butanamide
122 4-[6-(4-cyanophenyl)pyridin-3-yl]-N-hydroxy-2- >64 16 >64 8 100 0.28a methyl-2-(methylsulfonyl)butanamide
123 4-[3'-fluoro-4'-(hydroxymethyl)biphenyl-4-yl]-N- 0.000491 >64 16 16 1 100 1.23d hydroxy-2-methyl-2-(methylsulfonyl)butanamide
124 4-{4-[5-cyano-4-(trifluoromethyl)pyridin-2- >64 8 >64 8 100 0.44a yl]phenyl}-N-hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
125 4-(3',4'-dicyanobiphenyl-4-yl)-N-hydroxy-2- >64 8 32 4 97 0.4a methyl-2-(methylsulfonyl)butanamide
126 4-(3'-chloro-4'-cyanobiphenyl-4-yl)-N-hydroxy-2- 0.000329 8 0.5 2 0.5 0 na methyl-2-(methylsulfonyl)butanamide
127 4-(4'-cyano-3',5'-difluorobiphenyl-4-yl)-N- 0.00015 32 1 8 2 100 1.49D hydroxy-2-methyl-2-(methylsulfonyl)butanamide
128 4-(4'-cyano-2'-fluorobiphenyl-4-yl)-N-hydroxy-2- 0.000232 >64 0.5 8 0.5 100 0.42a methyl-2-(methylsulfonyl)butanamide
129 4-[4-(5-cyanopyridin-2-yl)phenyl]-N-hydroxy-2- >64 16 >64 4 100 0.35a methyl-2-(methylsulfonyl)butanamide
130 4-[4-(5-cyanopyrazin-2-yl)phenyl]-N-hydroxy-2- >64 16 >64 16 100 0.35a methyl-2-(methylsulfonyl)butanamide
131 4-[4-(5-cyano-6-methylpyridin-2-yl)phenyl]-N- >64 4 16 4 100 0.39a hydroxy-2-methyl-2-(methylsulfonyl)butanamide
132 4-[4-(benzyloxy)phenyl]-N-hydroxy-2-methyl-2- 0.000386 16 2 16 2 100 0.49a (methylsulfonyl)butanamide
133 4-[6-(4-acetylphenyl)pyridin-3-yl]-N-hydroxy-2- 0.000985 >64 16 >64 16 100 0.28a methyl-2-(methylsulfonyl)butanamide
134 4-[6-(2-fluoro-3-methoxyphenyl)pyridin-3-yl]-N- >64 4 16 4 100 0.27a hydroxy-2-methyl-2-(methylsulfonyl)butanamide
135 N-hydroxy-4-(4-methoxyphenyl)-2-methyl-2- >64 >64 >64 32 100 0.31a (methylsulfonyl)butanamide
136 N-hydroxy-4-[4'-(4-hydroxybutoxy)biphenyl-4- 0.000205 >64 0.125 1 1 100 0.38a yll-2-methyl-2-(methylsulfonyl)butanamide
137 N-hydroxy-4-(4'-hydroxy-3'-methylbiphenyl-4- >64 16 32 4 100 1.23d yl)-2-methyl-2-(methylsulfonyl)butanamide
138 4-(3'-fluoro-4'-hydroxybiphenyl-4-yl)-N-hydroxy- 0.000335 32 2 8 1 100 0.34a 2-methyl-2-(methylsulfonyl)butanamide
139 N-hydroxy-4-(4'-hydroxy-3'-methoxybiphenyl-4- >64 16 >64 16 100 1.12D yl)-2-metnyl-2-(methylsulfonyl)butanamide
140 N-hydroxy-4-(4'-hydroxy-2'-methylbiphenyl-4- >64 32 >64 4 100 1.17D yl)-2-methyl-2-(methylsulfonyl)butanamide
141 N-hydroxy-4-(4'-hydroxy-2'-methoxybiphenyl-4- >64 >64 >64 32 100 0.33a yl)-2-metnyl-2-(methylsulfonyl)butanamide
142 4-(4'-cyano-3'-hydroxybiphenyl-4-yl)-N-hydroxy- >64 >64 >64 32 100 0.35a 2-methyl-2-(methylsulfonyl)butanamide
143 N-hydroxy-4-[6-(2-hydroxyphenyl)pyridin-3-yl]- >64 4 32 4 na na 2-methyl-2-(methylsulfonyl)butanamide
144 4-[2'-fluoro-4'-(2-hydroxyethoxy)biphenyl-4-yl]- >64 1 4 1 100 0.35a
N-hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
145 4-[3'-fluoro-4'-(2-hydroxyethoxy)biphenyl-4-yl]- >64 2 4 1 100 0.35a
N-hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
146 N-hydroxy-4-[4'-(2-hydroxy-2- >64 8 32 8 100 0.41a methylpropyl)biphenyl-4-yl]-2-methyl-2-
(methylsulfonyl)butanamide
147 4-[2',3'-difluoro-4'-(2-hydroxyethoxy)biphenyl-4- 32 2 8 1 100 0.37a yl]-N-hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
148 4-[3'-cyano-4'-(2-hydroxyethoxy)biphenyl-4-yl]- >64 16 >64 16 100 0.35a
N-hydroxy-2-methyl-2-
(methylsulfonyl)butanamide 149 4-(2'-fluoro-4'-hydroxybiphenyl-4-yl)-N-hydroxy- >64 2 8 1 100 0.36a 2-methyl-2-(methylsulfonyl)butanamide
150 4-[3',5'-difluoro-4'-(2-hydroxyethoxy)biphenyl-4- 32 2 8 2 99 0.38a yl]-N-hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
151 N-hydroxy-4-[4'-(2-hydroxyethoxy)-2'- >64 8 32 4 99 0.37a methylbiphenyl-4-yl]-2-methyl-2-
(methylsulfonyl)butanamide
152 N-hydroxy-4-[4'-(2-hydroxyethyl)-3'- >64 4 16 2 99 0.38a methylbiphenyl-4-yl]-2-methyl-2-
(methylsulfonyl)butanamide
153 N-hydroxy-4-[2'-(1 -hydroxy- 1- >64 >64 >64 32 99 0.4a methylethyl)biphenyl-4-yl]-2-methyl-2-
(methylsulfonyl)butanamide
154 4-(2'-fluoro-3'-hydroxybiphenyl-4-yl)-N-hydroxy- >64 4 8 1 99 0.37a 2-methyl-2-(methylsulfonyl)butanamide
155 4-[2'-fluoro-4'-(2-hydroxyethyl)biphenyl-4-yl]-N- >64 2 8 1 99 0.37a hydroxy-2-methyl-2-(methylsulfonyl)butanamide
156 N-hydroxy-4-[4'-(2-hydroxyethyl)-2'- 16 16 8 8 100 0.38a methylbiphenyl-4-yl]-2-methyl-2-
(methylsulfonyl)butanamide
157 4-(4'-fluoro-3-methylbiphenyl-4-yl)-N-hydroxy-2- 0.000337 8 1 4 4 100 0.48a methyl-2-(methylsulfonyl)butanamide
158 N-hydroxy-4-[4'-(3-hydroxy-3- 0.000644 32 0.5 8 4 100 0.43a methylbutyl)biphenyl-4-yl]-2-methyl-2-
(methylsulfonyl)butanamide
159 N-hydroxy-2-methyl-4-(2-methylbiphenyl-4-yl)- 0.00558 32 4 16 8 100 0.47a 2-(methylsulfonyl)butanamide
160 4-(4'-fluoro-2-methylbiphenyl-4-yl)-N-hydroxy-2- 0.00254 16 2 8 4 100 0.48a methyl-2-(methylsulfonyl)butanamide
161 4-(4'-cyano-3-methylbiphenyl-4-yl)-N-hydroxy- 0.000725 >64 1 16 4 100 0.42a 2-methyl-2-(methylsulfonyl)butanamide
162 4-(4'-cyano-2-methylbiphenyl-4-yl)-N-hydroxy- 0.000241 16 2 16 4 100 0.43a 2-methyl-2-(methylsulfonyl)butanamide
163 4-[5-(4-cyanophenyl)pyridin-2-yl]-N-hydroxy-2- >64 32 32 8 na na methyl-2-(methylsulfonyl)butanamide
164 4-[5-(4-fluorophenyl)pyridin-2-yl]-N-hydroxy-2- >64 32 32 4 na na methyl-2-(methylsulfonyl)butanamide
165 N-hydroxy-2-methyl-2-(methylsulfonyl)-4-(4'- 0.000295 >64 0.5 8 8 100 0.37a morpholin-4-ylbiphenyl-4-yl)butanamide
166 N-hydroxy-2-methyl-4-[4'-(4-methylpiperazin-1- 0.00117 >64 4 16 2 100 0.28a yl)biphenyl-4-yl]-2-(methylsulfonyl)butanamide
167 4-(2,4'-difluorobiphenyl-4-yl)-N-hydroxy-2- 0.000235 8 1 4 0.5 100 0.46a methyl-2-(methylsulfonyl)butanamide
168 4-(4'-cyano-3-fluorobiphenyl-4-yl)-N-hydroxy-2- 0.000427 >64 1 2 1 100 0.41a methyl-2-(methylsulfonyl)butanamide
169 4-(4'-glycoloylbiphenyl-4-yl)-N-hydroxy-2- 0.0002 32 2 4 1 100 0.33a methyl-2-(methylsulfonyl)butanamide
170 (2R)-N-hydroxy-4-(3'-methoxybiphenyl-4-yl)-2- 0.054 16 >64 >64 >64 100 0.44a methyl-2-(methylsulfonyl)butanamide
171 N-hydroxy-4-(2-methoxybiphenyl-4-yl)-2- 0.0146 >64 4 16 32 100 0.45a methyl-2-(methylsulfonyl)butanamide
172 (2R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-4- 0.000512 >64 0.5 4 4 100 0.29a
[4'-(2-morpholin-4-ylethoxy)biphenyl-4- yllbutanamide
173 4-[4-(2,3-dihydro-1 H-isoindol-5-yl)phenyl]-N- 0.00268 >64 >64 >64 16 100 0.25a hydroxy-2-methyl-2-(methylsulfonyl)butanamide
174 4-[4-(2, 1 ,3-benzoxadiazol-5-yl)phenyl]-N- 0.00054 >64 4 8 2 100
hydroxy-2-methyl-2-(methylsulfonyl)butanamide 0.43a
175 (2S)-4-[4-(2,3-dihydro-1 ,4-benzodioxin-6- 0.0146 >64 32 >64 >64 100 0.43a yl)phenyl]-N-hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
176 4-[4-(1 ,3-benzodioxol-5-yl)phenyl]-N-hydroxy-2- 3.03E-05 16 0.5 2 0.5 100 0.43a methyl-2-(methylsulfonyl)butanamide
177 4-(2-fluoro-4'-hydroxybiphenyl-4-yl)-N-hydroxy- 0.000306 32 1 8 2 100 0.34a 2-methyl-2-(methylsulfonyl)butanamide
178 4-(3-fluoro-4'-hydroxybiphenyl-4-yl)-N-hydroxy- 5.92E-05 8 1 4 1 100 0.35a 2-methyl-2-(methylsulfonyl)butanamide 179 (2R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-4- 0.000172 2 0.125 2 2 100 0.3a
[4'-(3-morpholin-4-ylpropoxy)biphenyl-4- yllbutanamide
180 4-(3'-acetyl-4'-hydroxybiphenyl-4-yl)-N-hydroxy- 0.000826 16 4 16 8 100 0.43a 2-methyl-2-(methylsulfonyl)butanamide
181 4-(4'-acetyl-3'-hydroxybiphenyl-4-yl)-N-hydroxy- 0.000138 8 0.5 8 2 100 0.42a 2-methyl-2-(methylsulfonyl)butanamide
182 (2R)-4-(4'-acetylbiphenyl-4-yl)-N-hydroxy-2- 6.74E-05 16 0.5 1 0.5 95 1.43d methyl-2-(methylsulfonyl)butanamide
183 4-(3-fluoro-4'-glycoloylbiphenyl-4-yl)-N-hydroxy- 0.000387 >64 2 4 2 100 0.33a 2-methyl-2-(methylsulfonyl)butanamide
184 4-(4'-acetyl-3'-fluorobiphenyl-4-yl)-N-hydroxy-2- 0.000155 32 4 2 0.5 100 0.43a methyl-2-(methylsulfonyl)butanamide
185 N-hydroxy-2-methyl-2-(methylsulfonyl)-4-(4'- 0.00622 >64 16 >64 8 100 0.28a piperazin-1-ylbiphenyl-4-yl)butanamide
186 (2R)-4-(4'-glycoloylbiphenyl-4-yl)-N-hydroxy-2- 0.000238 >64 2 4 1 100 0.33a methyl-2-(methylsulfonyl)butanamide
187 4-[4-( 5-acetyl pyridi n-2-yl )-2-f I uorophenyl]- N- 0.000632 >64 16 16 4 100 0.36a hydroxy-2-methyl-2-(methylsulfonyl)butanamide
188 4-[4-( 6-acetyl pyridi n-3-yl )-2-f I uorophenyl]- N- 0.000348 >64 8 8 2 100 0.36a hydroxy-2-methyl-2-(methylsulfonyl)butanamide
189 (2R)-4-[4-(5-acetylpyridin-2-yl)phenyl]-N- 0.000711 >64 16 16 4 100 0.31a hydroxy-2-methyl-2-(methylsulfonyl)butanamide
190 (2R)-4-[4-(6-acetylpyridin-3-yl)phenyl]-N- 0.000246 >64 4 4 2 100 0.35a hydroxy-2-methyl-2-(methylsulfonyl)butanamide
191 (2R)-N-hydroxy-4-{4'-[2-(4-hydroxypiperidin-1- 0.00263 >64 >64 >64 16 100 0.32a yl)-2-oxoethyl]biphenyl-4-yl}-2-methyl-2-
(methylsulfonyl)butanamide
192 (2R)-N-hydroxy-4-{4'-[(4-hydroxypiperidin-1- 0.00339 >64 >64 >64 16 100 0.31a yl)carbonyl]biphenyl-4-yl}-2-methyl-2-
(methylsulfonyl)butanamide
193 N-hydroxy-2-methyl-2-(methylsulfonyl)-4-{4'-[4- 0.00108 >64 16 >64 >64 100 0.38a
(methylsulfonyl)piperazin-1-yl]biphenyl-4- yljbutanamide
194 (2R)-N-hydroxy-4-(4'-lactoylbiphenyl-4-yl)-2- 0.000195 >64 1 4 1 100 0.35a methyl-2-(methylsulfonyl)butanamide
195 4-(3-fluoro-4-quinolin-6-yl phenyl )-N-hydroxy-2- 0.000733 32 1 4 2 83 0.29a methyl-2-(methylsulfonyl)butanamide
196 4-[2-fluoro-4-(3-oxo-2,3-dihydro-1 H-isoindol-5- 0.000631 >64 4 16 4 100 0.33a yl)phenyl]-N-hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
197 4-(3-fluoro-4-pyridin-3-ylphenyl)-N-hydroxy-2- 0.00711 >64 >64 >64 8 100 0.24a methyl-2-(methylsulfonyl)butanamide
198 (2R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-4- 0.00384 >64 >64 >64 8 100 0.23a (4-pyridin-3-ylphenyl)butanamide
199 (2R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-4- 0.000266 >64 8 32 2 100 0.31a
[4-(1-oxo-2,3-dihydro-1 H-isoindol-5- yl)phenyl]butanamide
200 4-(2-fluoro-4-quinolin-3-yl phenyl )-N-hydroxy-2- 0.000463 >64 1 8 4 100 0.33a methyl-2-(methylsulfonyl)butanamide
201 (2R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-4- 0.00024 >64 1 8 2 100 0.31a
(4-quinolin-3-ylphenyl)butanamide
202 (2R)-4-[4-(5-cyanopyridin-2-yl)phenyl]-N- 0.000808 >64 8 16 1 100 0.37a hydroxy-2-methyl-2-(methylsulfonyl)butanamide
203 4-[3-fluoro-4-(3-oxo-2,3-dihydro-1 H-isoindol-5- 0.000659 >64 8 32 4 100 0.32a yl)phenyl]-N-hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
204 (2R)-4-[4-(6-aminopyridin-3-yl)phenyl]-N- 0.0182 >64 >64 >64 8 100 0.24a hydroxy-2-methyl-2-(methylsulfonyl)butanamide
205 (2R)-4-(4'-acetamidobiphenyl-4-yl)-N-hydroxy- 0.00174 >64 16 32 4 100 0.35a
2-methyl-2-(methylsulfonyl)butanamide
206 4-[4-(6-aminopyridin-3-yl)-3-fluorophenyl]-N- 0.0235 >64 >64 >64 16 100 0.25a hydroxy-2-methyl-2-(methylsulfonyl)butanamide
207 4-(4'-acetamido-2-fluorobiphenyl-4-yl)-N- 0.00709 >64 32 >64 16 100 0.36a hydroxy-2-methyl-2-(methylsulfonyl)butanamide
208 (2R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-4- 0.000374 >64 4 16 2 100 0.31a
[4-(3-oxo-2,3-dihydro-1 H-isoindol-5- yl)phenyllbutanamide 209 4-{2-fluoro-4'-[(methylsulfonyl)amino]biphenyl- 0.00204 >64 8 32 8 100 0.37a
4-yl}-N-hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
210 (2R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-4- 0.000706 >64 4 16 2 100 0.36a
{4'-[(methylsulfonyl)amino]biphenyl-4- yljbutanamide
211 (2R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-4- 0.0111 >64 >64 >64 32 71 0.26a
[4-(1 H-pyrrolo[3,2-b]pyridin-6- yl)phenyllbutanamide
212 (2R)-N-hydroxy-4-[4-(6-methoxypyridin-3- 0.000237 >64 4 16 1 100 0.38a yl)phenyl]-2-methyl-2-
(methylsulfonyl)butanamide
213 4-[3-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-N- 0.000518 >64 2 8 2 100 0.41a hydroxy-2-methyl-2-(methylsulfonyl)butanamide
214 (2R)-4-[4-(1-benzofuran-2-yl)phenyl]-N- 8 0.125 4 8 na na nydroxy-2-methyl-2-(methylsulfonyl)butanamide
215 (2R)-4-[4-(1 ,3-benzodioxol-5-yl)phenyl]-N- 8.42E-05 16 0.5 2 0.5 100 0.43a hydroxy-2-methyl-2-(methylsulfonyl)butanamide
216 (2R)-N-hydroxy-4-(4'-{[(2R)-2- 0.00402 >64 32 >64 32 100 0.33a
(hydroxymethyl)pyrrolidin-l- yl]carbonyl}biphenyl-4-yl)-2-methyl-2- (methylsulfonyl)butanamide
217 (2R)-N-hydroxy-4-[4'-(2-hydroxy-2- 0.000278 >64 0.5 4 4 100 0.41a methylpropanoyl)biphenyl-4-yl]-2-methyl-2-
(methylsulfonyl)butanamide
218 (2R)-N-hydroxy-4-[4-(1 H-indol-2-yl)phenyl]-2- 0.000034 32 0.5 2 0.5 100 0.47a methyl-2-(methylsulfonyl)butanamide
219 4-[6-(2-fluoro-4-methoxyphenyl)pyridin-3-yl]-N- 0.00121 >64 4 16 8 100 0.29a hydroxy-2-methyl-2-(methylsulfonyl)butanamide
220 (2R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-4- 0.000467 >64 8 32 16 100 0.35a
[4'-(3-piperidin-1-ylpropoxy)biphenyl-4- yllbutanamide
221 (2R)-N-hydroxy-4-{4'-[2-(4-hydroxypiperidin-1- 0.000533 >64 16 >64 16 100 0.35a yl)-2-oxoethoxy]biphenyl-4-yl}-2-methyl-2-
(methylsulfonyl)butanamide
222 (2R)-N-hydroxy-4-{4'-[2-(4-hydroxy-4- 0.000841 >64 16 >64 32 98 0.37a methylpiperidin-1-yl)-2-oxoethoxy]biphenyl-4- yl}-2-methyl-2-(methylsulfonyl)butanamide
223 (2R)-N-hydroxy-4-{4'-[2-(3-hydroxyazetidin-1- 0.000507 >64 16 32 8 100 0.34a yl)-2-oxoethoxy]biphenyl-4-yl}-2-methyl-2-
(methylsulfonyl)butanamide
224 4-(4-cyclohex-1-en-1-ylphenyl)-N-hydroxy-2- 0.000441 4 4 16 2 100 0.5a methyl-2-(methylsulfonyl)butanamide
225 4-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-N- 0.00188 >64 32 >64 4 100 0.45a hydroxy-2-methyl-2-(methylsulfonyl)butanamide
226 4-[4-(3,6-dihydro-2H-thiopyran-4-yl)phenyl]-N- 0.00032 16 8 8 1 na na hydroxy-2-methyl-2-(methylsulfonyl)butanamide
227 4-(4-cyclopent-1-en-1-ylphenyl)-N-hydroxy-2- 0.0114 >64 >64 >64 16 na 0.54a methyl-2-(methylsulfonyl)butanamide
228 4-{4-[(4-fluorophenoxy)methyl]phenyl}-N- 0.00328 16 8 16 8 100 1.51D hydroxy-2-methyl-2-(methylsulfonyl)butanamide
229 4-{4-[(3-fluorophenoxy)methyl]phenyl}-N- 0.00324 16 8 32 8 100 0.46a hydroxy-2-methyl-2-(methylsulfonyl)butanamide
230 N-hydroxy-4-[4'-(1 -hydroxy- 1- >64 8 32 8 100 0.38a methylethyl)biphenyl-4-yl]-2-methyl-2-
(methylsulfonyl)butanamide
231 (2S)-2-amino-3-{4'-[4-(hydroxyamino)-3-methyl- >64 32 >64 16 89 0.25a
3-(methylsulfonyl)-4-oxobutyl]biphenyl-4- yljpropanoic acid
232 (2R)-2-amino-3-{4'-[4-(hydroxyamino)-3-methyl- >64 >64 >64 32 96 0.25a
3-(methylsulfonyl)-4-oxobutyl]biphenyl-4- yljpropanoic acid Examples 233 - 318
In addition to the compounds above, a series of ether derivatives (i.e. L is O) were also prepared by combinatorial methods. Table 3 below lists these compounds by name, provides characterization data such as liquid chromatography-mass
spectrometry and retention times. Table 3 also provides selected biological data using the same protocols as described above for Examples 1-25.
The compounds described below in Table 3 form a subset of those described by Formula I. In all of these compounds R1 and R2 are methyl, X is CH2, A is unsubstituted phenyl, L is O, D is as described above and G and T may be absent or present and are as defined above.
These compounds were generally produced in the following manner.
Step 1 :
Phenol monomer ((+/-)-Ethyl 4-(4-hydroxyphenyl)-2-methyl-2- (methylsulfonyl)butanoate) (600ul, 125umol) of a 0.208M solution in anhydrous DMA was dispensed into 8ml_ vials. To this was added CS2CO3 (81 mg, 250umol, 2eq). The vials were capped and shaken at 30°C for 30mins. An appropriate alkyl/benzyl halide, i.e. one corresponding to the desired G-T-D moiety, (162umol, 1.3eq) was added to the vials. The vials were capped and shaken at 30°C for 16 hours. The reaction mixture was filtered and concentrated by Speedvac to give the crude intermediate.
Step 2:
THF (300ul) and MeOH (600ul) were added to each vial followed by manual addition of a freshly prepared 1 M solution of LiOH in water (300ul, 3umol, 3 eq.). The vials were capped and shaken at 30°C for 16 hours. THF and MeOH were removed via speedvac and the resulting contents were adjusted to pH 3-5 by the addition of a prepared solution of citric acid in water (50ul of a 12g citric acid in 15ml_ H20). The mixture was extracted with DCM 8ml_, dried over MgS04 and concentrated by speedvac to give crude intermediate.
Step 3:
Anhydrous DCM 2ml_ was added to each vial containing crude acid (approx. 75umol, 1 eq). Oxalyl chloride (23ul, 275umol, 3.6eq) and 5ul DMF was added to the vials. Nitrogen was bubbled for 1 minute to deoxygenate the reaction mixtures. The vials were capped and allowed to shake at 30°C for 60 mins. O-TMS-hydroxylamine (91 ul, 750umol- 10eq) was added to the vials. The vials were left to shake for a further 2hrs at 30°C. The solvent was removed by speedvac and the residue was purified by prep HPLC to give the final product. A few of the compounds below in Table 3 were produced individually, not by combinatorial methods, but the teachings above could be used to generate the compound. In Table 3 below, column 2 provides the lUPAC name, column's 3-7 provide in-vitro biological data generated in the same manner as in Table I, columns 8 and 9 provide the retention times and mass spectra generated via LCMS, using the same methodology as described in Table 2, except that the acidic gradient was used to generate all retention times. Some data is not available, as described in Table 2, and is labeled "na".
TABLE 3
Example lUPAC NAME PA LpxC AB- EC-1 KP- PA-7 Ret. LCMS enzyeme 3167 MIC 3700 MIC time ELSD IC50'
MIC MIC
μΜ
233 4-{4-[(4- >64 4 16 4 100 cyanobenzyl)oxy]phenyl}-N- hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
234 N-hydroxy-4-(4- >64 >64 >64 8 0.38 100 isopropoxyphenyl)-2-methyl-2-
(methylsulfonyl)butanamide
235 4-(4-ethoxyphenyl)-N-hydroxy- >64 32 >64 16 0.35 100
2-methyl-2-
(methylsulfonyl)butanamide
236 4-(4-butoxyphenyl)-N-hydroxy- 32 16 >64 8 0.44 100
2-methyl-2-
(methylsulfonyl)butanamide
237 N-hydroxy-2-methyl-2- >64 32 >64 8 0.4 100
(methylsulfonyl)-4-(4- propoxyphenyl)butanamide
238 4-[4-(cyclohexyloxy)phenyl]-N- 0.000753 32 32 >64 8 0.48 100 hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
239 4-[4-(2-ethylbutoxy)phenyl]-N- 0.00129 4 16 >64 8 0.58 100 hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
240 N-hydroxy-2-methyl-2- 0.0205 >64 32 >64 >64 0.55 100
(methylsulfonyl)-4-(4-{[3-(1- phenyl propyl )-1 ,2,4-oxadiazol- 5- yl]methoxy}phenyl)butanamide
241 4-(4-{[3-(3-fluorophenyl)-1 ,2,4- 0.00381 16 8 >64 32 0.5 100 oxadiazol-5- yl]methoxy}phenyl)-N-hydroxy- 2-methyl-2-
(methylsulfonyl)butanamide
242 4-{4-[(2- 0.000655 >64 4 8 >64 0.5 100 fluorobenzyl)oxy]phenyl}-N- hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
243 4-{4-[3- 0.0211 32 32 >64 >64 0.53 100
(benzyloxy)propoxy]phenyl}-N- hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
244 4-{4-[(3,5- 0.005 >64 4 16 >64 0.48 100 dimethoxybenzyl)oxy]phenyl}-
N-hydroxy-2-methyl-2-
(methylsulfonyl)butanamide 245 N-hydroxy-2-methyl-4-{4-[(2- 0.00559 >64 >64 >64 32 0.38 100 methylpyridin-3- yl)methoxy]phenyl}-2- (methylsulfonyl)butanamide
246 4-[4- 0.0105 >64 32 >64 >64 0.47 100
(cyclopropylmethoxy)phenyl]-
N-hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
247 4-{4-[(2,3- 0.000325 16 2 16 2 0.52 100 difluorobenzyl)oxy]phenyl}-N- hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
248 N-hydroxy-2-methyl-2- 0.00152 32 2 8 32 0.49 100
(methylsulfonyl)-4-[4-(2- phenoxyethoxy)phenyl]butana
mide
249 4-(4-{[4-fluoro-2- 0.00236 16 16 >64 16 0.54 100
(trifluoromethyl)benzyl]oxy}phe
nyl)-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide
250 4-{4-[(3- 0.00132 4 2 8 4 0.52 100 chlorobenzyl)oxy]phenyl}-N- hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
251 4-(4-{[2-(2-fluorophenyl)-5- 0.0216 >64 32 >64 >64 0.52 100 methyl-1 ,3-oxazol-4- yl]methoxy}phenyl)-N-hydroxy- 2-methyl-2-
(methylsulfonyl)butanamide
252 4-[4-(hexyloxy)phenyl]-N- 0.00631 4 8 32 16 0.58 100 hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
253 4-(4-{[3-(2,3-difluorophenyl)- 0.00531 >64 8 >64 32 0.51 100
1 ,2,4-oxadiazol-5- yl]methoxy}phenyl)-N-hydroxy- 2-methyl-2-
(methylsulfonyl)butanamide
254 4-{4-[(2,5- 0.00425 16 8 >64 16 0.56 100 dimethylbenzyl)oxy]phenyl}-N- hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
255 4-(4-{[3-(3,5-difluorophenyl)- 0.00581 16 16 >64 >64 0.52 100
1 ,2,4-oxadiazol-5- yl]methoxy}phenyl)-N-hydroxy- 2-methyl-2-
(methylsulfonyl)butanamide
256 4-(4-{[3-(2,5-difluorobenzyl)- 0.000714 >64 32 >64 >64 0.49 100
1 ,2,4-oxadiazol-5- yl]methoxy}phenyl)-N-hydroxy- 2-methyl-2-
(methylsulfonyl)butanamide
257 4-{4-[(3,5- 0.0045 >64 4 32 32 0.56 100 dimethylbenzyl)oxy]phenyl}-N- hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
258 4-{4-[(2,6- 0.000599 32 2 16 2 0.48 100 difluorobenzyl)oxy]phenyl}-N- hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
259 4-(4-{[3-(2-fluoro-5- 0.00639 >64 16 >64 >64 0.5 100 methoxyphenyl)-1 ,2,4- oxadiazol-5- yl]methoxy}phenyl)-N-hydroxy- 2-methyl-2-
(methylsulfonyl)butanamide
260 N-hydroxy-2-methyl-4-{4-[(2- 0.00145 32 16 >64 8 na na methylbenzyl)oxy]phenyl}-2- (methylsulfonyl)butanamide 261 N-hydroxy-2-methyl-2- 0.00493 >64 >64 >64 32 0.43 100 (methylsulfonyl)-4-[4- (tetrahydro-2H-pyran-4- ylmethoxy)phenyl]butanamide
262 4-{4-[(2-fluoro-3- 0.000525 16 1 8 2 0.54 100 methyl benzyl )oxy]phenyl}-N- hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
263 N-hydroxy-2-methyl-4-{4-[(4- 0.00102 16 2 8 4 0.54 100 methylbenzyl)oxy]phenyl}-2- (methylsulfonyl)butanamide
264 N-hydroxy-2-methyl-2- 0.0102 8 4 16 32 0.55 100
(methylsulfonyl)-4-[4-(3- phenylpropoxy)phenyl]
butanamide
265 N-hydroxy-2-methyl-2- 0.105 >64 >64 >64 16 0.43 100
(methylsulfonyl)-4-[4-(prop-2- yn- 1 -yloxy)phenyl)butanamide
266 4-[4- 0.00328 32 32 >64 16 0.52 100
(cyclobutylmethoxy)phenyl]-N- hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
267 N-hydroxy-2-methyl-4-{4-[(4- 0.00322 8 8 >64 16 0.58 100 methylpentyl)oxy]phenyl}-2-
(methylsulfonyl)butanamide
268 4-{4-[(3- 0.000834 16 2 8 8 0.51 100 fluorobenzyl)oxy]phenyl}-N- hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
269 N-hydroxy-2-methyl-4-(4-{[3-(4- 0.00348 >64 4 >64 >64 0.52 100 methylphenyl)- 1 ,2,4-oxadiazol- 5-yl]methoxy}phenyl)-2- (methylsulfonyl)butanamide
270 N-hydroxy-2-methyl-4-{4-[(6- 0.00596 >64 >64 >64 32 0.29 100 methylpyridin-3- yl)methoxy]phenyl}-2- (methylsulfonyl)butanamide
271 N-hydroxy-2-methyl-2- 0.00403 32 16 >64 >64 0.53 100
(methylsulfonyl)-4-[4-(2- phenylethoxy)phenyl]
butanamide
272 N-hydroxy-2-methyl-4-(4-{[3-(3- 0.00154 >64 32 >64 >64 399.2 74 methylbutyl)-1 ,2,4-oxadiazol-5- UV-215 yl]methoxy}phenyl)-2- m/z 0.52
(methylsulfonyl)butanamide
273 4-{4-[(3-cyclopentyl-1 ,2,4- 0.0072 >64 16 32 >64 0.51 100 oxadiazol-5- yl)methoxy]phenyl}-N-hydroxy- 2-methyl-2-
(methylsulfonyl)butanamide
274 N-hydroxy-2-methyl-2- 0.00271 16 4 16 16 0.56 100
(methylsulfonyl)-4-(4-{[3- (trifluoromethoxy)benzyl]oxy}
phenyl)butanamide
275 4-{4-[(5-cyano-2- 0.00136 >64 >64 >64 32 0.48 100 fluorobenzyl)oxy]phenyl}-N- hydroxy-2-methyl-2- (methylsulfonyl)butanamide
276 4-{4-[(2-chloro-6- 32 4 16 4 na fluorobenzyl)oxy]phenyl}-N- hydroxy-2-methyl-2- (methylsulfonyl)butanamide 277 4-[4-(1 ,3-benzothiazol-2- 0.000651 >64 4 16 32 0.49 100 ylmethoxy)phenyl]-N-hydroxy-
2-methyl-2-
(methylsulfonyl)butanamide
278 N-hydroxy-2-methyl-4-(4-{[5- 0.0104 >64 32 >64 >64 0.55 100 methyl-2-(3-methyl phenyl )-1 , 3- oxazol-4-yl]methoxy}phenyl)-2- (methylsulfonyl)butanamide
279 N-hydroxy-2-methyl-2- 0.0139 >64 16 >64 >64 0.39 100
(methylsulfonyl)-4-[4-(quinolin-
2- ylmethoxy)phenyllbutanamide
280 4-(4-{[5-fluoro-2- 0.0138 32 8 32 32 0.56 100
(trifluoromethyl)benzyl]oxy}phe
nyl)-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide
281 N-hydroxy-2-methyl-2- 0.00677 >64 >64 >64 32 0.39 100
(methylsulfonyl)-4-{4-[2- (tetrahydro-2 H- pyran-4- yl)ethoxylphenyl}butanamide
282 N-hydroxy-2-methyl-2- 0.00955 32 8 >64 >64 na na
(methylsulfonyl)-4-[4-( 1 - phenylethoxy)phenyl]
butanamide
283 N-hydroxy-2-methyl-4-(4-{[3- 0.00632 >64 16 >64 >64 na na
(4-methyl benzyl )-1 , 2,4- oxadiazol-5- yl]methoxy}phenyl)-2- (methylsulfonyl)butanamide
284 4-{4-[(2-cyano-4- 0.00536 >64 32 >64 >64 na na fluorobenzyl)oxy]phenyl}-N- hydroxy-2-methyl-2- (methylsulfonyl)butanamide
285 4-{4-[(2- 0.01 >64 32 >64 32 na na cyanobenzyl)oxy]phenyl}-N- hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
286 N-hydroxy-2-methyl-4-[4-({3- 0.0119 >64 32 >64 >64 na na
[(4-methylphenoxy)methylj-
1 ,2,4-oxadiazol-5- yl}methoxy)phenyl]-2-
(methylsulfonyl)butanamide
287 N-hydroxy-2-methyl-4-{4-[(3- 0.00314 >64 >64 >64 16 na na methylpyridin-2- yl)methoxy]phenyl}-2- (methylsulfonyl)butanamide
288 N-hydroxy-2-methyl-2- 0.00153 4 4 8 8 na na
(methylsulfonyl)-4-(4-{[4- (trifluoromethoxy)benzyl]oxy}
phenyl)butanamide
289 N-hydroxy-2-methyl-4-(4-{[3- 0.0104 >64 32 >64 >64 na na
(3-methyl benzyl )-1 , 2,4- oxadiazol-5- yl]methoxy}phenyl)-2- (methylsulfonyl)butanamide
290 N-hydroxy-2-methyl-2- 0.00356 >64 8 32 >64 na na
(methylsulfonyl)-4-(4-{2-[4-(3- methyl-4H-1 ,2,4-triazol-4- yl)phenoxy]ethoxy}phenyl)
butanamide
291 4- (4-{[3-(2-fluoro-5- 0.00927 >64 16 >64 >64 na na methylphenyl)-1 ,2,4-oxadiazol-
5- yl]methoxy}phenyl)-N- hydroxy-2-methyl-2- (methylsulfonyl)butanamide
292 N-hydroxy-2-methyl-4-[4-(3- 0.00111 16 16 >64 8 na na methylbutoxy)phenyl]-2-
(methylsulfonyl)butanamide 293 N-hydroxy-2-methyl-2- 0.000955 32 4 32 4 na na (methylsulfonyl)-4-{4-[(2,4,6- trifl uorobenzyl )oxy] phenyl}
butanamide
294 4-{4-[(2,4- 0.000992 32 4 16 4 na na difluorobenzyl)oxy]phenyl}-N- hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
295 N-hydroxy-2-methyl-2- 0.0125 >64 32 >64 >64 na na
(methylsulfonyl)-4-{4-[(3- pentyl-1 ,2,4-oxadiazol-5- yl)methoxylphenyl}butanamide
296 N-hydroxy-2-methyl-2- 0.0158 32 8 16 >64 na na
(methylsulfonyl)-4-[4-(quinolin- 8-ylmethoxy)
phenyl] butanamide
297 N-hydroxy-2-methyl-2- 0.0425 32 16 >64 >64 na na
(methylsulfonyl)-4-[4-(3- phenoxypropoxy)phenyl]
butanamide
298 4-(4-{[3-(3-chlorophenyl)-1 ,2,4- 0.00166 16 16 32 32 na na oxadiazol-5- yl]methoxy}phenyl)-N-hydroxy- 2-methyl-2-
(methylsulfonyl)butanamide
299 N-hydroxy-4-(4-{[3-(4- 0.00393 >64 16 >64 >64 na na isopropyl phenyl )-1 ,2,4- oxadiazol-5- yl]methoxy}phenyl)-2-methyl-2- (methylsulfonyl)butanamide
300 4-{4-[(3-cyclobutyl-1 ,2,4- 0.00756 >64 16 32 32 na na oxadiazol-5- yl)methoxy]phenyl}-N-hydroxy- 2-methyl-2-
(methylsulfonyl)butanamide
301 N-hydroxy-2-methyl-2- 0.00208 4 4 8 8 na na
(methylsulfonyl)-4-(4-{[4- (trifluoromethyl)benzyl]oxy}
phenyl)butanamide
302 4-(4-{[2-(3-fluorophenyl)-5- 0.0125 >64 16 >64 >64 na na methyl- 1 ,3-oxazol-4- yl]methoxy}phenyl)-N-hydroxy- 2-methyl-2-
(methylsulfonyl)butanamide
303 N-hydroxy-2-methyl-2- 0.00458 >64 >64 >64 16 na na
(methylsulfonyl)-4-[4-(pyridin-
3- ylmethoxy)phenyllbutanam ide
304 N-hydroxy-2-methyl-2- 0.00199 32 4 16 16 na na
(methylsulfonyl)-4-(4-{[4-(1 H- pyrazol-1- y I ) benzyl ] oxy} phenyl)
butanamide
305 N-hydroxy-2-methyl-2- 0.00753 >64 32 >64 32 na na
(methylsulfonyl)-4-{4-[(3- pyridin-3-yl-1 ,2,4-oxadiazol-5- yl)methoxylphenyl}butanamide
306 4-{4-[(2- 0.000813 16 8 32 16 na na ethyl benzyl )oxy] phenyl}- N- hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
307 4-{4-[(4-chloro-2- 0.000393 16 2 8 4 na na fluorobenzyl)oxy]phenyl}-N- hydroxy-2-methyl-2- (methylsulfonyl)butanamide
308 N-hydroxy-2-methyl-2- 0.00256 >64 4 16 32 na na
(methylsulfonyl)-4-{4-[(3- phenyl- 1 ,2,4-oxadiazol-5- yl)methoxy]phenyl}butanamide 309 N-hydroxy-2-methyl-2- 0.00121 >64 8 16 8 na na (methylsulfonyl)-4-(4-{[4- (methylsulfonyl)benzyl]oxy}
phenyl)butanamide
310 N-hydroxy-2-methyl-4-{4-[(3- 0.000883 16 2 8 4 na na methyl benzyl )oxy] phenyl}-2- (methylsulfonyl)butanamide
311 N-hydroxy-2-methyl-2- 0.0137 >64 >64 >64 32 0.24 100
(methylsulfonyl)-4-[4-(2- pyridin-4- ylethoxy)phenyll butanamide
312 4-[4-(2- 0.00127 2 8 >64 8 0.54 100 cyclopentylethoxy)phenyl]-N- hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
313 4-[4-(3- 0.00255 2 4 16 16 0.57 100 cyclopentylpropoxy)phenyl]-N- hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
314 4-[4-(2- 0.00279 2 16 >64 16 0.57 100 cyclohexylethoxy)phenyl]-N- hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
315 4-[4-(3- 0.00456 2 4 16 32 0.6 100 cyclohexylpropoxy)phenyl]-N- hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
316 N-hydroxy-2-methyl-2- 16 32 >64 8 na na
(methylsulfonyl)-4-[4-(pyridin-
4- ylmethoxy)phenyl]butanamide

Claims

Claims What is claimed is:
1. A compound of the formula:
Figure imgf000104_0001
or a pharmaceutically acceptable salt thereof, in which:
R1 is represented by C1-C3 alkyl;
R2 is represented by hydrogen or C1-C3 alkly;
X is represented CH2, O, NH, S or S02,
A is represented by phenyl or a 6-membered heteroaryl as depicted below:
Figure imgf000104_0002
R3 is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxy, amino, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, and
trifluoromethoxy;
L is absent, or is represented by S, SH, OH, -(CH2)p-0-(CH2)n,-(CH2)p-0-(CH2)z-0-
(CH2)n-, S-(CH2)Z, or (CH2)Z-S;
n is represented by an integer ranging from 0 to 3 ;
p is represented by an integer ranging from 0 to 3;
z is represented by an integer ranging from 1 to 3; D is absent, or is represented by a substituent selected from the group consisting of: i) (C3-C10)cycloalkyl, optionally substituted,
ii) (C3-C10) cycloalkyl(C1-C6)alkyl, in which the alkyl and cycloalkyi moieties may each be optionally substituted,
iii) (C6-C10)aryl optionally substituted,
iv) (C6-C10)aryl (C1-C6)alkyl, in which the alkyl and aryl moieties may each be optionally substituted,
v) heteroaryl, optionally substituted,
vi) heteroaryl^.C^alkyl, in which the heteroaryl and alkyl moieties may each be optionally substituted,
vii) heterocyclic, optionally substituted,
viii) heterocyclic(C1.C6)alkyl, in which the alkyl and heterocyclic moieties may each be substituted;
T is absent, or is represented by -(CH2)Z-, -(CH2)n-C(0)-(CH2) -,
0-(CH2)z-, -(CH2)z-0-, or -0-(CH2)p-C(0)-(CH2)n- and;
G 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, or;
iv) heterocyclic, optionally substituted;
with the proviso that:
a) at least one of D or L must be present
b) if D is absent, then Tand G are also absent.
2. A compound according to claim 1 in which in which X is CH2.
3. A compound according to claim 1 or 2 in which R1 and R2 are each methyl.
4. A compound according to claim 1 , 2 or 3 in which A is phenyl.
5. A compound according to claim 1 , 2 or 3 in which A is a 6-membered heteroaryl.
6. A compound according to any of claims 1-6 in which L is absent.
7. A compound according to any of claims 1-6 in which D is optionally substituted phenyl.
8. A compound according to any of claims 1-6 in which D is optionally substituted heteroaryl.
9. A compound according to any of claims 1-6 in which D is optionally substituted heterocyclic.
10. A compound according to any of claims 1-9 in which G and T are both absent.
1 1. A compound according to any of claims 1-9 in which G is optionally substituted heteroaryl.
12. A compound according to any of claims 1 -1 1 in which said compound is the R enantiomer.
13. A pharmaceutical compostion comprising a compound according to any of claims 1 -12 in admixture with at least one pharmaceutically acceptable excipient.
14. A method for treating bacterial infections comprising administering a compound according to any of claims 1-12 to a patient in need therof.
15. Use of a compound according to any of claims 1-12 in the manufacture of a medicament for bacterial infections.
PCT/IB2010/054463 2009-10-13 2010-10-04 C-linked hydroxamic acid derivatives useful as antibacterial agents WO2011045703A2 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US13/501,776 US8853258B2 (en) 2009-10-13 2010-10-04 C-linked hydroxamic acid derivatives useful as antibacterial agents
EP10818065A EP2488489A2 (en) 2009-10-13 2010-10-04 C-linked hydroxamic acid derivatives useful as antibacterial agents
CA2774250A CA2774250C (en) 2009-10-13 2010-10-04 C-linked hydroxamic acid derivatives useful as antibacterial agents
JP2012533716A JP5671545B2 (en) 2009-10-13 2010-10-04 C-bonded hydroxamic acid derivatives useful as antibacterial agents
US14/469,657 US20140364398A1 (en) 2009-10-13 2014-08-27 C-Linked Hydroxamic Acid Derivatives Useful As Antibacterial Agents

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US25101609P 2009-10-13 2009-10-13
US61/251,016 2009-10-13

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US13/501,776 A-371-Of-International US8853258B2 (en) 2009-10-13 2010-10-04 C-linked hydroxamic acid derivatives useful as antibacterial agents
US14/469,657 Continuation US20140364398A1 (en) 2009-10-13 2014-08-27 C-Linked Hydroxamic Acid Derivatives Useful As Antibacterial Agents

Publications (2)

Publication Number Publication Date
WO2011045703A2 true WO2011045703A2 (en) 2011-04-21
WO2011045703A3 WO2011045703A3 (en) 2011-06-16

Family

ID=43778193

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2010/054463 WO2011045703A2 (en) 2009-10-13 2010-10-04 C-linked hydroxamic acid derivatives useful as antibacterial agents

Country Status (5)

Country Link
US (2) US8853258B2 (en)
EP (1) EP2488489A2 (en)
JP (1) JP5671545B2 (en)
CA (1) CA2774250C (en)
WO (1) WO2011045703A2 (en)

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2725029A1 (en) 2012-10-29 2014-04-30 Laboratoire Biodim New antibacterial compounds and biological applications thereof
JP2014514299A (en) * 2011-04-08 2014-06-19 ファイザー・インク Imidazole, pyrazole and triazole derivatives useful as antibacterial agents
WO2014165075A1 (en) 2013-03-12 2014-10-09 Achaogen, Inc. Antibacterial agents
WO2015036964A1 (en) 2013-09-13 2015-03-19 Actelion Pharmaceuticals Ltd Antibacterial 2h-indazole derivatives
WO2015091741A1 (en) * 2013-12-19 2015-06-25 Actelion Pharmaceuticals Ltd Antibacterial 1h-indazole and 1h-indole derivatives
WO2015132228A1 (en) 2014-03-04 2015-09-11 Actelion Pharmaceuticals Ltd 1,2-dihydro-3h-pyrrolo[1,2-c]imidazol-3-one derivatives and their use as antibacterial agents
WO2015164458A1 (en) * 2014-04-22 2015-10-29 Novartis Ag Isoxazoline hydroxamic acid derivatives as lpxc inhibitors
WO2016079688A1 (en) 2014-11-19 2016-05-26 Actelion Pharmaceuticals Ltd Antibacterial benzothiazole derivatives
US9403758B2 (en) 2012-05-10 2016-08-02 Achaogen, Inc. Antibacterial agents
WO2017037221A1 (en) 2015-09-03 2017-03-09 Actelion Pharmaceuticals Ltd Substituted 1,2-dihydro-3h-pyrrolo[1,2-c]imidazol-3-one antibacterial compounds
US9617256B2 (en) 2007-06-12 2017-04-11 Achaogen, Inc. Antibacterial agents
US9738604B2 (en) 2010-09-03 2017-08-22 Duke University Ethynylbenzene derivatives
US9796686B2 (en) 2014-05-16 2017-10-24 Idorsia Pharmaceuticals Ltd Antibacterial quinazoline-4(3H)-one derivatives
WO2017198647A1 (en) * 2016-05-17 2017-11-23 Idorsia Pharmaceuticals Ltd 6-(buta-1,3-diyn-1-yl)benzo[d]thiazole derivatives
WO2017223349A1 (en) 2016-06-23 2017-12-28 Achaogen, Inc. Antibacterial agents
US9908851B2 (en) 2013-08-16 2018-03-06 Duke University 2-piperidinyl substituted N,3-dihydroxybutanamides
WO2018062924A1 (en) * 2016-09-28 2018-04-05 Dong-A St Co., Ltd. Tetrahydropyridine derivatives and their use as antibacterial agents
US10071973B2 (en) 2016-06-14 2018-09-11 Novartis Ag Crystalline isoxazole hydroxamic acid compounds
US10189786B2 (en) 2013-08-16 2019-01-29 Duke University Antibacterial compounds
US10441576B2 (en) 2015-08-11 2019-10-15 Idorsia Pharmaceuticals Ltd. Substituted 1,2-dihydro-3H pyrrolo[1,2-c]imidazol-3 one antibacterials
US10647664B2 (en) 2013-08-16 2020-05-12 Duke University Substituted hydroxamic acid compounds

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2488489A2 (en) * 2009-10-13 2012-08-22 Pfizer Inc. C-linked hydroxamic acid derivatives useful as antibacterial agents
EP2512474B1 (en) * 2009-12-16 2014-11-05 Pfizer Inc N-linked hydroxamic acid derivatives useful as antibacterial agents
PL3233843T3 (en) * 2014-12-16 2020-04-30 Novartis Ag Isoxazole hydroxamic acid compounds as lpxc inhibitors
WO2018048882A1 (en) 2016-09-06 2018-03-15 The Research Foundation For The State University Of New York Positron imaging tomography imaging agent composition and method for bacterial infection

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69823019T2 (en) * 1997-02-27 2005-03-31 Wyeth Holdings Corp. N-HYDROXY-2- (ALKYL, ARYL OR HETEROARYL SULFANYL, SULFINYL OR SULFONYL) -3-SUBSTITUTED ALKYL, ARYL OR HETEROARYLAMIDES AS MATRIX METALLOPROTEINASE INHIBITORS
EP1963262A2 (en) * 2005-12-15 2008-09-03 Vicuron Pharmaceuticals, Inc. N-hydroxyamide derivatives possessing antibacterial activity
US7879911B2 (en) * 2007-02-01 2011-02-01 Johnson Alan T Hydroxamic acid derivatives of phenoxy-acetic acids and analogs useful as therapeutic agents for treating anthrax poisoning
EP2488489A2 (en) * 2009-10-13 2012-08-22 Pfizer Inc. C-linked hydroxamic acid derivatives useful as antibacterial agents

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
"Bioreversible Carriers in Drug Design", 1987, PERGAMON PRESS
"Protective Groups in Organic Chemistry", 1973, PLENUM PRESS
ANN. REV. BIOCHEM, vol. 76, 2007, pages 295 - 329
BIOCHEM PHARM, vol. 71, 2006, pages 991
BIOCHEMISTRY, vol. 45, 2006, pages 7940 - 48
CID, vol. 42, 2006, pages 657 - 68
EXPERT OPIN. DRUG SAF., vol. 7, no. 3, 2008
RICHARD C. LAROCK: "Comprehensive Organic Transformations: A Guide to Functional Group Preparations", 2000, WILEY, JOHN & SONS, INC.
T. HIGUCHI, W. STELLA: "Pro-drugs as Novel Delivery Systems", ACS SYMPOSIUM SERIES, vol. 14
T.W. GREENE, P.G.M. WUTS: "Protective Groups in Organic Synthesis", 1999, WILEY-INTERSCIENCE

Cited By (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9617256B2 (en) 2007-06-12 2017-04-11 Achaogen, Inc. Antibacterial agents
US9738604B2 (en) 2010-09-03 2017-08-22 Duke University Ethynylbenzene derivatives
US10597361B2 (en) 2010-09-03 2020-03-24 Duke University Ethynylbenzene derivatives
JP2014514299A (en) * 2011-04-08 2014-06-19 ファイザー・インク Imidazole, pyrazole and triazole derivatives useful as antibacterial agents
US9701622B2 (en) 2012-05-10 2017-07-11 Achaogen, Inc. Antibacterial agents
US9403758B2 (en) 2012-05-10 2016-08-02 Achaogen, Inc. Antibacterial agents
WO2014067904A1 (en) 2012-10-29 2014-05-08 Laboratoire Biodim New antibacterial compounds and biological applications thereof
EP2725029A1 (en) 2012-10-29 2014-04-30 Laboratoire Biodim New antibacterial compounds and biological applications thereof
WO2014165075A1 (en) 2013-03-12 2014-10-09 Achaogen, Inc. Antibacterial agents
US9908851B2 (en) 2013-08-16 2018-03-06 Duke University 2-piperidinyl substituted N,3-dihydroxybutanamides
US10647664B2 (en) 2013-08-16 2020-05-12 Duke University Substituted hydroxamic acid compounds
US10189786B2 (en) 2013-08-16 2019-01-29 Duke University Antibacterial compounds
CN105531264A (en) * 2013-09-13 2016-04-27 埃科特莱茵药品有限公司 Antibacterial 2H-indazole derivatives
TWI646084B (en) * 2013-09-13 2019-01-01 愛杜西亞製藥有限公司 Antibacterial 2H-carbazole derivatives
US9802901B2 (en) 2013-09-13 2017-10-31 Idorsia Pharmaceuticals Ltd Antibacterial 2H-indazole derivatives
EA031562B1 (en) * 2013-09-13 2019-01-31 Идорсиа Фармасьютиклз Лтд Antibacterial 2h-indazole derivatives
WO2015036964A1 (en) 2013-09-13 2015-03-19 Actelion Pharmaceuticals Ltd Antibacterial 2h-indazole derivatives
CN105829288B (en) * 2013-12-19 2019-01-15 爱杜西亚药品有限公司 Antibacterial 1H- indazole and 1H- indole derivatives
EA030730B1 (en) * 2013-12-19 2018-09-28 Идорсиа Фармасьютиклз Лтд Antibacterial 1h-indazole and 1h-indole derivatives
WO2015091741A1 (en) * 2013-12-19 2015-06-25 Actelion Pharmaceuticals Ltd Antibacterial 1h-indazole and 1h-indole derivatives
CN105829288A (en) * 2013-12-19 2016-08-03 埃科特莱茵药品有限公司 Antibacterial 1h-indazole and 1h-indole derivatives
US9624206B2 (en) 2013-12-19 2017-04-18 Actelion Pharmaceuticals Ltd Antibacterial 1H-indazole and 1H-indole derivatives
AU2014368619B2 (en) * 2013-12-19 2018-11-22 Idorsia Pharmaceuticals Ltd Antibacterial 1H-indazole and 1H-indole derivatives
JP2017500336A (en) * 2013-12-19 2017-01-05 アクテリオン ファーマシューティカルズ リミテッドＡｃｔｅｌｉｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｌｔｄ Antibacterial 1H-indazole and 1H-indole derivatives
WO2015132228A1 (en) 2014-03-04 2015-09-11 Actelion Pharmaceuticals Ltd 1,2-dihydro-3h-pyrrolo[1,2-c]imidazol-3-one derivatives and their use as antibacterial agents
CN106061977A (en) * 2014-03-04 2016-10-26 埃科特莱茵药品有限公司 1,2-dihydro-3h-pyrrolo[1,2-c]imidazol-3-one derivatives and their use as antibacterial agents
CN106061977B (en) * 2014-03-04 2018-10-26 爱杜西亚药品有限公司 1,2- dihydro -3H- Bi Kabings [1,2-C]Imidazoles -3- ketone derivatives and its purposes as antiseptic
US10106544B2 (en) 2014-03-04 2018-10-23 Idorsia Pharmaceuticals Ltd 1,2-dihydro-3H-pyrrolo[1,2-C]imidazol-3-one derivatives and their use as antibacterial agents
WO2015164458A1 (en) * 2014-04-22 2015-10-29 Novartis Ag Isoxazoline hydroxamic acid derivatives as lpxc inhibitors
CN106573924A (en) * 2014-04-22 2017-04-19 诺华股份有限公司 Isoxazoline hydroxamic acid derivatives as LpxC inhibitors
US9718792B2 (en) 2014-04-22 2017-08-01 Novartis Ag Isoxazoline hydroxamic acid derivatives as LpxC inhibitors
US9637482B2 (en) 2014-04-22 2017-05-02 Novartis Ag Isoxazoline hydroxamic acid derivatives as LpxC inhibitors
US9796686B2 (en) 2014-05-16 2017-10-24 Idorsia Pharmaceuticals Ltd Antibacterial quinazoline-4(3H)-one derivatives
WO2016079688A1 (en) 2014-11-19 2016-05-26 Actelion Pharmaceuticals Ltd Antibacterial benzothiazole derivatives
EA031534B1 (en) * 2014-11-19 2019-01-31 Идорсиа Фармасьютиклз Лтд Antibacterial benzothiazole derivatives
CN107001300A (en) * 2014-11-19 2017-08-01 埃科特莱茵药品有限公司 Antibiotic property benzothiazole derivant
US10441576B2 (en) 2015-08-11 2019-10-15 Idorsia Pharmaceuticals Ltd. Substituted 1,2-dihydro-3H pyrrolo[1,2-c]imidazol-3 one antibacterials
WO2017037221A1 (en) 2015-09-03 2017-03-09 Actelion Pharmaceuticals Ltd Substituted 1,2-dihydro-3h-pyrrolo[1,2-c]imidazol-3-one antibacterial compounds
US10314823B2 (en) 2015-09-03 2019-06-11 Idorsia Pharmaceuticals Ltd Substituted 1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one antibacterial compounds
WO2017198647A1 (en) * 2016-05-17 2017-11-23 Idorsia Pharmaceuticals Ltd 6-(buta-1,3-diyn-1-yl)benzo[d]thiazole derivatives
US10071973B2 (en) 2016-06-14 2018-09-11 Novartis Ag Crystalline isoxazole hydroxamic acid compounds
WO2017223349A1 (en) 2016-06-23 2017-12-28 Achaogen, Inc. Antibacterial agents
US10160724B2 (en) 2016-09-28 2018-12-25 Dong-A St Co., Ltd. Tetrahydropyridine derivatives and their use as antibacterial agents
CN110088087A (en) * 2016-09-28 2019-08-02 东亚St株式会社 5,6-tetrahydropyridine derivative and its purposes as antibacterial agent
AU2017337946B2 (en) * 2016-09-28 2020-05-07 Dong-A St Co., Ltd. Tetrahydropyridine derivatives and their use as antibacterial agents
WO2018062924A1 (en) * 2016-09-28 2018-04-05 Dong-A St Co., Ltd. Tetrahydropyridine derivatives and their use as antibacterial agents
RU2722594C1 (en) * 2016-09-28 2020-06-02 Тон-А Ст Ко., Лтд. Tetrahydropyridine derivatives and use thereof as antibacterial agents
CN110088087B (en) * 2016-09-28 2022-08-09 东亚St株式会社 Tetrahydropyridine derivatives and their use as antibacterial agents

Also Published As

Publication number Publication date
JP5671545B2 (en) 2015-02-18
WO2011045703A3 (en) 2011-06-16
US8853258B2 (en) 2014-10-07
JP2013507434A (en) 2013-03-04
CA2774250C (en) 2013-12-17
EP2488489A2 (en) 2012-08-22
CA2774250A1 (en) 2011-04-21
US20120202777A1 (en) 2012-08-09
US20140364398A1 (en) 2014-12-11

Similar Documents

Publication Publication Date Title
CA2774250C (en) C-linked hydroxamic acid derivatives useful as antibacterial agents
US9180123B2 (en) N-link hydroxamic acid derivatives useful as antibacterial agents
CA2828337C (en) Fluoro-pyridinone derivatives useful as antibacterial agents
US5801170A (en) Heterocyclic biphenylylamides useful as 5HT1D antagonists
US6887871B2 (en) Use of phenylheteroakylamine derivatives
CN103459377B (en) Benzo [B] [Isosorbide-5-Nitrae] oxazine derivatives as calcium-sensing receptor modulating agent
IE57619B1 (en) Aminomethyl oxooxazolidinyl benzene derivatives useful as antibacterial agents
CS399991A3 (en) Amide derivatives
AU2008228898A1 (en) Biaryl and biheteroaryl compounds useful in treating iron disorders
AU608311B2 (en) Phenol derivatives as improved leukotriene antagonists
Godefroi et al. 1-alkyl-2-aryl-5-chloroimidazoles
NZ614205B2 (en) Fluoro-pyridinone derivatives useful as antibacterial agents
WO1997048676A1 (en) Triphenylalkyl antimicrobial agents

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10818065

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2774250

Country of ref document: CA

REEP Request for entry into the european phase

Ref document number: 2010818065

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2010818065

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 13501776

Country of ref document: US

Ref document number: 2012533716

Country of ref document: JP