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WO2001032655A2 - Quinoline and naphthyridine carboxylic acid antibacterials - Google Patents

Quinoline and naphthyridine carboxylic acid antibacterials Download PDF

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Publication number
WO2001032655A2
WO2001032655A2 PCT/US2000/030551 US0030551W WO0132655A2 WO 2001032655 A2 WO2001032655 A2 WO 2001032655A2 US 0030551 W US0030551 W US 0030551W WO 0132655 A2 WO0132655 A2 WO 0132655A2
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WO
WIPO (PCT)
Prior art keywords
oxo
dihydro
cyclopropyl
methoxy
tetrahydro
Prior art date
Application number
PCT/US2000/030551
Other languages
French (fr)
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WO2001032655A3 (en
Inventor
Steven W. Elmore
Curt S. Cooper
Colleen C. Schultz
Douglas K. Hutchinson
Pamela L. Donner
Brian E. Green
David D. Anderson
Qinghua Xie
Jurgen Dinges
Linda M. Lynch
Original Assignee
Abbott Laboratories
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 Abbott Laboratories filed Critical Abbott Laboratories
Priority to EP00976992A priority Critical patent/EP1226146A2/en
Priority to IL14873800A priority patent/IL148738A0/en
Priority to JP2001535357A priority patent/JP2003524633A/en
Priority to BR0010728-0A priority patent/BR0010728A/en
Priority to MXPA02004474A priority patent/MXPA02004474A/en
Priority to AU14689/01A priority patent/AU1468901A/en
Publication of WO2001032655A2 publication Critical patent/WO2001032655A2/en
Publication of WO2001032655A3 publication Critical patent/WO2001032655A3/en
Priority to NO20022156A priority patent/NO20022156L/en
Priority to BG106679A priority patent/BG106679A/en
Priority to HK02109077.5A priority patent/HK1047287A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • This invention relates to quinoline and naphthyridine carboxylic acid derivatives having antibacterial properties, processes for making of the compounds, methods of treatment using the compounds and pharmaceutical compositions containing the compounds. Specifically, it relates to quinoline and naphthyridine carboxylic acid derivatives having a carbon-carbon linkage at the C-7 position of the molecule.
  • quinoline carboxylic acid nucleus Many compounds having the quinoline carboxylic acid nucleus are known in the art for their antibacterial activity in curing infectious diseases.
  • Some of the known antibiotics on the market to-date include, for example, ciprofloxacin (U.S. Patent 4,670,444), norfloxacin (U.S. Patent 4,146,719), enoxacin (U.S. Patent 4,352,803), and tosufloxacin (U.S. Patent 4,704,459).
  • Most of these known quinoline carboxylic acid anitbacterial compounds have a carbon-nitrogen linkage at the C-7 position of the quinoline nucleus.
  • A is nitrogen or W ; wherein W is selected from the group consisting of
  • A is selected from the group consisting of
  • R is selected from the group consisting of
  • Z is nitrogen or , wherein R is selected from the group consisting of (1) hydrogen, (2) halide,
  • R is selected from the group consisting of (1) C 3 -C 6 alkenyl
  • R and R together are selected from the group consisting of
  • R and R together are alkylidene or C 3 -C 6 spiroalkyl
  • R is hydrogen or -OR , wherein R is hydrogen or a carboxyl protecting group
  • R and R together are a carbocyclic or a heterocyclic ring, wherein the carbocyclic ring and the heterocyclic ring can be optionally substituted with one, two, or three substituents independently selected from the group consisting of
  • R in (25)-(50) is independently selected from the group consisting of
  • compositions comprising the compounds in combination with a pharmaceutically acceptable carrier.
  • R , R , R , and Z are def fiinneedd aabboo ⁇ ve
  • Q is a first covalent bond precursor, with compounds of formula (lb) (lb), wherein A , A , and R and R are defined above, and Q is a second covalent bond precursor, in the presence of a catalyst, to provide a first product;
  • alkanoyl refers to an alkyl group attached to the parent molecular group through a carbonyl group.
  • the alkanoyl groups of this invention can be optionally substituted.
  • alkanoyloxy refers to an alkanoyl group attached to the parent molecular group throgh an oxygen atom.
  • the alkanoyloxy groups of this invention can be optionally substituted.
  • alkenyl refers to a monovalent straight or branched chain hydrocarbon having from two to six carbon atoms and at least one carbon-carbon double bond.
  • the alkenyl groups of this invention can be optionally substituted.
  • alkenylene refers to a divalent straight or branched chain hydrocarbon having from four to six carbons and at least one carbon-carbon double bond.
  • alkoxy refers to an alkyl group connected to the parent molecular group through an oxygen atom.
  • the alkoxy groups of this invention can be optionally substituted.
  • alkyl refers to a monovalent straight or branched chain saturated hydrocarbon having from one to six carbon atoms.
  • the alkyl groups of this invention can be optionally substituted.
  • alkylene refers to a divalent straight or branched chain saturated hydrocarbon having from one to six carbon atoms.
  • the alkylene groups of this invention can be optionally substituted.
  • alkynyl refers to a monovalent straight or branched chain hydrocarbon having from two to six carbon atoms and at least one carbon-carbon triple bond.
  • alkynyl groups of this invention can be optionally substituted.
  • alkynylene refers to a monovalent straight or branched chain hydrocarbon having from four to six carbon atoms and at least one one carbon- carbon triple bond.
  • amino refers to -NH 2 or a derivative thereof formed by independent replacement of one or both hydrogen atoms thereon with one or two groups selected from optionally substituted Cj-C 6 alkyl, optionally substituted aryl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, and heterocycle.
  • the amino groupsof this invention can be optionally protected with amino protecting groups.
  • amino protecting group refers to selectively removable groups which protect amino groups against undesirable side reactions during synthetic procedures and includes all conventional amino protecting groups.
  • amino groups include optionally substituted acyl groups such as butoxycarbonyl, 4- chlorobutoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl, methoxycarbonyl, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, para- nitrobenzylcarbonyl, ortho-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert- amyloxycarbonyl, tert-butoxycarbonyl, para-methoxybenzyloxycarbonyl, 3,4- dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-
  • aminosulfonyl refers to an optionally protected amino group connected to the parent molecular group through a sulfonyl group.
  • aryl refers to phenyl, naphthyl, 1,2-dihydronaphthyl, and 1,2,3,4-tetrahydronaphthyl.
  • the aryl groups of this invention can be optionally substituted.
  • arylsulfonyl refers to an optionally substituted aryl group connected to the parent molecular group through a sulfonyl group.
  • zido refers to -N 3 .
  • carboxydehyde refers to -CHO.
  • carbocyclic ring refers to a non-aromatic five- to eight- membered hydrocarbon ring.
  • the carbocyclic rings of this invention can be optionally substituted.
  • carboxyl refers to -CO 2 H.
  • carboxyl groupsof this invention can be optionally protected with carboxyl protecting groups.
  • cyano refers to -CN.
  • carboxyl protecting group refers to selectively removable groups which protect hydroxyl groups against undesirable side reactions during synthetic procedures and includes all conventional carboxyl protecting groups.
  • carboxyl groups include optionally substituted alkyl groups such as methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, and tert-butyl; aryl groups such as phenyl, and naphthyl; optionally substituted arylalkyl groups such as benzyl, diphenylmethyl, triphenylmethyl, para-nitrobenzyl, para-methoxybenzyl, and bis ara- methoxyphenyl)methyl; optionally substituted acylalkyl groups such as acetylmethyl, benzoylmethyl, para-nitrobenzoylmethyl, para-bromobenzoylmethyl, and para- methanesulfonylbenzoylmethyl; optionally substituted
  • cycloalkyl refers to a monovalent saturated cyclic or bicyclic hydrocarbon having three to ten carbon atoms.
  • the cycloalkyl groups of this invention can be optionally substituted.
  • halo or halide as used herein, refer to F, Cl, Br, or I.
  • haloalkyl refers to an alkyl group to which is attached at least one halide.
  • haloalkyl refers to perfluoroalkyl or perchloroalkyl.
  • heteroarylsulfonyl refers to an optionally substituted heterocycle connected to the parent molecular group through a sulfonyl group.
  • heterocycle refers to azetidinyl, benzofuranyl, benzothiazolyl, 2,1,3-benzoxadiazole, 2,1,3-benzothiadiazole, furyl, imidazolyl, imidazolinyl, imidazolidinyl, imidazo[2,l-b]thiazole, isoquinolinyl, isoxazolyl, isothiazolyl, oxazolyl, oxetanyl, morpholine, piperidinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, thiazolyl, thienyl, thietanyl, thiomorpholine, thiomorpholine sulfone, or thiomorph
  • heterocyclic ring refers to a non-aromatic five- to eight- membered ring consisting of hydrocarbon groups and one or two groups selected from -NR -, -O-, -S(O) n -, or -NR SO 2 -.
  • the heterocyclic rings of this invention can be optionally substituted.
  • hydroxyl refers to -OH.
  • hydroxyl groupsof this invention can be optionally protected with hydroxyl protecting groups.
  • hydroxyl protecting group refers to selectively introducible and movable groups which protect hydroxyl groups against undesirable side reactions during synthetic procedures.
  • hydroxyl protecting groups include optionally substituted acyl groups such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
  • nitro refers to -NO 2 .
  • oxo refers to a group formed by the replacement of two hydrogen atoms on the same carbon atom with a single oxygen atom.
  • perchloroalkyl refers to an alkyl group in which all of the hydrogen atoms have been replaced with chloride atoms.
  • perfluoroalkoxy refers to a perfluoroalkyl group attached to the parent molecular group through an oxygen atom.
  • perfluoroalkyl refers to an alkyl group in which all of the hydrogen atoms have been replaced with fluoride atoms.
  • perfluorothioalkoxy refers to a perfluoroalkyl group attached to the parent molecular group through a sulfur atom.
  • prodrugs represents prodrugs of the compounds which are suitable for treatment of bacterial infections without undue toxicity, irritation, and allergic response, which are commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.
  • prodrug represents compounds which are rapidly transformed in vivo to the parent compounds by hydrolysis in blood.
  • Prodrugs of the invention can include compounds wherein a nitrogen on the molecule has attached thereto an aminoacyl (1-mer), diaminoacyl (2-mer), or triaminoacyl (3-mer) group optionally capped with a carboxyl protecting group.
  • aminoacyl refers to a group derived from naturally or unnaturally occuring amino acid in the racemic, D or L configuration.
  • bisaminoacyl and trisaminoacyl,” as used herein, refer to di- and tri- aminoacyl groups, respectively.
  • prodrugs of the invention include compounds wherein a carboxylic acid or amine group of the compounds is attached thereto a 2-oxo-l,3-dioxol-4-yl)methyl group such as reported in Chem. Pharm. Bull. 1985, 33(1 1), 4870-4877. Still other prodrugs of the invention include compounds wherein a tertiary amine group on the compounds has attached thereto a N-phosphonooxymethyl group such as reported in I, Med. Chem. 1999, 42(16), 3094-3100.
  • salts or zwitterionic forms of the compounds which are water or oil-soluble or dispersible and are suitable for treatment of bacterial infections without undue toxicity, irritation, and allergic response, which are commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.
  • the salts may be prepared during the final isolation and purification of the compounds or separately by reacting a free base group with a suitable acid.
  • Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2- naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, trichloroacetic, trifluoro
  • the basic nitrogen-containing groups can be quaternized with alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl, and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; arylalkyl halides such as benzyl and phenethyl bromides.
  • alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates such as dimethyl, diethyl, dibutyl, and diamyl sulfates
  • long chain halides such as decyl, lauryl, myristyl, and steary
  • acids which may be employed to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric, hydrobromic, sulphuric, and phosphoric and organic acids such as oxalic, maleic, succinic, and citric.
  • Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxylic acid-containing group such as the one at the C-3 position of the quinoline or naphthyridine with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • Pharmaceutically acceptable salts include cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts and nontoxic quaternary ammonia and amine cations such as ammonium, tetramethyl ammonium, tetraethylammonium, methylamme, dimethyla ine, t ⁇ methylamine, triethylamine, diethylamine, ethylamine, t ⁇ butlyamme, pyridine, N,N-d ⁇ methylan ⁇ hne, N-methylpipe ⁇ dine, N-methylmorphohne, dicyclohexylamine, procaine, dibenzylamine, N-dibenzyl- -phenethylamine, 1- ephenamine, and N,N'-d ⁇ benzylethylened ⁇ amine.
  • Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, pipendine, and
  • protected amino refers to an amino group de ⁇ vatized by independent replacement of at least one hydrogen atom thereon by an amino protecting group.
  • spiroalkyl refers to an alkylene group of three to six carbon atoms, both ends of which are bonded to the same carbon atom of the parent group
  • spiroheterocycle refers to a heterocycle in which one of the ⁇ ng carbon atoms is shared with one of the ⁇ ng carbon atoms of the parent group.
  • the spirohetereocycle groups of this invention can be optionally substituted.
  • substituted alkanoyloxy refers to an alkanoyloxy group de ⁇ vatized by independent replacement of one, two, or three hydrogens thereon with a substituent or substituents independently selected from the group consisting of azido, cyano, halide, nitro, optionally protected ammo, optionally protected hydroxyl, optionally protected carboxyl, optionally substituted -C ⁇ alkoxy, optionally substituted aryl, optionally substituted C 3 -C6 cycloalkyl, optionally substituted heterocycle, oxo, C]-C 6 perfluoroalkoxy, -C ⁇ perfluorothioalkoxy, and thioxo.
  • substituted alkenyl refers to an alkenyl group de ⁇ vatized by independent replacement of one, two, or three hydrogens thereon with a substituent or substituents independently selected from the group consisting of
  • substituted alkoxy refers to an alkoxy group de ⁇ vatized by independent replacement of one, two, or three hydrogens thereon with a substituent or substituents independently selected from the group consisting of C ⁇ -C 6 alkanoyloxy, C ⁇ - C ⁇ alkoxy, aryl, azido, cyano, C 3 -C 6 cycloalkyl, halide, optionally protected amino, optionally protected carboxyl, optionally protected hydroxyl, oxo, C ⁇ -C 6 perfluoroalkoxy, C
  • substituted alkyl refers to an alkyl group de ⁇ vatized by independent replacement of one, two, or three hydrogens thereon with a substituent or substituents independently selected from the group consisting of C ⁇ -C 6 alkanoyloxy, Cj- C 6 alkoxy, aryl, heterocycle, azido, cyano, C 3 -C 5 cycloalkyl, dimethylamino, halide, optionally protected amino, optionally protected carboxyl, optionally protected hydroxyl, oxo, C ⁇ -C 6 perfluoroalkoxy, Cj-C 6 perfluorothioalkoxy, and thioxo.
  • substituted alkynyl refers to an alkynyl group derivatized by independent replacement of one, two, or three hydrogens thereon with a substituent or substituents independently selected from the group consisting of C ⁇ -C 6 alkanoyloxy, C ⁇ -C 6 alkoxy, aryl, azido, cyano, C 3 -C 6 cycloalkyl, halide, optionally protected amino, optionally protected carboxyl, optionally protected hydroxyl, oxo, C ⁇ -C 6 perfluoroalkoxy, C[-C 6 perfluorothioalkoxy, and thioxo.
  • substituted aryl refers to an aryl group derivatized by independent replacement of one, two, or three hydrogens thereon with a substituent or substituents independently selected from the group consisting of -C 5 alkanoyloxy, C 1 -C 6 alkoxy, optionally substituted alkyl, aryl, azido, cyano, C 3 -C 6 cycloalkyl, halide, optionally protected amino, optionally protected carboxyl, optionally protected hydroxyl, nitro, oxo, C ⁇ -C 6 perfluoroalkoxy, C ⁇ -C 6 perfluorothioalkoxy, and thioxo.
  • substituted carbocyclic ring refers to a carbocyclic ring derivatized by independent replacement of one, two, three, or four hydrogens thereon with a substituent or substituents independently selected from the group consisting of Cj-C 6 alkanoyloxy, C--C 6 alkoxy, aryl, heterocycle, azido, cyano, C 3 -C 6 cycloalkyl, halide, optionally substituted alkyl, optionally protected amino, optionally protected carboxyl, optionally protected hydroxyl, oxo, C]-C 6 perfluoroalkoxy, C]-C 6 perfluorothioalkoxy, and thioxo.
  • substituted heterocyclic ring refers to a heterocyclic ring derivatized by independent replacement of one, two, three, or four hydrogens thereon with a substituent or substituents independently selected from the group consisting of C ⁇ - C 6 alkanoyloxy, C ⁇ -C 6 alkoxy, aryl, heterocycle, azido, cyano, C 3 -C 6 cycloalkyl, halide, optionally substituted alkyl, optionally protected amino, optionally protected carboxyl, optionally protected hydroxyl, oxo, Cj-C perfluoroalkoxy, C ⁇ -C 6 perfluorothioalkoxy, and thioxo.
  • substituted cycloalkyl refers to a cycloalkyl group derivatized by independent replacement of one, two, or three hydrogens thereon with a substituent or substituents independently selected from the group consisting of C ⁇ -C 6 alkanoyloxy, C ⁇ -C 6 alkoxy, aryl, azido, cyano, C 3 -C 6 cycloalkyl, halide, optionally protected amino, optionally protected carboxyl, optionally protected hydroxyl, oxo, C ⁇ -C 6 perfluoroalkoxy, C ⁇ -C 6 perfluorothioalkoxy, and thioxo.
  • substituted heterocycle refers to a heterocycle de ⁇ vatized by independent replacement of one, two, or three hydrogens thereon with a substituent or substituents independently selected from the group consisting of C ⁇ -C 6 alkanoyloxy, C--C 6 alkoxy, optionally substituted alkyl, aryl, azido, cyano, C 3 -C 6 cycloalkyl, halide, heterocycle, optionally protected amino, optionally protected carboxyl, optionally protected hydroxyl, oxo, C ⁇ -C 6 perfluoroalkoxy, C ⁇ -C 6 perfluorothioalkoxy, and thioxo.
  • substituted spiroheterocycle refers to a spiroheterocycle group derivatized by independent replacement of one, two, or three hydrogens thereon with a substituent or substituents independently selected from the group consisting of C ⁇ - C alkanoyloxy, C ⁇ -C 6 alkoxy, aryl, heterocycle, azido, cyano, C 3 -C 6 cycloalkyl, halide, optionally substituted alkyl, optionally protected ammo, optionally protected carboxyl, optionally protected hydroxyl, oxo, C ⁇ -C 6 perfluoroalkoxy, C)-C 6 perfluorothioalkoxy, and thioxo.
  • substituted thioalkoxy refers to a thioalkoxy group de ⁇ vatized by independent replacement of one, two, or three hydrogens thereon with a substituent or substituents independently selected from the group consisting of C ⁇ -C 6 alkanoyloxy, -Cg alkoxy, aryl, azido, cyano, C3-C6 cycloalkyl, halide, optionally protected amino, optionally protected carboxyl, optionally protected hydroxyl, oxo, C--C 6 perfluoroalkoxy, -C ⁇ perfluorothioalkoxy, and thioxo.
  • sulfhydryl refers to -SH.
  • sulfomc refers to -SO3H.
  • sulfonyl refers to -SO 2 -.
  • thioalkoxy refers to an alkyl group attached to the parent molecular group through a sulfur atom.
  • the thioalkoxy groups of this invention can be optionally substituted.
  • thiolcarboxyl refers to -C(O)SH.
  • thioxo refers to a group formed by the replacement of two hydrogen atoms on the same carbon atom with a single sulfur atom. It is intended that the definition of any substituent or variable at a particular part in a molecule be independent of its definition elsewhere in the molecule.
  • substituents such as -(CH 2 ) a C(O)R 5 represent -CH 2 C(O)H, and -CH 2 C(O)CH ; and substituents such as -(CH 2 ) a N(R 5 )C(O)N(R 5 ) 2 represent CH 2 CH 2 N(H)C(O)N(CH 3 )(C 3 H 7 ) and -CH 2 N(CH 3 )C(O)NH(CH 3 ), and the like.
  • Asymmet ⁇ c centers can exist in the compounds of the invention.
  • the invention contemplates stereoisomers and mixtures thereof.
  • stereoisomers of compounds are prepared by synthesis from starting mate ⁇ als containing the chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, or direct separation of the enantiomers on chiral chromatographic columns.
  • Starting compounds of particular stereochemistry are either commercially available or are made by the methods described herein and resolved by techniques well-known in the art.
  • the compounds can be administered alone, in combination with, or in concurrent therapy with other antibacterial agents.
  • the specific therapeutically effective dose level for any particular patient will depend upon factors such as the disorder being treated and the severity of the disorder; the activity of the particular compound used; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration; the route of administration; the rate of excretion of the compound employed; the duration of treatment; and drugs used in combination with or coincidently with the compound used.
  • the compounds can be administered orally, parenterally, osmotically (nasal sprays), rectally, vaginally, or topically in unit dosage formulations containing carriers, adjuvants, diluents, vehicles, or combinations thereof.
  • parenteral includes infusion as well as subcutaneous, intravenous, intramuscular, and intrasternal injection.
  • Parenterally adminstered aqueous or oleaginous suspensions of the compounds can be formulated with dispersing, wetting, or suspending agents.
  • the injectable preparation can also be an injectable solution or suspension in a diluent or solvent.
  • acceptable diluents or solvents employed are water, saline, Ringer's solution, buffers, dilute acids or bases, dilute amino acid solutions, monoglycerides, diglycerides, fatty acids such as oleic acid, and fixed oils such as monoglycerides or diglycerides.
  • the antibacterial effect of parenterally administered compounds can be prolonged by slowing their absorption.
  • One way to slow the absorption of a particular compound is adminstering injectable depot forms comprising suspensions of crystalline, amorphous, or otherwise water-insoluble forms of the compound.
  • the rate of absorption of the compound is dependent on its rate of dissolution which is, in turn, dependent on its physical state.
  • Another way to slow absorption of a particular compound is administering injectable depot forms comprising the compound as an oleaginous solution or suspension.
  • injectable depot forms comprising microcapsule matrices of the compound trapped within liposomes, microemulsions, or biodegradable polymers such as polylactide-polyglycolide, polyorthoesters or polyanhydrides.
  • the rate of drug release can be controlled.
  • Transdermal patches also provide controlled delivery of the compounds. The rate of absorption can be slowed by using rate controlling membranes or by trapping the compound within a polymer matrix or gel.
  • absorption enhancers can be used to increase absorption.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound can optionally comprise diluents such as sucrose, lactose, starch, talc, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder, tableting lubricants, and tableting aids such as magnesium stearate or microcrystalline cellulose.
  • diluents such as sucrose, lactose, starch, talc, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder, tableting lubricants, and tableting aids such as magnesium stearate or microcrystalline cellulose.
  • Capsules, tablets and pills can also comprise buffering agents; and tablets and pills can be prepared with enteric coatings or other release-controlling coatings.
  • Powders and sprays can also contain excipients such as talc, silicic acid, aluminum hydroxide, calcium silicate, polyamide powder, or mixtures thereof. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons or substitutes therefor.
  • Liquid dosage forms for oral administration include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs comprising inert diluents such as water. These compositions can also comprise adjuvants such as wetting, emulsifying, suspending, sweetening, flavoring, and perfuming agents.
  • Topical dosage forms include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and transdermal patches.
  • the compound is mixed under sterile conditions with a carrier and any needed preservatives or buffers.
  • These dosage forms can also include excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Suppositories for rectal or vaginal administration can be prepared by mixing the compounds with a suitable nonirritating excipient such as cocoa butter or polyethylene glycol, each of which is solid at ordinary temperature but fluid in the rectum or vagina.
  • a suitable nonirritating excipient such as cocoa butter or polyethylene glycol, each of which is solid at ordinary temperature but fluid in the rectum or vagina.
  • Ophthalmic formulations comprising eye drops, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
  • a further possibility for delivery and utilization of the compounds is chemical conjugation of the compounds with other antibacterials. Similar dual-action conjugates are reported in US 5,281, 703.
  • a covalent bond can be formed between a functional group on a lactam and an amino group at the C-6 position or a carboxylic acid group at the C-3 position of the quinoline or naphthyridine.
  • the total daily dose of the compounds administered to a host in single or divided doses can be in amounts from about 0.1 to about 200 mg/kg body weight or preferably from about 0 25 to about 100 mg/kg body weight.
  • Single dose compositions can contain these amounts or submultiples thereof to make up the daily dose.
  • Specific compounds of the invention include l-cyclopropyl-4-oxo-7-(4,5,6,7-tetrahydroth ⁇ eno[3,2-c]py ⁇ d ⁇ n-2-yl)-l,4-d ⁇ hydro-3- quinohnecarboxylic acid, l-cyclopropyl-8-methoxy-4-oxo-7-(4,5,6,7-tetrahydroth ⁇ eno[3,2-c]pynd ⁇ n-2-yl)- l,4-d ⁇ hydro-3-qu ⁇ nohnecarboxyl ⁇ c acid, l-cyclopropyl-4-oxo-7-(4,5,6,7-tetrahydroth ⁇ eno[3,2-c]py ⁇ dm-2-yl)-l,4- d ⁇ hydro[l ,8]naphthy ⁇ dme-3-carboxyl ⁇ c acid, l-cyclopropyl-6-fluoro-4-oxo-7-(4,5,6,7-t
  • Representative compounds of the invention were assayed in vitro for antibacterial activity. Twelve petri dishes containing successive aqueous dilutions of the test compound mixed with sterilized Brain Heart Infusion (BHT) agar (Difco 0418-01-5) (10 mL) were prepared. Each plate was inoculated with 1:100 (or 1:10 for slow-growing strains, such as Micrococcus and Streptococcus) dilutions of up to 32 different microorganisms using a Steers replicator block. The inoculated plates were incubated at 35-37 °C for about 20 to about 24 hours. In addition, a control plate with BHI agar and no test compound was prepared and incubated at the beginning and end of each test.
  • BHT Brain Heart Infusion
  • MIC minimum inhibitory concentration
  • Representative compounds of the invention were assayed in vitro for antibacte ⁇ al activity
  • the susceptibilities of aerobic, nonfastidious species were determined visually by broth microdilution as described by the National Committee for Clinical Laboratory Standards (NCCLS) (National Committee for Clinical Laboratory Standards. 1997. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically Approved standard M7- A4 National Committee for Clinical Laboratory Standards. Wayne, PA ).
  • NCLS National Committee for Clinical Laboratory Standards
  • M7- A4 National Committee for Clinical Laboratory Standards. Wayne, PA
  • se ⁇ al twofold dilutions of test compounds were made in cation-adjusted Mueller Hinton broth at two-times the final concentration Inocula were prepared from overnight cultures of test strains.
  • Tests were inoculated with a suspension of bacte ⁇ a in Mueller Hinton broth to achieve a final density of approximately 5 x 10 ⁇ CFU/mL. Tests were incubated at 35°C in ambient air for 16 to 20 hr. Minimum Inhibitory Concentrations (MICs) were determined as the lowest drug concentration completely inhibiting growth Ciprofloxacin was included as a control. For testing S. pneumoniae, the cation-adjusted Mueller Hinton broth was supplemented with 3% lysed horse blood and the incubation period was extended to 20 to 24 hr. For testing H.
  • MICs Minimum Inhibitory Concentrations
  • m-CPBA meta-chloroperbenzoic acid
  • dba dibenzylidine acetone
  • dba dibenzylidine acetone
  • CDI carbonyldiimidazole
  • DMAP 4-(N, N- dimethylamino)pyridine
  • DME dimethoxyethane
  • DMF N,N-dimethylformamide
  • DMS dimethylsulfide
  • DMSO dimethylsulfoxide
  • EDCI for l-((3- (dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride
  • TEA triethylamine
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • Precursor compounds, intermediates, and reagents are commercially available or can be prepared from commercially available starting materials.
  • Functional group transformations useful for preparing compounds of the invention are reported in Larock, "Comprehensive Organic Transformations. A Guide to Functional Group Preparations," VCH Publishers, New York (1989).
  • a synthesis of compounds of formula (la) is shown in Scheme 1. Conversion of compounds of formula (i) to compounds of formula (la) can be achieved means such as those reported in U.S. Patent 5,282,703.
  • the starting materials are available commercially or can be prepared by well-known means. For example, commercially available 4-bromo- 2-fluorobenzoic acid (Alfa/Aesar, Ward Hill, MA), ethyl 3-hydroxybenzoate, and 2,6- dichloronicotinic acid (Aldrich Chemical Company, Milwaukee, WI) ultimately provide compounds of formula (la).
  • the synthesis of 3-amino-5-hydroxybenzoic acid, another precursor to compounds of formula (la) is reported in Tetrahedron 39(24), 4189 (1989).
  • compounds of formula (la) can be nitrated with fuming nitric acid in sulfuric acid to provide compounds of formula (ii). Conversion of compounds of formula (ii) to compounds of formula (la) can be achieved with metal powder such as zinc, iron, or tin in acids such as hydrochloric, hydrobromic, sulfuric, acetic, trifluoroacetic, or mixtures thereof. Additional compounds of formula (la) can be prepared by alkylating the amino group at the C-6 position of the compounds of formula (la) with alkyl chlorides, bromides, or iodides in the presence of a base such as cesium carbonate, potassium bicarbonate, sodium hydride, or potassium hydride.
  • compounds of formula (vii) which are commercially available or prepared by means well-known in the art, can be converted to compounds of formula (lb) by treatment with a base such as the lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, n-butyllithium, sec- butyllithium, tert-butyllithium, and lithium diisopropylamide followed by treatment of the lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, n-butyllithium, sec- butyllithium, tert-butyllithium, and lithium diisopropylamide followed by treatment of the lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, n-butyllithium, sec- butyllithium, tert-butyllithium, and lithium diis
  • the halide can be further derivatized by treatment with a metal such as magnesium or zinc to provide the corresponding magnesium halide or zinc halide.
  • the boronic ester can be hydrolyzed to the boronic acid with a base such as lithium hydroxide, sodium hydroxide, and potassium hydroxide or an acid such as hydrochloric or hydrobromic.
  • compounds of formula (I) can be prepared from precursor compounds of formulas (la) and (lb) in the presence of a catalyst.
  • catalysts include tetrakis(triphenylphosphine)palladium(0), palladium(U) chloride(dibenzylidine acetone), and palladium(II) chloride bis(triphenylphosphine).
  • these reactions can be run on the presence of base such as Na 2 CO 3 , CS 2 CO 3 , CsF, and K 2 HPO 4 , additives such as LiCl, or ligands such as triphenylphosphine, triphenylarsine, and trialkylphosphines such as tributylphosphine.
  • base such as Na 2 CO 3 , CS 2 CO 3 , CsF, and K 2 HPO 4
  • additives such as LiCl
  • ligands such as triphenylphosphine, triphenylarsine, and trialkylphosphines such as tributylphosphine.
  • ester group of compounds of formula (I) can be directly converted to aldehydes by treatment of the former with a hydride donating agents such as diisobutylaluminum hydride.
  • a hydride donating agents such as diisobutylaluminum hydride.
  • An alternative conversion of ester groups of compounds of formula (I) to aldehydes is conversion of the corresponding acid to a Weinreb amide,
  • ester group of compounds of formula (I) is conversion of the corresponding acid to a thioester followed by treatment of the thioester with a hydrogen source and a catalyst.
  • hydrogen sources are hydrogen gas or triethylsilane.
  • catalysts are palladium on carbon or platinum on carbon.
  • Example 1A N-methylene-2-(2-thienyl)ethanamine A solution, of 2-thiophenethylamine (10.0 g, 78.0 mmol) in 37% aqueous formaldehyde (2.81 g, 94.0 mmol) was heated to 100 °C for 3 hours, cooled to room temperature, and diluted with ethyl acetate. The layers separated, and the organic layer was washed with brine, dried (Na2SO 4 ) j filtered, and concentrated to provide 9.86 g (91%) of the desired product as a yellow oil. MS (DCI/NH 3 ) m/z 157 (M+H) + ;
  • Example IB 4,5,6 -tetrahvdrothienor3,2-c1pyri dine A solution of Example 1A (17.7 g, 127 mmol) in 5.5M HCI (23 mL) was treated with concentrated HCI (3.1 mL), stirred for 3 hours, and concentrated. The residue was partitioned between IM NaOH and ethyl acetate. The organic phase was washed with brine, dried (Na2SO 4 ), filtered, and concentrated. The residue was purified by flash flash column chromotography on silica gel with 20% methanol in chloroform to provide 4.50 g (25%) of the desired product as a colorless oil. MS (DCI/NH 3 ) m z 157 (M+18) + ;
  • Example IB A solution of Example IB (1.3 g, 9.3 mmol) in THF (5 mL) was added dropwise to a suspension of 60% oily NaH (0.632 g, 15.8 mmol) in THF (30 mL) at 0 °C, stirred for 30 minutes, treated dropwise with a solution of triphenylmethyl chloride (2.95 g, 10.6 mmol) in THF (10 mL), stirred an additional 1 hour, and quenched with water. The resulting mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the combined extracts were washed with brine, dried (Na 2 SO4), filtered, and concentrated.
  • Example ID 2-(tributylstannyl)-5-trityl-4,5,6,7-tetrahvdrothieno[3,2-clpyridine A solution of Example IC (1.77 g, 4.60 mmol) in THF (50 mL) at -78 °C was treated dropwise with 2.5M n-butyllithium in hexanes (2.5 mL, 6.40 mmol), warmed to -10 °C, stirred for 3 hours, cooled to -78 °C, treated dropwise with a solution of chlorotributylstannane (1.65 g, 5.1 mmol) in THF (5 mL), warmed to room temperature, and partitioned between ethyl acetate and water.
  • a solution of Example IE (0.046 g, 0.076 mmol) in absolute ethanol (10 mL) and a minimal amount of chloroform at 0 °C was treated with 4M HCI in dioxane (76 mL, 0.304 mmol), stirred for 30 minutes, and diluted with ethyl ether (10 mL). The precipitate which formed was filtered and washed with ethyl ether to provide 0.015 g (49%) of the desired product as a yellow solid.
  • Example 2A ethyl l-cvclopropyl-8-methoxy-4-oxo-7-(5-trityl-4,5,6,7-tetrahvdrothieno[3,2-clpyridin-2- yl)-l,4-dihydro-3-quinolinecarboxylate
  • Ethyl 7-bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3- quinolonecarboxylate and Example ID were processed as described in Example IE to provide the desired product.
  • Example 2A A solution of Example 2A (0.590 g, 0.884 mmol) in 3: l/THF:water (30 mL) was treated with LiOH ⁇ O (0.337 g, 8.21 mmol) and stirred overnight at room temperature. The reaction mixture was brought to pH 3.5-4.0 with 10% HCI, and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na 2 SO 4 ), filtered, and concentrated to provide 0.553 g (80%) of the desired product which was used without further purification. MS (DCI/NH 3 ) m/z 639 (M+H) + ;
  • Example 2C l-cyclopropyl-8-methoxy-4-oxo-7-(4,5,6,7-tetrahydrothienor3,2-c1pyridin-2-yl)-l,4- dihydro-3-quinolinecarboxylic acid hydrochloride
  • Example 2B was processed as described in Example IF to provide the desired product. mp 180 °C (decomp.); MS (DCI/NH 3 ) m/z 397 (M+H) + ;
  • Example 3 A l-cyclopropyl-4-oxo-7-(5-trityl-4,5,6,7-tetrahydrothieno[3,2-clpyridin-2-yl)-l,4- dihydrori,81naphthyridine-3-carboxylic acid Ethyl l-cyclopropyl-7-chloro-4-oxo-l,4-dihydro[l ,8]naphthyridine-3-carboxylate and Example ID were processed as described in Example IE to provide the desired product.
  • Example 3B l-cvclopropyl-4-oxo-7-(4,5,6,7-tetrahydrothienor3,2-clpyridin-2-yl)-l,4- dihydror 81naphthyridine-3-carboxylic acid hydrochloride
  • Example 3A was processed as described in Example IF to provide the desired product.
  • Example 4 l-cvclopiOpyl-6-fluoro-4-oxo-7-(4 5,6,7-tetrahydrothieno
  • Example 4A ethyl l-cvclopropyl-6-fluoro-4-oxo-7-(5-trityl-4,5,6,7-tetrahvdrothienor3,2-clpyridin-2-yl)- l ,4-dihvdrolT,81naphthyridine-3-carboxylate
  • Ethyl l-cyclopropyl-7-chloro-6-fluoro-4-oxo-l ,4-dihydro[l,8]naphthyridine-3- carboxylate and Example ID were processed as described in Example IE to provide the desired product.
  • Example 4A was processed as described in Example 2B to provide the desired product.
  • Example 4B was processed as described in Example IF to provide the desired product.
  • Example 5A ethyl l-cyclopropyl-8-((difluoromethyDperoxy)-4-oxo-7-(5-trityl-4, 5,6,7- tetrahvdrothienor3,2-clpyridin-2-yl)-l,4-dihvdro-3-quinolinecarboxylate
  • Ethyl l-cyclopropyl-7-bromo-8-difluoromethoxy-4-oxo-l,4-dihydroquinolone-3- carboxylate and Example ID were processed as described in Example IE to provide the desired product.
  • Example 5B l-cyclopropyl-8-(difluoromethoxy)-4-oxo-7-(5-trityl-4,5,6,7-tetrahydrothieno[3,2- clpyridin-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid
  • Example 5A was processed as described in Example 2B to provide the desired product.
  • Example 5C l-cvclopropyl-8-(difluoromethoxy)-4-oxo-7-(4,5,6,7-tetrahydrothieno[3,2-c1pyridin-2-yl)- l,4-dihvdro-3-quinolinecarboxylic acid hydrochloride
  • Example 5B was processed as described in Example IF to provide the desired product.
  • N-methylene-2-(3-thienyl)ethanamine 2-(3-Thienyl)ethylamine was processed according to Example 1A to provide the desired product.
  • Example 6B 4,5,6,7-tetrahydrothieno(2,3-c)pyridine
  • Example 6A was processed as described in Example IB to provide the desired product.
  • Example 6B was processed as described in Example IC to provide the desired product.
  • Example 6D 2-(tributylstannyl)-6-trityl-4,5,6,7-tetrahydrothieno(2,3-c)pyridine
  • Example 6C was processed as described in Example ID to provide the desired product.
  • Example 6E l-cyclopropyl-4-oxo-7-(6-trityl-4,5,6,7-tetrahydrothieno(2,3-c)pyridin-2-yl)-l,4-dihvdro-3- quinolinecarboxylic acid
  • Ethyl 7-bromo-l-cyclopropyl-4-oxo-l,4-dihydro-3-quinolone-3-carboxylate and Example 6D were processed as described in Example IE to provide the desired product.
  • Example 6F l-cyclopropyl-4-oxo-7-(4,5,6,7-tetrahvdrothieno(2,3-c)pyridin-2-yl)-l,4-dihydro-3- quinolinecarboxylic acid hydrochloride
  • Example 6E was processed as described in Example IF to provide the desired product. mp >300 °C;
  • Example 7B l-cyclopropyl-8-methoxy-4-oxo-7-(4,5,6,7-tetrahvdrothieno(2,3-c)pyridin-2-yl)-l,4- dihydro-3-quinolinecarboxylic acid hydrochloride
  • Example 7A was processed as described in Example IF to provide the desired product. mp 188-189 °C; MS (DCI/NH 3 ) m/z 397 (M+H) + ;
  • Example 8A l-cyclopropyl-4-oxo-7-(6-trityl-4,5,6,7-tetrahvdrothieno(2,3-c)pyridin-2-yl)-l,4- dihydrofl,81naphthyridine-3-carboxylic acid
  • Ethyl l-cyclopropyl-7-chloro-4-oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylate and Example 6D were processed as described in Example IE to provide the desired product.
  • Example 8B 1 -cyclopropyl -4-oxo-7-(4,5,6,7-tetrahvdrothieno(2,3-c)pyridin-2-yl)- 1,4- dihvdro[l,81naphthyridine-3-carboxylic acid hydrochloride
  • Example 8A was processed as described in Example IF to provide the desired product. mp 298-300 °C;
  • Example 9A l-cvclopropyl-6-fluoro-4-oxo-7-(6-trityl-4,5,6,7-tetrahvdrothieno(2,3-c)pyridin-2-yl)-l,4- dihydro[l,81naphthyridine-3-carboxylic acid
  • Ethyl l-cyclopropyl-7-chloro-6-fluoro-4-oxo-l,4-dihydro[l,8]naphthyridine-3- carboxylate and Example 6D were processed as described in Example IE to provide the desired product.
  • Example 9B l-cyclopropyl-6-fluoro-4-oxo-7-(4,5,6,7-tetrahydrothieno(2,3-c)pyridin-2-yl)-l,4- dihydro
  • Example 9A was processed as described in Example IF to provide the desired product. mp 290-291 °C;
  • Example 10A ethyl l-cyclopropyl-8-(d ⁇ fluoromethoxy)-4-oxo-7-(6-trityl-4,5,6,7-tetrahydrothieno(2,3- c)pyridin-2-yl)- 1 ,4-dihydro-3-quinolinecarboxylate
  • Ethyl l-cyclopropyl-7-bromo-8-difluoromethoxy-4-oxo-l,4-dihydroquinolone-3- carboxylate and Example 6D were processed as described in Example IE to provide the desired product.
  • Example 10B l-cvclopropyl-8-(d ⁇ fluorometho ⁇ v)-4-oxo-7-(6-t ⁇ tyl-4,5,6,7-tetrahvdroth ⁇ eno(2,3- c)pyr ⁇ d ⁇ n-2-yl)-l,4-d ⁇ hydro-3-qu ⁇ nol ⁇ necarboxyl ⁇ c acid
  • Example 10A was processed as desc ⁇ bed in Example 2B to provide the desired product. MS (DCI NH 3 ) m/z 675 (M+H) + ;
  • Example 10C l-cvclopropyl-8-(d ⁇ fluoromethoxy)-4-oxo-7-(4,5,6,7-tetrahvdroth ⁇ eno(2,3-c)py ⁇ d ⁇ n-2-yl)- l,4-d ⁇ hydro-3-qu ⁇ nol ⁇ necarboxyl ⁇ c acid hydrochlonde
  • Example 10B was processed as described in Example IF to provide the desired product. mp 198-200 °C;
  • Example 11 A was processed as desc ⁇ bed in Example IB to provide the desired product.
  • Example 11C benzyl 6-methyl-6,7-dihydrothieno[3,2-clpyridine-5(4H)-carboxylate
  • THF 20 mL
  • benzyl chloroformate 3.16 g, 18.5 mmol
  • Example I IP benzyl 6-methyl-2-(tributylstannyl)-6,7-dihydrothienof3,2-c1pyridine-5(4H)-carboxylate
  • THF 10 mL
  • 2.5M n-butyllithium in hexanes 1.3 L, 3.36 mmol
  • Example 1 IC This solution was added dropwise via canulae to a solution of Example 1 IC (0.80 g, 2.80 mmol) in THF (10 mL) at -78 °C, stirred for 1 hour at -78 °C, treated with chlorotributylstannane (0.96 g, 2.90 mmol), and warmed to room temperature overnight.
  • the reaction mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate, the combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated to provide 1.50 g (90%) of the desired product as a yellow oil.
  • Example HE ethyl 7-(5-((benzyloxy)carbonyl)-6-methyl-4,5,6,7-tetrahvdrothienor3,2-clpyridin-2-yl)-l- cyclopropyl-4-oxo-l ,4-dihvdro[l ,81naphthyridine-3-carboxylate
  • Ethyl l-cyclopropyl-7-chloro-4-oxo-l,4-dihydro[l ,8]naphthyridine-3-carboxylate and Example 1 ID were processed as described in Example IE to provide the desired product.
  • Example HE was processed as described in Example 2B to provide the desired product. MS (DCI/NH 3 ) m/z 516 (M+H) + ;
  • Example 11G l-cvclopropyl-7-(6-methyl-4,5,6,7-tetrahydrothieno[3,2-c1pyridin-2-yl)-4-oxo-l,4- dihydrori,81naphthyridine-3-carboxylic acid hydrobromide
  • acetic acid 10 mL
  • HBr 30% HBr
  • Example 12A ethyl 7-(5-((benzyloxy)carbonyl)-6-methyl-4,5,6,7-tetrahvdrothienor3,2-clpyridin-2-yl)-l- cyclopropyl-6-fluoro-4-oxo-l,4-dihydrori,81naphthyridine-3-carboxylate
  • Ethyl l-cyclopropyl-7-chloro-6-fluoro-4-oxo-l,4-dihydro[l,8]naphthyridine-3- carboxylate and Example 1 ID were processed as described in Example IE to provide the desired product.
  • Example 12B 7-(5-((benzyloxy)carbonyl)-6-methyl-4,5,6,7-tetrahvdrothienor3,2-clpyridin-2-yl)-l- cyclopropyl-6-fluoro-4-oxo-l,4-dihydrofl,81naphthyridine-3-carboxylic acid
  • Example 12A was processed as described in Example 2B to provide the desired product.
  • Example 12C l-cyclopropyl-6-fluoro-7-(6-methyl-4,5,6,7-tetrahvdrothieno[3,2-clpyridin-2-yl)-4-oxo- l,4-dihydrofl,81naphthyridine-3-carboxylic acid hydrobromide
  • Example 12B was processed as described in Example 11G to provide the desired product.
  • Example 13 A was processed as described in Example 11G to provide the desired product.
  • Example 14A ethyl 7-(5-((benzyloxy)carbonyl)-6-methyl-4,5,6,7-tetrahvdrothieno[3,2-clpyridin-2-yl)-l- cyclopropyl-8-(difluoromethoxy)-4-oxo-l,4-dihvdro-3-quinolinecarboxylate
  • Ethyl l-cyclopropyl-7-bromo-8-difluoromethoxy-4-oxo-l ,4-dihydroquinolone-3- carboxylate and Example 1 ID were processed as described in Example IE to provide the desired product.
  • Example 14B 7-(5-((benzyloxy)carbonyl)-6-methyl-4,5,6,7-tetrahydrothienor3,2-c1pyridin-2-yl)-l- cyclopropyl-8-(difluoromethoxy)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid
  • Example 14A was processed as described in Example 2B to provide the desired product. MS (APCI(+)) m/z 581 (M+H) + ;
  • Example 14C l-cvclopropyl-8-(difluoromethoxy)-7-(6-methyl-4,5,6,7-tetrahvdrothienor3,2-clpyridin-2- yl)-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid hydrobromide
  • Example 14B was processed as described in Example 11G to provide the desired product. mp 210 °C (decomp.); MS (APCI(-)) m/z 481 (M+Cl) " ;
  • Example 15A 7-(5-((benzyloxy)carbonyl)-6-methyl-4,5,6,7-tetrahydrothieno[3,2-clpyridin-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid
  • Ethyl l-cyclopropyl-7-bromo-8-methoxy-4-oxo-l ,4-dihydroquinolone-3- carboxylate and Example 1 ID were processed as described in Example IE to provide the desired product.
  • Example 15B l-cvclopropyl-8-methoxy-7-(6-methyl-4,5,6,7-tetrahvdrothienor3,2-c1pyridin-2-yl)-4-oxo- l ,4-dihvdro-3-quinolinecarboxylic acid hydrobromide
  • Example 15A was processed as described in Example 1 1G to provide the desired product.
  • Example 16A benzyl 4-methyl-6,7-dihvdrothienor3,2-clpyridine-5(4H)-carboxylate 4-Methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (prepared by the method of Descamps, et. al., Binon Bull Soc. Chim. Belg. 1962, 71, 599) was processed as described in Example 11C to provide the desired product. MS (APCI(+)) m/z 288 (M+H) + ;
  • Example 16B benzyl 4-methyl-2-(tributylstannyl)-6,7-dihydrothienor3,2-clpyridine-5(4H)-carboxylate
  • Example 16A was processed according to Example 1 ID to provide the desired product.
  • Example 16C 7-(5-((benzyloxy)carbonyl)-4-methyl-4,5,6,7-tetrahydrothienor3,2-c1pyridin-2-yl)-l- cyclopropyl-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid Ethyl 7-bromo-l-cyclopropyl-4-oxo-l,4-dihydro-3-quinolone-3-carboxylate and
  • Example 16B were processed as described in Example IE to provide the desired product. MS (DCI/NH 3 ) m/z 609 (M+H) + ;
  • Example 16C was processed as described in Example 11G to provide the desired product. mp 203-207 °C (decomp.); MS (APCI(+)) m/z 381 (M+H) + ;
  • Example 17A 7-(5-((benzyloxy)carbonyl)-4-methyl-4,5,6,7-tetrahydrothienor3,2-clpyridin-2-yl)-l- cyclopropyl-4-oxo-l,4-dihydrori,81naphthyridine-3-carboxylic acid
  • Ethyl l-cyclopropyl-7-chloro-4-oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylate and Example 16B were processed as described in Example IE to provide the desired product as a mixture of interconverting conformational isomers.
  • Example 17B l-cyclopropyl-7-(4-methyl-4,5,6,7-tetrahydrothienor3,2-clpyridin-2-yl)-4-oxo-l,4- dihvdro
  • a solution of Example 17A (0.170 g, 0.31 mmol) in trifluoroacetic acid (2 mL) was stirred for 16 hours, concentrated, treated with 4M HCI in dioxane (1 mL), stirred for 30 minutes, concentrated, triturated in diethyl ether, filtered, and washed with diethyl ether to provide 0.047 g (35%) of the desired product as a tan solid, mp 243-245 °C (decomp.); MS (APCI(+)) m/z 382 (M+H) + ;
  • Example 18A 7-(5-((benzyloxy)carbonyl)-4-methyl-4,5,6,7-tetrahydrothienof3,2-clpyridin-2-yl)-l- cvclopropyl-6-fluoro-4-oxo-l,4-dihydrori,81naphthyridine-3-carboxylic acid
  • Ethyl l-cyclopropyl-7-chloro-6-fluoro-4-oxo-l,4-dihydro[l,8]naphthyridine-3- carboxylate and Example 16B were processed as described in Example IE to provide the desired product.
  • Example 18B l-cyclopropyl-6-fluoro-7-(4-methyl-4,5,6,7-tetrahvdrothienof3,2-c1pyridin-2-yl)-4-oxo- l,4-dihydro
  • Example 18A was processed as described in Example 17B to provide the desired product.
  • Example 19B l-cvclopropyl-8-methoxy-7-(4-methyl-4.5,6,7-tetrahvdrothienor3,2-c1pyridin-2-yl)-4-oxo- L4-dihvdro-3-quinolinecarboxylic acid hydrobromide
  • Example 19A was processed as described in Example 11G to provide the desired product. mp 202-205 °C (decomp.); MS (APCI(+)) m/z 411 (M+H) + ;
  • Example 20 A 7-(5-((benzyloxy)carbonyl)-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c1pyridin-2-yl)-l- cvclopropyl-8-(difluoromethoxy)-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid Ethyl 7-bromo-l-cyclopropyl-8-difluoromethoxy-4-oxo-l,4-dihydro-3- quinolonecarboxylate and Example 16B were processed as described in Example IE to provide the desired product as an inseparable mixture of interconverting rotational isomers.
  • Example 20B l-cyclopropyl-8-(difluoromethoxy)-7-(4-methyl-4,5,6,7-tetrahydrothienor3,2-clpyridin-2- yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrobromide
  • Example 20A was processed as described in Example 11G to provide the desired product.
  • Example 21A A solution of Example 21A (1.0 g, 5.9 mmol) in phosphorous oxychloride (6.0 mL, 6.4 mmol) ) at room temperature was treated with phosphorous pentachloride (2.58 g, 12.4 mmol and stirred for 4 hours. The resulting precipitate was collected by filtration and washed with ethyl ether. The solid was suspended in methanol (65 mL), treated with triethylamine (8.42 mL, 6.1 mmol), stirred for 16 hours, cooled to 0 °C, treated with sodium borohydride (0.89 g, 23.5 mmol), stirred for 1 hour at 0 °C and at room temperature for 6 hours.
  • Example 21C benzyl 7-methyl-4,7-dihydrothieno(2,3-c)pyridine-6(5H)-carboxylate
  • Example 21B was processed as described in Example 1 IC to provide the desired product.
  • Example 2 ID benzyl 7-methyl-2-(tributylstannyl)-4,7-dihvdrothieno(2,3-c)pyridine-6(5H)-carboxylate
  • Example 21C was processed as described in Example 11C to provide the desired product.
  • Example 2 IE 7-(6-((benzyloxy)carbonyl)-7-methyl-4,5,6,7-tetrahvdrothieno(2,3-c)pyridin-2-yl)-l- cvclopropyl-4-oxo-l,4-dihvdrori,81naphthyridine-3-carboxylic acid Ethyl l-cyclopropyl-7-chloro-4-oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylate and Example 21D were processed as described in Example IE to provide the desired product.
  • Example 2 IE was processed as described in Example 17B to provide the desired product, mp 310-312 °C;
  • Example 22A 7-(6-((benzyloxy)carbonyl)-7-methyl-4,5,6,7-tetrahydrothieno(2,3-c)pyridin-2-yl)-l- cvclopropyl-6-fluoro-4-oxo-l,4-dihvdrori,81naphthyridine-3-carboxylic acid
  • Example 21D were processed as described in Example IE to provide the desired product.
  • MS (DCI/NH 3 ) m/z 559 (M-2) + .
  • Example 22B l-cyclopropyl-6-fluoro-7-(7-methyl-4,5,6,7-tetrahydrothieno(2,3-c)pyridin-2-yl)-4-oxo- l,4-dihydro[T,81naphthyridine-3-carboxylic acid hydrochloride
  • Example 22A was processed as described in 17B to provide the desired product, mp 293-294 °C;
  • Example 23 A 7-(6-((benzyloxy)carbonyl)-7-methyl-4,5,6,7-tetrahydrothieno(2,3-c)pyridin-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid
  • Example 23B l-cvclopropyl-8-methoxy-7-(7-methyl-4,5,6,7-tetrahydrotheino(2,3-c)pyrindin-2-yl)-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride
  • Example 23A was processed as described in Example 17B to provide the desired product mp 225-227 °C;
  • Example 24 A 2-methyl-2-(2-thienyl)- 1 -propanamine
  • Example 24B N-methylene-N-(2-methyl-2-(2-thienyl)propyl)amine
  • Example 24A was processed as described in Example 1A to provide the desired product.
  • Example 24C 7,7-dimethyl-4,5,6,7-tetrahydrothienor3,2-c]pyridine
  • Example 24B was processed as described in Example IB to provide the desired product.
  • Example 24D benzyl 7,7-dimethyl-6,7-dihvdrothienor3,2-clpyridine-5(4H)-carboxylate
  • Example 24C was processed as described in Example 11C to provide the desired product.
  • Example 24E benzyl 7,7-dimethyl-2-(tributylstannyl)-6,7-dihydrothienor3,2-clpyridine-5(4H)- carboxylate
  • Example 24D was processed as described in Example 11D to provide the desired product. MS (APCI(+)) m/z 591 (M+H) + ;
  • Example 24F 7-(5-((benzyloxy)carbonyl)-7,7-dimethyl-4,5,6,7-tetrahydrothienor3,2-c1pyridin-2-yl)-l- cvclopropyl-4-oxo-l ,4-dihvdro[l,81naphthyridine-3-carboxylic acid
  • Ethyl l-cyclopropyl-7-chloro-4-oxo-l ,4-dihydro[l,8]naphthyridine-3-carboxylate and Example 24E were processed as described in Example IE to provide the desired product.
  • Example 24G l-cvclopropyl-7-(7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-clpyridin-2-yl)-4-oxo-l,4- dihydrori ,81naphthyridine-3-carboxylic acid hydrobromide
  • Example 24F was processed as desc ⁇ bed in 11G to provide the desired product, mp >300 °C (decomp.); MS (APCI(+)) m/z 396 (M+H) + ;
  • Example 24E Ethyl l-cyclopropyl-7-bromo-4-oxo-l,4-d ⁇ hydroqu ⁇ nolone-3-carboxylate and Example 24E were processed as described in Example IE to provide the desired product.
  • Example 25B l-cyclopropyl-7-(7,7-dimethyl-4,5,6,7-tetrahvdrothieno[3,2-clpyridin-2-yl)-4-oxo-l,4- d ⁇ hydro-3-qu ⁇ nol ⁇ necarboxyl ⁇ c acid hydrobromide
  • Example 25A was processed as desc ⁇ bed in 11G to provide the desired product. mp >300 °C (decomp.);
  • Example 26A 7-(5-((benzyloxy)carbonyl)-7,7-d ⁇ methyl-4,5,6,7-tetrahydroth ⁇ enor3,2-clpy ⁇ d ⁇ n-2-yI)-l- cyclopropyI-8-methoxy-4-oxo-l,4-d ⁇ hydro-3-qu ⁇ nol ⁇ necarboxyl ⁇ c acid
  • Ethyl l-cyclopropyl-7-bromo-8-methoxy-4-oxo-l,4-dihydroquinolone-3- carboxylate and Example 24E were processed as described in Example IE to provide the desired product.
  • Example 26B l-cvclopropyl-7-(7,7-dimethyl-4,5,6,7-tetrahydrothienor3,2-clpyridin-2-yl)-8-methoxy-4- oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid hydrobromide
  • Example 26A was processed as described in HG to provide the desired product, mp 212-217 °C (decomp.);
  • Example 27A ethyl 7-(5-((benzyloxy)carbonyl)-7,7-dimethyl-4,5,6,7-tetrahydrothienor3,2-clpyridin-2- yl)-l-cvclopropyl-6-fluoro-4-oxo-l,4-dihvdro[l,81naphthyridine-3-carboxylate
  • Ethyl l-cyclopropyl-7-chloro-6-fluoro-4-oxo-l,4-dihydro[l,8]naphthyridine-3- carboxylate and Example 24E were processed as described in Example IE to provide the desired product.
  • Example 27B 7-(5-((benzyloxy)carbonyl)-7,7-dimethyl-4,5,6,7-tetrahvdrothieno
  • Example 27 A was processed as described in Example 2B to provide the desired product. MS (APCI(-)) m/z 582 (M+Cl) " ;
  • Example 27C l-cvclopropyl-7-(7,7-dimethyl-4,5,6,7-tetrahvdrothienof3,2-c1pyridin-2-yl)-6-fluoro-4- oxo-l,4-dihydro
  • Example 27B was processed as described in Example 11G to provide the desired product. mp 258-262 °C (decomp.);
  • Example 24E were processed as described in Example IE to provide the desired product.
  • Example 28B l-cvclopropyl-8-(difluoromethoxy)-7-(7,7-dimethyl-4,5,6,7-tetrahvdrothienor3,2- clpyridin-2-yl)-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid hydrobromide
  • Example 28A was processed as described in Example 11B to provide the desired product. mp 210-214 °C (decomp.); MS (APCI(+)) m/z 461 (M+H) + ;
  • Example 29A A solution of Example 29A (2.91 g, 21.2 mmol) in THF (10 mL) was added dropwise to a solution of 2M borane-dimethylsulfide in THF (31.8 mL, 63.5 mmol) in THF (100 mL) at 0 °C, warmed to room temperature, stirred for 1 hour, and heated at 60 °C for 3 hours, cooled to 0 °C, treated dropwise with methanol until evolution of gas ceased, diluted with 6M HCI, heated at 50 °C for 3 hours, cooled to room temperature, poured into water, and adjusted to pH 10 with sodium hydroxide, and extracted with dichloromethane.
  • Example 29C 4-methyl-4,5,6,7-tetrahvdrothieno(2,3-c)pyridine
  • Example 29B was processed as described in Example 1A and IB to provide the desired product.
  • Example 29D 4-methyl-6-trityl-4,5,6,7-tetrahvdrothieno(2,3-c)pyridine
  • Example 29C was processed as described in Example IC to provide the desired product.
  • Example 29D was processed as described in Example ID to provide the desired product.
  • Example 29F l-cvclopropyl-7-(4-methyl-6-trityl-4,5,6,7-tetrahvdrothieno(2,3-c)pyridin-2-yl)-4-oxo-l,4- dihydro-3-quinolinecarboxylic acid
  • Ethyl l-cyclopropyl-7-bromo-4-oxo-l,4-dihydroquinoline-3-carboxylate and Example 29E were processed as described in Example IE to provide the desired product.
  • Example 29F was processed as described in Example IF to provide the desired product. mp 295-298 °C;
  • Example 29E 4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid Ethyl l-cyclopropyl-7-bromo-8-methoxy-4-oxo-l,4-dihydroquinoline-3- carboxylate and Example 29E were processed as described in Example IE to provide the desired product. MS (DCI/NH 3 ) m/z 653 (M+H) + .
  • Example 30B l-cvclopropyl-8-methoxy-7-(4-methyl-4,5,6,7-tetrahydrothieno(2,3-c)pyridin-2-yl)-4-oxo- l,4-dihydro-3-quinoIinecarboxylic acid hydrochloride
  • Example 30A was processed as described in Example IF to provide the desired product, mp 254-259 °C;
  • Example 31 A l-cvclopropyl-8-(difluoromethoxy)-7-(4-methyl-6-trityl-4,5,6,7-tetrahydrothieno(2,3- c)pyridin-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid Ethyl l-cyclopropyl-7-bromo-8-difluoromethoxy-4-oxo-l,4-dihydroquinoline-3- carboxylate and Example 29E were processed as described in Example IE to provide the desired product.
  • Example 3 IB l-cyclopropyl-8-(difluoromethoxy)-7-(4-methyl-4,5,6,7-tetrahydrothieno(2,3-c)pyridin-2- yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride
  • Example 31 A was processed as described in Example IF to provide the desired product. mp 218-222 °C;
  • Example 32A l-cyclopropyl-7-(4-methyl-6-trityl-4,5,6,7-tetrahvdrothieno(2,3-c)pyridin-2-yl)-4-oxo-l,4- dihydro
  • Ethyl l-cyclopropyl-7-chloro-4-oxo-l,4-dihydro[l,8]naphthyridine-3-carboxyIate and Example 29E were processed as described in Example IE to provide the desired product.
  • MS (DCI/NH3) m/z 625 (M+H) + .
  • Example 32B l-cvclopropyl-7-(4-methyl-4,5,6,7-tetrahydrothieno(2,3-c)pyridin-2-yl)-4-oxo-l ,4- dihydro l,81naphthyridine-3-carboxylic acid hydrochloride
  • Example 32A was processed as described in Example IF to provide the desired product, mp 284-286 °C; MS (DCI/NH3) m/z 382 (M+H) + ;
  • Example 33 l-cyclopropyl-6-fluoro-7-(4-methyl-4,5,6,7-tetrahydrothieno(2,3-c)pyridin-2-yl)-4-oxo- l ,4-dihydro[l,81naphthyridine-3-carboxylic acid hydrochloride
  • Example 33A l-cvclopropyl-6-fluoro-7-(4-methyl-6-trityl-4,5,6,7-tetrahydrothieno(2,3-c)pyridin-2-yl)-4- oxo-l,4-dihydro
  • Example 29E Ethyl l-cyclopropyl-7-chloro-6-fluoro-4-oxo-l,4-dihydro[l,8]naphthyridine-3- carboxylate and Example 29E were processed as described in Example IE to provide the desired product.
  • Example 33B l-cvclopropyl-6-fluoro-7-(4-methyl-4,5,6,7-tetrahydrothieno(2,3-c)pyridin-2-yl)-4-oxo- l,4-dihydro[l,81naphthyridine-3-carboxylic acid hydrochloride
  • Example 33A was processed as described in Example IF to provide the desired product. mp 288-290 °C;
  • Example 34A was processed as described in Example 29B to provide the desired product. MS (DCI/NH 3 ) m/z 156 (M+H) + .
  • Example 34B was processed as described in Examples 1A, IB, IC, and ID to provide the desired product.
  • Example 34D l-cvclopropyl-7-(4,4-dimethyl-6-trityl-4,5,6,7-tetrahydrothieno(2,3-c)pyridin-2-yl)-8- methoxy-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid
  • Ethyl l-cyclopropyl-7-bromo-8-methoxy-4-oxo-l,4-dihydroquinoline-3- carboxylate and Example 34C were processed as described in Example IE to provide the desired product.
  • Example 34D was processed as described in Example IF to provide the desired product.
  • Example 35A ((2-bromo-4,5,6,7-tetrahydro-l-benzothien-4-yl)oxy)(te ⁇ t-butyl)dimethylsilane
  • 2-bromo-4-keto-4,5,6,7-tetrahydrothianapthene prepared by the method of Pinna, et. al. Eur. J. Med. Chem. Chim.
  • Example 35B 4-(l-methyl-l-(trimethyIsilyl)ethoxy)-4,5,6,7-tetrahydro-l-benzothien-2-ylboronic acid
  • a solution of Example 35 A (1.032 g, 2.97 mmol) in THF (60 mL) at -78 °C was treated dropwise with 1.6M n-butyllithium in hexanes (1.4 L, 3.56 mmol), stirred for 1.5 hours, treated dropwise with triisopropylborate (1.0 mL, 4.45 mmol), stirred for 30 minutes, warmed to room temperature, and stirred for 2 hours.
  • the reaction mixture at 0 °C, treated dropwise with 5% HCI until pH 2, and partitioned between ethyl acetate and water.
  • the aqueous phase was extracted with ethyl acetate, and the combined extracts washed with brine, dried (MgSO 4 ), filtered, and concentrated.
  • the concentrate was purified by flash column chromatography on silica gel with 20% then 33% ethyl acetate in hexanes to provide 0.355 g (38%) of the desired product as a slightly yellow solid.
  • Example 35C ethyl 7-(4-((tert-butyl(d ⁇ methyl)s ⁇ lyl)oxy)-4,5,6,7-tetrahydro-l-benzoth ⁇ en-2-yl)-l- cyclopropyl-6-fluoro-4-oxo-1.4-d ⁇ hvdrori,81naphthy ⁇ d ⁇ ne-3-carboxylate
  • Example 35B (0 102 g, 0.326 mmol), ethyl l-cyclopropyl-7-chloro-6-fluoro-4-oxo- l,4-d ⁇ hydro[l,8]naphthy ⁇ d ⁇ ne-3-carboxylate (0.078 g, 0.251 mmol), cesium carbonate (0.123 g, 0.377 mmol), and Pd(PPH 3 ) 2 Cl 2 (0.018 g, 0.025 mmol) were combined in DMF (5 mL), heated to 100 °C
  • Example 35D 7-(4-((tert-butyl(d ⁇ methyl)s ⁇ lyl)oxy)-4,5,6,7-tetrahydro-l-benzoth ⁇ en-2-yl)-l-cyclopropyl- 6-fluoro-4-oxo-l,4-d ⁇ hydroFl,81naphthy ⁇ d ⁇ ne-3-carboxyl ⁇ c acid
  • Example 35C was processed according to Example 2B to provide the desired product
  • Example 35E l-cyclopropyl-6-fluoro-7-(4-hydroxy-4,5,6,7-tetrahydro-l-benzoth ⁇ en-2-yl)-4-oxo-l,4- d ⁇ hydro ⁇ ,81naphthynd ⁇ ne-3-carboxyhc acid
  • a solution of Example 35D (0.038 g, 0 074 mmol) in THF (5 mL) at 0 °C was treated with IM tetrabutylammonium fluo ⁇ de in THF (0.30 mL, 0.30 mmol), warmed to room temperature, and stirred for 3 hours. The reaction mixture was diluted with saturated ammonium chloride and extracted with ethyl acetate.
  • the extracts were washed with brine, dried (Na 2 SO 4 ), filtered, and concentrated.
  • the concentrate was t ⁇ turated with 5% ethyl ether in pentane, filtered, and washed with pentane to provide 0.020 g (67%) of the desired product as a yellow solid.
  • Example 36A was processed as described in Example 35A to provide the desired product.
  • Example 36C tert-butyl(dimethyl)((2-(tributylstannyl)-5,6-dihydro-4H-thieno[2,3-blthiopyran-4- yl)oxy)silane
  • a solution of Example 36B (0.71 g, 1.94 mmol) in THF (20 ml) at -78 °C was treated dropwise with 1.6M n-butyllithium in hexanes (1.3 ml, 2.14 mmol), stirred for 1 hour, warmed to -30 °C for 30 minutes, recooled to -78 C, and treated dropwise with chlorot ⁇ butylstannane (0.70 g, 2.14 mmol).
  • the reaction mixture was warmed to room temperature over 12 hours, partitioned between saturated ammonium chlo ⁇ de and ethyl acetate, and extracted with ethyl acetate.
  • the combined extracts were washed with water and b ⁇ ne, d ⁇ ed (MgSO 4 ), filtered, and concentrated to provide 1.12 g (100%) of the desired product as an amber oil which was used without further pu ⁇ fication.
  • Example 36D ethyl 7-(4-((tert-butyl(d ⁇ methyl)s ⁇ lyl)oxy)-5,6-d ⁇ hydro-4H-th ⁇ enor2,3-b1th ⁇ opyran-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-d ⁇ hydro-3-qu ⁇ nol ⁇ necarboxylate
  • Ethyl 1 -cyclopropyl-7-bromo-8-methoxy-4-oxo- 1 ,4-d ⁇ hydroqu ⁇ nol ⁇ ne-3- carboxylate and Example 36C were processed as desc ⁇ bed in Example IE to provide the desired product.
  • Example 36E 7-(4-((tert-butyl(d ⁇ methyl)s ⁇ lyl)oxy)-5,6-d ⁇ hydro-4H-th ⁇ enor2,3-blth ⁇ opyran-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-d ⁇ hvdro-3-qu ⁇ nol ⁇ necarboxyl ⁇ c acid
  • Example 36D was processed as described in Example 2B to provide the desired product
  • Example 36F l-cvclopropyI-7-(4-hvdroxy-5,6-d ⁇ hydro-4H-th ⁇ enor2,3-blth ⁇ opyran-2-yl)-8-methoxy-4- oxo-l,4-d ⁇ hydro-3-qu ⁇ nol ⁇ necarboxyl ⁇ c acid
  • Example 36E was processed as described in Example 35E to provide the desired product
  • Example 37A ethyl l-cyclopropyl-7-(4-hydroxy-5,6-dihvdro-4H-thieno[2,3-blthiopyran-2-yl)-8- methoxy-4-oxo- 1 ,4-dihvdro-3-quinolinecarboxylate
  • Example 36D was processed as described in Example 35E to provide the desired product.
  • Example 37B ethyl 7-(4-azido-5,6-dihydro-4H-thienof2,3-blthiopyran-2-yl)-l-cyclopropyl-8-methoxy-4- oxo- 1 ,4-dih ydro-3-quinolinecarboxylate
  • DPPA DPPA
  • DBU 83 mL, 0.553 mmol
  • Example 37C 7-(4-am ⁇ no-5,6-d ⁇ hydro-4H-th ⁇ eno[2,3-b1th ⁇ opyran-2-yl)-l-cyclopropyl-8-methoxy-4-oxo- l,4-d ⁇ hydro-3-qu ⁇ nol ⁇ necarboxyl ⁇ c acid hydrochlo ⁇ de
  • reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride, and the organic phase was washed with water and brine, d ⁇ ed (Na 2 SO 4 ), filtered, and concentrated.
  • the residue was pu ⁇ fied by flash column chromatography on silica gel with 33% acetone in hexanes to provide the desired product as an inseparable mixture with tnphenylphosphine oxide.
  • Example 2B The mixture was processed as desc ⁇ bed in Example 2B to provide a carboxylic acid that was used without further purification.
  • Example 38A tert-butyl(d ⁇ methyl)(4,5,6,7-tetrahvdro-l-benzoth ⁇ en-4-yloxy)s ⁇ Iane 4-Keto-4,5,6,7-tetrahydroth ⁇ anapthene was processed as desc ⁇ bed in Example 35A to provide the desired product.
  • Example 38B tert-butyl(dimethyl)((2-(tributylstannyI)-4,5,6,7-tetrahydro-l-benzothien-4-yl)oxy)silane
  • Example 38A was processed as desc ⁇ bed in Example ID to provide the desired product.
  • ⁇ NMR (300 MHz, CDC1 3 ) ⁇ 7.02 (s, IH), 4.82 (m, IH), 2.78 (m, 2H), 2.00 (m, 2H), 1.73 (m, 2H), 1.56 (m, 6H), 1.33 (m, 6H), 1.05 (m, 6H), 0.93 (s, 9H), 0.89 (t, 9H), 0.12 (s, 3H), 0.15 (2, 3H).
  • Example 38B Ethyl 7-bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3- quinolonecarboxylate and Example 38B were processed as described in Example IE to provide the desired product.
  • Example 38D l-cvclopropyl-7-(4-hvdroxy-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-8-methoxy-4-oxo-l,4- dihydro-3-quinolinecarboxylic acid
  • Example 38C was processed as described in Example 35E to provide the desired product. mp 237-239 °C;
  • Example 39A methyl 7-(4-((tert-butyl(dimeth yl)si I yI)oxy)-4,5,6,7-tetrah ydro- 1 -benzothien-2-yl)- 1 - cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate
  • a solution of Example 38C (2.15 g, 4.10 mmol) in 1: 1 methanol:THF (50 mL) at 0 °C was treated with 2M trimethylsilyldiazomethane in hexanes (9.70 mL, 19.4 mmol), warmed to room temperature over 5 hours, treated with acetic acid (15 drops), and poured into water.
  • Example 39B methyl l-cyclopropyl-7-(4-hvdroxy-4,5,6,7-tetrahydro-l-benzothien-2-yI)-8-methoxy-4- oxo- 1 ,4-dihydro-3-quinolinecarboxylate
  • Example 39A was processed as described in Example 35E to provide the desired product. MS (DCI/NH 3 ) m/z 426 (M+H) + ;
  • Example 39C methyl 7-(4-azido-4,5,6,7-tetrahydro-l-benzothien-2-yI)-l-cyclopropyl-8-methoxy-4-oxo- l,4-dihydro-3-quinolinecarboxyIate
  • Example 39B was processed as described in Example 37B to provide the desired product. MS (DCI/NH 3 ) m/z 451 (M+H) + ;
  • Example 39C was processed as described in Example 2B to provide the desired product. mp 134-136 °C;
  • Example 40A methyl 7-(4-((tert-butoxycarbonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate
  • a solution of Example 39C (0.30 g, 0.7 mmol) in 10: 1 THF:water (33 mL) was treated with triphenylphosphine (0.70 g, 2.7 mmol), heated at 60 °C for 17 hours, cooled, treated sequentially with sodium bicarbonate (0.22 g, 2.6 mmol) and di-(tert- butyl)dicarbonate (0.26 g, 1.2 mmol), stirred for 6 hours, and poured into water.
  • Example 40A was processed as described in Example 2B to provide the desired product. MS (DCI/NH 3 ) m/z 511 (M+H) + ;
  • Example 40C 7-(4-amino-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4- dihydro-3-quinolinecarboxylic acid hydrochloride
  • a solution of Example 40B (0.087 g, 0.20 mmol) in dichloromethane (2 mL) at room temperature was treated with 4M HCI in dioxane (6 mL, 24.0 mmol), stirred for 2 hours, and concentrated. The concentrate was triturated with diethyl ether and filtered. The solid was rinsed with diethyl ether and dried to provide 0.059 g (76%) of the desired product as a yellow solid, mp 219-222 °C;
  • Example 41 A tert-butyl(dimethyl)(4,5,6,7-tetrahvdro-l-benzothien-7-yloxy)silane 7-keto-4,5,6,7-tetrahydrothienanapthene (prepared by the method of MacDowell, et al. J. Heterocycl Chem. 1965, 44-48) was processed as described in Example 35A to provide the desired product. MS (APCI(+)) m/z 267 (M+H) + ;
  • Example 41B tert-butyl(dimethyl)((2-(tributylstannyl)-4,5,6,7-tetrahydro-l-benzothien-7-yl)oxy)silane
  • Example 41 A was processed as described in Example ID to provide the desired product.
  • Example 41C ethyl 7-(7-((tert-butyl(dimethyl)silyl)oxy)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo- l ,4-dihydro-3-quinolinecarboxylate
  • Ethyl 7-bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3- quinolonecarboxylate and Example 41A were processed as described in Example IE to provide the desired product.
  • Example 4 ID ethyl 4-cyclopropyl-6-(7-hydroxy-4,5,6,7-tetrahydro-l-benzothien-2-yl)-5-methoxy-l-oxo- l,4-dihydro-2-naphthalenecarboxylate
  • Example 41C was processed as described in Example 35E to provide the desired product, mp 183-185 °C; MS (APCI(+)) m/z 440 (M+H) + ;
  • Example 4 IE l-cvclopropyl-7-(7-hvdroxy-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-8-methoxy-4-oxo-l,4- dihydro-3-quinolinecarboxylic acid
  • Example 4 ID was processed as described in Example 2B to provide the desired product. mp 238-240 °C;
  • Example 42A tert-butyl(dimethyl)(4,5,6,7-tetrahvdro-l-benzothien-5-yloxy)silane 5-keto-4,5,6,7-tetrahydrothianapthene (prepared by the method of Padwa, et al. I. Org. Chem. 1989, 54, 299-308) was processed as described in Example 35A to provide the desired product.
  • Example 42B tert-butyl(dimethyl)((2-(tributylstannyl)-4,5,6,7-tetrahydro-l-benzothien-5-yl)oxy)silane
  • Example 42A was processed as described in Example ID to provide the desired product.
  • Example 42C 7-(5-((tert-butyl(dimethyl)silyl)oxy)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl- 8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid
  • Ethyl 7-bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3- quinolonecarboxylate and Example 42B were processed as described in Example IE to provide the desired product.
  • Example 42D l-cvclopropyl-7-(5-hydroxy-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-8-methoxy-4-oxo-l,4- dihydro-3-quinolinecarboxylic acid
  • Example 42C was processed as described in Example 35E to provide the desired product, mp 232-233 °C;
  • Example 43A and Example 44A tert-butyl(dimethyl)(4,5,6,7-tetrahvdro-l-benzothien-5-ylmethoxy)silane and tert-butyl(6,7-dihvdro-l-benzothien-5-ylmethoxy)dimethylsilane
  • a solution of methyl 6,7-dihydrobenzothiophene-5-carboxylate (5.0 g, 25.77 mmol) (prepared by the method of Amemiya, et al. J. Med. Chem.
  • a solution of first oil (3.5 g, 17.86 mmol) in diethyl ether (38 ml) at 5 °C was treated with lithium aluminum hydride powder (0.68 g, 17.86 mmol), stirred for 10 minutes at 5 °C and for 30 minutes at room temperature, and quenched with Na 2 SO4.10 H 2 O (6.56 g), and filtered. The filtrate was concentrated to provide 3.0 g (100%) of a second oil comprising 5-hydroxymethyl 4,5,6,7-tetrahydrobenzothiophene and 5- hydroxymethyl 6,7-dihydrobenzothiophene.
  • Example 43 A tert-butyl(dimethyl)(4,5,6,7-tetrahydro-l-benzothien-5- ylmethoxy)silane, 1.0 g, (20%). MS (DCI NH 3 ) m/z 283 (M+H) + ;
  • Example 43B tert-butyl(dimethyl)((2-(tributylstannyl)-4,5,6,7-tetrahvdro-l-benzothien-5- yl)methoxy)silane
  • Example 43A was processed as described in Example ID to provide the desired product.
  • Example 43C ethyl 7-(5-(((tert-butyl(dimethyl)silv ⁇ oxy)methyl)-4,5,6,7-tetrahydro-l-benzothien-2-yl)- l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate
  • Ethyl 7-bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3- quinolonecarboxylate and Example 43B were processed as described in Example IE to provide the desired product.
  • Example 43D ethyl l-cyclopropyl-7-(5-(hydroxymethyl)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylate
  • Example 43C was processed as described in Example 35E to provide the desired product.
  • Example 43E l-cvclopropyl-7-(5-(hvdroxymethyl)-4.5,6,7-tetrahvdro-l-benzothien-2-yl)-8-methoxy-4- oxo-l,4-dihvdro-3-quinolinecarboxylic acid
  • Example 43C was processed as described in Example 2B to provide the desired product, mp 218-219 °C; MS (ESI(+)) m/z 412 (M+H) + ;
  • Example 44B tert-butyl(dimethyl)((2-(tributylstannyl)-6,7-dihydro-l-benzothien-5-yl)methoxy)silane
  • Example 44A was processed as described in Example ID to provide the desired product.
  • Example 44D ethyl l-cyclopropyl-7-(5-(hydroxymethyl)-6,7-dihydro-l-benzothien-2-yl)-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxylate
  • Example 44C was processed as described in Example 35E to provide the desired product.
  • Example 44D was processed as described in Example 2B to provide the desired product, mp 205-206 °C; MS (ESI(+)) m/z 424 (M+H) + ; 1H NMR (300 MHz, CDCI3) 8.90 (s, IH), 8.23 (d, IH), 7.76 (d, IH), 7.42 (s, IH), 6.51 (m, IH), 4.86 (s, IH), 4.27 (s, 2H), 4.11 (m, IH), 3.68 (s, 3H), 3.01 (t, 2H), 2.50 (t, 2H), 1.28 (m, 2H), 1.06 (m, 2H).
  • Example 45A 4,6-dihvdro-5H-cvclopentarblthiophen-5-one
  • dichloromethane 1.55 mL
  • dirhodium tetraacetate 125 mg
  • the residue was purified by flash column chromatography on silica gel with hexanes then 5% ethyl acetate in hexanes to provide 2.83 g (31%) of the desired product as a white solid.
  • 1H NMR 300 MHz, CDCI 3 ) 7.26 (ddd, IH), 6.97 (d, IH), 3.54 (s, 2H), 3.42 (s, 2H).
  • Example 45B A solution of Example 45B (1.69 g, 12.23 mmol) in THF (61 mL) at 0 °C was treated dropwise over 10 minutes with IM solution of lithium aluminum hydride in THF
  • Example 45D tert-butyl(5,6-dihydro-4H-cyclopentarblthien-5-yloxy)dimethylsilane
  • Example 45E tert-butyl(d ⁇ methyl)((2-(tr ⁇ butylstannyl)-5,6-d ⁇ hvdro-4H-cyclopenta
  • Example 45D was processed as desc ⁇ bed in Example ID to provide the desired product.
  • Example 45F ethyl 7-(5-((tert-butyl(d ⁇ methyl)s ⁇ lyl)oxy)-5,6-d ⁇ hvdro-4H-cyclopentarblth ⁇ en-2-yl)-l- cvclopropyl-8-methoxy-4-oxo-l,4-d ⁇ hydro-3-qu ⁇ nol ⁇ necarboxyIate
  • Ethyl 7-bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-d ⁇ hydro-3- quinolonecarboxylate and Example 45E were processed as desc ⁇ bed in Example IE to provide the desired product.
  • Example 45G ethyl l-cvclopropyl-7-(5-hydroxy-5,6-d ⁇ hydro-4H-cyclopenta[blth ⁇ en-2-yl)-8-methoxy-4- oxo-l,4-d ⁇ hydro-3-qu ⁇ nol ⁇ necarboxylate
  • THF trifluoride
  • py ⁇ dinium hydrofluonde 15 mL
  • Example 45G was processed as described in Example 2B to provide the desired product. mp 254-255 °C; MS (ESI(+)) m/z 398 (M+H) + ;
  • Example 46A 4-methoxy-5,6-dihydro-4H-cycIopentarblthiophene
  • 56-dihydrocyclopenta[b]thiophene-4-one (1.25 g, 9.06 mmol, prepared by the method of Balenkova, E. S., et al Tetrahedron Lett. 1996, 37, 4199) in methanol at 0 °C was treated portionwise with NaBHi, stirred at room temperature for 45 minutes, quenched with IM HCI, and extracted 3 times with ethyl acetate.
  • Example 46B methyl 2-(tributylstannyl)-5,6-dihydro-4H-cyclopentafblthien-4-yl ether
  • Example 46A was processed as described in Example ID to provide the desired product.
  • Example 47A tert-butyl(dimethyl)(4,5,6,7-tetrahydro-l-benzothien-6-vIoxy)silane 4,5-Dihydrobenzo[b]thiophene-6(7H)-one (prepared by the method of Padwa, A., et al. J. Org. Chem. 1989, 54, 299) was processed according to Example 35A to provide the desired product.
  • Example 47B tert-butyl(dimethyl)((2-(tributylstannyl)-4,5,6,7-tetrahydro-l-benzothien-6-yl)oxy)silane
  • Example 47A was processed as described in Example ID to provide the desired product.
  • ⁇ NMR (300 MHz, DMSO-d 6 ) ⁇ 6.79 (s, IH), 4.18-4.10 ( , IH), 3.05-2.93 (m, IH),
  • Example 47C 7-(6-((tert-butyl(dimethyl)silyl)oxyV4.5.6,7-tetrahydro-l-benzothien-2-yl)-l-cvclopropyl- 8-methoxy-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid
  • Ethyl 7-bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3- quinolonecarboxylate and Example 47B were processed as described in Example IE to provide the desired product.
  • Example 47C was processed as described in Example 35E to provide the desired product.
  • Example 48A tert-butyl(6,7-dihydro-l-benzothien-4-yloxy)dimethylsilane
  • a solution of 1.0M lithium bis(trimethylsilyl)amide in THF (26.4 mL, 26.4 mmol) at -40 °C was treated dropwise with a solution of 4-keto-4,5,6,7-tetrahydrothianaphthene (3.64 g, 24.0 mmol) in THE (30 mL), stirred for 2 hours, and treated dropwise with a solution of t-butyldimethylsilyl chloride (3.72 g, 24.8 mmol) in THF (30 mL).
  • Example 48B was processed as described in Example ID to provide the desired product.
  • Example 48C ethyl 1 -cyclopropyl-6-fluoro-4-oxo-7-(4-oxo-4,5 ,6,7-tetrahydro- 1 -benzothien-2-yl)- 1 ,4- dihydrori,81naphthyridine-3-carboxylate
  • Ethyl 7-chloro-l-cyclopropyl-6-fluoro-4-oxo-l,4-dihydro[l,8]napthyridine-3- carboxylate and Example 48B were processed as described in Example IE to provide the desired product.
  • Example 48C A solution of Example 48C (0.155 g, 0.37 mmol) in ethanol (3 mL) was treated with IM HCI (3.7 mL, 3.7 mmol), heated at 90 °C for 5 hours, and concentrated. The residue was dissolved in dichloromethane, washed with water, dried (Na 2 SO 4 ), filtered, and concentrated to provide 0.065 g (44%) of the desired product as a pale yellow solid. mp 298-299 °C (decomp.);
  • Example 49 l-cvclopropyl-6-fluoro-7-((4E)-4-(hvdroxyimino -4,5,6,7-tetrahydro-l-benzothien-2-yl)-4- oxo-l,4-dihydrorL81naphthyridine-3-carboxylic acid
  • Example 48D (0.250 g, 0.62 mmol) was suspended in 2:1 ethanol/THF (8 mL), and treated with hydroxylamine hydrochloride (0.161 g, 2.50 mmol) and sodium bicarbonate (0.218 g, 2.60 mmol) in water (3 mL), heated at 75 °C for 24 hours, cooled to room temperature, and diluted with to form a precipitate.
  • Example 50A ethyl l-cyclopropyl-8-methoxy-4-oxo-7-(4-oxo-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l,4- dihvdro-3-quinolinecarboxylate
  • Ethyl 7-bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3- quinolonecarboxylate and Example 48B were processed as described in Example IE to provide the desired product.
  • Example 50B l-cvclopropyl-8-methoxy-4-oxo-7-(4-oxo-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l,4- dihydro-3-quinolinecarboxylic acid
  • Example 50A was processed as described in Example 48D to provide the desired product. mp 266-267 °C;
  • Example 51 l-cvclopropyl-7-((4E)-4-(hydroxyimino)-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid
  • Example 50B was processed as described in Example 49 to provide the desired product. mp 296-297 °C;
  • Example 52 l-cyclopropyl-8-diflouromethoxy-7-(7-methyl-4,5,6,7-tetrahvdrotheino(2,3-c)pyrindin-2- yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride Ethyl 7-bromo-l-cyclopropyl-8-difluoromethoxy-4-oxo-l,4-dihydro-3- quinolinecarboxylate and Example 2 ID were processed as described in Example IE to provide the desired product, mp 222-225 °C;
  • Example 53A A solution of 5-keto-4,5,6,7-tetrahydrothianapthene (prepared by the method of Padwa, et al. J. Org. Chem. 1989, 54, 299-308.) (3.00g, 19.7 mmol), ethylene glycol (2.50g, 40.0 mmol), and p-toluenesulfonic acid (0.380g, 2.00 mmol) in toluene was heated to 100°C overnight. After cooling, the mixture was partitioned between ethyl acetate and water. The organic phase was washed with saturated aqueous sodium bicarbonate, water, and brine, dried (Na 2 SO 4 ), and concentrated. The resulting residue was purified by chromatography on silica gel eluting with 10% ethyl acetate in hexane to provide the desired product (3.44g, 89%) as a yellow oil.
  • Example 53B The desired product was prepared by substituting example 53A for examplelC in example ID.
  • the desired product was prepared by substituting example 53B and ethyl 7-bromo- l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate for example ID and ethyl 7-bromo-l-cyclopropyl-4-oxo-l,4-dihydro-3-quinolinecarboxylate, respectively in example IE.
  • Example 53D l-cyclopropyI-8-methoxy-4-oxo-7-(5-oxo-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l,4- dihydro-3-quinolinecarboxylic acid
  • the desired product was prepared by substituting example 53C for example 48C in example 48D.
  • Example 54 7-r5-(azidomethyl)-4,5,6,7-tetrahvdro-l-benzothien-2-yll-l-cyclopropyl-8-methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid
  • 70A 0.040 g, 0 084mmol
  • aqueous sodium hydroxide 1 mL of a 1 M solution
  • ethanol ethanol
  • the mixture was cooled to room temperature and acidified with 6 N HCI (0.2 mL) then extracted with ethyl acetate, dried (MgSO 4 ), and concentrated.
  • the desired product was prepared by substituting example 53D for example 48D in example 49.
  • Example 57A N-methylene-l-(3-th ⁇ enyl)-2-propanam ⁇ ne
  • the desired product was prepared by substituting 3-(2-am ⁇ nopropyl)-th ⁇ ophene (prepared by the method of Anne-Archard, et al. Eur. Pat. Appl. 82-401132) for 2- thiophenethylamine in example 1-A
  • Example 57B The desired product was prepared by substituting example 57 A for example 1 A in example IB
  • Example 57C The desired product was prepared by substituting example 57B for example 1 IB in example l lC.
  • Example 57D The desired product was prepared by substituting example 57C for example 218B in example 218C
  • Example 57E ethyl 7- ⁇ 6-r(benzyloxy)carbonyll-5-methyl-4,5,6,7-tetrahydrothieno[2,3-clpyridin-2-yl ⁇ -l- cyclopropyl-8-methoxy-4-oxo-l,4-d ⁇ hydro-3-qu ⁇ nol ⁇ necarboxylate
  • the desired product was prepared by substituting example 57D and ethyl 7-bromo- l-cyclopropyl-8-methoxy-4-oxo-l,4-d ⁇ hydro-3-qu ⁇ nohnecarboxylate and a reaction time of 4 hours for example ID and 7-bromo-l-cyclopropyl-4-oxo-l,4-d ⁇ hydro-3- quinohnecarboxylate and a reaction time of 24 hours, respectively in example IE.
  • the desired product was prepared by substituting example 57E for example 2A in example 2B.
  • the desired product was prepared by substituting example 57F for example 40B in example 40C. mp 156-157° C; MS (APCI) m/z 367 (M+H) + ;
  • the desired product was prepared by substituting example 48B and ethyl 7-bromo- l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate for example ID and ethyl 7-bromo-l-cyclopropyl-4-oxo-l,4-dihydro-3-quinolinecarboxylate in example IE.
  • example 58A (1.64 g, 3.0 mmol) in dichloromethane (40 mL) was treated with 4-(dimethylamino)pyridinium tribromide (1.45 g, 4.0 mmol) and stirred at room temperature for 3 hours.
  • the reaction mixture was partitioned between water and dichloromethane, dried (Na 2 SO 4 ) and concentrated.
  • the resulting mixture was separated by silica gel chromatography eluting with 1% methanol in dichloromethane to give example 58B (0.1 lg, 8%) and example 62A .
  • Example 59A The desired product was prepared by substituting example 47B and ethyl 7-bromo- l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate for example ID and ethyl 7-bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate, respectively in example IE and was purified by chromatography on silica gel eluting with 20% ethyl acetate in hexanes.
  • Example 59B The desired product was prepared by substituting example 59A for example 35D in example 35E and was purified by chromatography on silica gel eluting with 50% ethyl acetate in hexane.
  • Example 59C The desired product was prepared by substituting example 59B for example 41C in example 324511A and was used without further purification.
  • Example 59D l-cyclopropyl-8-methoxy-4-oxo-7-(6-oxo-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l,4- dihydro-3-quinolinecarboxylic acid
  • the desired product was prepared by substituting example 59C and THF as reaction solvent for example 59C and EtOH as reaction solvent, respectively in example 59D.
  • the desired product was prepared by substituting example 59D for example 59D in example 49 and the product isolated by partitioning the reaction mixture between ethyl acetate and water, the organic phase dried (Na 2 SO 4 ), and the concentrated residue triturated with hexanes to afford a white solid.
  • Example 6 IB l-cyclopropyl-8-methoxy-4-oxo-7-(7-oxo-4,5,6,7-tetrahydro- l-benzothien-2-yl)-l,4- dihvdro-3-quinolinecarboxylic acid
  • the desired product was prepared by substituting example 61A for example 2A in example 2B.
  • example 58 A A solution of example 58 A (1.64 g, 3.0 mmol) in dichloromethane (40 mL) was treated with 4-(dimethylamino)pyridinium tri bromide (1.45 g, 4.0 mmol) and stirred at room temperature for 3 hours. The reaction mixture was partitioned between water and dichloromethane, dried (Na 2 SO ) and concentrated. The resulting mixture was separated by silica gel chromatography eluting with 1% methanol in dichloromethane to give example 58B (0.1 lg, 8%) and example 62A .
  • Example 62B A solution of example 62A (0.10 g, 0.19 mmol) in DMSO (5 mL) was treated with sodium azide (0.015 g, 0.23 mmol) and stirred at room temperature for 2 hours. The reaction mixture was partitioned between water and dichloromethane, the aqueous layer extracted with dichloromethane, the combined organic layers washed with brine, dried (Na2SO4), and concentrated to yield the desired product (0.054 g, 58%).
  • Example 63 l-cyclopropyl-8-methoxy-7-((7E/Z)-7-(methoxy ⁇ m ⁇ no)-4,5,6,7-tetrahvdro-l-benzoth ⁇ en-2- yl)-4-oxo-l,4-d ⁇ hvdro-3-qu ⁇ nol ⁇ necarboxyl ⁇ c acid
  • MS (ESI) m/z 408 (M-OCH 3 +H) "
  • Example 64 l-cyclopropyl-8-methoxy-7-((4E/Z)-4-(methoxyim ⁇ no)-4,5,6,7-tetrahydro-l-benzoth ⁇ en-2- yl)-4-oxo-l,4-d ⁇ hydro-3-qu ⁇ nol ⁇ necarboxyl ⁇ c acid
  • a solution of example 50 (0.120 g, 0.3 mmol) was suspended in 4 mL of MeOH and treated with NaOAc (0.125 g, 1.5 mmol) and methoxylamine hydrochlo ⁇ de (0.218 g, 1.6 mmol) The reaction mixture was heated at 90° C for 18 hours. The solvent was removed and 20 mL of 10% NH C1 was added. The product was isolated by suction filtration and was d ⁇ ed under vacuum giving the desired product as a white solid (0.100 g, 76%). mp 232-233° C;
  • the desired product was prepared by substituting O- ethylhydroxylamine hydrochlo ⁇ de for hydroxylamine hydrochloride in example 49. mp 208-210° C; MS (APCI) m/z 453 (M+H) + ; ⁇ NMR (300MHz, DMSO-cf 6 ) ⁇ 8.82 (s, IH), 8.13 (d, IH), 8.05 (d, IH), 7.88 (s, IH), 4.27 (m, IH), 4.15 (q, 2H), 3.69 (s, 3H), 3.30(s, IH), 2.90 (dd, 2H), 2.67 (dd, 2H), 1.92 (m, 2H), 1.28 (t, 3H), 1.15 ( , 2H), 1.05 (m, 2H).
  • the desired product was prepared by substituting example 59D and O- methylhydroxylamine for example 59D and hydroxylamine hydorchloride, respectively in example 49 and the product isolated by partitioning the reaction mixture between ethyl acetate and water, the organic phase dried (Na 2 SO 4 ), and the concentrated residue triturated with hexanes to afford a white solid.
  • Example 67B The desired product was prepared by substituting example 67A for example IC in example ID.
  • Example 67C The desired product was prepared by substituting example 67B and ethyl 7-bromo- l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate for example ID and ethyl 7-bromo-l-cyclopropyl-4-oxo-l,4-dihydro-3-quinolinecarboxylate, respectively in example IE.
  • Example 67D l-cvclopropyl-7-(6,7-dihydro-l-benzothien-2-yl)-8-methoxy-4-oxo-l,4-dihydro-3- quinolinecarboxylic acid
  • Example 68 l-cyclopropyl-8-methoxy-7-((4E/Z)-4-(4-mo holinylimino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid
  • the desired product was prepared by substituting N-aminomorpholine and a reaction time of 48 hours for 1-aminopyrrolidine hydrochloride and a reaction time of 24 hours in example 74. mp 118-120° C; MS (APCI) m/z 494 (M+H) + ;
  • Example 69A A solution of example 67C (0.130g, 0.30mmol) in 1: 1:1 t-butanol acetone:H 2 O was treated with 4-methyl mo ⁇ hohne N-oxide (0 060g, 0.51 mmol) and osmium tetraoxide ( 0.005g, 0.02 mmol). The mixture was stirred at 0°C for 7 h Sodium sulfite (0.400g) was added, the reaction was warmed to 25°C, stirred for 1 h, and partitioned between CH 2 C1 2 and water. The layers were separated, and the aqueous layer was extracted 3 times with CH 2 C1 2 .
  • Example 70 7-(5-(am ⁇ nomethyl)-4,5,6,7-tetrahydro-l-benzoth ⁇ en-2-yl)-l-cyclopropyl-8-methoxy-4- oxo-l,4-d ⁇ hydro-3-qu ⁇ nol ⁇ necarboxyl ⁇ c acid hydrochlonde
  • Example 70A The desired product was prepared by substituting example 43D for example 37A and DMF at 65°C for toluene:dichloromethane at room temperature in example 37B.
  • Example 70B The desired product was prepared by substituting example 70A for example 20 IC in example 201D.
  • example 70B (0.660 g, 1.2 mmol) in ethanol (3 mL) was treated with aqueous sodium hydroxide (3 mL of a 1 M solution) for 17 h at room temperature. The mixture was acidified with acetic acid (8mL) then concentrated. The resulting acid was purified by chromatography on silica gel eluting with 30% acetone in hexane with 0.5% acetic acid then 40% acetone in hexane with 0.5% acetic acid to provide the desired product (0.590 g, 94%) as an off white solid.
  • Example 70D 7-(5-(aminomethyl)-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride
  • Example 71 A solution of example 59C (0.061 g, 0.139 mmol) in MeOH (6 ml) was treated with 3 A molecular sieves, ammonium acetate (0 107 g, 1.39 mmol) and sodium cyanoborohyd ⁇ de (0.009 g, 0.139mmol) and was stirred at room temperature for 2 hours. The reaction mixture was treated with 2 drops AcOH followed by di-tert-butyldicarbonate (0.303 g, 1.39 mmol), stirred for an additional 2 hours and partitioned between saturated aqueous NH4C1 and ethyl acetate.
  • Example 7 IB The desired product was prepared by substituting example 71 A for example 2 A in example 2B.
  • Example 72 7-((4E/Z)-4-(tert-butoxyimino)-4,5,6 -tetrahydro-l-benzothien-2-yI)-l-cyclopropyl-8- methoxy-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid
  • the desired product was prepared by substituting O-t-butylhydroxylamine hydrochloride for hydroxylamine in example 49. mp 238-240° C; MS (APCI) m/z 481 (M+H) + ;
  • Example 73 7-((4E/Z)-4-((benzyloxy)imino)-4,5,6 -tetrahvdro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid
  • the desired product was prepared by substituting O-benzylhydroxylamine hydrochloride and a reaction time of 9 hours for hydroxylamine hydrochloride and a reaction time of 5hours, respectively in example 49.
  • Example 74 l-cyclopropyl-8-methoxy-4-oxo-7-((4E/Z)-4-(l-pyrrol ⁇ d ⁇ nyl ⁇ m ⁇ no)-4,5,6,7-tetrahvdro-l- benzoth ⁇ en-2-yl)-l,4-d ⁇ hvdro-3-qu ⁇ nol ⁇ necarboxyl ⁇ c acid
  • a solution of example 48C (0.180 g, 0.41 mmol) in absolute EtOH (6 mL) under a positive N 2 atmosphere was treated with 1-am ⁇ nopyrrol ⁇ d ⁇ ne hydrochlo ⁇ de (0.151 g, 1.23 mmol) and Et 3 N (210 ⁇ L, 1.50 mmol).
  • the reaction mixture was heated at 75° C for 24 hours the solvent removed and the residue dissolved in CH 2 C1 2 , washed with water, d ⁇ ed (Na 2 SO 4 ), and concentrated.
  • Example 75B The desired product was prepared by substituting example 75A, and ethyl 7- bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-d ⁇ hydro-3-qu ⁇ nohnecarboxylate for example ID and ethyl 7-bromo-l-cyclopropyl-4-oxo-l,4-d ⁇ hydro-3-qu ⁇ nol ⁇ ne-3-carboxylate respectively in example IE and the resulting ethyl ester was purified by chromatography on silica gel eluting with 10% acetone in hexane
  • Example 75C The desired product was prepared by substituting example 75B for example 35D in example 35E and the resulting alcohol was pu ⁇ fied by chromatography on silica gel eluting with 30% acetone in hexane.
  • the desired product was prepared by substituting example 75C for example 37A in example 37B and the resulting azide was pu ⁇ fied by chromatography on silica gel eluting with 20% acetone in hexane.
  • Example 75E The desired product was prepared by substituting example 75D for example 20 IC in example 201D and the resulting alcohol was pu ⁇ fied by chromatography on silica gel eluting with 20% acetone in hexane.
  • Example 75F The desired product was prepared by substituting example 75E and a reaction time of 4 h for example 2A and a reaction time of 2 h in example 2B. The resulting acid was purified by chromatography on silica gel eluting with 30% acetone in hexane.
  • Example 75G 7-(4-amino-4,5,6,7-tetrahvdro-l-benzothien-3-yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4- dihydro-3-quinolinecarboxylic acid
  • MS (ESI) m/z 411 (M+H) + ;

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Abstract

Compounds having formula (I), or pharmaceutically acceptable salts or prodrugs thereof, wherein A1 is nitrogen or (II), wherein W is selected from the group consisting of (1) hydrogen and (2) optionally substituted alkyl; A2 is selected from the group consisting of (1) -S-, (2) -O-, and (3) -N(R7)-, wherein R7 is hydrogen or C¿1?-C6 alkyl; and R?5 and R6¿ together are a carbocyclic or a heterocyclic ring, are useful as antibacterial agents.

Description

QUINOLINE AND NAPHTHYRIDINE CARBOXYLIC ACID ANTEBACTERIALS
Technical Field
This invention relates to quinoline and naphthyridine carboxylic acid derivatives having antibacterial properties, processes for making of the compounds, methods of treatment using the compounds and pharmaceutical compositions containing the compounds. Specifically, it relates to quinoline and naphthyridine carboxylic acid derivatives having a carbon-carbon linkage at the C-7 position of the molecule.
Background of The Invention
Many compounds having the quinoline carboxylic acid nucleus are known in the art for their antibacterial activity in curing infectious diseases. Some of the known antibiotics on the market to-date include, for example, ciprofloxacin (U.S. Patent 4,670,444), norfloxacin (U.S. Patent 4,146,719), enoxacin (U.S. Patent 4,352,803), and tosufloxacin (U.S. Patent 4,704,459). Most of these known quinoline carboxylic acid anitbacterial compounds have a carbon-nitrogen linkage at the C-7 position of the quinoline nucleus.
There is a continuing need for discovering compounds which are more effective against resistant bacteria, have improved intestinal absorption, metabolic stability, and exhibit less phototoxicity and cytotoxicity.
Summary of The Invention
In one embodiment of the invention are disclosed compounds of formula (I)
Figure imgf000003_0001
(I), or pharmaceutically acceptable salts or prodrugs thereof, wherein
^C"
A is nitrogen or W ; wherein W is selected from the group consisting of
(1) hydrogen and
(2) optionally substituted alkyl;
2
A is selected from the group consisting of
(D -S-, (2) -O-, and
7 7 (3) -N(R )-, wherein R is hydrogen or -C6 alkyl;
R is selected from the group consisting of
(1) hydrogen,
(2) halide, and
(3) optionally protected amino;
l 2 2
Z is nitrogen or , wherein R is selected from the group consisting of (1) hydrogen, (2) halide,
(3) optionally protected hydroxyl,
(4) -OR8, and o
(5) -S(O)nR , wherein n is zero, one, or two, and wherein R in (4) and (5) is selected from the group consisting of
(a) C3-C6 alkenyl, (b) C,-C6 alkyl, and (c) C3-C6 alkynyl, wherein (a)-(c) can be optionally substituted with one, two, or three substituents independently selected from the group consisting of (i) alkoxy, (ii) aryl, (iii) C3-C6 cycloalkyl,
(iv) azido, (v) cyano, (vi) halide,
(vii) optionally protected amino, (viii) optionally protected carboxyl, and (ix) optionally protected hydroxyl;
R is selected from the group consisting of (1) C3-C6 alkenyl,
(2) C,-C6 alkyl, (3) C3-C6 alkynyl, wherein (l)-(3) can be optionally substituted with one, two, or three substutuents independently selected from the group consisting of (a) Cι-C6 alkanoyloxy,
(b) Cj-Ce alkoxy,
(c) aryl,
(d) azido,
(e) cyano, (f) C3-C6 cycloalkyl,
(g) halide,
(h) optionally protected amino,
(i) optionally protected carboxyl,
(j) optionally protected hydroxyl, (k) oxo,
(1) Cι-C6 perfluoroalkoxy, and
(n) thioxo,
(4) aryl,
(5) C3-C6 cycloalkyl, and
(6) heterocycle, wherein (4)-(6) can be optionally substituted with one, two, or three substituents independently selected from the group consisting of (a) Cι-C6 alkanoyloxy, (b) Cι-C6 alkoxy,
(c) C2-C6 alkenyl, (d) Cι-C6 alkyl,
(e) C2-C6 alkynyl,
( ) aryl, (g) azido,
(h) cyano,
(i) C3-C6 cycloalkyl, (j) halide,
(k) optionally protected amino (1) optionally protected carboxyl,
(m) optionally protected hydroxyl, (n) Cj-Cό perfluoroalkoxy, and (o) C]-C6 perfluorothioalkoxy;
or
2 3
R and R together are selected from the group consisting of
Figure imgf000005_0001
Figure imgf000006_0001
and
Figure imgf000006_0002
and
9 10 wherein one of R or R in (l)-(5) is hydrogen and the other is selected from the group consisting of
(1) hydrogen,
(2) Ci-Ce alkyl,
(3) Cι-C6 haloalkyl, and
(4) optionally protected hydroxyl, or
9 10 wherein R and R together are alkylidene or C3-C6 spiroalkyl;
R is hydrogen or -OR , wherein R is hydrogen or a carboxyl protecting group;
and
R and R together are a carbocyclic or a heterocyclic ring, wherein the carbocyclic ring and the heterocyclic ring can be optionally substituted with one, two, or three substituents independently selected from the group consisting of
(1) optionally substituted aryl,
(2) azido,
(3) carboxaldehyde,
(4) cyano, (5) halide,
(6) nitro,
(7) optionally substituted Cι-C6 alkyl,
(8) optionally substituted C3-C6 alkenyl,
(9) optionally substituted C3-C6 alkynyl, (10) optionally protected amino,
(11) optionally protected hydroxyl,
(12) optionally protected carboxyl,
(13) optionally substituted C]-C6 alkanoyloxy, (14 ) optionally substituted Cι-C6 alkoxy,
(15 ) optionally substituted aryl,
(16 ) optionally substituted C3- cycloalkyl,
(17 ) optionally substituted heterocycle,
(18 ) oxo,
(19 ) Cι-C6 perfluoroalkoxy,
(20 ) Cι-C6 perfluorothioalkoxy,
(21 ) optionally substituted Cι-C6 thioalkoxy,
(22 ) thioxo,
(23 ) a nitrogen protecting group,
(24 ) heterocycle,
(25 ) -C(O)N(R12)2,
(26 ) -C(O)SR12,
(27; ) -N(R12)2
(28^ ) =N-,
(29; ) -OC(O)N(Rl 2)2,
(3o; ) =N-N(R12)2, or ) =N(R12)-N(R12)2,
(32; ) -N(R12)-C(=NR12)-N(R12)2,
(33^ ) =NOR12,
(34; ) =NN(R12)C(O)N(R12)2,
(35; ) -N(R12)C(O)N(R12)2,
(36; ) -C(O)R12,
(37; ) -OC(O)R12,
(38; ) -N(R12)C(O)R12,
(39; ) -N(R12)S(O)nR12,
(4o; > -OR12,
(4i; -S(O)nR12,
(42; -SC(O)R12,
(43; -OC(O)OR12,
(44; =N(R12)OR12,
(45; -OC(=N(R12))R12,
(46; -N(R12)C(=NR12)R12,
(47) -C(O)OC(O)R12,
(48) =N-N(R ' 2)-C(O)C(O)N(R ! 2)2,
(49) =NN(RI 2)C(S)N(RI2)2, (50) =C(R12)OR12,
(51) alkylidene,
(52) optionally substituted spiroheterocycle, and (53) =N-N(RI 3)(R14),
12 wherein R in (25)-(50) is independently selected from the group consisting of
(1) hydrogen,
(2) optionally substituted aryl,
(3) optionally substituted C]-C6 alkyl, (4) optionally substituted C3-C6 alkenyl,
(5) optionally substituted aryl, and
(6) optionally substituted heterocycle, and
13 14 wherein R and R in (53) together with the nitrogen atom to which they are attached from a heterocycle selected form the group consisting of pyrrol i din yl, piperidinyl, imidazolidinyl, pyrazolidinyl, piperazinyl, morpholinyl, and thiomorpholinyl,
13 14 wherein the heterocycle defined by R and R together can be optionally substituted with optionally substituted alkyl.
In another embodiment of the present invention are disclosed pharmaceutical compositions comprising the compounds in combination with a pharmaceutically acceptable carrier.
In yet another embodiment of the present invention are disclosed methods of inhibiting the growth of bacteria which comprises contacting the bacteria with an effective amount of the compounds.
In still yet another embodiment of the present invention is disclosed a method for preparing the compounds, the method comprising (a) reacting compounds of formula (la)
Figure imgf000008_0001
da), wherein R , R , R , and Z are def fiinneedd aabboo\ve, and Q is a first covalent bond precursor, with compounds of formula (lb)
Figure imgf000009_0001
(lb), wherein A , A , and R and R are defined above, and Q is a second covalent bond precursor, in the presence of a catalyst, to provide a first product; and
(b) optionally hydrolyzing the first product.
Detailed Description of The Invention Definition of Terms The term "alkanoyl" as used herein, refers to an alkyl group attached to the parent molecular group through a carbonyl group. The alkanoyl groups of this invention can be optionally substituted.
The term "alkanoyloxy," as used herein, refers to an alkanoyl group attached to the parent molecular group throgh an oxygen atom. The alkanoyloxy groups of this invention can be optionally substituted.
The term "alkenyl," as used herein, refers to a monovalent straight or branched chain hydrocarbon having from two to six carbon atoms and at least one carbon-carbon double bond. The alkenyl groups of this invention can be optionally substituted.
The term "alkenylene," as used herein, refers to a divalent straight or branched chain hydrocarbon having from four to six carbons and at least one carbon-carbon double bond.
The term "alkoxy," as used herein, refers to an alkyl group connected to the parent molecular group through an oxygen atom. The alkoxy groups of this invention can be optionally substituted. The term "alkyl," as used herein, refers to a monovalent straight or branched chain saturated hydrocarbon having from one to six carbon atoms. The alkyl groups of this invention can be optionally substituted.
The term "alkylidine," as used herein, refers to =CH2-
The term "alkylene," as used herein, refers to a divalent straight or branched chain saturated hydrocarbon having from one to six carbon atoms. The alkylene groups of this invention can be optionally substituted.
The term "alkynyl," as used herein, refers to a monovalent straight or branched chain hydrocarbon having from two to six carbon atoms and at least one carbon-carbon triple bond. The alkynyl groups of this invention can be optionally substituted. The term "alkynylene," as used herein, refers to a monovalent straight or branched chain hydrocarbon having from four to six carbon atoms and at least one one carbon- carbon triple bond.
The terms "amino," and "amino group," as used herein, refer to -NH2 or a derivative thereof formed by independent replacement of one or both hydrogen atoms thereon with one or two groups selected from optionally substituted Cj-C6 alkyl, optionally substituted aryl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, and heterocycle. The amino groupsof this invention can be optionally protected with amino protecting groups. The term "amino protecting group," as used herein, refers to selectively removable groups which protect amino groups against undesirable side reactions during synthetic procedures and includes all conventional amino protecting groups. Examples of amino groups include optionally substituted acyl groups such as butoxycarbonyl, 4- chlorobutoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl, methoxycarbonyl, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, para- nitrobenzylcarbonyl, ortho-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert- amyloxycarbonyl, tert-butoxycarbonyl, para-methoxybenzyloxycarbonyl, 3,4- dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, phthaloyl, succinyl, glycyl, alanyl, D-alanyl, prolyl, D-prolyl, leucyl, D-leucyl, tyrosyl, N- methylleucyl, N-methyl -D-leucyl, norleucyl, D-norleucyl, D-tyrosyl, O-methyl tyrosyl, O- methyl-D-tyrosyl, methionyl, D-methionyl, aspartyl, D-aspartyl, β-O-methylaspartyl, β-O- methyl-D-aspartyl, 1-adamantyloxycarbonyl, and 8-quinolyloxycarbonyl; optionally substituted arylalkyl groups such as benzyl, diphenylmethyl, and triphenylmethyl; optionally substituted arylthio groups such as 2-nitrophenylthio and 2,4-dinitrophenylthio; optionally substituted alkyl sulfonyl and optionally substituted arylsulfonyl groups such as methanesulfonyl, and para-toluenesulfonyl; optionally substituted dialkylaminoalkylidene groups such as N,N-dimethylaminomethylene; optionally substituted arylalkylidene groups such as benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, and 2- hydroxy-1-naphthylmethylene; optionally substituted nitrogen-containing heterocyclic alkylidene groups such as 3-hydroxy-4-pyridylmethylene; optionally substituted cycloalkylidene groups such as cyclohexylidene, 2-ethoxycarbonylcyclohexylidene, 2- ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, and 3,3-dimethyl-5- oxycyclohexylidene; optionally substituted diarylalkylphosphoryl and optionally substituted diarylalkylphosphoryl groups such as diphenylphosphoryl and dibenzylphosphoryl; optionally substituted oxygen-containing heterocyclic alkyl groups such as 5-methyl-2-oxo-2H-l,3-dioxol-4-yl-methyl; and optionally substituted silyl groups such as trimethylsilyl, triethylsilyl, and triphenylsilyl.
The term "aminosulfonyl," as used herein, refers to an optionally protected amino group connected to the parent molecular group through a sulfonyl group. The term "aryl," as used herein, refers to phenyl, naphthyl, 1,2-dihydronaphthyl, and 1,2,3,4-tetrahydronaphthyl. The aryl groups of this invention can be optionally substituted.
The term "arylsulfonyl," as used herein, refers to an optionally substituted aryl group connected to the parent molecular group through a sulfonyl group. The term "azido," as used herein, refers to -N3.
The term "carboxaldehyde," as used herein, refers to -CHO.
The term "carbocyclic ring," as used herein, refers to a non-aromatic five- to eight- membered hydrocarbon ring. The carbocyclic rings of this invention can be optionally substituted. The term "carboxyl," as used herein, refers to -CO2H. The carboxyl groupsof this invention can be optionally protected with carboxyl protecting groups. The term "cyano," as used herein, refers to -CN.
The term "carboxyl protecting group," as used herein, refers to selectively removable groups which protect hydroxyl groups against undesirable side reactions during synthetic procedures and includes all conventional carboxyl protecting groups. Examples of carboxyl groups include optionally substituted alkyl groups such as methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, and tert-butyl; aryl groups such as phenyl, and naphthyl; optionally substituted arylalkyl groups such as benzyl, diphenylmethyl, triphenylmethyl, para-nitrobenzyl, para-methoxybenzyl, and bis ara- methoxyphenyl)methyl; optionally substituted acylalkyl groups such as acetylmethyl, benzoylmethyl, para-nitrobenzoylmethyl, para-bromobenzoylmethyl, and para- methanesulfonylbenzoylmethyl; optionally substituted oxygen-containing heterocyclic groups such as 2-tetrahydropyranyl and 2-tetrahydrofuranyl; optionally substituted haloalkyl groups such as 2,2,2-trichloroethyl; optionally substituted alkylsilylalkyl groups such as 2-(trimethylsilyl)ethyl; optionally substituted acyloxyalkyl groups such as acetoxymethyl, propionyloxymethyl, and pivaloyloxymethyl; optionally substituted nitrogen-containing heterocyclic groups such as phthalimidomethyl and succinimidomethyl; optionally substituted cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; optionally substituted alkoxyalkyl groups such as methoxymethyl, methoxyethoxymethyl, and 2-(trimethylsilyl)ethoxymethyl; optionally substituted arylalkoxyalkyl groups such as benzyloxymethyl; optionally substituted alkylthioalkyl groups such as methylthiomethyl and 2-methylthioethyl; optionally substituted arylthioalkyl groups such as phenylthiomethyl; optionally substituted alkenyl groups such as l,l-dimethyl-2-propenyl, 3-methyl-3-butenyl, and allyl; and optionally substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert- butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, and tert- butylmethoxyphenylsilyl.
The term "cycloalkyl," as used herein, refers to a monovalent saturated cyclic or bicyclic hydrocarbon having three to ten carbon atoms. The cycloalkyl groups of this invention can be optionally substituted. The terms "halo" or "halide" as used herein, refer to F, Cl, Br, or I.
The term "haloalkyl," as used herein, refers to an alkyl group to which is attached at least one halide. The term "haloalkyl," as used herein, also refers to perfluoroalkyl or perchloroalkyl.
The term "heteroarylsulfonyl," as used herein, refers to an optionally substituted heterocycle connected to the parent molecular group through a sulfonyl group.
The term "heterocycle," as used herein, refers to azetidinyl, benzofuranyl, benzothiazolyl, 2,1,3-benzoxadiazole, 2,1,3-benzothiadiazole, furyl, imidazolyl, imidazolinyl, imidazolidinyl, imidazo[2,l-b]thiazole, isoquinolinyl, isoxazolyl, isothiazolyl, oxazolyl, oxetanyl, morpholine, piperidinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, thiazolyl, thienyl, thietanyl, thiomorpholine, thiomorpholine sulfone, or thiomorpholine sulfoxide. The heterocycle groups of this invention can be optionally substituted.
The term "heterocyclic ring," as used herein, refers to a non-aromatic five- to eight- membered ring consisting of hydrocarbon groups and one or two groups selected from -NR -, -O-, -S(O)n-, or -NR SO2-. The heterocyclic rings of this invention can be optionally substituted.
The term "hydroxyl," as used herein, refers to -OH. The hydroxyl groupsof this invention can be optionally protected with hydroxyl protecting groups.
The term "hydroxyl protecting group," as used herein, refers to selectively introducible and movable groups which protect hydroxyl groups against undesirable side reactions during synthetic procedures. Examples of hydroxyl protecting groups include optionally substituted acyl groups such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-(phenylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphonio)ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, S-benzylthiocarbonyl, 4-ethoxy-l- naphthyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, for yl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, and benzoyl; optionally substituted alkyl groups such as methyl, tert-butyl, 2,2,2-trichloroethyl, and 2- trimethylsilylethyl; optionally substituted alkenyl groups such as as l,l-dimethyl-2- propenyl, 3-methyl-3-butenyl, and allyl; optionally substituted arylalkyl groups such as benzyl, para-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, and triphenylmethyl; oxygen-containing and sulfur-containing heterocyclic groups such as tetrahydrofuryl, tetrahydropyranyl, and tetrahydrothiopyranyl; optionally substituted alkoxy and optionally substituted alkylthioalkyl groups such as methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, and 1-ethoxyethyl; alkylsulfonyl; optionally substituted arylsulfonyl groups such as methanesulfonyl, and para-toluenesulfonyl; and optionally substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethyl silyl, and tert-butylmethoxyphenylsilyl.
The term "nitro," as used herein, refers to -NO2.
The term "oxo," as used herein, refers to a group formed by the replacement of two hydrogen atoms on the same carbon atom with a single oxygen atom.
The term "perchloroalkyl," as used herein, refers to an alkyl group in which all of the hydrogen atoms have been replaced with chloride atoms.
The term "perfluoroalkoxy," as used herein, refers to a perfluoroalkyl group attached to the parent molecular group through an oxygen atom. The term "perfluoroalkyl," as used herein, refers to an alkyl group in which all of the hydrogen atoms have been replaced with fluoride atoms.
The term "perfluorothioalkoxy," as used herein, refers to a perfluoroalkyl group attached to the parent molecular group through a sulfur atom.
The term "pharmaceutically acceptable prodrugs," as used herein, represents prodrugs of the compounds which are suitable for treatment of bacterial infections without undue toxicity, irritation, and allergic response, which are commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.
The term "prodrug," as used herein, represents compounds which are rapidly transformed in vivo to the parent compounds by hydrolysis in blood. Prodrugs of the invention can include compounds wherein a nitrogen on the molecule has attached thereto an aminoacyl (1-mer), diaminoacyl (2-mer), or triaminoacyl (3-mer) group optionally capped with a carboxyl protecting group. The term "aminoacyl," as used herein, refers to a group derived from naturally or unnaturally occuring amino acid in the racemic, D or L configuration. The terms "bisaminoacyl" and "trisaminoacyl," as used herein, refer to di- and tri- aminoacyl groups, respectively. Other prodrugs of the invention include compounds wherein a carboxylic acid or amine group of the compounds is attached thereto a 2-oxo-l,3-dioxol-4-yl)methyl group such as reported in Chem. Pharm. Bull. 1985, 33(1 1), 4870-4877. Still other prodrugs of the invention include compounds wherein a tertiary amine group on the compounds has attached thereto a N-phosphonooxymethyl group such as reported in I, Med. Chem. 1999, 42(16), 3094-3100.
The term "pharmaceutically acceptable salt," as used herein, represents salts or zwitterionic forms of the compounds which are water or oil-soluble or dispersible and are suitable for treatment of bacterial infections without undue toxicity, irritation, and allergic response, which are commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use. The salts may be prepared during the final isolation and purification of the compounds or separately by reacting a free base group with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2- naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, trichloroacetic, trifluoroacetic, phosphate, glutamate, bicarbonate, para-toluenesulfonate, and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl, and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; arylalkyl halides such as benzyl and phenethyl bromides. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric, hydrobromic, sulphuric, and phosphoric and organic acids such as oxalic, maleic, succinic, and citric. Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxylic acid-containing group such as the one at the C-3 position of the quinoline or naphthyridine with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts and nontoxic quaternary ammonia and amine cations such as ammonium, tetramethyl ammonium, tetraethylammonium, methylamme, dimethyla ine, tπmethylamine, triethylamine, diethylamine, ethylamine, tπbutlyamme, pyridine, N,N-dιmethylanιhne, N-methylpipeπdine, N-methylmorphohne, dicyclohexylamine, procaine, dibenzylamine, N-dibenzyl- -phenethylamine, 1- ephenamine, and N,N'-dιbenzylethylenedι amine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, pipendine, and piperazine.
The term "protected amino," as used herein, refers to an amino group deπvatized by independent replacement of at least one hydrogen atom thereon by an amino protecting group.
The term "spiroalkyl," as used herein, refers to an alkylene group of three to six carbon atoms, both ends of which are bonded to the same carbon atom of the parent group The term "spiroheterocycle," as used herein, refers to a heterocycle in which one of the πng carbon atoms is shared with one of the πng carbon atoms of the parent group. The spirohetereocycle groups of this invention can be optionally substituted.
The term "substituted alkanoyloxy," as used herein, refers to an alkanoyloxy group deπvatized by independent replacement of one, two, or three hydrogens thereon with a substituent or substituents independently selected from the group consisting of azido, cyano, halide, nitro, optionally protected ammo, optionally protected hydroxyl, optionally protected carboxyl, optionally substituted -Cό alkoxy, optionally substituted aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted heterocycle, oxo, C]-C6 perfluoroalkoxy, -Cβ perfluorothioalkoxy, and thioxo.
The term "substituted alkenyl," as used herein, refers to an alkenyl group deπvatized by independent replacement of one, two, or three hydrogens thereon with a substituent or substituents independently selected from the group consisting of
C1-C5 alkanoyloxy, Cι-C6 alkoxy, aryl, azido, cyano, C3-C6 cycloalkyl, halide, optionally protected amino, optionally protected carboxyl, optionally protected hydroxyl, oxo, C1-C5 perfluoroalkoxy, \-C perfluorothioalkoxy, and thioxo
The term "substituted alkoxy," as used herein, refers to an alkoxy group deπvatized by independent replacement of one, two, or three hydrogens thereon with a substituent or substituents independently selected from the group consisting of Cι-C6 alkanoyloxy, C\- Cζ alkoxy, aryl, azido, cyano, C3-C6 cycloalkyl, halide, optionally protected amino, optionally protected carboxyl, optionally protected hydroxyl, oxo, Cι-C6 perfluoroalkoxy, C|-C6 perfluorothioalkoxy, and thioxo. The term "substituted alkyl," as used herein, refers to an alkyl group deπvatized by independent replacement of one, two, or three hydrogens thereon with a substituent or substituents independently selected from the group consisting of Cι-C6 alkanoyloxy, Cj- C6 alkoxy, aryl, heterocycle, azido, cyano, C3-C5 cycloalkyl, dimethylamino, halide, optionally protected amino, optionally protected carboxyl, optionally protected hydroxyl, oxo, Cι-C6 perfluoroalkoxy, Cj-C6 perfluorothioalkoxy, and thioxo.
The term "substituted alkynyl," as used herein, refers to an alkynyl group derivatized by independent replacement of one, two, or three hydrogens thereon with a substituent or substituents independently selected from the group consisting of Cι-C6 alkanoyloxy, Cι-C6 alkoxy, aryl, azido, cyano, C3-C6 cycloalkyl, halide, optionally protected amino, optionally protected carboxyl, optionally protected hydroxyl, oxo, Cι-C6 perfluoroalkoxy, C[-C6 perfluorothioalkoxy, and thioxo. The term "substituted aryl," as used herein, refers to an aryl group derivatized by independent replacement of one, two, or three hydrogens thereon with a substituent or substituents independently selected from the group consisting of -C5 alkanoyloxy, C1-C6 alkoxy, optionally substituted alkyl, aryl, azido, cyano, C3-C6 cycloalkyl, halide, optionally protected amino, optionally protected carboxyl, optionally protected hydroxyl, nitro, oxo, Cι-C6 perfluoroalkoxy, Cι-C6 perfluorothioalkoxy, and thioxo.
The term "substituted carbocyclic ring," as used herein, refers to a carbocyclic ring derivatized by independent replacement of one, two, three, or four hydrogens thereon with a substituent or substituents independently selected from the group consisting of Cj-C6 alkanoyloxy, C--C6 alkoxy, aryl, heterocycle, azido, cyano, C3-C6 cycloalkyl, halide, optionally substituted alkyl, optionally protected amino, optionally protected carboxyl, optionally protected hydroxyl, oxo, C]-C6 perfluoroalkoxy, C]-C6 perfluorothioalkoxy, and thioxo.
The term "substituted heterocyclic ring," as used herein, refers to a heterocyclic ring derivatized by independent replacement of one, two, three, or four hydrogens thereon with a substituent or substituents independently selected from the group consisting of C\- C6 alkanoyloxy, Cι-C6 alkoxy, aryl, heterocycle, azido, cyano, C3-C6 cycloalkyl, halide, optionally substituted alkyl, optionally protected amino, optionally protected carboxyl, optionally protected hydroxyl, oxo, Cj-C perfluoroalkoxy, Cι-C6 perfluorothioalkoxy, and thioxo. The term "substituted cycloalkyl," as used herein, refers to a cycloalkyl group derivatized by independent replacement of one, two, or three hydrogens thereon with a substituent or substituents independently selected from the group consisting of Cι-C6 alkanoyloxy, Cι-C6 alkoxy, aryl, azido, cyano, C3-C6 cycloalkyl, halide, optionally protected amino, optionally protected carboxyl, optionally protected hydroxyl, oxo, Cι-C6 perfluoroalkoxy, Cι-C6 perfluorothioalkoxy, and thioxo. The term "substituted heterocycle," as used herein, refers to a heterocycle deπvatized by independent replacement of one, two, or three hydrogens thereon with a substituent or substituents independently selected from the group consisting of Cι-C6 alkanoyloxy, C--C6 alkoxy, optionally substituted alkyl, aryl, azido, cyano, C3-C6 cycloalkyl, halide, heterocycle, optionally protected amino, optionally protected carboxyl, optionally protected hydroxyl, oxo, Cι-C6 perfluoroalkoxy, Cι-C6 perfluorothioalkoxy, and thioxo.
The term "substituted spiroheterocycle," as used herein, refers to a spiroheterocycle group derivatized by independent replacement of one, two, or three hydrogens thereon with a substituent or substituents independently selected from the group consisting of C\- C alkanoyloxy, Cι-C6 alkoxy, aryl, heterocycle, azido, cyano, C3-C6 cycloalkyl, halide, optionally substituted alkyl, optionally protected ammo, optionally protected carboxyl, optionally protected hydroxyl, oxo, Cι-C6 perfluoroalkoxy, C)-C6 perfluorothioalkoxy, and thioxo. The term "substituted thioalkoxy," as used herein, refers to a thioalkoxy group deπvatized by independent replacement of one, two, or three hydrogens thereon with a substituent or substituents independently selected from the group consisting of Cι-C6 alkanoyloxy, -Cg alkoxy, aryl, azido, cyano, C3-C6 cycloalkyl, halide, optionally protected amino, optionally protected carboxyl, optionally protected hydroxyl, oxo, C--C6 perfluoroalkoxy, -Cβ perfluorothioalkoxy, and thioxo.
The term "sulfhydryl," as used herein, refers to -SH.
The term "sulfomc," as used herein, refers to -SO3H.
The term "sulfonyl," as used herein, refers to -SO2-.
The term "thioalkoxy," as used herein, refers to an alkyl group attached to the parent molecular group through a sulfur atom. The thioalkoxy groups of this invention can be optionally substituted.
The term "thiolcarboxyl," as used herein, refers to -C(O)SH.
The term "thioxo," as used herein, refers to a group formed by the replacement of two hydrogen atoms on the same carbon atom with a single sulfur atom. It is intended that the definition of any substituent or variable at a particular part in a molecule be independent of its definition elsewhere in the molecule. Thus, for example, substituents such as -(CH2)aC(O)R5 represent -CH2C(O)H, and -CH2C(O)CH ; and substituents such as -(CH2)aN(R5)C(O)N(R5)2 represent CH2CH2N(H)C(O)N(CH3)(C3H7) and -CH2N(CH3)C(O)NH(CH3), and the like. Asymmetπc centers can exist in the compounds of the invention. The invention contemplates stereoisomers and mixtures thereof. Individual stereoisomers of compounds are prepared by synthesis from starting mateπals containing the chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, or direct separation of the enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry are either commercially available or are made by the methods described herein and resolved by techniques well-known in the art.
According to the methods of treatment of the invention, the compounds can be administered alone, in combination with, or in concurrent therapy with other antibacterial agents. When using the compounds for antibacterial therapy, the specific therapeutically effective dose level for any particular patient will depend upon factors such as the disorder being treated and the severity of the disorder; the activity of the particular compound used; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration; the route of administration; the rate of excretion of the compound employed; the duration of treatment; and drugs used in combination with or coincidently with the compound used. The compounds can be administered orally, parenterally, osmotically (nasal sprays), rectally, vaginally, or topically in unit dosage formulations containing carriers, adjuvants, diluents, vehicles, or combinations thereof. The term "parenteral" includes infusion as well as subcutaneous, intravenous, intramuscular, and intrasternal injection. Parenterally adminstered aqueous or oleaginous suspensions of the compounds can be formulated with dispersing, wetting, or suspending agents. The injectable preparation can also be an injectable solution or suspension in a diluent or solvent. Among the acceptable diluents or solvents employed are water, saline, Ringer's solution, buffers, dilute acids or bases, dilute amino acid solutions, monoglycerides, diglycerides, fatty acids such as oleic acid, and fixed oils such as monoglycerides or diglycerides.
The antibacterial effect of parenterally administered compounds can be prolonged by slowing their absorption. One way to slow the absorption of a particular compound is adminstering injectable depot forms comprising suspensions of crystalline, amorphous, or otherwise water-insoluble forms of the compound. The rate of absorption of the compound is dependent on its rate of dissolution which is, in turn, dependent on its physical state. Another way to slow absorption of a particular compound is administering injectable depot forms comprising the compound as an oleaginous solution or suspension. Yet another way to slow absorption of a particular compound is administering injectable depot forms comprising microcapsule matrices of the compound trapped within liposomes, microemulsions, or biodegradable polymers such as polylactide-polyglycolide, polyorthoesters or polyanhydrides. Depending on the ratio of drug to polymer and the composition of the polymer, the rate of drug release can be controlled. Transdermal patches also provide controlled delivery of the compounds. The rate of absorption can be slowed by using rate controlling membranes or by trapping the compound within a polymer matrix or gel. Conversely, absorption enhancers can be used to increase absorption. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound can optionally comprise diluents such as sucrose, lactose, starch, talc, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder, tableting lubricants, and tableting aids such as magnesium stearate or microcrystalline cellulose. Capsules, tablets and pills can also comprise buffering agents; and tablets and pills can be prepared with enteric coatings or other release-controlling coatings. Powders and sprays can also contain excipients such as talc, silicic acid, aluminum hydroxide, calcium silicate, polyamide powder, or mixtures thereof. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons or substitutes therefor. Liquid dosage forms for oral administration include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs comprising inert diluents such as water. These compositions can also comprise adjuvants such as wetting, emulsifying, suspending, sweetening, flavoring, and perfuming agents.
Topical dosage forms include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and transdermal patches. The compound is mixed under sterile conditions with a carrier and any needed preservatives or buffers. These dosage forms can also include excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Suppositories for rectal or vaginal administration can be prepared by mixing the compounds with a suitable nonirritating excipient such as cocoa butter or polyethylene glycol, each of which is solid at ordinary temperature but fluid in the rectum or vagina. Ophthalmic formulations comprising eye drops, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention. A further possibility for delivery and utilization of the compounds is chemical conjugation of the compounds with other antibacterials. Similar dual-action conjugates are reported in US 5,281, 703. In the manner suggested by these references, a covalent bond can be formed between a functional group on a lactam and an amino group at the C-6 position or a carboxylic acid group at the C-3 position of the quinoline or naphthyridine. The total daily dose of the compounds administered to a host in single or divided doses can be in amounts from about 0.1 to about 200 mg/kg body weight or preferably from about 0 25 to about 100 mg/kg body weight. Single dose compositions can contain these amounts or submultiples thereof to make up the daily dose.
Preferred embodiments for the practice of the invention include
Compounds of formula (I) wherein A is methine, Compounds of formula (I) wherein A is -S-,
Compounds of formula (I) wherein R is hydrogen,
Compounds of formula (I) wherein R is fluoπde,
l 2 2
Compounds of formula (I) wherein Z is R , and R is methoxy or difluoromethoxy,
3 Compounds of formula (I) wherein R is cyclopropyl,
Compounds of formula (I) wherein R and R together are an optionally substituted carbocyclic πng,
Compounds of formula (I) wherein R and R together are an optionally substituted carbocyclic ring and the substituent is amino, and
Compounds of formula (I) wherein R and R together are an optionally substituted heterocyclic ring.
Specific compounds of the invention include l-cyclopropyl-4-oxo-7-(4,5,6,7-tetrahydrothιeno[3,2-c]pyπdιn-2-yl)-l,4-dιhydro-3- quinohnecarboxylic acid, l-cyclopropyl-8-methoxy-4-oxo-7-(4,5,6,7-tetrahydrothιeno[3,2-c]pyndιn-2-yl)- l,4-dιhydro-3-quιnohnecarboxylιc acid, l-cyclopropyl-4-oxo-7-(4,5,6,7-tetrahydrothιeno[3,2-c]pyπdm-2-yl)-l,4- dιhydro[l ,8]naphthyπdme-3-carboxylιc acid, l-cyclopropyl-6-fluoro-4-oxo-7-(4,5,6,7-tetrahydrothιeno[3,2-c]pyπdm-2-yl)-l,4- dιhydro[l,8]naphthyπdme-3-carboxylιc acid, l-cyclopropyl-8-(dιfluoromethoxy)-4-oxo-7-(4,5,6,7-tetrahydrothιeno[3,2- c]pyπdιn-2-yl)-l,4-dιhydro-3-quιnolιnecarboxylιc acid, l-cyclopropyl-4-oxo-7-(4,5,6,7-tetrahydrothιeno[2,3-c]pyndιn-2-yl)-l,4-dιhydro-3- quinohnecarboxylic acid, l-cyclopropyl-8-methoxy-4-oxo-7-(4,5,6,7-tetrahydrothιeno[2,3-c]pyπdιn-2-yl)- l,4-dιhydro-3-quιnolιnecarboxyhc acid, l-cyclopropyl-4-oxo-7-(4,5,6,7-tetrahydrothιeno[2,3-c]pyndιn-2-yl)-l,4- dihydrof 1 ,8]naphthyπdιne-3-carboxyhc acid, l-cyclopropyl-6-fluoro-4-oxo-7-(4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-l,4- dihydro[ 1 ,8]naphthyridine-3-carboxylic acid, l-cyclopropyl-8-(difluoromethoxy)-4-oxo-7-(4,5,6,7-tetrahydrothieno[2,3- c]pyridin-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-4-oxo-l,4- dihydro[l,8]naphthyridine-3-carboxylic acid, l-cyclopropyl-6-fluoro-7-(6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-4- oxo- 1 ,4-di hydro[ 1 ,8]naphthyridine-3-carboxylic acid, l-cyclopropyl-7-(6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-4-oxo-l,4- dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-8-(difluoromethoxy)-7-(6-methyl-4,5,6,7-tetrahydrothieno[3,2- c]pyridin-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-8-methoxy-7-(6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)- 4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-4-oxo-l,4- dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-4-oxo-l,4- dihydro[l,8]naphthyridine-3-carboxylic acid, l-cyclopropyl-6-fluoro-7-(4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridιn-2-yl)-4- oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylic acid, l-cyclopropyl-8-methoxy-7-(4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)- 4-oxo-l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-8-(difluoromethoxy)-7-(4-methyl-4,5,6,7-tetrahydrothieno[3,2- c]pyridin-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-4-oxo-l,4- dihydro[l,8]naphthyridine-3-carboxylic acid, l-cyclopropyl-6-fluoro-7-(7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-4- oxo-l ,4-dihydro[l,8]naphthyridine-3-carboxylic acid, l-cyclopropyl-8-methoxy-7-(7-methyl-4,5,6,7-tetrahydrotheino[2,3-c]pyrindin-2- yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-4-oxo- 1 ,4-dihydro[ 1 ,8]naphthyridine-3-carboxylic acid, l-cyclopropyl-7-(7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-8- methoxy-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-6- fluoro-4-oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylic acid, l-cyclopropyl-8-(difluoromethoxy)-7-(7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2- c]pyridin-2-yl)-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(4-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-4-oxo-l,4- dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-8-methoxy-7-(4-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)- 4-oxo-l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-8-(difluoromethoxy)-7-(4-methyl-4,5,6,7-tetrahydrothieno[2,3- c]pyridin-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(4-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-4-oxo-l,4- dihydro[l,8]naphthyridine-3-carboxylic acid, l-cyclopropyl-6-fluoro-7-(4-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-4- oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylic acid, l-cyclopropyl-7-(4,4-dimethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-8- methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-6-fluoro-7-(4-hydroxy-4,5,6,7-tetrahydro-l-benzothien-2-yl)-4-oxo- l,4-dihydro[l,8]naphthyridine-3-carboxylic acid, l-cyclopropyl-7-(4-hydroxy-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid,
7-(4-amino-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(4-hydroxy-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid, 7-(4-azido-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4-oxo- l,4-dihydro-3-quinolinecarboxylic acid,
7-(4-amino-4,5 ,6,7-tetrahydro- 1 -benzothien-2-yl)- 1 -cyclopropyl-8-methoxy-4-oxo- l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(7-hydroxy-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(5-hydroxy-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8-methoxy-4- oxo-l ,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(5-(hydroxymethyl)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(5-(hydroxymethyl)-6,7-dihydro-l-benzothien-2-yl)-8-methoxy-4- oxo-l ,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(5-hydroxy-5,6-dihydro-4H-cyclopenta[b]thien-2-yl)-8-methoxy- 4-oxo-l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-8-methoxy-7-(4-methoxy-5,6-dihydro-4H-cyclopenta[b]thien-2-yl)- 4-oxo-l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(6-hydroxy-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-6-fluoro-4-oxo-7-(4-oxo-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l,4- dihydro[l,8]naphthyridine-3-carboxylic acid, l-cyclopropyl-6-fluoro-7-((4E/Z)-4-(hydroxyimino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihydro(l,8)naphthyridine-3-carboxylic acid; l-cyclopropyI-8-methoxy-4-oxo-7-(4-oxo-4,5,6,7-tetrahydro-l-benzothien-2-yl)- 1 ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-((4E/Z)-4-(hydroxyimino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)- 8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-diflouromethoxy-7-(7-methyl-4,5,6,7-tetrahydrotheino(2,3- c)pyrindin-2-yl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylιc acid; l-cyclopropyl-8-methoxy-4-oxo-7-(5-oxo-4,5,6,7-tetrahydro-l-benzothien-2-yl)- 1 ,4-dihydro-3-quinolinecarboxylic acid;
7-[5-(azidomethyl)-4,5,6,7-tetrahydro-l-benzothien-2-yl]-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-((5E/Z)-5-(hydroxyimino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)- 8-methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-((5E/Z)-5-(methoxyimino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(5-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-4-oxo-l,4- dihydro[l,8]naphthyridine-3-carboxylic acid;
7-(5-bromo-4-oxo-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy- 4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid; l-cycloρropyl-8-methoxy-4-oxo-7-(6-oxo-4,5,6,7-tetrahydro-l-benzothien-2-yl)- l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-((6E/Z)-6-(hydroxyimino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)- 8-methoxy-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(7-oxo-4,5,6,7-tetrahydro-l-benzothien-2-yl)- 1 ,4-dihydro-3-quinolinecarboxylic acid; 7-(5-azido-4-oxo-4,5,6,7-tetrahydro-l -benzothien-2-yl)-l-cyclopropyl-8-methoxy-
4-oxo-l,4-dιhydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-((7E/Z)-7-(methoxyimino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-((4E/Z)-4-(methoxyimino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-((4E/Z)-4-(ethoxyimino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-((6E/Z)-6-(methoxyimino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyc!opropyl-7-(6,7-dihydro-l-benzothien-2-yl)-8-methoxy-4-oxo-l,4-dihydro-3- quinohnecarboxylic acid; l-cyclopropyl-8-methoxy-7-((4E/Z)-4-(4-morpholinylimino)-4, 5,6,7 -tetrahydro- 1 - benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4,5-dihydroxy-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8-methoxy- 4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; 7-(5-(aminomethyl)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(6-amino-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4-oxo- l,4-dihydro-3-quinolinecarboxylic acid;
7-((4E/Z)-4-(tert-butoxyimino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid;
7-((4E/Z)-4-((benzyloxy)imino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-((4E/Z)-4-(l-pyrrolidinylimino)-4, 5,6,7- tetrahydro- 1 -benzothien-2-yl)- 1 ,4-dihydro-3-quinolinecarboxylic acid; 7-(4-amino-4,5,6,7-tetrahydro-l-benzothien-3-yl)-l-cyclopropyl-8-methoxy-4-oxo-
1 ,4-dihydro-3-quinolinecarboxylic acid;
7-(5-amino-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-[4-(methylamino)-4,5,6,7-tetrahydro-l-benzothien-2- yl]-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-((5E/Z)-5-(ethoxyimino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-((5E/Z)-5-((benzyloxy)imino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; 7-((4E/Z)-4-((aminocarbonyl)hydrazono)-4,5,6,7-tetrahydro-l-benzothien-2-yl)l- cyclopropyl-8-methoxy-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid; ethyl l-cyclopropyl-8-methoxy-7-((4E/Z)-4-((4-methyl-l-piperazinyl)imino)- 4,5,6,7-tetrahydro-l-benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylate; ethyl l-cyclopropyl-8-methoxy-7-((4E/Z)-4-(((2R)-2- (methoxymethyl)pyrrolidinyl)imino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-4-oxo-l,4- dihydro-3-quinolinecarboxylate; l-cyclopropyl-7-(4-(dimethylamino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-((4E/Z)-4-[(aminocarbothioyl)hydrazono)-4,5,6,7-tetrahydro-l-benzothien-2-yl)- l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-((4E/Z)-4-(((methylamino)carbothioyl)hydrazono)-
4,5,6,7-tetrahydro-l-benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-(5-methylene-4-oxo-4,5,6,7-tetrahydro-l-benzothien- 2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; ethyl l-cyclopropyl-8-methoxy-7-(5-methylene-4-oxo-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylate; l-cyclopropyl-8-methoxy-7-(4-((methylsulfonyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-(lH-pyrrol-l-yl)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-((4E/Z)-4-(((ethylamino)carbothioyl)hydrazono)-4,5,6,7- tetrahydro-l-benzothien-2-yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-((4E/Z)-4-((amino(oxo)acetyl)hydrazono)-4,5,6,7-tetrahydro-l-benzothien-2-yl)- l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-((4E/Z)-4-((4-methyl-l-piperazinyl)imino)-4, 5,6,7- tetrahydro-l-benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-((tert-butyl(dimethyl)silyl)oxy)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-((3-pyridinylmethyl)amino)-4, 5,6,7- tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid; ethyl 7-(4-((tert-butyl(dimethyl)silyl)oxy)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate;
7-((4E/Z)-4-(acetylhydrazono)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-(benzylamino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4-(ethylamino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8-methoxy- 4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-(difluoromethoxy)-7-(4-hydroxy-4,5,6,7-tetrahydro-l-benzothien- 2-yl)-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-((4E/Z)-4-(4,5-dihydro-lH-imidazol-2-ylhydrazono)-4, 5,6,7- tetrahydro-l-benzothien-2-yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-amino-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- (difluoromethoxy)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4-hydroxy-2-methyl-l,l-dioxido-3,4-dihydro-2H-thieno[3,2- e][l,2]thiazin-6-yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; ethyl l -cyclopropyl-8-methoxy-7-(5-methyl-4-oxo-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylate; l-cyclopropyl-7-(4-((3-fluorobenzyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)- 8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; 7-((4E/Z)-4-[(aminocarbothioyl)(methyl)hydrazono)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-(5-methyl-4-oxo-4,5,6,7-tetrahydro-l-benzothien-2- yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-(difluoromethoxy)-7-(4-(methylamino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-6-fluoro-7-(4-(methylamino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)- 4-oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylic acid;
7-(4-amino-2-methyl-l,l-dioxido-3,4-dihydro-2H-thieno[3,2-e][l,2]thiazin-6-yl)- l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4-(hydroxymethyl)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
1 -cyclopropyl-8-methoxy-4-oxo-7-(4-( 1 -pyrrolidinylmethyl)-4,5,6,7-tetrahydro- 1 - benzothien-2-yl)-l ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-((2-pyrrolidinylmethyl)amino)-4, 5,6,7- tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-(acetylamino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-(propionylamino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)- 1 ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-(4-((methoxyacetyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-((tetrahydrofuranyl-2-carbonyl)armno)- 4,5,6,7-tetrahydro-l-benzothιen-2-yl)-l,4-dιhydro-3-quιnolιnecarboxyhc acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-((tetrahydrofuranyl-3-carbonyl)amιno)- 4,5,6,7-tetrahydro-l-benzothιen-2-yl)-l,4-dιhydro-3-quιnolιnecarboxyhc acid, l-cyclopropyl-8-methoxy-7-(4-((4-moφholιnylacetyl)amιno)-4,5,6,7-tetrahydro-l- benzothιen-2-yl)-4-oxo-l,4-dιhydro-3-quιnolιnecarboxyhc acid; l-cyclopropyl-8-methoxy-7-(4-((3-(4-morpholιnyl)propanoyl)amιno)-4, 5,6,7- tetrahydro- l-benzothιen-2-yl)-4-oxo-l,4-dιhydro-3-quιnohnecarboxylιc acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-((lH-pyrrol-2-ylcarbonyl)amιno)-4, 5,6,7- tetrahydro-l-benzothιen-2-yl)-l,4-dιhydro-3-quιnolιnecarboxyhc acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-((3-pyπdιnylacetyl)amιno)-4,5,6,7- tetrahydro-l-benzothιen-2-yl)-l,4-dιhydro-3-quιnolιnecarboxyhc acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-((3-pyπdazιnylcarbonyl)amιno)-4, 5,6,7- tetrahydro-l-benzothιen-2-yl)-l,4-dιhydro-3-quιnolιnecarboxyhc acid; l-cyclopropyl-7-(4-((lH-ιmιdazol-2-ylcarbonyl)amιno)-4,5,6,7-tetrahydro- l- benzothιen-2-yl)-8-methoxy-4-oxo-l,4-dιhydro-3-quιnolιnecarboxyhc acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-((l ,3-thιazol-2-ylcarbonyl)amιno)-4,5,6,7- tetrahydro-l-benzothιen-2-yl)-l,4-dιhydro-3-quιnohnecarboxyhc acid; l-cyclopropyl-8-methoxy-7-(5-(methylamιno)-4,5,6,7-tetrahydro-l-benzothιen-2- yl)-4-oxo-l,4-dιhydro-3-quιnolιnecarboxyhc acid, l-cyclopropyl-8-methoxy-7-(4-(4-morphohnylmethyl)-4,5,6,7-tetrahydro-l- benzothιen-2-yl)-4-oxo- 1 ,4-dιhydro-3-quιnohnecarboxylιc acid; l-cyclopropyl-7-(4-((dιmethylamιno)methyl)-4,5,6,7-tetrahydro-l-benzothιen-2- yl)-8-methoxy-4-oxo-l ,4-dιhydro-3-quιnohnecarboxylιc acid; l-cyclopropyl-7-(4-(((dιmethylamιno)acetyl)amιno)-4,5,6,7-tetrahydro-l- benzothιen-2-yl)-8-methoxy-4-oxo-l,4-dιhydro-3-quιnolιnecarboxyhc acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-((2-pyπdιnylacetyl)amιno)-4, 5,6,7- tetrahydro-l-benzothιen-2-yl)-l,4-dιhydro-3-qumolιnecarboxylιc acid;
7-(4-(amιnomethyl)-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l ,4-dιhydro-3-quιnolιnecarboxyhc acid; l-cyclopropyl-8-methoxy-4-oxo-7-((4E/Z)-4-((4-pyπdιnylmethoxy)ιmιno)-4,5,6,7- tetrahydro-l-benzothιen-2-yl)-l,4-dιhydro-3-quιnolιnecarboxylιc acid;
7-(4-((2-amιnoethyl)ammo)-4,5,6,7-tetrahydro- l-benzothιen-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dιhydro-3-quιnolιnecarboxylιc acid; l -cyclopropyl-8-methoxy-7-(4-((l-methyl-4-pιpeπdιnyl)amιno)-4,5,6,7-tetrahydro- l-benzothιen-2-yl)-4-oxo-l,4-dιhydro-3-quιnohnecarboxylιc acid; l-cyclopropyl-7-((4E/Z)-4-(hydroxyimino)-5-methyl-4,5,6,7-tetrahydro-l- benzothien-2-yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4-hydroxy-7,7-dioxido-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2- yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; 7-(4-(((5-chloro-l,3-dimethyl-lH-pyrazol-4-yl)sulfonyl)amino)-4,5,6,7-tetrahydro- l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-(((4-cyanophenyl)sulfonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-((phenylsulfonyl)amino)-4,5,6,7-tetrahydro- l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-(((2-cyanophenyl)sulfonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-(4-(((4-methoxyphenyl)sulfonyl)amino)-4,5,6,7- tetrahydro-l-benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-(4-(((3-nitrophenyl)sulfonyl)amino)-4,5,6,7- tetrahydro-l-benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(5-((2-pyrrolidinylmethyl)amino)-4, 5,6,7- tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid; 7-(4-amino-7,7-dioxido-5,6-dihydro-4H-thieno[2,3- ?]thiopyran-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4-(((3,5-dimethyl-4-isoxazolyl)sulfonyl)amino)-4, 5,6,7- tetrahydro-l-benzothien-2-yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-((2,l,3-benzoxadiazol-4-ylsulfonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2- yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4-(((dimethylamino)sulfonyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-((2-thienylsulfonyl)amino)-4, 5,6,7- tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid; 7-(4-(((3-cyanophenyl)sulfonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-(((4-(acetylamino)phenyl)sulfonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2- yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-((2,l,3-benzothiadiazol-4-ylsulfonyl)amino)-4,5,6,7-tetrahydro-l-benzothien- 2-yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4-(((5-(3-ιsoxazolyl)-2-thιenyl)sulfonyl)amιno)-4,5,6,7- tetrahydro-l-benzothιen-2-yl)-8-methoxy-4-oxo-l,4-dιhydro-3-quιnolιnecarboxyhc acid; l-cyclopropyl-7-(4-(((4-fluorophenyl)sulfonyl)amιno)-4,5,6,7-tetrahydro-l- benzothιen-2-yl)-8-methoxy-4-oxo-l,4-dιhydro-3-quιnolιnecarboxyhc acid; 7-(4-(((6-chloroιmιdazo[2,l-&][l,3]thιazol-5-yl)sulfonyl)amιno)-4,5,6,7- tetrahydro-l-benzothιen-2-yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4-dιhydro-3- quinolinecarboxyhc acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-((4-pyπdιnylacetyl)amιno)-4,5,6,7- tetrahydro-l-benzothιen-2-yl)-l,4-dιhydro-3-quιnolιnecarboxylιc acid; l-cyclopropyl-7-(4-((2-hydroxyethyl)amιno)-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-
8-methoxy-4-oxo-l,4-dιhydro-3-quιnolιnecarboxyhc acid,
7-(4-amιno-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-l-cyclopropyl-6-fluoro-4-oxo- l,4-dιhydro[l,8]naphthyπdιne-3-carboxylιc acid;
7-(4-((glycyl)ammo)-4, 5 ,6,7-tetrahydro- 1 -benzothιen-2-yl)- 1 -cyclopropyl-8- methoxy-4-oxo-l,4-dιhydro-3-quιnohnecarboxylιc acid;
7-(4-((D-alanyl)amιno)-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-l-cyclopropyl-8- methoxy-4-oxo- 1 ,4-dιhydro-3-quιnolmecarboxylιc acid, l-cyclopropyl-8-methoxy-4-oxo-7-(4-((D-prolyl)amιno)-4,5,6,7-tetrahydro-l- benzothιen-2-yl)-l,4-dιhydro-3-quιnohnecarboxylιc acid; 7-(4-(((2R)-2-amιno-3-(lH-ιmιdazol-5-yl)propanoyl)amιno)-4,5,6,7-tetrahydro-l- benzothιen-2-yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4-dιhydro-3-quιnohnecarboxylιc acid;
7-(4-((leucyl)amιno)-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dιhydro-3-quιnolιnecarboxyhc acid,
7-(4-((D-tyrosyl)amιno)-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dιhydro-3-quιnohnecarboxylιc acid,
7-(4-((O-methyl-D-tyrosyl)amιno)-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dιhydro-3-quιnolιnecarboxyhc acid;
7-(4-((D-methιonyl)amιno)-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dιhydro-3-quιnolιnecarboxyhc acid; 7-(4-(((2R)-2-amιno-3-(3-pyrιdιnyl)propanoyl)ammo)-4,5,6,7-tetrahydro-l- benzothιen-2-yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4-dιhydro-3-quιnolιnecarboxylιc acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-(((2R)-pιpeπdιnylcarbonyl)amιno)-4, 5,6,7- tetrahydro-l-benzothιen-2-yl)-l,4-dιhydro-3-quιnolιnecarboxyhc acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-((4-pyrimidinylcarbonyl)amino)-4,5,6,7- tetrahydro-l-benzothien-2-yl)-l ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-((l,3-thiazol-2-ylcarbonyl)amino)-4,5,6,7- tetrahydro-l-benzothien-2-yl)-l ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-((phenylacetyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4-(3-furoylamino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-((2-pyridinylcarbonyl)amino)-4,5,6,7- tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-((lH-pyrazol-4-ylcarbonyl)amino)-4, 5,6,7- tetrahydro-l-benzothien-2-yl)- 1 ,4-dihydro-3-quinolinecarboxylic acid;
7-(4-((D-aspartyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-((4R)-4-((N-methyl-D-leucyl)amino)-4,5,6,7- tetrahydro-l-benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-((4R)-4-((D-norleucyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid; methyl l-cyclopropyl-8-methoxy-4-oxo-7-(4-((4-pyrimidinylcarbonyl)amino)- 4,5,6,7-tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylate; methyl l-cyclopropyl-8-methoxy-4-oxo-7-(4-((l,3-thiazol-2-ylcarbonyl)amino)- 4,5,6,7-tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylate; methyl l-cyclopropyl-8-methoxy-4-oxo-7-(4-((2-pyridinylcarbonyl)amino)-4,5,6,7- tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylate; 7-(4-((β-O-methyl-D-aspartyl)amino)-4,5 ,6,7-tetrahydro- 1 -benzothien-2-yl)- 1 - cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-((4E)-4-((3-pyridinylmethoxy)imino)-4,5,6,7- tetrahydro-l-benzothien-2-yl)- 1 ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-((4E)-4-((2-pyridinylmethoxy)imino)-4, 5,6,7- tetrahydro-l-benzothien-2-yl)-l ,4-dihydro-3-quinolinecarboxylic acid; ethyl 7-(4-((tert-butyl(dimethyl)silyl)oxy)-5-methyl-4,5,6,7-tetrahydro-l- benzothien-2-yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate; l-cyclopropyl-7-(4-hydroxy-5-methyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-(4-(((methylanilino)carbonyl)amino)-4,5,6,7- tetrahydro-l-benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4-(((diethylamino)carbonyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4-(((diisopropylamino)carbonyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-8-methoxy-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-(4-((4-moφholinylcarbonyl)amino)-4,5,6,7-tetrahydro- l-benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-(4-((methoxycarbonyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-(((benzyloxy)carbonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4-((isobutoxycarbonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2- yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4-((ethoxycarbonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2- yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-((butoxycarbonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-(((4-chlorobutoxy)carbonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-((5E/Z)-5-(hydroxymethylene)-4-oxo-4,5,6,7-tetrahydro-l- benzothien-2-yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-((4E/Z)-4-((3-pyridinylmethoxy)imino)-4,5,6,7- tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid; 1 -cyclopropyl-7-(4-(3-hydroxy- 1 -azetidinyl)-4,5,6,7-tetrahydro- 1 -benzothien-2-yl)-
8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-amino-5-methyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid;
7-(4-amino-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-4-oxo-l,4- dihydro[l ,8]naphthyridine-3-carboxylic acid;
7-(7-amino-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(7-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(7-oxo-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2- yl)-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; ethyl 7-(4-azido-5-methyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate; 7-(4-amino-5,5-difluoro-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(5-(hydroxymethyl)-5-methyl-4-oxo-4,5,6,7-tetrahydro-l- benzothien-2-yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(7-amino-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-l-cyclopropyl-8-methoxy- 4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-6-fluoro-8-methoxy-7-(4-(methylamino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride; l-cyclopropyl-8-methoxy-4-oxo-7-(4-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2- yl)- 1 ,4-dihydro-3-quinolinecarboxylic acid;
7-[4-(3-amino-l-azetidinyl)-4,5,6,7-tetrahydro-l-benzothien-2-yl]-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4-hydroxy-5,5-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-((tert-butoxycarbonyl)amino)-5-methyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)- l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; methyl 7-[4-(acetyloxy)-4,5,6,7-tetrahydro-l-benzothien-2-yl]-l-cyclopropyl-8- methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylate; l-cyclopropyl-8-methoxy-7-(7-(methylamino)-4,5,6,7-tetrahydro-l-benzothien-2- yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; methyl l-cyclopropyl-6-fluoro-7-(4-hydroxy-4,5,6,7-tetrahydro-l-benzothien-2-yl)- 8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate; l-cyclopropyl-7-(7-hydroxy-4,4-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; methyl 7-(4-azido-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-6-fluoro-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate; methyl 7-(4-((tert-butoxycarbonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-6-fluoro-8-methoxy-4-oxo-l ,4-dihydro-3-quinolinecarboxylate; 7-(4-((tert-butoxycarbonyl)amino)-4,5,6,7-tetrahydro- l-benzothien-2-yl)-l - cyclopropyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; 7-(7-amιno-4,4-dιmethyl-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-l-cyclopropyl-8- methoxy-4-oxo- 1 ,4-dιhydro-3-quιnohnecarboxylιc acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-oxo-5-spιro-3'-(N-benzylpyrrolιdιne)-4, 5,6,7- tetrahydro-l-benzothιen-2-yl)-l ,4-dιhydro-3-quιnolιnecarboxylιc acid; 7-(4-amιno-4, 5 ,6,7-tetrahydro- 1 -benzothιen-2-yl)- 1 -cyclopropyl-6-fluoro-8- methoxy-4-oxo-l,4-dιhydro-3-quιnohnecarboxylιc acid;
7-(4-amιno-4,5,6,7-tetrahydrothιeno[2,3-c]pyπdιn-2-yl)-l-cyclopropyl-8-methoxy- 4-oxo-l,4-dιhydro-3-quιnolιnecarboxyhc acid;
7-(7-azιdo-4,5,6,7-tetrahydrothιeno[3,2-c]pyπdιn-2-yl)-l-cyclopropyl-8-methoxy- 4-oxo-l,4-dιhydro-3-qumohnecarboxylιc acid; l-cyclopropyl-7-(4,4-dιmethyl-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-8-methoxy-4- oxo- 1 ,4-dιhydro-3-quιnolιnecarboxyhc acid;
7-(7-amιno-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-l-cyclopropyl-6-fluoro-8- methoxy-4-oxo- 1 ,4-dιhydro-3-quιnohnecarboxylιc acid; 7-(5-acetyl-7-amιno-4,5,6,7-tetrahydrothιeno[3,2-c]pyπdιn-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dιhydro-3-quιnohnecarboxylιc acid;
7-(7-amιno-5-(methylsulfonyl)-4,5,6,7-tetrahydrothιeno[3,2-c]pyπdιn-2-yl)-l- cyclopropyl-8-methoxy-4-oxo- 1 ,4-dιhydro-3-quιnohnecarboxylιc acid;
7-(4-amιno-5,5-dιfluoro-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dιhydro-3-quιnohnecarboxylιc acid;
7-(4-amιno-3-methyl-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-l-cyclopropyl-8- methoxy-4-oxo- 1 ,4-dιhydro-3-qumohnecarboxylιc acid; l-cyclopropyl-7-((4E/Z)-4-(hydroxyιmιno)-5,5-dιmethyl-4,5,6,7-tetrahydro-l- benzothιen-2-yl)-8-methoxy-4-oxo- 1 ,4-dιhydro-3-quιnolιnecarboxylιc acid; l-cyclopropyl-7-(4-hydroxy-6,6-dιmethyl-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-8- methoxy-4-oxo- 1 ,4-dιhydro-3-qumohnecarboxylιc acid,
7-(7-amιno-6-methyl-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-l-cyclopropyl-8- methoxy-4-oxo- 1 ,4-dιhydro-3-qumolιnecarboxylιc acid hydrochloπde; l-cyclopropyl-7-(6,6-dιmethyl-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-8-methoxy-4- oxo-l,4-dihydro-3-qumohnecarboxyhc acid;
7-(7-amιno-6-fluoro-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dιhydro-3-quιnohnecarboxylιc acid,
7-(4-amιno-6,6-dιmethyl-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-l-cyclopropyl-8- methoxy-4-oxo- 1 ,4-dιhydro-3-quιnolιnecarboxyhc acid; l-cyclopropyl-8-methoxy-4-oxo-7-(7-oxo-4,5,6,7-tetrahydro- l ,3-benzothιazol-2- yl)-l,4-dιhydro-3-quιnolιnecarboxyhc acid; l-cyclopropyl-7-(6-fluoro-7-hydroxy-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-8- methoxy-4-oxo-l,4-dιhydro-3-quιnolmecarboxyhc acid, l-cyclopropyl-7-(7-hydroxy-6,6-dιmethyl-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-8- methoxy-4-oxo- 1 ,4-dιhydro-3-quιnohnecarboxylιc acid; l-cyclopropyl-7-((65,75)-7-hydroxy-6-methyl-4,5,6,7-tetrahydro-l-benzothιen-2- yl)-8-methoxy-4-oxo-l,4-dιhydro-3-quιnolιnecarboxyhc acid, l-cyclopropyl-8-methoxy-4-oxo-7-(4,5,6,7-tetrahydro-l-benzothιen-2-yl)-l,4- dιhydro-3-quιnohnecarboxylιc acid;
7-(7-amιno-6,6-dιfluoro-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dιhydro-3-quιnolιnecarboxyhc acid;
7-(7-amιno-6,6-dιmethyl-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dιhydro-3-quιnolιnecarboxyhc acid, l-cyclopropyl-6-fluoro-8-methoxy-7-(7-(methylamιno)-4,5,6,7-tetrahydro-l- benzothιen-2-yl)-4-oxo- 1 ,4-dιhydro-3-quιnohnecarboxylιc acid; l-cyclopropyl-8-methoxy-4-oxo-7-(5-oxo-5,6-dιhydro-4H-cyclopenta[b]thιen-2- yl)-l,4-dιhydro-3-quιnohnecarboxylιc acid; l-cyclopropyl-8-methoxy-7-((5E/Z)-5-(methoxyιmιno)-5,6-dιhydro-4H- cyclopenta[fo]thιen-2-yl)-4-oxo- 1 ,4-dιhydro-3-quιnohnecarboxylιc acid;
7-(5-amιno-5,6-dιhydro-4H-cyclopenta[b]thιen-2-yI)-l-cyclopropyl-8-methoxy-4- oxo-l,4-dιhydro-3-quιnohnecarboxylιc acid; l-cyclopropyl-7-(5-((ethoxycarbonyl)amιno)-5,6-dιhydro-4H-cyclopenta[/ ]thιen-2- yl)-8-methoxy-4-oxo-l,4-dιhydro-3-quιnolιnecarboxyhc acid; l-cyclopropyl-8-methoxy-7-(5-((methoxycarbonyl)amιno)-5,6-dιhydro-4H- cyclopenta[fr]thιen-2-yl)-4-oxo-l,4-dιhydro-3-quιnolιnecarboxyhc acid; 7-(5-(acetylamιno)-5,6-dιhydro-4H-cyclopenta[b]thιen-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dιhydro-3-qumolιnecarboxylιc acid, l-cyclopropyl-8-methoxy-7-(5-(((4-methylphenyl)sulfonyl)amιno)-5,6-dιhydro-4H- cyclopenta[b]thien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxyhc acid; l-cyclopropyl-8-methoxy-7-(5-((methylsulfonyl)amιno)-5,6-dιhydro-4H- cyclopenta[£]thιen-2-yl)-4-oxo-l,4-dιhydro-3-quιnolιnecarboxyhc acid;
7-((5E/Z)-5-((benzyloxy)ιmιno)-5,6-dιhydro-4H-cyclopenta[b]thιen-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dιhydro-3-quιnolιnecarboxyhc acid, l-cyclopropyl-7-((5E/Z)-5-(hydroxyιmιno)-5,6-dιhydro-4H-cyclopenta[£]thιen-2- yl)-8-methoxy-4-oxo- 1 ,4-dιhydro-3-qumolιnecarboxylιc acid; 7-(4-amιno-4-methyl-4,5,6,7-tetrahydro-l -benzothιen-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l ,4-dιhydro-3-quιnolιnecarboxyhc acid, l-cyclopropyl-7-(5-(dimethylamino)-5,6-dihydro-4H-cyclopenta[b]thien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-azido-5,5-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; 7-(7-amino-4,5,6,7-tetrahydro-l-benzothien-3-yl)-l-cyclopropyl-8-methoxy-4-oxo-
1 ,4-dihydro-3-quinolinecarboxylic acid;
7-(7-amino-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- (difluoromethoxy)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(7-hydroxy-5,5-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(7-amino-5,5-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4-hydroxy-4,5,6,7-tetrahydro-l-benzofuran-2-yl)-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid; and
7-(4-amino-4,5,6,7-tetrahydro-l-benzofuran-2-yl)-l-cyclopropyl-8-methoxy-4-oxo- l,4-dihydro-3-quinolinecarboxylic acid.
Assay A. Determination of Biological Activity In Vitro Assay of Antibacterial Activity
Representative compounds of the invention were assayed in vitro for antibacterial activity. Twelve petri dishes containing successive aqueous dilutions of the test compound mixed with sterilized Brain Heart Infusion (BHT) agar (Difco 0418-01-5) (10 mL) were prepared. Each plate was inoculated with 1:100 (or 1:10 for slow-growing strains, such as Micrococcus and Streptococcus) dilutions of up to 32 different microorganisms using a Steers replicator block. The inoculated plates were incubated at 35-37 °C for about 20 to about 24 hours. In addition, a control plate with BHI agar and no test compound was prepared and incubated at the beginning and end of each test.
An additional plate containing a compound having known susceptibility patterns for the organisms being tested and belonging to the same antibiotic class as the test compound was also prepared and incubated as a further control and to provide test-to-test comparability. Ciprofloxacin was used for this puφose.
After incubation, each plate was visually inspected. The minimum inhibitory concentration (MIC) was defined as the lowest concentration of drug yielding no growth, a slight haze, or sparsely isolated colonies on the inoculum spot as compared to the growth control. The results of this assay, shown in Table 1, demonstrate the antibacteπal activity of the compounds of the invention.
Microorganism Code
Staphylococcus aureus ATCC 6538P A
Enterococcus faecahs PIU 1967 B
Moraxella catarrahahs 2604 C
Escherichia coli JUHL D
Haemophilus influenzae DILL AMP R E
Streptococcus pneumoniae ATCC 6303 F
Table 1 Antibacterial Activity (MIC's) of Selected Compounds
Figure imgf000037_0001
Assay B. Determination of Biological Activity In Vitro Assay of Antibacteπal Activity
Representative compounds of the invention were assayed in vitro for antibacteπal activity The susceptibilities of aerobic, nonfastidious species were determined visually by broth microdilution as described by the National Committee for Clinical Laboratory Standards (NCCLS) (National Committee for Clinical Laboratory Standards. 1997. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically Approved standard M7- A4 National Committee for Clinical Laboratory Standards. Wayne, PA ). In bπef, seπal twofold dilutions of test compounds were made in cation-adjusted Mueller Hinton broth at two-times the final concentration Inocula were prepared from overnight cultures of test strains. Tests were inoculated with a suspension of bacteπa in Mueller Hinton broth to achieve a final density of approximately 5 x 10^ CFU/mL. Tests were incubated at 35°C in ambient air for 16 to 20 hr. Minimum Inhibitory Concentrations (MICs) were determined as the lowest drug concentration completely inhibiting growth Ciprofloxacin was included as a control. For testing S. pneumoniae, the cation-adjusted Mueller Hinton broth was supplemented with 3% lysed horse blood and the incubation period was extended to 20 to 24 hr. For testing H. influenzae, the cation-adjusted Mueller Hinton broth was supplemented with 5 g/L yeast extract, 0.3 mmol/L hematin and 15 mg/L NAD and incubation was extended to 20 to 24 hr.. The results of this assay, shown in Table 2, demonstrate the antibacterial activity of the compounds of the invention.
Microorganism Code Staphylococcus aureus ATCC 6538P A
Enterococcus faecalis PIU 1967 B
Escherichia coli JUHL D
Haemophilus influenzae DILL AMP R E
Streptococcus pneumoniae ATCC 6303 F
Table 2
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Abbreviations
Abbreviations which have been used in the descriptions of the scheme and the examples that follow are: m-CPBA for meta-chloroperbenzoic acid; dba for dibenzylidine acetone; dba for dibenzylidine acetone; CDI for carbonyldiimidazole; DMAP for 4-(N, N- dimethylamino)pyridine DME for dimethoxyethane; DMF for N,N-dimethylformamide; DMS for dimethylsulfide; DMSO for dimethylsulfoxide; EDCI for l-((3- (dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride; TEA for triethylamine; TFA for trifluoroacetic acid; and THF for tetrahydrofuran.
Synthetic Methods
The compounds and processes of the invention will be better understood in connection with the following synthetic schemes which illustrate methods by which the compounds can be prepared. The compounds can be prepared by a variety of synthetic routes. Representative procedures are shown in Schemes 1-6. It will be readily apparent that the compounds can be synthesized by substitution of the appropriate reactants and agents in the syntheses shown below. It will also be apparent that the selective protection and deprotection steps, as well as the order of the steps themselves, can be carried out in varying order, depending on the nature of the reactions. A thorough discussion of protecting'groups is provided in Greene and Wuts, "Protective Groups in Organic Synthesis," 2nd Ed., John Wiley & Son, Inc., 1991. Precursor compounds, intermediates, and reagents are commercially available or can be prepared from commercially available starting materials. Functional group transformations useful for preparing compounds of the invention are reported in Larock, "Comprehensive Organic Transformations. A Guide to Functional Group Preparations," VCH Publishers, New York (1989).
Scheme 1
Figure imgf000043_0001
A synthesis of compounds of formula (la) is shown in Scheme 1. Conversion of compounds of formula (i) to compounds of formula (la) can be achieved means such as those reported in U.S. Patent 5,282,703. The starting materials are available commercially or can be prepared by well-known means. For example, commercially available 4-bromo- 2-fluorobenzoic acid (Alfa/Aesar, Ward Hill, MA), ethyl 3-hydroxybenzoate, and 2,6- dichloronicotinic acid (Aldrich Chemical Company, Milwaukee, WI) ultimately provide compounds of formula (la). The synthesis of 3-amino-5-hydroxybenzoic acid, another precursor to compounds of formula (la), is reported in Tetrahedron 39(24), 4189 (1989).
Scheme 2
Figure imgf000043_0002
(la) (ϋ) (la)
As shown in Scheme 2, compounds of formula (la) can be nitrated with fuming nitric acid in sulfuric acid to provide compounds of formula (ii). Conversion of compounds of formula (ii) to compounds of formula (la) can be achieved with metal powder such as zinc, iron, or tin in acids such as hydrochloric, hydrobromic, sulfuric, acetic, trifluoroacetic, or mixtures thereof. Additional compounds of formula (la) can be prepared by alkylating the amino group at the C-6 position of the compounds of formula (la) with alkyl chlorides, bromides, or iodides in the presence of a base such as cesium carbonate, potassium bicarbonate, sodium hydride, or potassium hydride. Scheme 3
Figure imgf000044_0001
A synthesis of compounds of formula (la) wherein R and R are taken together is shown in Scheme 3. Conversion of ethyl 3-aminobenzoate to ethyl 3-amino-2,4- dibromobenzoate can be achieved by means well-known in the art. The ethyl 3-amino- 2,4-dibromobenzoate can then be converted to ethyl 2,4-dibromo-3-chlorobenzoate by diazotization/chlorination according to the procecure described in Chem. Pharm. Bull. 37(8) 2103 (1989) or alternatively converted ethyl 3-amino-2,4-dibromobenzoate by diazotization/reduction as described in J. Am. Chem. Soc. 72, 3013 (1950) and I. Org. Chem. 42, 1469 (1977). Each of these substituted benzoic acids can then be elaborated to compounds of formulas (v), (vi), and (la) as described in Scheme 1 and in U.S. Patents 4,382,892 and 4,762,831. The functionalized amines of formula (iv) can be optionally protected amino acids, amino sulfhydryls, or amino alcohols, the latter two of which can be derived from amino acids of known stereochemistry by preparations such as those described in Tetrahedron Lett. 36(8) 1223 (1995).
Scheme 4
Figure imgf000045_0001
(vii) (lb)
As shown in Scheme 4, compounds of formula (vii), which are commercially available or prepared by means well-known in the art, can be converted to compounds of formula (lb) by treatment with a base such as the lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, n-butyllithium, sec- butyllithium, tert-butyllithium, and lithium diisopropylamide followed by treatment of the
2 resulting anion with a Q precursor such as bromine, N-bromosuccinimide, a
2 trialkoxyborane, and a trialkylstannyl halide. For compounds of formula (lb) wherein Q is halide, the halide can be further derivatized by treatment with a metal such as magnesium or zinc to provide the corresponding magnesium halide or zinc halide. For
2 compounds of formula (lb), wherein Q is a boronic ester, the boronic ester can be hydrolyzed to the boronic acid with a base such as lithium hydroxide, sodium hydroxide, and potassium hydroxide or an acid such as hydrochloric or hydrobromic.
Scheme 5
Figure imgf000045_0002
(la) (lb) (I)
As shown in Scheme 5, compounds of formula (I) can be prepared from precursor compounds of formulas (la) and (lb) in the presence of a catalyst. Examples of catalysts include tetrakis(triphenylphosphine)palladium(0), palladium(U) chloride(dibenzylidine acetone), and palladium(II) chloride bis(triphenylphosphine). If necessary, these reactions can be run on the presence of base such as Na2CO3, CS2CO3, CsF, and K2HPO4, additives such as LiCl, or ligands such as triphenylphosphine, triphenylarsine, and trialkylphosphines such as tributylphosphine.
Scheme 6
Figure imgf000046_0001
Figure imgf000046_0002
(viii)
As shown in Scheme 6, the ester group of compounds of formula (I) can be directly converted to aldehydes by treatment of the former with a hydride donating agents such as diisobutylaluminum hydride. An alternative conversion of ester groups of compounds of formula (I) to aldehydes is conversion of the corresponding acid to a Weinreb amide,
12 exemplified by compounds of formula (viii) wherein R is -N(CH3)(OCH3), followed by treatment with the aformentioned hydride donating agents.
Yet another alternative conversion of the ester group of compounds of formula (I) to aldehydes is conversion of the corresponding acid to a thioester followed by treatment of the thioester with a hydrogen source and a catalyst. Examples of hydrogen sources are hydrogen gas or triethylsilane. Examples of catalysts are palladium on carbon or platinum on carbon.
The compounds and processes of the present invention will be better understood in connection with the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention.
Example 1 l-cyclopropyl-4-oxo-7-(4,5.6,7-tetrahydrothienor3.2-clpyridin-2-yl)- 4-dihydro-3- quinolinecarboxylic acid hydrochloride
Example 1A N-methylene-2-(2-thienyl)ethanamine A solution, of 2-thiophenethylamine (10.0 g, 78.0 mmol) in 37% aqueous formaldehyde (2.81 g, 94.0 mmol) was heated to 100 °C for 3 hours, cooled to room temperature, and diluted with ethyl acetate. The layers separated, and the organic layer was washed with brine, dried (Na2SO4)j filtered, and concentrated to provide 9.86 g (91%) of the desired product as a yellow oil. MS (DCI/NH3) m/z 157 (M+H)+;
Η NMR (300 MHz, CDC13) 7.11 (dd, IH), 6.91 (m, IH), 6.82 (dd, IH), 3.47 (br s, 2H), 2.96 (t, 2H), 2.78 (t, 2H).
Example IB 4,5,6 -tetrahvdrothienor3,2-c1pyri dine A solution of Example 1A (17.7 g, 127 mmol) in 5.5M HCI (23 mL) was treated with concentrated HCI (3.1 mL), stirred for 3 hours, and concentrated. The residue was partitioned between IM NaOH and ethyl acetate. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash flash column chromotography on silica gel with 20% methanol in chloroform to provide 4.50 g (25%) of the desired product as a colorless oil. MS (DCI/NH3) m z 157 (M+18)+;
!H NMR (300 MHz, CDC13) 7.05 (d, IH), 6.74 (d, IH), 3.93 (m, 2H), 3.15 (t, 2H), 2.81 (t, 2H).
Example IC 5-trityl-4,5,6,7-tetrahydrothienor3,2-c1pyridine
A solution of Example IB (1.3 g, 9.3 mmol) in THF (5 mL) was added dropwise to a suspension of 60% oily NaH (0.632 g, 15.8 mmol) in THF (30 mL) at 0 °C, stirred for 30 minutes, treated dropwise with a solution of triphenylmethyl chloride (2.95 g, 10.6 mmol) in THF (10 mL), stirred an additional 1 hour, and quenched with water. The resulting mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash flash column chromatography on silica gel with 5% then 10% ethyl acetate in hexanes to provide 1.80 g (50%) of the desired product as a tan solid. MS (DCI/NH3) m/z 382 (M+H)+;
!H NMR (300 MHz, CDC13) 7.55 (d, 6H), 7.26 (m, 6H), 7.17 (m, 3H), 7.11 (d, IH), 6.63 (d, IH), 3.41 (br s, 2H), 2.98 (br s, 2H), 2.60 (br s, 2H).
Example ID 2-(tributylstannyl)-5-trityl-4,5,6,7-tetrahvdrothieno[3,2-clpyridine A solution of Example IC (1.77 g, 4.60 mmol) in THF (50 mL) at -78 °C was treated dropwise with 2.5M n-butyllithium in hexanes (2.5 mL, 6.40 mmol), warmed to -10 °C, stirred for 3 hours, cooled to -78 °C, treated dropwise with a solution of chlorotributylstannane (1.65 g, 5.1 mmol) in THF (5 mL), warmed to room temperature, and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the combined extracts washed with water and brine, dried (Na2SO4), filtered, and concentrated to provide 1.50 g (87%) of the desired product as a yellow oil that was used without further purification. MS (DCI/NH3) m z 671 (M+H)+; 1H NMR (300 MHz, CDCI3) 7.55 (d, 6H), 7.25 (t, 7H), 7.16 (m, 2H), 6.71 (s, IH), 3.45 (br s, 2H), 3.01 (br s, 2H), 2.57 (br s, 2H), 1.52-0.89 (m, 27H).
Example IE l-cvclopropyl-4-oxo-7-(5-trityl-4,5,6,7-tetrahvdrothienor3,2-clpyridin-2-yl)-l,4-dihydro-3- quinolinecarboxylic acid
Ethyl 7-bromo-l-cyclopropyl-4-oxo-l,4-dihydro-3-quinolone-3-carboxylate (0.104 g, 0.280 mmol), Example ID (0.288 g, 0.430 mmol) and Pd(PPh3)2Cl2 (0.020 g, 0.028 mmol) were combined in toluene (20 mL), heated at 90-110 °C for 24 hours, cooled, partitioned between ethyl acetate and 15% potassium fluoride, and filtered though
® diatomaceous earth (Celite ). The layers were separated, and the aqueous layer" was extracted with ethyl acetate. The combined extracts were washed with brine, dried
(Na2SO4), filtered, and concentrated. The residue was purified by flash flash column chromatography on silica gel with dichloromethane followed by 2% then 5% methanol in dichloromethane to provide 0.099 g (58%) of the desired product as an off-white solid. MS (DCI/NH3) m/z 609 (M+H)+;
1H NMR (300 MHz,CDCl3) 8.85 (s, IH), 8.44 (d, IH), 8.13 (s, IH), 7.76-7.70 (m, 2H),
7.53 (d, 5H), 7.26 (m, 6H), 7.17 (m, 2H), 7.12 (s, IH), 3.58 (m, IH), 3.46 (br s, 2H), 3.03
(br s, 2H), 2.65 (br s, 2H), 1.33 (m, 2H), 1.21 (m, 2H).
Example IF l-cyclopropyl-4-oxo-7-(4,5,6,7-tetrahvdrothienor3,2-clpyridin-2-yl)-l,4-dihydro-3- quinolinecarboxylic acid hydrochloride A solution of Example IE (0.046 g, 0.076 mmol) in absolute ethanol (10 mL) and a minimal amount of chloroform at 0 °C was treated with 4M HCI in dioxane (76 mL, 0.304 mmol), stirred for 30 minutes, and diluted with ethyl ether (10 mL). The precipitate which formed was filtered and washed with ethyl ether to provide 0.015 g (49%) of the desired product as a yellow solid. MS (DCI/NH3) m/z 367 (M+H)+;
Η NMR (300 MHz, DMSO-d6) 9.35 (s, 2H), 8.77 (s, IH), 8.39 (d, IH), 8.37 (m, IH), 7.92 (d, IH), 7.71 (s, IH), 4.27 (br s, 2H), 3.93 (m, IH), 3.47 (br s, 2H), 3.14 (br s, 2H), 1.34 (m, 2H), 1.24 (m, 2H).
Example 2 l-cyclopropyl-8-methoxy-4-oxo-7-(4,5,6,7-tetrahydrothienof3,2-clpyridin-2-yl)-l,4- dihydro-3-quinolinecarboxylic acid hydrochloride
Example 2A ethyl l-cvclopropyl-8-methoxy-4-oxo-7-(5-trityl-4,5,6,7-tetrahvdrothieno[3,2-clpyridin-2- yl)-l,4-dihydro-3-quinolinecarboxylate Ethyl 7-bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3- quinolonecarboxylate and Example ID were processed as described in Example IE to provide the desired product.
MS (DCI/NH3) m/z 667 (M+H)+;
1H NMR (300 MHz, CDCI3) 8.62 (s, IH), 8.18 (d, IH), 7.58 (m, 6H), 7.26 (m, 7H), 7.19 (m, 2H), 4.42 (q, 2H), 3.94 (m, IH), 3.62 (s, 3H), 3.46 (br s, 2H), 3.05 (m, 2H), 2.65 (br s,
2H), 1.41 (t, 3H), 1.17 (m, 2H), 0.96 (m, 2H).
Example 2B l-cvclopropyl-8-methoxy-4-oxo-7-(5-trityl-4,5,6 -tetrahvdrothienor3,2-c1pyridin-2-yl)- 1 ,4-dihydro-3-quinolinecarboxylic acid
A solution of Example 2A (0.590 g, 0.884 mmol) in 3: l/THF:water (30 mL) was treated with LiOH ^O (0.337 g, 8.21 mmol) and stirred overnight at room temperature. The reaction mixture was brought to pH 3.5-4.0 with 10% HCI, and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated to provide 0.553 g (80%) of the desired product which was used without further purification. MS (DCI/NH3) m/z 639 (M+H)+;
Η NMR (300 MHz, CDCI3) 14.75 (s, IH), 8.89 (s, IH), 8.20 (d, IH), 7.70 (d, IH), 7.57 (d, 6H), 7.25 (m, 7H), 7.20 (m, 3H), 4.12 (m, IH), 3.65 (s, 3H), 3.47 (s, 2H), 3.06 (m, 2H), 2.66 (br s, 2H), 1.24 (m, 2H), 1.05 (m, 2H).
Example 2C l-cyclopropyl-8-methoxy-4-oxo-7-(4,5,6,7-tetrahydrothienor3,2-c1pyridin-2-yl)-l,4- dihydro-3-quinolinecarboxylic acid hydrochloride Example 2B was processed as described in Example IF to provide the desired product. mp 180 °C (decomp.); MS (DCI/NH3) m/z 397 (M+H)+;
Η NMR (300 MHz, DMSO-d6) 9.70 (s, 2H), 8.80 (s, IH), 8.15 (d, IH), 7.98 (d, IH), 7.71 (s, IH), 4.27-4.22 (br , 3H), 3.70 (s, 3H), 3.41 (br s, 2H), 3.16 (m, 2H), 1.16 (m, 2H), 1.05 (m, 2H).
Example 3 l-cvclopropyl-4-oxo-7-(4,5,6,7-tetrahydrothienof3,2-clpyridin-2-yl)-l,4- dihydrori,81naphthyridine-3-carboxylic acid hydrochloride
Example 3 A l-cyclopropyl-4-oxo-7-(5-trityl-4,5,6,7-tetrahydrothieno[3,2-clpyridin-2-yl)-l,4- dihydrori,81naphthyridine-3-carboxylic acid Ethyl l-cyclopropyl-7-chloro-4-oxo-l,4-dihydro[l ,8]naphthyridine-3-carboxylate and Example ID were processed as described in Example IE to provide the desired product.
MS (DCI/NH3) m/z 610 (M+H)+;
Η NMR (300 MHz, CDCI3) 14.6 (s, IH), 8.90 (s, IH), 8.63 (d, IH), 7.68 (d, IH), 7.55 (m, 6H), 7.26 (m, 8H), 7.18 (m, 2H), 3.80 (m, IH), 3.45 (br s, 2H), 3.05 (m, 2H), 2.66 (br s, 2H), 1.40 (m, 2H), 1.15 (m, 2H).
Example 3B l-cvclopropyl-4-oxo-7-(4,5,6,7-tetrahydrothienor3,2-clpyridin-2-yl)-l,4- dihydror 81naphthyridine-3-carboxylic acid hydrochloride Example 3A was processed as described in Example IF to provide the desired product.
MS (DCI/NH3) m/z 367 (M+H)+;
Η NMR (500 MHz, CF3CO2D) 10.01 (s, IH), 9.51 (d, IH), 8.83 (d, IH), 8.48 (s, IH),
4.92 (m, 2H), 4.43 (m, 2H), 4.02 (m, 2H), 2.23 (m, 2H), 1.96 (m, 2H).
Example 4 l-cvclopiOpyl-6-fluoro-4-oxo-7-(4 5,6,7-tetrahydrothieno|3,2-clpyridin-2-yl)-l,4- dihydrori,81naphthyridine-3-carboxylic acid hydrochloride Example 4A ethyl l-cvclopropyl-6-fluoro-4-oxo-7-(5-trityl-4,5,6,7-tetrahvdrothienor3,2-clpyridin-2-yl)- l ,4-dihvdrolT,81naphthyridine-3-carboxylate Ethyl l-cyclopropyl-7-chloro-6-fluoro-4-oxo-l ,4-dihydro[l,8]naphthyridine-3- carboxylate and Example ID were processed as described in Example IE to provide the desired product.
MS (APCI(+)) m/z 656 (M+H)+;
1H NMR (300 MHz, DMSO-d6) 8.64 (s, IH), 8.34 (d, IH), 7.60-7.52 (m, 7H), 7.35-7.14 (m, 9H), 4.40 (q, 2H), 3.66 (m, IH), 3.45 (br s, 2H), 3.07 (m, 2H), 2.65 (m, 2H), 1.41 (t, 3H), 1.36-1.15 (m, 2H), 1.08 (m, 2H).
Example 4B l-cyclopropyl-6-fluoro-4-oxo-7-(5-trityl-4,5,6,7-tetrahvdrothieno[3,2-c1pyridin-2-yl)-L4- dihydro[l,81naphthyridine-3-carboxylic acid
Example 4A was processed as described in Example 2B to provide the desired product.
MS (APCI(+)) m/z 628 (M+H)+;
1H NMR (300 MHz, DMSO-d6) 14.40 (s, IH), 8.90 (s, IH), 8.34 (d, IH), 7.59-7.50 (m, 7H), 7.35-7.12 (m, 9H), 3.80 (m, IH), 3.47 (m, 2H), 3.08 (m, 2H), 2.67 (m, 2H), 1.23 (m, 2H), 1.13 (m, 2H).
Example 4C l-cyclopropyl-6-fluoro-4-oxo-7-(4,5,6,7-tetrahydrothieno[3,2-clpyridin-2-yl)-l,4- dihydro[l,81naphthyridine-3-carboxylic acid hydrochloride
Example 4B was processed as described in Example IF to provide the desired product.
MS (APCI(+)) m/z 386 (M+H)+;
Η NMR (300 MHz, DMSO-d6) 9.41 (br s, 2H), 8.82 (s, IH), 8.57 (d, IH), 7.91 (d, IH), 4.29 (br s, 2H), 3.83 (m, IH), 3.46 (m, 2H), 3.18 (m, 2H), 1.37-1.23 (m, 2H), 1.22- 1.14 (m, 2H).
Example 5 l-cvclopropyl-8-(difluoromethoxy)-4-oxo-7-(4,5,6,7-tetrahvdrothienor3,2-c1pyridin-2-yl)- l ,4-dihydro-3-quinolinecarboxylic acid hydrochloride
Example 5A ethyl l-cyclopropyl-8-((difluoromethyDperoxy)-4-oxo-7-(5-trityl-4, 5,6,7- tetrahvdrothienor3,2-clpyridin-2-yl)-l,4-dihvdro-3-quinolinecarboxylate Ethyl l-cyclopropyl-7-bromo-8-difluoromethoxy-4-oxo-l,4-dihydroquinolone-3- carboxylate and Example ID were processed as described in Example IE to provide the desired product.
MS (APCI(+)) m/z 703 (M+H)+;
Η NMR (300 MHz, DMSO-d6) 8.64 (s, IH), 8.34 (d, IH), 7.59-7.50 (m, 8H), 7.34-7.13 (m, 9H), 6.13 (t, IH), 4.40 (q, 2H), 4.10 (m, 1H), 3.45 (m, 2H), 3.05 (m, 2H), 2.65 (m, 2H), 1.43 (t, 3H), 1.45-1.20 (m, 4H).
Example 5B l-cyclopropyl-8-(difluoromethoxy)-4-oxo-7-(5-trityl-4,5,6,7-tetrahydrothieno[3,2- clpyridin-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid Example 5A was processed as described in Example 2B to provide the desired product.
MS (APCI(+)) m/z 675 (M+H)+;
Η NMR (300 MHz, DMSO-d6) 8.93 (s, IH), 8.37 (d, IH), 7.69 (d, IH), 7.61-7.50 (m, 7H), 7.35-7.10 (m, 9H), 6.17 (t, IH), 4.23 (m, IH), 3.47 ( , 2H), 3.06 (m, 2H), 2.67 (m, 2H), 1.37-1.23 (m, 2H), 1.09-0.99 (m, 2H).
Example 5C l-cvclopropyl-8-(difluoromethoxy)-4-oxo-7-(4,5,6,7-tetrahydrothieno[3,2-c1pyridin-2-yl)- l,4-dihvdro-3-quinolinecarboxylic acid hydrochloride Example 5B was processed as described in Example IF to provide the desired product.
MS (APCI(+)) m/z 433 (M+H)+;
Η NMR (300 MHz, DMSO-d6) 9.37 (br s, 2H), 8.87 (s, IH), 8.31 (d, IH), 7.95 (d, IH), 7.64 (s, IH), 7.00 (t, IH), 4.26 (m, IH), 4.14 (m, 2H), 3.46 (m, 2H), 3.14 ( , 2H), 1.18 (m, 2H), 1.04 (m, 2H).
Example 6 l-cyclopropyl-4-oxo-7-(4,5,6,7-tetrahvdrothieno(2,3-c)pyridin-2-yl)-l,4-dihydro-3- quinolinecarboxylic acid hydrochloride
Example 6A
N-methylene-2-(3-thienyl)ethanamine 2-(3-Thienyl)ethylamine was processed according to Example 1A to provide the desired product.
MS (DCI NH3) m/z 140 (M+H)+ and 157 (M+NH4)+;
Η NMR (300 MHz, CDCI3) 7.08 (d, IH), 6.95 (d, IH), 6.89 (d, IH), 3.64 (m, 2H), 2.98 (dd, 2H), 2.78 (dd, 2H).
Example 6B 4,5,6,7-tetrahydrothieno(2,3-c)pyridine Example 6A was processed as described in Example IB to provide the desired product.
MS (DCI/NH3) m/z 140 (M+H)+ and 157 (M+NH4)+;
Η NMR (300 MHz, CDCI3) 7.09 (d, IH), 6.77 (d, IH), 3.82 (s, 2H), 2.93 (dd, 2H), 2.70
(m, 2H), 1.64 (br s, IH).
Example 6C
6-trityl-4,5,6,7-tetrahvdrothieno(2,3-c)pyridine Example 6B was processed as described in Example IC to provide the desired product.
MS (DCI/NH3) m/z 382 (M+H)+; Η NMR (300 MHz, CDCI3) 7.55 (d, 6H), 7.26 (m, 6H), 7.17 (m, 3H), 7.11 (d, IH), 6.80 (d, IH), 3.52 (br s, 2H), 2.84 (dd, 2H), 2.55 (m, 2H).
Example 6D 2-(tributylstannyl)-6-trityl-4,5,6,7-tetrahydrothieno(2,3-c)pyridine Example 6C was processed as described in Example ID to provide the desired product.
MS (DCI/NH3) m/z 575 (M+NH4)+; Η NMR (300 MHz, CDCI3) 7.55 (d, 6H), 7.25 (m, 6H), 7.17 (m, 3H), 6.83 (s, IH), 3.55
(m, 2H), 2.84 (dd, 2H), 2.51 (m, 2H), 1.53-1.05 (m, 18H), 0.90 (t, 9H).
Example 6E l-cyclopropyl-4-oxo-7-(6-trityl-4,5,6,7-tetrahydrothieno(2,3-c)pyridin-2-yl)-l,4-dihvdro-3- quinolinecarboxylic acid Ethyl 7-bromo-l-cyclopropyl-4-oxo-l,4-dihydro-3-quinolone-3-carboxylate and Example 6D were processed as described in Example IE to provide the desired product. MS (DCI/NH3) m/z 609 (M+H)+; Η NMR (300 MHz, CDC13) 8.93 (s, IH), 8.46 (d, IH), 8.40 (d, IH), 7.90 (dd, IH), 7.60- 7.20 (br m, 16H), 4.53 (s, 2H), 3.84 (m, IH), 3.61 (dd, 2H), 3.12 (dd, 2H), 1.45 ( , 2H), 1.26 (m, 2H).
Example 6F l-cyclopropyl-4-oxo-7-(4,5,6,7-tetrahvdrothieno(2,3-c)pyridin-2-yl)-l,4-dihydro-3- quinolinecarboxylic acid hydrochloride Example 6E was processed as described in Example IF to provide the desired product. mp >300 °C;
MS (DCI/NH3) m/z 367 (M+H)+;
Η NMR (300 MHz, CD3OD) 8.91 (s, IH), 8.44 (d, IH), 8.42 (d, IH), 7.90 (dd, IH), 7.60 (s, IH), 4.5 l(s, 2H), 3.84 (m, IH), 3.59 (dd, 2H), 3.10 (dd, 2H), 1.45 (m, 2H), 1.26 (m, 2H).
Example 7 l-cyclopropyl-8-methoxy-4-oxo-7-(4,5,6,7-tetrahydrothieno(2,3-c)pyridin-2-yl)-l,4- dihvdro-3-quinolinecarboxylic acid hydrochloride
Example 7A l-cvclopropyl-8-methoxy-4-oxo-7-(6-trityl-4,5,6,7-tetrahydrothieno(2,3-c)pyridin-2-yl)-
1 ,4-dihydro-3-quinolinecarboxylic acid Ethyl 7-bromo-l-cyclopropyl-8-methoxy-4-oxo- 1 ,4-dihydro-3- quinolonecarboxylate and Example 6D were processed as described in Example IE to provide the desired product.
MS (DCI NH3) m/z 639 (M+H)+;
1H NMR (300 MHz, CDCI3) 14.75 (s, IH), 8.90 (s, IH), 8.20 (d, IH), 7.75 (d, IH), 7.60- 7.10 (br m, 16H), 4.10 (m, IH), 3.65 (s, 3H), 3.57 (m, 2H), 2.90 (dd, 2H), 2.60 (m, 2H), 1.12 (m, 2H), 1.00 (m, 2H).
Example 7B l-cyclopropyl-8-methoxy-4-oxo-7-(4,5,6,7-tetrahvdrothieno(2,3-c)pyridin-2-yl)-l,4- dihydro-3-quinolinecarboxylic acid hydrochloride Example 7A was processed as described in Example IF to provide the desired product. mp 188-189 °C; MS (DCI/NH3) m/z 397 (M+H)+;
Η NMR (300 MHz, DMSO-d6) 9.40 (br s, 2H), 9.25 (br s, IH), 8.80 (s, IH), 8.13 (d, IH), 8.02 (d, IH), 7.71 (s, IH), 4.45 (m, 2H), 4.26 (m, IH), 3.70 (s, 3H), 3.40 (dd, 2H), 2.96 (dd, 2H), 1.15 (m, 2H), 1.08 (m, 2H).
Example 8 l-cvclopiOpyl-4-oxo-7-(4,5,6,7-tetrahvdrothieno(2,3-c)pyridin-2-yl)-l,4- dihydro[l,81naphthyridine-3-carboxylic acid hydrochloride
Example 8A l-cyclopropyl-4-oxo-7-(6-trityl-4,5,6,7-tetrahvdrothieno(2,3-c)pyridin-2-yl)-l,4- dihydrofl,81naphthyridine-3-carboxylic acid Ethyl l-cyclopropyl-7-chloro-4-oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylate and Example 6D were processed as described in Example IE to provide the desired product.
MS (DCI/NH3) m/z 610 (M+H)+;
Η NMR (300 MHz, CDC13) 8.90 (s, IH), 8.73 (d, IH), 8.24 (d, IH), 8.00 (s, IH), 7.60- 7.10 (m, 15H), 4.52 (s, 2H), 3.90 (m, IH), 3.41 (m, 2H), 2.97 (dd, 2H), 1.28 (m, 2H), 1.15 (m, 2H).
Example 8B 1 -cyclopropyl -4-oxo-7-(4,5,6,7-tetrahvdrothieno(2,3-c)pyridin-2-yl)- 1,4- dihvdro[l,81naphthyridine-3-carboxylic acid hydrochloride Example 8A was processed as described in Example IF to provide the desired product. mp 298-300 °C;
MS (DCI/NH3) m/z 368 (M+H)+;
1H NMR (300 MHz, DMSO-d6) 9.65 (br s, 2H), 9.50 (br s, IH), 8.80 (s, IH), 8.68 (d, IH), 8.17 (d, IH), 8.02 (s, IH), 4.45 (s, 2H), 3.83 (m, IH), 3.40 (dd, 2H), 2.95 (dd, 2H), 1.28 (m, 2H), 1.15 ( , 2H).
Example 9 l-cvclopropyl-6-fluoro-4-oxo-7-(4,5,6,7-tetrahydrothieno(2,3-c)pyridin-2-yl)-l,4- dihydro|T,81naphthyridine-3-carboxylic acid hydrochloride
Example 9A l-cvclopropyl-6-fluoro-4-oxo-7-(6-trityl-4,5,6,7-tetrahvdrothieno(2,3-c)pyridin-2-yl)-l,4- dihydro[l,81naphthyridine-3-carboxylic acid Ethyl l-cyclopropyl-7-chloro-6-fluoro-4-oxo-l,4-dihydro[l,8]naphthyridine-3- carboxylate and Example 6D were processed as described in Example IE to provide the desired product.
MS (DCI/NH3) m/z 628 (M+H)+;
Η NMR (300 MHz, CDCI3) 14.40 (s, IH), 8.90 (s, IH), 8.65 (d, IH), 8.30 (d, IH), 7.60- 7.10 (m, 15H), 3.83 (m, IH), 3.60 (m, 2H), 2.90 (m, 2H), 2.62 (m, 2H), 1.32 (m, 2H), 1.25 (m, 2H).
Example 9B l-cyclopropyl-6-fluoro-4-oxo-7-(4,5,6,7-tetrahydrothieno(2,3-c)pyridin-2-yl)-l,4- dihydro|T,81naphthyridine-3-carboxylic acid hydrochloride Example 9A was processed as described in Example IF to provide the desired product. mp 290-291 °C;
MS (DCI/NH3) m/z 386 (M+H)+;
1H NMR (300 MHz, DMS.O-d6) 9.30 (br s, 2H), 9.10 (br s, IH), 8.82 (s, IH), 8.57 (d, IH), 7.91 (d, IH), 4.50 (br s, 2H), 3.83 (m, IH), 3.45 (dd, 2H), 3.00 (dd, 2H), 1.32 (m, 2H), 1.25 (m, 2H).
Example 10 l-cyclopropyl-8-(difluoromethoxy)-4-oxo-7-(4,5,6,7-tetrahydrothieno(2,3-c)pyridin-2-yl)- l,4-dihydro-3-quinolinecarboxylic acid hydrochloride
Example 10A ethyl l-cyclopropyl-8-(dιfluoromethoxy)-4-oxo-7-(6-trityl-4,5,6,7-tetrahydrothieno(2,3- c)pyridin-2-yl)- 1 ,4-dihydro-3-quinolinecarboxylate Ethyl l-cyclopropyl-7-bromo-8-difluoromethoxy-4-oxo-l,4-dihydroquinolone-3- carboxylate and Example 6D were processed as described in Example IE to provide the desired product.
MS (DCI/NH3) m/z 703 (M+H)+;
Η NMR (300 MHz, CDCI3) 8.90 (s, IH), 8.60(d, IH), 8.37 (d, IH), 7.70 (d, IH), 7.60- 7.10 (m, 16H), 6.18 (dd, IH), 4.40 (q, 2H), 4.23 (m, IH), 3.60 (m, 2H), 2.90 (dd, 2H), 2.62 (m, 2H), 1.20 (m, 2H), 1.05 (m, 2H), 0.93 (t, 3H).
Example 10B l-cvclopropyl-8-(dιfluoromethoχv)-4-oxo-7-(6-tπtyl-4,5,6,7-tetrahvdrothιeno(2,3- c)pyrιdιn-2-yl)-l,4-dιhydro-3-quιnolιnecarboxylιc acid Example 10A was processed as descπbed in Example 2B to provide the desired product. MS (DCI NH3) m/z 675 (M+H)+;
Η NMR (300 MHz, CDCI3) 8.90 (s, IH), 8.47 (d, IH), 7.70 (d, IH), 7.60-7.10 (br m, 16H), 6.27 (dd, IH), 4.23 (m, IH), 3.60 (m, 2H), 2.90 (dd, 2H), 2.63 (m, 2H), 1.20 (m, 2H), 1.08 (m, 2H).
Example 10C l-cvclopropyl-8-(dιfluoromethoxy)-4-oxo-7-(4,5,6,7-tetrahvdrothιeno(2,3-c)pyπdιn-2-yl)- l,4-dιhydro-3-quιnolιnecarboxylιc acid hydrochlonde Example 10B was processed as described in Example IF to provide the desired product. mp 198-200 °C;
MS (APCI(+)) m/z 433 (M+H)+;
Η NMR (300 MHz, DMSO-d6) 9.48 (br s, 2H), 9.35 (br s, IH), 8.88 (s, IH), 8.30 (d, IH), 7.98 (d, IH), 7.65 (s, IH), 7.01 (dd, IH), 4.44 (br s, 2H), 4.35 (dd, 2H), 4.13 (m, IH), 3.42 (dd, 2H), 3.08 (dd, 2H), 1.20 (dd, 2H), 1.05 (m, 2H).
Example 11 l-cyclopropyl-7-(6-methyl-4,5,6,7-tetrahydrothιenor3,2-c1pyndιn-2-yl)-4-oxo-L4- dιhydro[l,81naphthvndιne-3-carboxylιc acid hydrobromide
Example I IA
N-methylene-l-(2-thιenyl)-2-propanamιne 2-(2-Amιnopropyl)-thιophene (prepared by the method of Gilsdorf, et. al. J. Org. Chem. 1950, 15, 807) was processed as descπbed in Example 1A to provide the desired product. MS (DCI/NH3) m/z 154 (M+H)+;
' H NMR (300 MHz, CDCI3) 7.13 (d, IH), 6.91 (m, IH), 6.79 (d, IH), 3.70 (s, 2H), 3.17- 3.07 (m, 2H), 2.80-2.73 (m, IH), 1.05 (d, 3H).
Example 11B 6-methyl-4,5,6,7-tetrahvdrothιenoF3,2-clpyπdιne
Example 11 A was processed as descπbed in Example IB to provide the desired product. MS (DCI/NH3) m/z 154 (M+H)+;
Η NMR (300 MHz, CDCI3) 7.06 (d, IH), 6.73 (d, IH), 3.75-3.68 (m, IH), 3.03-2.97 (m,
IH), 2.78-2.74 (m, IH), 2.56-2.44 (m, 2H), 1.06 (d, 3H).
Example 11C benzyl 6-methyl-6,7-dihydrothieno[3,2-clpyridine-5(4H)-carboxylate A solution of Example 1 IB (2.60 g, 16.8 mmol) in THF (20 mL) at 0 °C was treated with triethylamine (2.37 g, 23.5 mmol) and benzyl chloroformate (3.16 g, 18.5 mmol), stirred for 4 hours, and partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate, the combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 10% then 20% ethyl acetate in hexanes to provide 1.50 g (34%) of the desired product. MS (DCI/NH3) m/z 305 (M+NH3)+; Η NMR (500 MHz, CDCI3) 7.37 (m, 5H), 7.1 (d, IH), 6.77 (d, IH), 5.13 (s, 2H), 4.94- 4.90 (br s, 2H), 4.15 (m, IH), 3.08 (m, IH), 2.63 (m, IH), 1.15 (d, IH).
Example I IP benzyl 6-methyl-2-(tributylstannyl)-6,7-dihydrothienof3,2-c1pyridine-5(4H)-carboxylate A solution of diisopropylamine (0.47 mL, 3.36 mmol) in THF (10 mL) at 0 °C was treated dropwise with 2.5M n-butyllithium in hexanes (1.3 L, 3.36 mmol), cooled to -78 °C, and stirred for 1 hour. This solution was added dropwise via canulae to a solution of Example 1 IC (0.80 g, 2.80 mmol) in THF (10 mL) at -78 °C, stirred for 1 hour at -78 °C, treated with chlorotributylstannane (0.96 g, 2.90 mmol), and warmed to room temperature overnight. The reaction mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate, the combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated to provide 1.50 g (90%) of the desired product as a yellow oil. MS (APCI(+)) m/z 577 (M+H)+; Η NMR (300 MHz, CDCI3) 7.38 (m, 5H), 6.82 (s, IH), 5.17 (s, 2H), 4.21-4.16 (m, 2H), 3.14-3.09 (m, IH), 2.72-2.62 (m, 2H), 1.56-0.98 (m, 30H).
Example HE ethyl 7-(5-((benzyloxy)carbonyl)-6-methyl-4,5,6,7-tetrahvdrothienor3,2-clpyridin-2-yl)-l- cyclopropyl-4-oxo-l ,4-dihvdro[l ,81naphthyridine-3-carboxylate Ethyl l-cyclopropyl-7-chloro-4-oxo-l,4-dihydro[l ,8]naphthyridine-3-carboxylate and Example 1 ID were processed as described in Example IE to provide the desired product.
MS (DCI/NH3) m/z 544 (M+H)+; Η NMR (300 MHz, CDCI3) 8.61 (s, IH), 8.59 (d, IH), 7.49 (m, 5H), 7.38 (d, IH), 7.19 (s, IH), 5. 13 (s, 2H), 4.93-4.88 (br s, 2H), 4.32 (q, 2H), 4.16 (s, IH), 4.10 (s, IH), 3.60 (m, IH), 3.12 (m, IH), 2.67 (s, IH), 2.61 (s, IH), 1.61 (br s, 2H), 1.35 (t, 3H), 1.25 (m, 2H), 1.22 (d, 3H), 0.98 (m, 2H).
Example 11F
7-(5-((benzyloxy)carbonyl)-6-methyl-4,5,6,7-tetrahydrothieno[3,2-clpyridin-2-yl)-l- cyclopropyl-4-oxo-l,4-dihvdrori,81naphthyridine-3-carboxylic acid Example HE was processed as described in Example 2B to provide the desired product. MS (DCI/NH3) m/z 516 (M+H)+;
1H NMR (300 MHz, CDCI3) 14.5 (s, IH), 8.92 (s, IH ), 8.71 (d, IH), 7.7 (d, IH), 7.37 (m, 5H), 6.98 (s, IH), 5.20 (s, 2H), 5.02-4.96 (m, 2H), 4.24-4.19 (m, IH), 3.80 (m, IH), 3.18 (m, IH), 2.76-2.73 (m, IH), 1.22 (d, 3H), 1.15 (m, 2H), 0.89 (m, 2H).
Example 11G l-cvclopropyl-7-(6-methyl-4,5,6,7-tetrahydrothieno[3,2-c1pyridin-2-yl)-4-oxo-l,4- dihydrori,81naphthyridine-3-carboxylic acid hydrobromide A solution of Example 11F (0.038 g, 0.075 mmol) in acetic acid (10 mL) at 0 °C, treated with 30% HBr (0.202 mL) in acetic acid, warmed to room temperature, and stirred for 2 hours, and concentrated. The concentrate was triturated in diethyl ether, filtered, and washed sequentially with diethyl ether, hexanes, and dichloromethane to provide 0.020 g (59%) of the desired product. MS (APCI(+)) m z 445 (M+2Na+NH4)+;
Η NMR (300 MHz, DMSO-d6) 9.22 (s, IH), 9.05 (s, IH), 8.81 (s, IH), 8.71 (d, IH ), 8.15 (d, IH ), 7.98 (s, IH), 4.35-4.32 (br s, 2H), 3.81 (m, IH), 3.48-3.25 (m, IH), 2.94-2.82 (m, 2H), 1.41 (d, 3H), 1.28 (m, 2H), 1.17 (m, 2H).
Example 12 l-cyclopropyl-6-fluoro-7-(6-methyl-4,5,6,7-tetrahydrothienor3,2-clpyridin-2-yl)-4-oxo- l,4-dihydro[l,81naphthyridine-3-carboxylic acid hydrobromide
Example 12A ethyl 7-(5-((benzyloxy)carbonyl)-6-methyl-4,5,6,7-tetrahvdrothienor3,2-clpyridin-2-yl)-l- cyclopropyl-6-fluoro-4-oxo-l,4-dihydrori,81naphthyridine-3-carboxylate Ethyl l-cyclopropyl-7-chloro-6-fluoro-4-oxo-l,4-dihydro[l,8]naphthyridine-3- carboxylate and Example 1 ID were processed as described in Example IE to provide the desired product.
MS (APCI(+)) m/z 562 (M+H)+;
Η NMR (300 MHz, CDC13) 8.66 (s, IH), 8.38 (d, IH), 7.38 (m, 6H), 5.20 (s, 2H), 5.02- 4.96 (m, 2H), 4.42 (q, 2H), 4.25 (s, IH), 4.19 (s, IH), 3.67 (m, IH), 3.15 (m, IH), 2.76 (s, IH), 2.71 (s, IH), 1.41 (t, 3H), 1.33 (m, 2H), 1.21 (d, 3H), 1.09 (m, 2H).
Example 12B 7-(5-((benzyloxy)carbonyl)-6-methyl-4,5,6,7-tetrahvdrothienor3,2-clpyridin-2-yl)-l- cyclopropyl-6-fluoro-4-oxo-l,4-dihydrofl,81naphthyridine-3-carboxylic acid Example 12A was processed as described in Example 2B to provide the desired product.
MS (APCI(-)) m/z 568 (M+Cl)";
Η NMR (300 MHz, CDCI3) 14.33 (s, IH), 8.92 (s, IH), 8.40 (d, IH), 7.36 (m, 6H), 5.20 (s, 2H), 5.02-4.98 (m, 2H), 4.25-4.20 (m, IH), 3.82 (m, IH), 3.16 (m, IH), 2.78-2.73 (m, IH,), 1.42 (m, 2H), 1.22 (d, 3H), 1.13 (m, 2H).
Example 12C l-cyclopropyl-6-fluoro-7-(6-methyl-4,5,6,7-tetrahvdrothieno[3,2-clpyridin-2-yl)-4-oxo- l,4-dihydrofl,81naphthyridine-3-carboxylic acid hydrobromide Example 12B was processed as described in Example 11G to provide the desired product.
MS (APCI(+)) m/z 400 (M+H)+;
Η NMR (300 MHz, DMSO-d6) 9.39 (br s,. lH), 9.15 (br s, IH), 8.81 (s, IH), 8.57 (d, IH ), 7.92 (s, IH), 4.43-4.32 (m, 3H), 3.83 (m, IH), 3.30 (m, IH), 2.97-2.91 (m, IH), 1.42 (d, 3H), 1.29 (m, 2H), 1.18 (m, 2H).
Example 13 l-cyclopropyl-7-(6-methyl-4,5,6,7-tetrahvdrothienor3,2-clpyridin-2-yl)-4-oxo-l,4-dihydro-
3-quinolinecarboxylic acid hydrobromide
Example 13A
7-(5-((benzyloxy)carbonyl)-6-methyl-4,5,6 -tetrahydrothieno[3,2-c1pyridin-2-yl)-l- cyclopropyl-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid Ethyl l-cyclopropyl-7-bromo-4-oxo-l,4-dihydroquinolone-3-carboxylate and Example 11D were processed as described in Example IE to provide the desired product. MS (APCI(-)) m/z 549 (M+Cl)";
Η NMR (300 MHz, DMSO-d6) 15.0 (s, IH), 8.75 (s, IH), 8.37 (s, IH), 8.36 (d, IH), 7.89 (d, IH), 7.39 (m, 6H), 5.15 (s, 2H), 4.91-4.85 (m, 2H), 4.20 (m, IH), 3.91 (m, IH), 2.82 (s, IH), 2.76 (s, IH), 1.34 (m, 2H), 1.26 (m, 2H), 1.18 (d, 3H).
Example 13B l-cyclopropyl-7-(6-methyl-4,5,6,7-tetrahydrothieno[3,2-clpyridin-2-yl)-4-oxo-l,4-dihydro- 3-quinolinecarboxylic acid hydrobromide
Example 13 A was processed as described in Example 11G to provide the desired product.
MS (APCI(+)) m/z 381 (M+H)+;
Η NMR (300 MHz, DMSO-d6) 9.22 (br s, IH), 9.07 (br s, IH), 8.77 (s, IH), 8.39 (d, IH), 8.35 (s, IH), 7.92 (d, IH), 7.72 (s, IH), 4.33-4.25 (br s, 3H), 3.93 (m, IH), 3.27 (m, IH), 2.93-2.84 (m, IH), 1.42 (d, 3H), 1.36 (m, 2H), 1.23 (m, 2H).
Example 14 l-cyclopropyl-8-(difluoromethoxy)-7-(6-methyl-4,5,6,7-tetrahydrothieno[3,2-clpyridin-2- yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrobromide
Example 14A ethyl 7-(5-((benzyloxy)carbonyl)-6-methyl-4,5,6,7-tetrahvdrothieno[3,2-clpyridin-2-yl)-l- cyclopropyl-8-(difluoromethoxy)-4-oxo-l,4-dihvdro-3-quinolinecarboxylate Ethyl l-cyclopropyl-7-bromo-8-difluoromethoxy-4-oxo-l ,4-dihydroquinolone-3- carboxylate and Example 1 ID were processed as described in Example IE to provide the desired product.
MS (APCI(-)) m/z 643 (M+Cl)";
Η NMR (300 MHz, CDC13) 8.65 (s, IH), 8.37 (d, IH), 7.68 (d, IH), 7.34 (m, 6H), 6.14 (dd, IH), 5.20 (s, 2H), 4.41 (q, 2H), 4.10 (m, IH), 3.18 (br s, IH), 2.73 (s, IH), 2.68 (s, IH), 1.41 (t, 3H), 1.27 (m, 2H), 0.98 (m, 2H).
Example 14B 7-(5-((benzyloxy)carbonyl)-6-methyl-4,5,6,7-tetrahydrothienor3,2-c1pyridin-2-yl)-l- cyclopropyl-8-(difluoromethoxy)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid
Example 14A was processed as described in Example 2B to provide the desired product. MS (APCI(+)) m/z 581 (M+H)+;
Η NMR (300 MHz, CDC13) 8.94 (s, IH), 8.39 (d, IH), 7.70 (d, IH), 7.39 (m, 6H), 6.18 (dd, IH), 5.20 (s, 2H), 5.03-4.98 (br s, 2H), 4.25 ( , IH), 3.18 (m, IH), 2.75 (s, IH), 2.69 (s, IH), 1.35 (m, 2H), 1.23 (d, 3H), 1.03 (m, 2H).
Example 14C l-cvclopropyl-8-(difluoromethoxy)-7-(6-methyl-4,5,6,7-tetrahvdrothienor3,2-clpyridin-2- yl)-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid hydrobromide Example 14B was processed as described in Example 11G to provide the desired product. mp 210 °C (decomp.); MS (APCI(-)) m/z 481 (M+Cl)";
Η NMR (300 MHz, DMSO-d6) 9.25 (br s, IH), 9.07 (br s, IH), 8.87 (s, IH), 8.30 (d, IH), 7.94 (d, IH), 7.65 (s, IH), 7.01 (dd, IH), 4.36-4.25 (m, 2H), 4.14 (m, IH), 3.24 (m, IH), 2.92-2.84 (m, 2H), 1.41 (d, 3H), 1.20 (m, 2H), 1.05 (m, 2H).
Example 15 l-cvclopropyl-8-methoxy-7-(6-methyl-4,5,6,7-tetrahydrothienor3,2-clpyridin-2-yl)-4-oxo- l,4-dihydro-3-quinolinecarboxylic acid hydrobromide
Example 15A 7-(5-((benzyloxy)carbonyl)-6-methyl-4,5,6,7-tetrahydrothieno[3,2-clpyridin-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid Ethyl l-cyclopropyl-7-bromo-8-methoxy-4-oxo-l ,4-dihydroquinolone-3- carboxylate and Example 1 ID were processed as described in Example IE to provide the desired product.
MS (APCI(+)) m/z 545 (M+H)+;
Η NMR (300 MHz, DMSO-d6) 10.0 (s, IH), 8.68 (s, IH), 8.03 (d, IH), 7.76 (d, IH), 7.62 (s, IH), 7.40 (m, 5H), 5.15 (s, 2H), 4.89-4.80 (m, 2H), 4.22 (br s, IH), 4.09 (m, IH), 3.65 (s, 3H), 3.09 (m, IH), 2.79 (s, IH), 2.74 (s, IH), 1.15-1. 12 (m, 5H), 0.86 ( , 2H).
Example 15B l-cvclopropyl-8-methoxy-7-(6-methyl-4,5,6,7-tetrahvdrothienor3,2-c1pyridin-2-yl)-4-oxo- l ,4-dihvdro-3-quinolinecarboxylic acid hydrobromide Example 15A was processed as described in Example 1 1G to provide the desired product. MS (APCI(+)) m/z 411 (M+H)+;
Η NMR (500 MHz, DMSO-d6) 8.81 (s, IH), 8.15 (d, IH), 7.98 (d, IH), 7.71 (s, IH), 4.35-4.26 ( , 4H), 3.69 (s, 3H), 3.27-3.23 (m, IH), 2.92-2.87 (m, IH), 1.42 (d, 3H), 1.16 (m, 2H), 1.05 (m, 2H).
Example 16 l-cvclopropyl-7-(4-methyl-4,5,6,7-tetrahvdrothieno[3,2-clpyridin-2-yl)-4-oxo-l,4-dihvdro-
3-quinolinecarboxylic acid hydrobromide
Example 16A benzyl 4-methyl-6,7-dihvdrothienor3,2-clpyridine-5(4H)-carboxylate 4-Methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (prepared by the method of Descamps, et. al., Binon Bull Soc. Chim. Belg. 1962, 71, 599) was processed as described in Example 11C to provide the desired product. MS (APCI(+)) m/z 288 (M+H)+;
Η NMR (300 MHz, CDC13) 7.38-7.26 (m, 5H), 7.10 (dd, IH), 6.77 (m, IH), 5.18 (m, 2H), 4.43 (m, IH), 3.72 -2.32 ( , 4H), 1.41 (d, 3H).
Example 16B benzyl 4-methyl-2-(tributylstannyl)-6,7-dihydrothienor3,2-clpyridine-5(4H)-carboxylate Example 16A was processed according to Example 1 ID to provide the desired product.
MS (APCI(+)) m/z 577 (M+H)+;
Η NMR (300 MHz, CDC13) 7.38-7.26 (m, 5H), 7.10 (s, IH), 5.18 (m, 2H), 4.45 (m, IH), 3.20-2.70 (m, 4H), 1.66-0.87 (m, 30H).
Example 16C 7-(5-((benzyloxy)carbonyl)-4-methyl-4,5,6,7-tetrahydrothienor3,2-c1pyridin-2-yl)-l- cyclopropyl-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid Ethyl 7-bromo-l-cyclopropyl-4-oxo-l,4-dihydro-3-quinolone-3-carboxylate and
Example 16B were processed as described in Example IE to provide the desired product. MS (DCI/NH3) m/z 609 (M+H)+;
Η NMR (300 MHz, DMSO-d6) 8.75 (s, IH), 8.37 (d, IH), 8.33 (d, IH), 7.91 (dd, IH), 7.75 (s, IH), 7.66-7.32 (m, 5H), 5.16 (m, 2H), 4.28 (m, IH), 3.91 ( , IH), 3.25 (m, 2H), 3.14 (m, 2H), 1.45-1.15 (m, 4H), 1.44 (d, 3H). Example 16D l-cvclopropyl-7-(4-methyl-4,5,6,7-tetrahvdrothienof3,2-clpyridin-2-yl)-4-oxo-l,4-dihydro-
3-quinolinecarboxylic acid hydrobromide Example 16C was processed as described in Example 11G to provide the desired product. mp 203-207 °C (decomp.); MS (APCI(+)) m/z 381 (M+H)+;
Η NMR (300 MHz, DMSO-d6) 8.76 (s, IH), 8.39 (d, IH), 8.36 (d, IH), 7.96 (dd, IH), 7.84 (s, IH), 4.59 (m, IH), 3.94 (m, IH), 3.61 (m, 2H), 3.14 (m, 2H), 1.64 (d, 3H), 1.39- 1.19 (m, 4H).
Example 17 l-cyclopropyl-7-(4-methyl-4,5,6,7-tetrahvdrothienor3,2-clpyridin-2-yl)-4-oxo-l,4- dihydrofl,81naphthyridine-3-carboxylic acid hydrochloride
Example 17A 7-(5-((benzyloxy)carbonyl)-4-methyl-4,5,6,7-tetrahydrothienor3,2-clpyridin-2-yl)-l- cyclopropyl-4-oxo-l,4-dihydrori,81naphthyridine-3-carboxylic acid Ethyl l-cyclopropyl-7-chloro-4-oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylate and Example 16B were processed as described in Example IE to provide the desired product as a mixture of interconverting conformational isomers. MS (APCI(-)) m/z 550 (M+Cl)";
Η NMR (300 MHz, CDC13) 8.93 (s, 0.2H), 8.92 (s, 0.8H), 8.72 (d, 0.2H), 8.70 (d, 0.8H), 7.77 (d, IH), 7.70-7.35 (m, 6H), 5.20 (m, 2H), 4.40 (m, IH), 3.82 (m, IH), 3.15 (m, 2H), 2.85 (m, 2H), 1.48 (d, 3H), 1.54-1.12 (m, 4H).
Example 17B l-cyclopropyl-7-(4-methyl-4,5,6,7-tetrahydrothienor3,2-clpyridin-2-yl)-4-oxo-l,4- dihvdro|T,81naphthyridine-3-carboxylic acid hydrochloride A solution of Example 17A (0.170 g, 0.31 mmol) in trifluoroacetic acid (2 mL) was stirred for 16 hours, concentrated, treated with 4M HCI in dioxane (1 mL), stirred for 30 minutes, concentrated, triturated in diethyl ether, filtered, and washed with diethyl ether to provide 0.047 g (35%) of the desired product as a tan solid, mp 243-245 °C (decomp.); MS (APCI(+)) m/z 382 (M+H)+;
Η NMR (300 MHz, DMSO-d6) 8.81 (s, IH), 8.72 (d, IH), 8.20 (d, IH), 8.13 (s, IH), 4.57 ( , IH), 3.85 -3.81 (m, IH), 3.58 (m, 2H), 3.15 (m, 2H), 1.63 (d, 3H), 1.35-1.17 (m, 4H). Example 18 l-cyclopropyl-6-fluoro-7-(4-methyl-4,5,6,7-tetrahvdrothienor3,2-clpyridin-2-yl)-4-oxo- l,4-dihydro[l,81naphthyridine-3-carboxylic acid hydrochloride
Example 18A 7-(5-((benzyloxy)carbonyl)-4-methyl-4,5,6,7-tetrahydrothienof3,2-clpyridin-2-yl)-l- cvclopropyl-6-fluoro-4-oxo-l,4-dihydrori,81naphthyridine-3-carboxylic acid Ethyl l-cyclopropyl-7-chloro-6-fluoro-4-oxo-l,4-dihydro[l,8]naphthyridine-3- carboxylate and Example 16B were processed as described in Example IE to provide the desired product.
MS (APCI(+)) m/z 534 (M+H)+;
Η NMR (300 MHz, DMSO-d6) 8.81 (s, IH), 8.53 (d, IH), 7.94 (d, IH), 7.66-7.33 (m, 5H), 5.15 (s, 2H), 4.30 (m, IH), 3.83 (m, IH), 3.20 (m, 2H), 2.94 (m, 2H), 1.43 (d, 3H), 1.35-1.17 (m, 4H).
Example 18B l-cyclopropyl-6-fluoro-7-(4-methyl-4,5,6,7-tetrahvdrothienof3,2-c1pyridin-2-yl)-4-oxo- l,4-dihydro|T,81naphthyridine-3-carboxylic acid hydrochloride Example 18A was processed as described in Example 17B to provide the desired product.
MS (APCI(+)) m/z 400 (M+H)+;
1H NMR (300 MHz, DMSO-d6) 8.83 (s, IH), 8.58 (d, IH), 7.94 (d, IH), 4.61 (m, IH), 3.84 (m, IH), 3.40 (m, 2H), 3.18 (m, 2H), 1.63 (d, 3H), 1.36-1.17 (m, 4H).
Example 19 l-cyclopropyl-8-methoxy-7-(4-methyl-4,5,6,7-tetrahvdrothienof3,2-clpyridin-2-yl)-4-oxo- l,4-dihydro-3-quinolinecarboxylic acid hydrobromide
Example 19A
7-(5-((benzyloxy)carbonyl)-4-methyl-4,5,6,7-tetrahydrothienor3,2-clpyridin-2-yl)-l- cvclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid Ethyl 7-bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3- quinolonecarboxylate and Example 16B were processed as described in Example IE to provide the desired product as an inseparable mixture of interconverting rotational isomers. MS (ESI(-)) m/z 543 (M-H)"; Η NMR (300 MHz, DMSO-d6) 14.91 (s, 0.8H), 14.67 (s, 0.2), 8.81 (s, 0.8H), 8.79 (s, 0.2H), 8.12 (d, 0.8H), 8.06 (d, 0.2H), 8.02 (d, 0.8H), 7.82 (d, 0.2H), 7.76 (s, IH), 7.66-7.31 (m, 5H), 5.16 (m, 2H), 4.60 (m, IH), 4.25 (m, IH), 3.69 (s, 3H), 3.21 (m, 2H), 2.86 (m, 2H), 1.44 (d, 3H), 1.16-1.03 (m, 4H).
Example 19B l-cvclopropyl-8-methoxy-7-(4-methyl-4.5,6,7-tetrahvdrothienor3,2-c1pyridin-2-yl)-4-oxo- L4-dihvdro-3-quinolinecarboxylic acid hydrobromide Example 19A was processed as described in Example 11G to provide the desired product. mp 202-205 °C (decomp.); MS (APCI(+)) m/z 411 (M+H)+;
Η NMR (300 MHz, DMSO-d6) 8.81 (s, IH), 8.15 (d, IH), 8.08 (d, IH), 7.84 (s, IH), 4.58 (m, IH), 4.26 (m, IH), 3.70 (s, 3H), 3.21 (m, 2H), 3.13 (m, 2H), 1.63 (d, 3H), 1.03-1.16 (m, 4H).
Example 20 l-cyclopropyl-8-(difluoromethoxy)-7-(4-methyl-4,5,6,7-tetrahydrothienor3,2-c1pyridin-2- yl)-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid hydrobromide
Example 20 A 7-(5-((benzyloxy)carbonyl)-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c1pyridin-2-yl)-l- cvclopropyl-8-(difluoromethoxy)-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid Ethyl 7-bromo-l-cyclopropyl-8-difluoromethoxy-4-oxo-l,4-dihydro-3- quinolonecarboxylate and Example 16B were processed as described in Example IE to provide the desired product as an inseparable mixture of interconverting rotational isomers.
MS (APCI(+)) m/z 581 (M+H)+;
Η NMR (300 MHz, DMSO-d6) 14.63 (s, 0.8H), 14.39 (s, 0.2H), 8.85 (s, 0.8H), 8.80 (s, 0.2H), 8.26 (d, 0.8H), 8.21 (d, 0.2H), 7.98 (d, IH), 7.71 (s, IH), 7.71 -7.31 (m, 5H), 6.95 (dd, IH), 5.15 (m, 2H), 4.31 (m, IH), 4.14 (m, IH), 3.24 (m, 2H), 2.88 (m, 2H), 1.43 (d, 3H), 1.23-1.03 (m, 4H).
Example 20B l-cyclopropyl-8-(difluoromethoxy)-7-(4-methyl-4,5,6,7-tetrahydrothienor3,2-clpyridin-2- yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrobromide Example 20A was processed as described in Example 11G to provide the desired product. mp 176-180 °C (decomp.); MS (APCI(+)) m/z 447 (M+H)+; Η NMR (300 MHz, DMSO-d6) 8.87 (s, IH), 8.31 (d, IH), 8.03 (d, IH), 7.77 (s, IH), 7.01 (dd, IH), 4.58 (m, IH), 4.14 (m, IH), 3.41 (m, 2H), 3.15 (m, 2H), 1.62 (d, 3H), 1.20-1.03 (m, 4H).
Example 21 l-cyclopropyl-7-(7-methyl-4,5,6,7-tetrahvdrothieno(2,3-c)pyridin-2-yl)-4-oxo-l,4- dihydro|T,81naphthyridine-3-carboxylic acid hydrochloride
Example 21 A N-(2-(3-thienyl)ethyl)acetamide A solution of 2-(3-thiophene)-ethylamine (6.83 g, 53.7 mmol) in dichloromethane
(50 mL) at room temperature was treated with acetyl chloride (4.20 mL, 59.1 mmol), potassium carbonate (44.52 g, 322 mmol) and catalytic tetrabutylammonium iodide, stirred for 5 hours, and partitioned between water and dichloromethane. The organic phase dried (Na2SO4), filtered, and concentrated to provide 6.85g (75%) of the desired product. MS (DCI/NH3) m/z 170 (M+H)+;
Η NMR (300 MHz, CDCI3) δ 7.29 (dd, IH), 7.01 (m, IH), 6.95 (dd, IH), 5.62 (m, IH), 3.51 (q, 2H), 2.85 (t, 2H), 1.94 (s, 3H).
Example 2 IB 7-methyl-4,5,6,7-tetrahvdrothieno(2,3-c)pyridine
A solution of Example 21A (1.0 g, 5.9 mmol) in phosphorous oxychloride (6.0 mL, 6.4 mmol) ) at room temperature was treated with phosphorous pentachloride (2.58 g, 12.4 mmol and stirred for 4 hours. The resulting precipitate was collected by filtration and washed with ethyl ether. The solid was suspended in methanol (65 mL), treated with triethylamine (8.42 mL, 6.1 mmol), stirred for 16 hours, cooled to 0 °C, treated with sodium borohydride (0.89 g, 23.5 mmol), stirred for 1 hour at 0 °C and at room temperature for 6 hours. The reaction mixture was partitioned between 10% NaOH and dichloromethane, and the organic phase dried (Na2SO4) filtered, and concentrated to provide 1.35 g of the crude desired product that was used without further purification. MS (DCI/NH3) m/z 154 (M+H)+;
Η NMR (300 MHz, CDC13) δ 7.10 (d, IH), 6.77 (d, IH), 4.14 (m, IH), 3.32 (m, IH), 2.99 (m, I H), 2.65 (m, 2H), 1.45 (d, 3H). Example 21C benzyl 7-methyl-4,7-dihydrothieno(2,3-c)pyridine-6(5H)-carboxylate Example 21B was processed as described in Example 1 IC to provide the desired product.
MS (DCI/NH3) m/z 288 (M+H)+;
1H NMR (300 MHz, CDCI3) δ 7.37 (m, 5H), 7.13 (d, IH), 6.75 (d, IH), 5.18 (m, 2H), 4.38
(m, IH), 3.12 (m, IH), 2.72 (m, IH), 2.62 ( , 2H), 1.48 (d, 3H).
Example 2 ID benzyl 7-methyl-2-(tributylstannyl)-4,7-dihvdrothieno(2,3-c)pyridine-6(5H)-carboxylate Example 21C was processed as described in Example 11C to provide the desired product.
1H NMR (300 MHz, CDCI3) δ 7.37 (m, 5H), 6.79 (s, IH), 5.17 (m, 2H), 3.11 (m, 2H), 2.68 (m, 3H), 1.68-0.85 (m, 30H).
Example 2 IE 7-(6-((benzyloxy)carbonyl)-7-methyl-4,5,6,7-tetrahvdrothieno(2,3-c)pyridin-2-yl)-l- cvclopropyl-4-oxo-l,4-dihvdrori,81naphthyridine-3-carboxylic acid Ethyl l-cyclopropyl-7-chloro-4-oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylate and Example 21D were processed as described in Example IE to provide the desired product.
MS (DCI, NH3) m z 544 (M+H)+;
1H NMR (300 MHz, CDCI3) δ 8.92 (s, IH), 8.70 (d, IH), 7.78 (d, IH), 7.51 (s, IH), 7.38 (m, 5H), 5.21 (m, 2H), 4.40 (m, IH), 3.72 (m, IH), 3.16 (m, 2H), 2.71 (m, 2H), 1.57 (d, 3H), 1.33 (m, 2H), 1.13 (m, 2H).
Example 2 IF l-cvclopropyl-7-(7-methyl-4,5,6,7-tetrahvdrothieno(2,3-c)pyridin-2-yl)-4-oxo-l,4- dihvdro|T,81naphthyridine-3-carboxylic acid hydrochloride
Example 2 IE was processed as described in Example 17B to provide the desired product, mp 310-312 °C;
MS (DCI/NH3) m/z 382 (m+H)+; 1H NMR (300 MHz, CD3OD) δ 8.97 (s, IH), 8.75 (d, IH), 8.09 (d, IH), 7.85 (s, IH), 4.89 (m, IH), 3.89 (m, IH), 3.73 (m, IH), 3.50 (m, IH), 3.10 ( , 2H), 1.76 (d, 3H), 1.39 (m, 2H), 1.20 (m, 2H). Example 22 l-cyclopropyl-6-fluoro-7-(7-methyl-4,5.6.7-tetrahvdrothieno(2,3-c)pyridin-2-yl)-4-oxo- l,4-dihydro|T,81naphthyridine-3-carboxylic acid hydrochloride
Example 22A 7-(6-((benzyloxy)carbonyl)-7-methyl-4,5,6,7-tetrahydrothieno(2,3-c)pyridin-2-yl)-l- cvclopropyl-6-fluoro-4-oxo-l,4-dihvdrori,81naphthyridine-3-carboxylic acid Ethyl l-cyclopropyl-7-chloro-6-fluoro-4-oxo-l,4-dihydro[l,8]naphthyridine-3- carboxylate and Example 21D were processed as described in Example IE to provide the desired product. MS (DCI/NH3) m/z 559 (M-2)+.
Example 22B l-cyclopropyl-6-fluoro-7-(7-methyl-4,5,6,7-tetrahydrothieno(2,3-c)pyridin-2-yl)-4-oxo- l,4-dihydro[T,81naphthyridine-3-carboxylic acid hydrochloride Example 22A was processed as described in 17B to provide the desired product, mp 293-294 °C;
MS (DCI/NH3) m/z 400 (M+H)+; !H NMR (300 MHz, CD3OD) δ 8.98 (s, IH), 8.52 (d, IH), 7.91 (s, IH), 4.88 (m, IH), 3.88 (m, IH), 3.73 (m, IH), 3.52 (m, IH), 3.1 1 (m, 2H), 1.78 (d, 3H), 1.41 (m, 2H), 1.20 (m, 2H).
Example 23 l-cyclopropyl-8-methoxy-7-(7-methyl-4,5,6,7-tetrahydrotheino(2,3-c)pyrindin-2-yl)-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride
Example 23 A 7-(6-((benzyloxy)carbonyl)-7-methyl-4,5,6,7-tetrahydrothieno(2,3-c)pyridin-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid
Ethyl 7-bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3- quinolinecarboxylate and Example 21D were processed as described in Example IE to provide the desired product. MS (DCI/NH3) m/z 573 (M+H)+; 1H NMR (300 MHz, CDCI3) δ 8.91 (s, IH), 8.23 (d, IH), 7.74 (d, IH), 7.38 (m, 5H), 7.33 (s, IH), 5.21 (m, 2H), 4.68 (m, IH), 4.10 (m, IH), 3.67 (s, 3H), 3.17 (m, 2H), 2.70-2.52 (m, 2H), 1.57 (d, 3H), 1.29 (m, 2H), 1.06 (m, 2H). Example 23B l-cvclopropyl-8-methoxy-7-(7-methyl-4,5,6,7-tetrahydrotheino(2,3-c)pyrindin-2-yl)-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride Example 23A was processed as described in Example 17B to provide the desired product mp 225-227 °C;
MS (DCI/NH3) m/z 411 (M+H)+;
Η NMR (300 MHz, CD3OD) δ 8.98 (s, IH), 8.24 (d, IH), 7.95 (d, IH), 7.63 (s, IH), 4.86 (m, IH), 4.30 (m, IH), 3.72 (s, 3H), 3.72 (m, IH), 3.50 (m, IH), 3.10 (m, 2H), 1.76 (d, 3H), 1.28 (m, 2H), 1.08 (m, 2H).
Example 24 l-cyclopropyl-7-(7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-clpyridin-2-yl)-4-oxo-l,4- dihvdrori,81naphthyridine-3-carboxylic acid hydrobromide
Example 24 A 2-methyl-2-(2-thienyl)- 1 -propanamine A solution of 2-methyl-2-(2-thienyl)propanenitrile (7.55 g, 49.0 mmol) in THF (50 mL) at 0 °C, treated with IM lithium aluminum hydride in THF (100 mL, 100 mmol), warmed to room temperature over 16 hours, and partitioned between ice water and ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated to provide 5.32 g (70%) of the desired product which was used without purification. MS (DCI/NH3) m/z 156 (M+H)+; 1H NMR (300 MHz, CDC13) 7.17 (dd, IH), 6.95 (dd, IH), 6.84 (dd, IH), 2.77 (s, 2H), 1.36 (s, 6H).
Example 24B N-methylene-N-(2-methyl-2-(2-thienyl)propyl)amine Example 24A was processed as described in Example 1A to provide the desired product.
MS (APCI(+)) m/z 168 (M+H)+; 1H NMR (300 MHz, CDCI3) 7.13 (m, IH), 6.92 (m, IH), 6.83 (m, IH), 3.02 (s, 2H), 2.36
(s, 2H), 1.27 (s, 6H).
Example 24C 7,7-dimethyl-4,5,6,7-tetrahydrothienor3,2-c]pyridine Example 24B was processed as described in Example IB to provide the desired product.
MS (APCI(+)) m/z 168 (M+H)+;
Η NMR (300 MHz, CDC13) 7.07 (d, IH), 6.69 (d, IH), 3.58 (s, 2H), 2.65 (m, 2H), 1.35 (s, 6H).
Example 24D benzyl 7,7-dimethyl-6,7-dihvdrothienor3,2-clpyridine-5(4H)-carboxylate Example 24C was processed as described in Example 11C to provide the desired product.
MS (APCI(+)) m/z 302 (M+H)+;
1H NMR (300 MHz, CDCI3) 7.38-7.30 (m, 5H), 7.12 (d, IH), 6.75-6.69 (m, IH), 5.19 (s,
2H), 4.58 (s, 2H), 3.53 (d, 2H), 1.31 (s, 6H).
Example 24E benzyl 7,7-dimethyl-2-(tributylstannyl)-6,7-dihydrothienor3,2-clpyridine-5(4H)- carboxylate Example 24D was processed as described in Example 11D to provide the desired product. MS (APCI(+)) m/z 591 (M+H)+;
1H NMR (500 MHz, DMSO-d6) 7.56-7.33 (m, 5H), 7.26 (s, IH), 5.18 (s, 2H), 4.61 (s, 2H), 3.53 (m, 2H), 1.63-0.87 (m, 33H).
Example 24F 7-(5-((benzyloxy)carbonyl)-7,7-dimethyl-4,5,6,7-tetrahydrothienor3,2-c1pyridin-2-yl)-l- cvclopropyl-4-oxo-l ,4-dihvdro[l,81naphthyridine-3-carboxylic acid Ethyl l-cyclopropyl-7-chloro-4-oxo-l ,4-dihydro[l,8]naphthyridine-3-carboxylate and Example 24E were processed as described in Example IE to provide the desired product. MS (APCI(+)) m/z 530 (M+H)+;
Η NMR (300 MHz, DMSO-d6) 8.79 (s, IH), 8.67 (d, IH), 8.10 (m, IH), 7.92 (s, IH), 7.40-7.30 ( , 5H), 5.16 (s, 2H), 4.57 (m, 2H), 3.85 ( , IH), 3.55 (s, 2H), 1.32 (s, 6H), 1.30-1.15 (m, 4H).
Example 24G l-cvclopropyl-7-(7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-clpyridin-2-yl)-4-oxo-l,4- dihydrori ,81naphthyridine-3-carboxylic acid hydrobromide Example 24F was processed as descπbed in 11G to provide the desired product, mp >300 °C (decomp.); MS (APCI(+)) m/z 396 (M+H)+;
Η NMR (500 MHz, DMSO-d6, 80 °C) 8.80 (s, IH), 8 69 (d, IH), 8.08 (d, IH), 7.86 (s, IH), 4.21 (s, 2H), 3.89 (m, IH), 3.28 (s, 2H), 1 47 (s, 6H), 1.32-1.17 (m, 4H).
Example 25 l-cyclopropyl-7-(7,7-dιmethyl-4,5,6,7-tetrahvdrothιenor3,2-clpyπdιn-2-yl)-4-oxo-l,4- dιhydro-3-quιnolιnecarboxylιc acid hydrobromide
Example 25A
7-(5-((benzyloxy)carbonyl)-7,7-dimethyl-4,5,6,7-tetrahydrothienof3,2-c1pyndin-2-yl)-l- cyclopropyl-4-oxo-l,4-dιhydro-3-quιnolιnecarboxylιc acid
Ethyl l-cyclopropyl-7-bromo-4-oxo-l,4-dιhydroquιnolone-3-carboxylate and Example 24E were processed as described in Example IE to provide the desired product.
MS (APCI(-)) m/z 563 (M+Cl)";
1H NMR (300 MHz, DMSO-d6) 8.75 (s, IH), 8 36 (d, IH), 8.34 (s, IH), 7.90 (d, IH), 7.65-7.36 (m, 6H), 5.16 (s, 2H), 4.60 ( , 2H), 3.93 (m, IH), 3.56 (m, 2H), 1.41-1.15 (m, 10H).
Example 25B l-cyclopropyl-7-(7,7-dimethyl-4,5,6,7-tetrahvdrothieno[3,2-clpyridin-2-yl)-4-oxo-l,4- dιhydro-3-quιnolιnecarboxylιc acid hydrobromide Example 25A was processed as descπbed in 11G to provide the desired product. mp >300 °C (decomp.);
MS (APCI(+)) m/z 395 (M+H)+;
1H NMR (300 MHz, DMSO-d6) 8.77 (s, IH), 8.40 (d, IH), 8.35 (d, IH), 7.92 (dd, IH),
7.66 (s, IH), 4.24 (m, 2H), 3.93 (m, IH), 3.35 (m, 2H), 1.46 (s, 6H), 1 38-1 23 (m, 4H).
Example 26 l-cyclopropyl-7-(7,7-dιmethyl-4,5,6,7-tetrahydrothιenor3,2-clpyπdιn-2-yI)-8-methoxy-4- oxo-L4-dιhydro-3-quιnolιnecarboxylιc acid hydrobromide
Example 26A 7-(5-((benzyloxy)carbonyl)-7,7-dιmethyl-4,5,6,7-tetrahydrothιenor3,2-clpyπdιn-2-yI)-l- cyclopropyI-8-methoxy-4-oxo-l,4-dιhydro-3-quιnolιnecarboxylιc acid Ethyl l-cyclopropyl-7-bromo-8-methoxy-4-oxo-l,4-dihydroquinolone-3- carboxylate and Example 24E were processed as described in Example IE to provide the desired product.
MS (APCI(-)) m/z 593 (M+Cl)"; Η NMR (300 MHz, DMSO-d6) 8.79 (s, IH), 8.12 (d, IH), 7.97 (d, IH), 7.66-7.33 (m, 6H), 5.16 (s, 2H), 4.58 (m, 2H), 4.24 (m, IH), 3.68 (s, 3H), 3.55 (m, 2H), 1.27 (s, 6H), 1.25-1.00 (m, 4H).
Example 26B l-cvclopropyl-7-(7,7-dimethyl-4,5,6,7-tetrahydrothienor3,2-clpyridin-2-yl)-8-methoxy-4- oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid hydrobromide Example 26A was processed as described in HG to provide the desired product, mp 212-217 °C (decomp.);
MS (APCI(+)) m/z 425 (M+H) ;
1H1H NNMMRR ((330000 MMHHzz,, DDMMSSOO--dd66)) < 9.10 (br s, IH), 8.81 (s, IH), 8.17 (d, IH), 7.98 (d, IH),
7.66 (s, IH), 4.25 (m, 3H), 3.69 (s, 3H), 3.34 (m, 2H), 1.47 (s, 6H), 1.17-1.04 (m, 4H).
Example 27 l-cvclopropyl-7-(7,7-dimethyl-4,5,6,7-tetrahvdrothienor3,2-clpyridin-2-yl)-6-fluoro-4- oxo-l,4-dihydro|T,81naphthyridine-3-carboxylic acid hydrobromide
Example 27A ethyl 7-(5-((benzyloxy)carbonyl)-7,7-dimethyl-4,5,6,7-tetrahydrothienor3,2-clpyridin-2- yl)-l-cvclopropyl-6-fluoro-4-oxo-l,4-dihvdro[l,81naphthyridine-3-carboxylate Ethyl l-cyclopropyl-7-chloro-6-fluoro-4-oxo-l,4-dihydro[l,8]naphthyridine-3- carboxylate and Example 24E were processed as described in Example IE to provide the desired product.
MS (APCI(+)) m/z 576 (M+H)+;
1H NMR (300 MHz, DMSO-d6) 8.56 (s, IH), 8.30 (d, IH), 7.79 (d, IH), 7.66-7.34 (m, 5H), 5.16 (s, 2H), 4.60 (m, 2H), 4.23 (q, 2H), 3.70 (m, IH), 3.54 (m, 2H), 1.50-1.00 (m, 13H).
Example 27B 7-(5-((benzyloxy)carbonyl)-7,7-dimethyl-4,5,6,7-tetrahvdrothieno|"3,2-clpyridin-2-yl)-l- cyclopropyl-6-fluoro-4-oxo-l,4-dihvdro[l ,81naphthyridine-3-carboxylic acid
Example 27 A was processed as described in Example 2B to provide the desired product. MS (APCI(-)) m/z 582 (M+Cl)";
Η NMR (300 MHz, DMSO-d6) 8.81 (s, IH), 8.51 (d, IH), 7.88 (d, IH), 7.65-7.30 (m,
5H), 5.16 (s, 2H), 4.60 (m, 2H), 3.85 (m, IH), 3.57 (m, 2H), 1.50-1.00 (m, 10H).
Example 27C l-cvclopropyl-7-(7,7-dimethyl-4,5,6,7-tetrahvdrothienof3,2-c1pyridin-2-yl)-6-fluoro-4- oxo-l,4-dihydro|T,81naphthyridine-3-carboxylic acid hydrobromide Example 27B was processed as described in Example 11G to provide the desired product. mp 258-262 °C (decomp.);
MS (APCI(+)) m/z 414 (M+H)+;
1H NMR (300 MHz, DMSO-d6) 9.14 (br s, IH), 8.83 (s, IH), 8.58 (d, IH), 7.90 (d, IH),
4.28 (m, 2H), 3.85 (m, IH), 3.35 (m, 2H), 1.48 (s, 6H), 1.33-1.18 (m, 4H).
Example 28 l-cyclopropyl-8-(difluoromethoxy)-7-(7,7-dimethyl-4,5,6,7-tetrahydrothienor3,2- clpyridin-2-yl)-4-oxo- 1 ,4-dihvdro-3-quinolinecarbox ylic acid hydrobromide
Example 28A
7-(5-((benzyloxy)carbonyl)-7,7-dimethyl-4,5,6,7-tetrahvdrothienor3,2-c1pyridin-2-yl)-l- cvclopropyl-8-(difluoromethoxy)-4-oxo-L4-dihydro-3-quinolinecarboxylic acid Ethyl l-cyclopropyl-7-bromo-8-difluoromethoxy-4-oxo-l,4-dihydroquinolone-3- carboxylate and Example 24E were processed as described in Example IE to provide the desired product.
MS (APCI(-)) m/z 629 (M+Cl)";
Η NMR (300 MHz, DMSO-d6) 8.86 (s, IH), 8.27 (d, IH), 7.80 (d, IH), 7.68-7.33 (m, 6H), 6.95 (dd, IH), 5.16 (s, 2H), 4.57 (m, 2H), 4.14 (m, IH), 3.56 (m, 2H), 1.30 (s, 6H), 1.25-1.00 (m, 4H).
Example 28B l-cvclopropyl-8-(difluoromethoxy)-7-(7,7-dimethyl-4,5,6,7-tetrahvdrothienor3,2- clpyridin-2-yl)-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid hydrobromide Example 28A was processed as described in Example 11B to provide the desired product. mp 210-214 °C (decomp.); MS (APCI(+)) m/z 461 (M+H)+;
Η NMR (300 MHz, DMSO-d6) 9.13 (br s, IH), 8.87 (s, IH), 8.31 (d, IH), 8.08 (d, IH), 7.60 (s, IH), 6.99 (t, IH), 4.25 (m, 2H), 4.15 (m, IH), 3.36 (m, 2H), 1.46 (s, 6H), 1.28- 1.04 (m, 4H).
Example 29 l-cyclopropyl-7-(4-methyl-4,5,6,7-tetrahvdrothieno(2,3-c)pyridin-2-yl)-4-oxo-l,4-dihydro-
3-quinolinecarboxylic acid hydrochloride
Example 29 A
2-(3-thienyl)propanenitrile A solution of 3-thiopheneacetonitrile (3.0 g, 24.4 mmol) in THF ( 15 mL) was added dropwise to a solution comprising IM lithium bis(trimethylsilyl)amide (25.5 mL, 25.5 mmol) in THF (100 mL) at -70 °C, stirred for 30 minutes, warmed to -50 °C, stirred for 2 hours, treated dropwise with iodomethane (1.67 mL, 26.8 mmol), warmed to room temperature, and stirred for 18 hours. The reaction mixture was partitioned between 10% NH4CI solution and dichloromethane, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 25% ethyl acetate in hexanes to provide 1.53g (46%)the desired product. MS (DCJJNH3) m/z 138 (M+H)+;
1H NMR (300 MHz, CDC13) δ 7.36 (dd, IH), 7.25 (m, IH), 7.06 (dd, IH), 3.99 (q, IH), 1.66 (d, 3H).
Example 29B 2-(3-thienyl)propanenitrile
A solution of Example 29A (2.91 g, 21.2 mmol) in THF (10 mL) was added dropwise to a solution of 2M borane-dimethylsulfide in THF (31.8 mL, 63.5 mmol) in THF (100 mL) at 0 °C, warmed to room temperature, stirred for 1 hour, and heated at 60 °C for 3 hours, cooled to 0 °C, treated dropwise with methanol until evolution of gas ceased, diluted with 6M HCI, heated at 50 °C for 3 hours, cooled to room temperature, poured into water, and adjusted to pH 10 with sodium hydroxide, and extracted with dichloromethane. The extract was dried (Na2SU4), filtered, and concentrated to provide 3.32 g of the crude desired product which was used without further purification. MS (DCI/NH3) m/z 142 (M+H)+; Η NMR (300 MHz, CDC13) δ 7.28 (m, IH), 6.99 ( , 2H), 3.63 (m, IH), 2.85 (m, 4H), 1.27 (d, 3H). Example 29C 4-methyl-4,5,6,7-tetrahvdrothieno(2,3-c)pyridine Example 29B was processed as described in Example 1A and IB to provide the desired product.
MS (DCI/NH3) m/z 154 (M+H)+.
Example 29D 4-methyl-6-trityl-4,5,6,7-tetrahvdrothieno(2,3-c)pyridine Example 29C was processed as described in Example IC to provide the desired product. MS (DCI/NH3) m/z 396 (M+H)+.
Example 29E 4-methyl-2-(tributylstannvI)-6-trityl-4,5,6,7-tetrahydrothieno(2,3-c)pyridine
Example 29D was processed as described in Example ID to provide the desired product.
Example 29F l-cvclopropyl-7-(4-methyl-6-trityl-4,5,6,7-tetrahvdrothieno(2,3-c)pyridin-2-yl)-4-oxo-l,4- dihydro-3-quinolinecarboxylic acid Ethyl l-cyclopropyl-7-bromo-4-oxo-l,4-dihydroquinoline-3-carboxylate and Example 29E were processed as described in Example IE to provide the desired product. MS (DCI/NH3) m z 623 (M+H)+.
Example 29G l-cvclopropyl-7-(4-methyl-4,5,6,7-tetrahvdrothieno(2,3-c)pyridin-2-yl)-4-oxo-l,4-dihydro-
3-quinolinecarboxylic acid hydrochloride Example 29F was processed as described in Example IF to provide the desired product. mp 295-298 °C;
MS (DCI/NH3) m z 381 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 8.77 (s, IH), 8.39 (d, IH), 8.36 (d, IH), 7.98 (dd, IH), 7.86 (s, IH), 4.42 (m, 2H), 3.94 (m, IH), 3.56 (m, 2H), 3.19 (m, IH), 1.36 (d, 3H), 1.33 (m, 2H), 1.24 (m, 2H).
Example 30 l-cyclopropyl-8-methoxy-7-(4-methyl-4.5.6.7-tetrahvdrothieno(2,3-c)pyridin-2-yl)-4-oxo- l,4-dihydro-3-quinolinecarboxylic acid hydrochloride
Example 30A l-cvclopropyl-8-methoxy-7-(4-methyl-6-trityl-4,5,6,7-tetrahvdrothieno(2,3-c)pyridin-2-yl)-
4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid Ethyl l-cyclopropyl-7-bromo-8-methoxy-4-oxo-l,4-dihydroquinoline-3- carboxylate and Example 29E were processed as described in Example IE to provide the desired product. MS (DCI/NH3) m/z 653 (M+H)+.
Example 30B l-cvclopropyl-8-methoxy-7-(4-methyl-4,5,6,7-tetrahydrothieno(2,3-c)pyridin-2-yl)-4-oxo- l,4-dihydro-3-quinoIinecarboxylic acid hydrochloride Example 30A was processed as described in Example IF to provide the desired product, mp 254-259 °C;
MS (DCI/NH3) m/z 411 (M+H)+;
Η NMR (300 MHz, CD3OD) δ 8.97 (s, IH), 8.23 (d, IH), 7.98 (d, IH), 7.75 (s, IH), 4.52 (m, 2H), 4.28 (m, IH), 3.72 (s, 3H), 3.68 (m, 2H), 3.12 (m, IH), 1.45 (d, 3H), 1.27 (m, 2H), 1.08 (m, 2H).
Example 31 l-cyclopropyl-8-(difluoromethoxy)-7-(4-methyl-4,5,6,7-tetrahydrothieno(2,3-c)pyridin-2- yl)-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid hydrochloride
Example 31 A l-cvclopropyl-8-(difluoromethoxy)-7-(4-methyl-6-trityl-4,5,6,7-tetrahydrothieno(2,3- c)pyridin-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid Ethyl l-cyclopropyl-7-bromo-8-difluoromethoxy-4-oxo-l,4-dihydroquinoline-3- carboxylate and Example 29E were processed as described in Example IE to provide the desired product.
MS (DCI/NH3) m/z 689 (M+H)+;
1H NMR (300 MHz, CDCI3) δ 8.93 (s, IH), 8.37 (d, IH), 7.72 (d, IH), 7.56 (m, 5H), 7.45 (s, IH), 7.31 (m, 5H), 7.20 (m, 5H), 6.66 (dd, IH), 4.25 (m, 2H), 3.95 (m, IH), 3.25 (m, IH), 3.16 (m, 2H), 1.34 (d, 3H), 1.29 (m, 2H), 1.04 (m, 2H). Example 3 IB l-cyclopropyl-8-(difluoromethoxy)-7-(4-methyl-4,5,6,7-tetrahydrothieno(2,3-c)pyridin-2- yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride Example 31 A was processed as described in Example IF to provide the desired product. mp 218-222 °C;
MS (DCI/NH3) m/z 447 (M+H)+;
Η NMR (300 MHz, CD3OD) δ 9.00 (s, IH), 8.41 (d, IH), 7.92 (d, IH), 7.68 (s, IH), 6.62 (dd, IH), 4.52 (m, 2H), 4.27 (m, IH), 3.65 (m, 2H), 3.14 (m, IH), 1.45 (d, 3H), 1.31 (m, 2H), 1.09 ( , 2H).
Example 32 l-cvcIopropyl-7-(4-methyl-4,5,6,7-tetrahydrothieno(2,3-c)pyridin-2-yl)-4-oxo-l,4- dihvdrori,81naphthyridine-3-carboxylic acid hydrochloride
Example 32A l-cyclopropyl-7-(4-methyl-6-trityl-4,5,6,7-tetrahvdrothieno(2,3-c)pyridin-2-yl)-4-oxo-l,4- dihydro|T,81naphthyridine-3-carboxylic acid Ethyl l-cyclopropyl-7-chloro-4-oxo-l,4-dihydro[l,8]naphthyridine-3-carboxyIate and Example 29E were processed as described in Example IE to provide the desired product. MS (DCI/NH3) m/z 625 (M+H)+.
Example 32B l-cvclopropyl-7-(4-methyl-4,5,6,7-tetrahydrothieno(2,3-c)pyridin-2-yl)-4-oxo-l ,4- dihydro l,81naphthyridine-3-carboxylic acid hydrochloride Example 32A was processed as described in Example IF to provide the desired product, mp 284-286 °C; MS (DCI/NH3) m/z 382 (M+H)+;
Η NMR (300 MHz, CD3OD) δ 8.97 (s, IH), 8.75 (d, IH), 8.13 (d, IH), 8.00 (s, IH), 4.53 (m, 2H), 3.88 (m, IH), 3.69 (m, 2H), 3.13 (m, IH), 1.46 (d, 3H), 1.38 (m, 2H), 1.20 (m, 2H).
Example 33 l-cyclopropyl-6-fluoro-7-(4-methyl-4,5,6,7-tetrahydrothieno(2,3-c)pyridin-2-yl)-4-oxo- l ,4-dihydro[l,81naphthyridine-3-carboxylic acid hydrochloride Example 33A l-cvclopropyl-6-fluoro-7-(4-methyl-6-trityl-4,5,6,7-tetrahydrothieno(2,3-c)pyridin-2-yl)-4- oxo-l,4-dihydro|T ,8"lnaphthyridine-3-carboxylic acid l-cvclopropyl-6-fluoro-7-(4-methyl-6-trityl-4,5,6,7-tetrahvdrotheino(2,3-c)pyrindin-2-yl)- 4-oxo-l,4-dihvdro-3-naphtheridinecarboxylic acid
Ethyl l-cyclopropyl-7-chloro-6-fluoro-4-oxo-l,4-dihydro[l,8]naphthyridine-3- carboxylate and Example 29E were processed as described in Example IE to provide the desired product. MS (DCI/NH3) m/z 642 (M+H)+;
1H NMR (300 MHz, CDCI3) δ 8.90 (s, IH), 8.38 (d, IH), 7.86 (d, IH), 7.57 (m, 5H), 7.30 ( , 5H), 7.19 (m, 5H), 3.97 (m, 2H), 3.76 (m, IH), 3.62 (m, IH), 3.17 (m, 2H), 1.27 (d, 3H), 1.14 (m, 2H), 1.05 (m, 2H).
Example 33B l-cvclopropyl-6-fluoro-7-(4-methyl-4,5,6,7-tetrahydrothieno(2,3-c)pyridin-2-yl)-4-oxo- l,4-dihydro[l,81naphthyridine-3-carboxylic acid hydrochloride Example 33A was processed as described in Example IF to provide the desired product. mp 288-290 °C;
MS (DCI/NH3) m/z 400 (M+H)+;
Η NMR (300 MHz, CD3OD) δ 8.98 (s, IH), 8.52 (d, IH), 8.01 (s, IH), 4.57 (m, 2H), 3.87
(m, IH), 3.69 (m, 2H), 3.14 (m, IH), 1.45 (d, 3H), 1.40 (m, 2H), 1.22 (m, 2H).
Example 34 l-cyclopropyl-7-(4,4-dimethyl-4,5,6,7-tetrahvdrothieno(2,3-c)pyridin-2-yl)-8-methoxy-4- oxo- 4-dihydro-3-quinolinecarboxylic acid hydrochloride
Example 34A 2-methyl-2-(3-thienyl)propanenitrile
A solution of 3-thiopheneacetonitrile (3.0 g, 24.4 mmol) in THF (50 mL) was treated with IM lithium bis(trimethylsilyl)amide in THF (51.2 mL, 51.2 mmol) at -50 °C, stirred for 2 hours, treated with iodomethane (3.18 mL, 51.1 mmol), warmed to room temperature, stirred for 2 hours, and partitioned between 10% ammonium chloride and dichloromethane. The organic fraction was dried (Na2SO4), filtered, and concentrated.
The concentrate was purified by flash column chromatography on silica gel with 15% ethyl acetate in hexanes to provide 2.40 g (65%) of the desired product. MS (DCI/NH3) m/z 152 (M+H)+;
Η NMR (300 MHz, CDC13) δ 7.36 (dd, IH), 7.25 (m, IH), 7.12 (dd, IH), 1.72 (s, 6H).
Example 34B 2-methyl-2-(3-thienyl)-l-propanamine
Example 34A was processed as described in Example 29B to provide the desired product. MS (DCI/NH3) m/z 156 (M+H)+.
Example 34C
4,4-dimethyl-2-(tributylstannyl)-6-trityl-4,5,6,7-tetrahvdrothieno(2,3-c)pyridine Example 34B was processed as described in Examples 1A, IB, IC, and ID to provide the desired product.
Example 34D l-cvclopropyl-7-(4,4-dimethyl-6-trityl-4,5,6,7-tetrahydrothieno(2,3-c)pyridin-2-yl)-8- methoxy-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid Ethyl l-cyclopropyl-7-bromo-8-methoxy-4-oxo-l,4-dihydroquinoline-3- carboxylate and Example 34C were processed as described in Example IE to provide the desired product.
MS (DC1/NH3) m/z 667 (M+H)+.
Example 34E l-cyclopropyl-7-(4,4-dimethyl-4,5,6,7-tetrahvdrothieno(2,3-c)pyridin-2-yl)-8-methoxy-4- oxo-l,4-dihvdro-3-quinolinecarboxylic acid hydrochloride
Example 34D was processed as described in Example IF to provide the desired product.
MS (DCI/NH3) m/z 425 (M+H)+;
Η NMR (300 MHz, CDCI3) δ 8.94 (s, IH), 8.28 (d, IH), 7.78 (d, IH), 7.49 (s, IH), 4.54 (m, 2H), 4.10 (m, IH), 3.30, (m, 2H), 1.56 (s, 6H), 1.30 (m, 2H), 1.05 (m, 2H).
Example 35 l-cyclopropyl-6-fluoro-7-(4-hydroxy-4,5,6,7-tetrahydro-l-benzothien-2-yl)-4-oxo-l,4- dihvdro[l,81naphthyridine-3-carboxylic acid
Example 35A ((2-bromo-4,5,6,7-tetrahydro-l-benzothien-4-yl)oxy)(teιt-butyl)dimethylsilane A solution of 2-bromo-4-keto-4,5,6,7-tetrahydrothianapthene (prepared by the method of Pinna, et. al. Eur. J. Med. Chem. Chim. Ther 1994, 447-54) (0.50 g, 2.16 mmol) in methanol (20 mL) at 0 °C, treated dropwise with a solution of sodium borohydride (0.082 g, 2.16 mmol) in 2M NaOH (3 mL), warmed to room temperature, stirred for 1 hour, treated dropwise with 5% HCI until evolution of hydrogen ceased, and partitioned between ethyl acetate and brine. The aqueous layer was extracted with ethyl acetate, and the combined extracts were washed sequentially with water, 5% HCI, and brine, dried (MgSO4), filtered, and concentrated to provide 0.495 g (98%) of the desired product as a yellow oil.
A solution of the yellow oil in DMF (10 mL) was treated with imidazole (0.215 g, 3.15 mmol), tert-butyldimethylchlorosilane (0.412 g, 2.73 mmol), and several crystals of DMAP, stirred for 12 hours at room temperature, and poured into saturated ammonium chloride. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5% then 10% ethyl acetate in hexanes to provide 0.676 g (91%) of the desired product as an amber oil. MS (DCI/NH3) m/z 364 (M+NH4)+; 1H NMR ( 300 MHz, CDC13) 6.84 (s, IH), 4.68 (m, IH), 2.65-2.53 (m, 2H), 2.10-1.87 (m, 2H), 1.84-1.65 (m, 2H), 0.93 (s, 9H), 0.15 (s, 3H), 0.13 (s, 3H).
Example 35B 4-(l-methyl-l-(trimethyIsilyl)ethoxy)-4,5,6,7-tetrahydro-l-benzothien-2-ylboronic acid A solution of Example 35 A (1.032 g, 2.97 mmol) in THF (60 mL) at -78 °C was treated dropwise with 1.6M n-butyllithium in hexanes (1.4 L, 3.56 mmol), stirred for 1.5 hours, treated dropwise with triisopropylborate (1.0 mL, 4.45 mmol), stirred for 30 minutes, warmed to room temperature, and stirred for 2 hours. The reaction mixture at 0 °C, treated dropwise with 5% HCI until pH 2, and partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate, and the combined extracts washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 20% then 33% ethyl acetate in hexanes to provide 0.355 g (38%) of the desired product as a slightly yellow solid. MS (APCI(-)) m/z 347 (M+Cl)"; Η NMR (300 MHz, DMSO-d6) 8.04 (s, 2H), 7.46 (s, IH), 4.77 (m, IH), 2.83-2.58 ( , 2H), 1.97- 1.57 (m, 4H), 0.89 (s, 9H), 0.14 (s, 3H). Example 35C ethyl 7-(4-((tert-butyl(dιmethyl)sιlyl)oxy)-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-l- cyclopropyl-6-fluoro-4-oxo-1.4-dιhvdrori,81naphthyπdιne-3-carboxylate Example 35B (0 102 g, 0.326 mmol), ethyl l-cyclopropyl-7-chloro-6-fluoro-4-oxo- l,4-dιhydro[l,8]naphthyπdιne-3-carboxylate (0.078 g, 0.251 mmol), cesium carbonate (0.123 g, 0.377 mmol), and Pd(PPH3)2Cl2 (0.018 g, 0.025 mmol) were combined in DMF (5 mL), heated to 100 °C for 12 hours, cooled to room temperature, diluted with ethyl acetate and saturated ammonium chloride, and filtered through diatomaceous earth (Celite ). The layers were eparated, and the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50% ethyl acetate in hexanes to provide 0.042 g (31 %) of the desired product as a tan solid
MS (APCI(+)) m/z 543 (M+H)+; Η NMR (300 MHz, DMSO-d6) 8.56 (s, IH), 8.30 (d, IH), 7.80 (d, IH), 4.86 (m, IH), 4.24 (q, 2H), 3.66 (m, IH), 2 94-2 70 (m, 2H), 2.03-1.61 (m, 2H), 1.29 (t, 3H), 1.22 (m, 2H), 1.09 (m, 2H), 0.91 (s, 9H), 0.18 (s, 3H), 0.15 (s, 3H).
Example 35D 7-(4-((tert-butyl(dιmethyl)sιlyl)oxy)-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-l-cyclopropyl- 6-fluoro-4-oxo-l,4-dιhydroFl,81naphthyπdιne-3-carboxylιc acid Example 35C was processed according to Example 2B to provide the desired product
MS (APCI(+)) m/z 515 (M+H)+, MS (APCI(-)) m/z 549 (M+Cl)";
Η NMR (300 MHz, DMSO-d6) 14.53 (s, IH), 8.80 (s, IH), 8.53 (d, IH), 7.87 (d, IH), 4 87 (m, IH), 3.82 (m, IH), 2.83 (m, 2H), 2.05-1.61 (m, 4H), 1.31-1.13 (m, 4H), 0 91 (s, 9H), 0.19 (s, 3H), 0.16 (s, 3H).
Example 35E l-cyclopropyl-6-fluoro-7-(4-hydroxy-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-4-oxo-l,4- dιhydroϋ,81naphthyndιne-3-carboxyhc acid A solution of Example 35D (0.038 g, 0 074 mmol) in THF (5 mL) at 0 °C was treated with IM tetrabutylammonium fluoπde in THF (0.30 mL, 0.30 mmol), warmed to room temperature, and stirred for 3 hours. The reaction mixture was diluted with saturated ammonium chloride and extracted with ethyl acetate. The extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The concentrate was tπturated with 5% ethyl ether in pentane, filtered, and washed with pentane to provide 0.020 g (67%) of the desired product as a yellow solid. MS (APCI(+)) m/z 401 (M+H)+; MS (APCI(-)) m/z 435 (M+Cl)"; Η NMR (300 MHz, DMSO-d6) 14.55 (br s, IH), 8.80 (s, IH), 8.51 (d, IH), 7.97 (d, IH), 5.29 (m, IH), 4.63 (m, IH), 3.83 (m, IH), 2.88-2.70 (m, 2H), 2.03-1.84 (m, 2H), 1.84-1.59 (m, 2H), 1.35-1.23 (m, 2H), 1.21-1.12 ( , 2H).
Example 36 l-cyclopropyl-7-(4-hydroxy-5,6-dihydro-4H-thieno[2,3-b1thiopyran-2-yl)-8-methoxy-4- oxo- 1 ,4-dihvdro-3-quinolinecarbox ylic acid
Example 36A 2-bromo-5,6-dihydiO-4H-thienor2,3-b1thiopyran-4-one A solution of 5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-one (0.74 g, 4.35 mmol)
(prepared by the method of Jones, et. al., I. Org. Chem. 1991, 56, 763) in 50% aqueous acetic acid (10 ml) at 0 °C was treated dropwise with a solution of bromine (0.76 g, 4.78 mmol) in acetic acid (5 ml), stirred for 30 minutes, and treated dropwise with saturated aqueous sodium acetate solution until precipitation was complete. The concentrate was collected by filtration, washed with water, and dried to provide 0.56 g (52%) of the desired product as a yellow-green solid. MS (APCI(+)) m/z 249 (M+H)+; 'H NMR (300 MHz, CDC13) δ 7.41 (s, IH), 3.37 (m, 2H), 2.84 (m, 2H).
Example 36B
((2-bromo-5,6-dihvdro-4H-thienor2,3-blthiopyran-4-yl)oxy)(tert-butyl)dimethyIsilane Example 36A was processed as described in Example 35A to provide the desired product.
Η NMR (300 MHz, CDCI3) δ 6.80 (s, IH), 4.71 (dd, IH), 3.25 (ddd, IH), 2.91 (ddd, IH), 2.18 (m, IH), 2.08 (m, IH), 0.90 (s, 3H), 0.13 (s, 3H), 0.12 (s, 3H).
Example 36C tert-butyl(dimethyl)((2-(tributylstannyl)-5,6-dihydro-4H-thieno[2,3-blthiopyran-4- yl)oxy)silane A solution of Example 36B (0.71 g, 1.94 mmol) in THF (20 ml) at -78 °C was treated dropwise with 1.6M n-butyllithium in hexanes (1.3 ml, 2.14 mmol), stirred for 1 hour, warmed to -30 °C for 30 minutes, recooled to -78 C, and treated dropwise with chlorotπbutylstannane (0.70 g, 2.14 mmol). The reaction mixture was warmed to room temperature over 12 hours, partitioned between saturated ammonium chloπde and ethyl acetate, and extracted with ethyl acetate. The combined extracts were washed with water and bπne, dπed (MgSO4), filtered, and concentrated to provide 1.12 g (100%) of the desired product as an amber oil which was used without further puπfication.
Η NMR (300 MHz, CDC13) δ 6.97 (s, IH), 4.89 (dd, IH), 3 27 (ddd, IH), 2.92 (ddd, IH), 2.22 (m, IH), 2.05 (m, IH), 1 71-1 46 (m, 6H), 1.40-1.24 (m, 6H), 1.13-1.01 (m, 6H), 0.90 (s, 9H), 0.89 (t, 9H), 0.14 (s, 3H), 0.10 (s, 3H)
Example 36D ethyl 7-(4-((tert-butyl(dιmethyl)sιlyl)oxy)-5,6-dιhydro-4H-thιenor2,3-b1thιopyran-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dιhydro-3-quιnolιnecarboxylate Ethyl 1 -cyclopropyl-7-bromo-8-methoxy-4-oxo- 1 ,4-dιhydroquιnolιne-3- carboxylate and Example 36C were processed as descπbed in Example IE to provide the desired product.
1H NMR (300 MHz, CDC13) δ 8.62 (s, IH), 8.22 (d, IH), 7 56 (d, IH), 7.43 (s, IH), 4 87 (dd, IH), 4.40 (q, 2H), 3.95 (m, IH), 3.64 (s, 3H), 3.34 (ddd, IH), 3.00 (ddd, IH), 2.26 (m, IH), 2.12 (m, IH), 1.41 (t, 3H), 1.18 (m, 2H), 0.97 (m, 2H), 0.93 (s, 9H), 0.18 (s, 3H), 0.17 (s, 3H).
Example 36E 7-(4-((tert-butyl(dιmethyl)sιlyl)oxy)-5,6-dιhydro-4H-thιenor2,3-blthιopyran-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dιhvdro-3-quιnolιnecarboxylιc acid Example 36D was processed as described in Example 2B to provide the desired product
MS (APCI(+)) m/z 544 (M+H)+;
Η NMR (300 MHz, DMSO-d6) 8.78 (s, IH), 8.12 (d, IH), 7.93 (d, IH), 7.69 (s, IH), 4.96 (m, IH), 4.24 (m, IH), 3 68 (s, 3H), 3.35-3.11 (m, 2H), 2.23-2.09 (m, 2H), 2.08-1.95 (m, 2H), 1.14 ( , 2H), 1 02 (m, 2H), 0.89 (s, 9H), 0.19 (s, 3H), 0.17 (s, 3H).
Example 36F l-cvclopropyI-7-(4-hvdroxy-5,6-dιhydro-4H-thιenor2,3-blthιopyran-2-yl)-8-methoxy-4- oxo-l,4-dιhydro-3-quιnolιnecarboxylιc acid Example 36E was processed as described in Example 35E to provide the desired product
MS (APCI(+)) m/z 444 (M+H)+; Η NMR (300 MHz, DMSO-d6) 14.94 (s, IH), 8.78 (s, IH), 8.11 (d, IH), 8.00 (d, IH), 7.81 (s, IH), 5.38 (d, IH). 4.72 (q, IH), 4.24 (m, IH), 3.69 (s, 3H), 3.30-3.08 (m, 2H), 2.24-2.09 (m, IH), 2.07-1.93 (m, IH), 1.16 (m, 2H), 1.03 (m, 2H).
Example 37
7-(4-amino-5,6-dihydro-4H-thienor2.3-blthiopyran-2-yl)-l-cyclopropyl-8-methoxy-4-oxo- l,4-dihvdro-3-quinolinecarboxylic acid hydrochloride
Example 37A ethyl l-cyclopropyl-7-(4-hydroxy-5,6-dihvdro-4H-thieno[2,3-blthiopyran-2-yl)-8- methoxy-4-oxo- 1 ,4-dihvdro-3-quinolinecarboxylate Example 36D was processed as described in Example 35E to provide the desired product.
MS (APCI(+)) m/z 458 (M+H)+; Η NMR (300 MHz, CDC13) 8.63 (s, IH), 8.18 (d, IH), 7.58 (d, IH), 7.55 (s, IH), 4.90 (m, IH), 4.40 (q, 2H), 3.94 (m, IH), 3.64 (s, 3H), 3.36 (dt, IH), 2.99 (ddd, IH), 2.47-2.37 (m, IH), 2.33 (br s, IH), 2.12 (m, IH), 1.41 (t, 3H), 1.19 (m, 2H), 0.98 (m, 2H).
Example 37B ethyl 7-(4-azido-5,6-dihydro-4H-thienof2,3-blthiopyran-2-yl)-l-cyclopropyl-8-methoxy-4- oxo- 1 ,4-dih ydro-3-quinolinecarboxylate A solution of Example 37A (0.1 10 g, 0.240 mmol) in 1 : 1 toluene:dichloromethane (7 ml) was treated with sequentially with DPPA (0.104 ml, 0.481 mmol) and DBU (83 mL, 0.553 mmol), stirred for 16 hours at room temperature, and partitioned between ethyl acetate and saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate, and the combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 3% methanol in dichloromethane to provide 0.096 g (83%) of the desired product as an off-white solid. MS (APCI(+)) m/z 483 (M+H)+;
Η NMR (300 MHz, CDC13) 8.63 (s, IH), 8.23 (d, IH), 7.60 (d, IH), 7.49 (s, IH), 4.72 (t, IH), 4.40 (q, 2H), 3.96 (m, IH), 3.65 (s, 3H), 3.40-3.22 (m, IH), 3.03 (ddd, IH), 2.48-2.35 (m, IH), 2.26-2.11 (m, IH), 1.41 (s, 3H), 1.19 (m, 2H), 0.97 (m, 2H).
Example 37C 7-(4-amιno-5,6-dιhydro-4H-thιeno[2,3-b1thιopyran-2-yl)-l-cyclopropyl-8-methoxy-4-oxo- l,4-dιhydro-3-quιnolιnecarboxylιc acid hydrochloπde A solution of Example 37B (0.095 g, 0.197 mmol) and tπphenylphosphine (0.155 g, 0.591 mmol) in 10: 1 THF*water (10 ml) was heated to reflux for 4 hours, cooled to room temperature, treated with methanol (0.5 mL) and dι-(tert-butyl)dιcarbonate (0.065 g, 0.296 mmol), and stirred for 12 hours. The reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride, and the organic phase was washed with water and brine, dπed (Na2SO4), filtered, and concentrated. The residue was puπfied by flash column chromatography on silica gel with 33% acetone in hexanes to provide the desired product as an inseparable mixture with tnphenylphosphine oxide.
The mixture was processed as descπbed in Example 2B to provide a carboxylic acid that was used without further purification.
A solution of the carboxylic acid in dichloromethane (3 ml) was treated with 4M HCI in dioxane (3 ml), heated to reflux, cooled to room temperature, and treated with hexanes (1 mL). The resulting precipitate was filtered, washed with hexanes, and dried to provide 0.035 g (38% over three steps) of the desired product as a tan solid. MS (APCI(-)) m/z 463 (M+Cl) ;
Η NMR (300 MHz, DMSO-d6) 8.80 (s, IH), 8.60 (br s, 3H), 8.18 (d, IH), 8.10 (s, IH), 7 89 (d, IH), 4.60 (m, IH), 4.25 (m, IH), 3.71 (s, 3H), 3.42-3.20 (m, 2H), 2.43-2.24 (m, 2H), 1.17 (m, 2H), 1.04 (m, 2H).
Example 38 l-cvclopropyl-7-(4-hvdroxy-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-8-methoxy-4-oxo-l,4- dιhydro-3-quιnolιnecarboxylιc acid
Example 38A tert-butyl(dιmethyl)(4,5,6,7-tetrahvdro-l-benzothιen-4-yloxy)sιIane 4-Keto-4,5,6,7-tetrahydrothιanapthene was processed as descπbed in Example 35A to provide the desired product. MS (DCI NH3) m/z 269 (M+H)+;
Η NMR (300 MHz, CDCI3) δ 7 04 (d, IH), 6.93 (d, IH), 4.78 (m, IH), 2.85-2 65 ( , 2H), 2.11-1.92 (m, 2H), 1.85-1.69 (m, 2H), 0.92 (s, 9H), 0.14 (s, 3H), 0.12 (s, 3H).
Example 38B tert-butyl(dimethyl)((2-(tributylstannyI)-4,5,6,7-tetrahydro-l-benzothien-4-yl)oxy)silane Example 38A was processed as descπbed in Example ID to provide the desired product. Η NMR (300 MHz, CDC13) δ 7.02 (s, IH), 4.82 (m, IH), 2.78 (m, 2H), 2.00 (m, 2H), 1.73 (m, 2H), 1.56 (m, 6H), 1.33 (m, 6H), 1.05 (m, 6H), 0.93 (s, 9H), 0.89 (t, 9H), 0.12 (s, 3H), 0.15 (2, 3H).
Example 38C
7-(4-((tert-butyl(dimethyl)silyl)oxy)-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l-cyclopropyl- 8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid Ethyl 7-bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3- quinolonecarboxylate and Example 38B were processed as described in Example IE to provide the desired product.
MS (DCI/NH3) m/z 526 ((M+H)+;
Η NMR (300 MHz, CDCI3) δ 14.78 (s, IH), 8.90 (s, IH), 8.23 (d, IH), 7.71 (d, IH), 7.55 (s, IH), 4.83 (m, IH), 4.11 (m, IH), 3.67 (s, 3H), 2.93-2.72 ( , 2H), 2.13-1.99 (m, 2H), 1.88-1.72 (m, 2H), 1.32 (m, 2H), 1.06 (m, 2H), 0.96 (s, 9H), 0.22 (s, 3H), 0.18 (s, 3H).
Example 38D l-cvclopropyl-7-(4-hvdroxy-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-8-methoxy-4-oxo-l,4- dihydro-3-quinolinecarboxylic acid Example 38C was processed as described in Example 35E to provide the desired product. mp 237-239 °C;
MS (DCI/NH3) m/z 412 (M+H)+;
Η NMR (300 MHz, CDCI3) δ 8.91 (s, IH), 8.23 (d, IH), 7.77 (d, IH), 7.63 (s, IH), 4.85 (m, IH), 4.10 (m, IH), 3.68 (s, 3H), 3.38 (m, IH), 2.97-2.74 (m, 2H), 2.11-2.02 (m, 2H), 1.96-1.83 (m, 2H), 1.28 (m, 2H), 1.04 (m, 2H).
Example 39 7-(4-azido-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4- dihydro-3-quinolinecarboxylic acid
Example 39A methyl 7-(4-((tert-butyl(dimeth yl)si I yI)oxy)-4,5,6,7-tetrah ydro- 1 -benzothien-2-yl)- 1 - cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate A solution of Example 38C (2.15 g, 4.10 mmol) in 1: 1 methanol:THF (50 mL) at 0 °C was treated with 2M trimethylsilyldiazomethane in hexanes (9.70 mL, 19.4 mmol), warmed to room temperature over 5 hours, treated with acetic acid (15 drops), and poured into water. The layers were separated, and the aqueous layer was extracted with dichloromethane. The combined extracts were dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 1% methanol in dichloromethane to provide 1.68 g (75%) of the desired product as a tan solid. MS (DCI NH3) m/z 540 (M+H)+;
Η NMR (300Hz, CDCI3) δ 8.65 (s,lH), 8.22 (d, IH), 7.58 (d, IH), 7.48 (s, IH), 4.83 (m, IH), 3.98 ( , IH), 3.93 (s, 3H), 3.13 (s, 3H), 2.80 (m, 2H), 2.04 (m, 2H), 1.80 (m, 2H), 1.18 (m, 2H), 0.98 (m, 2H), 0.95 (s, 9H), 0.21 (s, 3H), 0.18 (s, 3H).
Example 39B methyl l-cyclopropyl-7-(4-hvdroxy-4,5,6,7-tetrahydro-l-benzothien-2-yI)-8-methoxy-4- oxo- 1 ,4-dihydro-3-quinolinecarboxylate Example 39A was processed as described in Example 35E to provide the desired product. MS (DCI/NH3) m/z 426 (M+H)+;
Η NMR (300 MHz, CDC13) δ 8.65 (s, IH), 8.22 (d, IH), 7.63 (d, IH), 7.56 (s, IH), 4.84 (m, IH), 3.98 (m, IH), 3.92 (s, 3H), 3.64 (s, 3H), 3.25 (m, IH), 2.96-2.72 (m, 2H), 2.07 (m, 2H), 1.89 (m, 2H), 1.20 (m, 2H), 0.98 (m, 2H).
* Example 39C methyl 7-(4-azido-4,5,6,7-tetrahydro-l-benzothien-2-yI)-l-cyclopropyl-8-methoxy-4-oxo- l,4-dihydro-3-quinolinecarboxyIate Example 39B was processed as described in Example 37B to provide the desired product. MS (DCI/NH3) m/z 451 (M+H)+;
Η NMR (300 MHz, CDCI3) δ 8.66 (s, IH), 8.22 (d, IH), 7.62 (d, IH), 7.46 (s, IH), 5.95 (m, IH), 3.97 (m, IH), 3.93 (s, 3H), 3.63 (s, 3H), 3.01-2.72 (m, 2H), 2.05-1.92 (m, 4H), 1.20 (m, 2H), 0.97 (m, 2H).
Example 39D
7-(4-azido-4,5,6,7-tetrahvdro- l-benzothien-2-yl)-l-cvclopropyl-8-methoxy-4-oxo-l,4- dihvdro-3-quinolinecarboxylic acid Example 39C was processed as described in Example 2B to provide the desired product. mp 134-136 °C;
MS (DCI NH3) m/z 437 (M+H)+; Η NMR (300 MHz, CD3OD) δ 8.96 (s, IH), 8.22 (d, IH), 7.90 (d, IH), 7.67 (s, IH), 4.67 (m, IH), 4.31 (m, IH), 3.62 (s, 3H), 3.02-2.77 (m, 2H), 2.23-1.94 (m, 4H), 1.29 (m, 2H), 1.10 (m, 2H).
Example 40
7-(4-amino-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4- dihvdro-3-quinolinecarboxylic acid hydrochloride
Example 40A methyl 7-(4-((tert-butoxycarbonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate A solution of Example 39C (0.30 g, 0.7 mmol) in 10: 1 THF:water (33 mL) was treated with triphenylphosphine (0.70 g, 2.7 mmol), heated at 60 °C for 17 hours, cooled, treated sequentially with sodium bicarbonate (0.22 g, 2.6 mmol) and di-(tert- butyl)dicarbonate (0.26 g, 1.2 mmol), stirred for 6 hours, and poured into water. The layers were separated, and the aqueous phase was extracted with dichloromethane. The extract was dried (Na2SU4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 1% methanol in dichloromethane to provide 0.090 g (26%) of the desired product as a yellow solid. MS (DCI/NH3) m/z 526 (M+H)+;
1H NMR (300 MHz, CDCI3) δ 8.65 (s, IH), 8.22 (d, IH), 7.62 (d, IH), 7.47 (s, IH), 4.80 (m, IH), 3.97 (m, IH), 3.93 (s, 3H), 3.64 (s, 3H), 2.82 (m, 2H), 2.13-1.72 (m, 4H), 1.53 (s, 9H), 1.20 (m, 2H), 0.98 (m, 2H).
Example 40B
7-(4-((tert-butoxycarbonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinoIinecarboxylic acid Example 40A was processed as described in Example 2B to provide the desired product. MS (DCI/NH3) m/z 511 (M+H)+;
Η NMR (300 MHz, CDCI3) δ 8.91 (s, IH), 8.23 (d, IH), 7.75 (d, IH), 7.53 (s, IH), 4.80 (m, IH), 4.10 (m, IH), 3.66 (s, 3H), 2.82 (m, 2H), 2.08 (m, 2H), 1.94 (m, 2H), 1.27 (m, 2H), 1.94 (m, 2H).
Example 40C 7-(4-amino-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4- dihydro-3-quinolinecarboxylic acid hydrochloride A solution of Example 40B (0.087 g, 0.20 mmol) in dichloromethane (2 mL) at room temperature was treated with 4M HCI in dioxane (6 mL, 24.0 mmol), stirred for 2 hours, and concentrated. The concentrate was triturated with diethyl ether and filtered. The solid was rinsed with diethyl ether and dried to provide 0.059 g (76%) of the desired product as a yellow solid, mp 219-222 °C;
MS (DCI/NH3) m/z 411 (M+H)+; 1H NMR (300 MHz, CD3OD) δ 8.98 (s, IH), 8.24 (d, IH), 7.90 (d, IH), 7.74 (s, IH), 4.53 (m, IH), 4.29 (m, IH), 3.22 (s, 3H), 2.96 (m, 2H), 2.33-1.94 (m, 4H), 1.28 (m, 2H), 1.08 (m, 2H).
Example 41 l-cyclopropyl-7-(7-hvdroxy-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8-methoxy-4-oxo-l,4- dihydro-3-quinolinecarboxylic acid
Example 41 A tert-butyl(dimethyl)(4,5,6,7-tetrahvdro-l-benzothien-7-yloxy)silane 7-keto-4,5,6,7-tetrahydrothienanapthene (prepared by the method of MacDowell, et al. J. Heterocycl Chem. 1965, 44-48) was processed as described in Example 35A to provide the desired product. MS (APCI(+)) m/z 267 (M+H)+;
1H NMR (300 MHz, DMSO-d6) 7.34 (d, IH), 6.76 (d, IH), 4.91 (m, IH), 2.57-2.51 (br m, 2H), 1.98-1.88 (br m, 2H), 1.70-1.66 (m, 2H), 0.91 (s, 9H), 0.15 (s, 3H), 0.13 (s, 3H).
Example 41B tert-butyl(dimethyl)((2-(tributylstannyl)-4,5,6,7-tetrahydro-l-benzothien-7-yl)oxy)silane Example 41 A was processed as described in Example ID to provide the desired product.
MS (DCI/NH3) m/z 427 (M-C6H15SiO)+;
1H NMR (300 MHz, CDCI3) 6.78 (s, IH), 4.96 (m, IH), 2.61-2.59 (m, 2H), 2.10-1.99 (br m, 2H), 1.79-1.74 (m, 2H), 1.54-0.94 (m, 36H), 0.18 (s, 3H), 0.15 (s, 3H).
Example 41C ethyl 7-(7-((tert-butyl(dimethyl)silyl)oxy)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo- l ,4-dihydro-3-quinolinecarboxylate Ethyl 7-bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3- quinolonecarboxylate and Example 41A were processed as described in Example IE to provide the desired product. MS (APCI(+)) m/z 554 (M+H)+; Η NMR (300 MHz, CDC13) 8.63 (s, IH), 8.20 (d, IH), 7.62 (d, IH), 7.27 (s, IH), 4.97 (m, IH), 4.43 (q, 2H), 3.63 (s, 3H), 2.66-2.64 (br m, 2H), 2.07-2.04 (m, 2H), 1.85-1.79 (m, 2H), 1.42 (q, 3H), 0.97 (s, 9H), 0.22 (s, 3H), 0.18 (s, 3H).
Example 4 ID ethyl 4-cyclopropyl-6-(7-hydroxy-4,5,6,7-tetrahydro-l-benzothien-2-yl)-5-methoxy-l-oxo- l,4-dihydro-2-naphthalenecarboxylate Example 41C was processed as described in Example 35E to provide the desired product, mp 183-185 °C; MS (APCI(+)) m/z 440 (M+H)+;
1H NMR (300 MHz, CDCI3) 8.56 (s, IH), 7.96 (d, IH), 7.78 (d, IH), 7.45 (s, IH), 5.44 (d, IH), 4.74 (m, IH), 4.23 (q, 2H), 4.08 (m, IH), 3.64 (s, 3H), 2.59 (br s, 2H), 1.99-1.93 (m, 2H), 1.72-1.67 (m, 2H), 1.28 (t, 3H), 1.11 (m, 2H), 0.95 (s, 2H).
Example 4 IE l-cvclopropyl-7-(7-hvdroxy-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-8-methoxy-4-oxo-l,4- dihydro-3-quinolinecarboxylic acid Example 4 ID was processed as described in Example 2B to provide the desired product. mp 238-240 °C;
MS (APCI(+)) m/z 412 (M+H)+;
1H NMR (300 MHz, CDCI3) 8.79 (s, IH), 8.11 (d, IH), 7.98 (d, IH), 7.54 (s, IH), 5.47 (d, IH), 4.75 (m, IH), 4.25 (m, IH), 3.68 (s, 3H), 2.60 (br s, 2H), 2.05-1.95 (br s, 2H), 1.72- 1.68 (br m, 2H), 1.15 (m, 2H), 1.04 (m, 3H).
Example 42 l-cvclopropyl-7-(5-hydroxy-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8-methoxy-4-oxo-l,4- dihydro-3-quinolinecarboxylic acid
Example 42A tert-butyl(dimethyl)(4,5,6,7-tetrahvdro-l-benzothien-5-yloxy)silane 5-keto-4,5,6,7-tetrahydrothianapthene (prepared by the method of Padwa, et al. I. Org. Chem. 1989, 54, 299-308) was processed as described in Example 35A to provide the desired product.
MS (DCI/NH3) m/z 286 (M+NH4)+; Η NMR (300 MHz, CDCI3) 7.06 (d, IH), 6.71 (d, IH), 4.1 (m, IH), 3.00-2.78 (m, 3H), 2.55 (m, IH), 2.00 (m, IH), 1.85 (m, IH), 0.90 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H).
Example 42B tert-butyl(dimethyl)((2-(tributylstannyl)-4,5,6,7-tetrahydro-l-benzothien-5-yl)oxy)silane Example 42A was processed as described in Example ID to provide the desired product.
MS (DCI/NH3) m/z 558 (M+H)+; 1H NMR (300 MHz, CDCI3) 6.77 (s, IH), 4.1 (m, IH), 3.00-2.78 (m, 3H), 2.55 (m, IH),
2.00 (m, IH), 1.85 (m, IH), 1.65 -0.95 ( , 36), 0.09 (s, 3H), 0.08 (s, 3H).
Example 42C 7-(5-((tert-butyl(dimethyl)silyl)oxy)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl- 8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid Ethyl 7-bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3- quinolonecarboxylate and Example 42B were processed as described in Example IE to provide the desired product. MS (DCI/NH3) m/z 526 (M+H)+;
1H NMR (300 MHz, CDCI3) 14.77 (s, IH), 8.90 (s, IH), 8.22 (d, IH), 7.75 (d, IH), 7.32 (s, IH), 4.23-4.05 (m, 2H), 3.67 (s, 3H), 3.05-2.80 (m, 3H), 2.63 (m, IH), 2.00 (m, IH), 1.90 (m, IH), 1.26 (m, 2H), 1.05 (m, 2H), 0.91 (m, 9H), 0.12 (s, 3H), 0.11 (s, 3H).
Example 42D l-cvclopropyl-7-(5-hydroxy-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-8-methoxy-4-oxo-l,4- dihydro-3-quinolinecarboxylic acid Example 42C was processed as described in Example 35E to provide the desired product, mp 232-233 °C;
MS (DCI/NH3) m/z 412 (M+H)+;
Η NMR (300 MHz, DMSO-d6) 8.78 (s, IH), 8.10 (d, IH), 7.98 (d, IH), 7.55 (s, IH), 4.84 (d, IH), 4.25 (m, IH), 4.00 (m, 2H), 3.67 (s, 3H), 3.00-2.70 (m, 4H), 1.95 (m, IH), 1.80 (m, IH), 1.20-1.00 (m, 4H). Example 43 l-cyclopropyl-7-(5-(hvdroxymethyl)-4.5.6.7-tetrahvdro-l-benzothien-2-yl)-8-methoxy-4- oxo-l,4-dihvdro-3-quinoIinecarboxylic acid
Example 43A and Example 44A tert-butyl(dimethyl)(4,5,6,7-tetrahvdro-l-benzothien-5-ylmethoxy)silane and tert-butyl(6,7-dihvdro-l-benzothien-5-ylmethoxy)dimethylsilane A solution of methyl 6,7-dihydrobenzothiophene-5-carboxylate (5.0 g, 25.77 mmol) (prepared by the method of Amemiya, et al. J. Med. Chem. 1989, 32, 1265-72) and 10% Pd/C (3.5 g) in absolute ethanol (200 mL) was stirred at room temperature under hydrogen for 6.5 hours and filtered. The filtrate was concentrated to provide 3.5 g (69%) of a first oil comprising one part methyl 4,5,6,7-tetrahydrobenzothiophene-5-carboxylate and two parts methyl 6,7-dihydrobenzothiophene-5-carboxylate. A solution of first oil (3.5 g, 17.86 mmol) in diethyl ether (38 ml) at 5 °C was treated with lithium aluminum hydride powder (0.68 g, 17.86 mmol), stirred for 10 minutes at 5 °C and for 30 minutes at room temperature, and quenched with Na2SO4.10 H2O (6.56 g), and filtered. The filtrate was concentrated to provide 3.0 g (100%) of a second oil comprising 5-hydroxymethyl 4,5,6,7-tetrahydrobenzothiophene and 5- hydroxymethyl 6,7-dihydrobenzothiophene.
A solution of the second oil (3.0 g, 17.86 mmol), tert-butyldimethylchlorosilane (10.7 g, 71.44 mmol), and imdazole (4.9 g, 71.44 mmol) in DMF (20 ml) at room temperature was stirred for 17 hours and distilled at 35 °C under high vacuum to remove excess tert-butyldimethylchlorosilane. The residue was partitioned between diethyl ether and water, and the aqueous phase extracted with diethyl ether. The combined extracts were washed with IM HCI and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with hexanes then 2% ethyl acetate in hexanes to provide the following desired products as oils: Example 43 A: tert-butyl(dimethyl)(4,5,6,7-tetrahydro-l-benzothien-5- ylmethoxy)silane, 1.0 g, (20%). MS (DCI NH3) m/z 283 (M+H)+;
Η NMR (300 MHz, CDCI3) 7.04 (d, IH), 6.74 (d, IH), 3.58 (dd, 2H), 2.90-2.69 (m, 4H), 2.34-2.24 (m, IH), 2.06-1.89 (m, 2H), 0.90 (s, 9H), 0.05 (s, 6H). and Example 44A: tert-butyl(6,7-dihydro-l-benzothien-5-ylmethoxy)dimethylsilane,
2.3 g, (46%). MS (DCI/NH3) m/z 298 (M+NH4)+;
Η NMR (300 MHz, CDCI3) 7.01 (d, IH), 6.83 (d, IH), 6.41 (m, IH), 4.22 (br s, 2H), 2.90
(t, 2H), 2.36 (t, 2H), 0.94 (s, 9H), 0.10 (s, 6H).
Example 43B tert-butyl(dimethyl)((2-(tributylstannyl)-4,5,6,7-tetrahvdro-l-benzothien-5- yl)methoxy)silane Example 43A was processed as described in Example ID to provide the desired product. MS (DCI/NH3) m/z 573 (M+H)+;
1H NMR (300 MHz, CDCI3) 6.81 (s, IH), 3.59 (dd, 2H), 2.95- 2.70 (m, 4H), 2.36-2.27 (m, IH), 2.05-1.90 ( , 2H), 1.62-0.90 (m, 36H), 0.05 (s, 6H).
Example 43C ethyl 7-(5-(((tert-butyl(dimethyl)silvπoxy)methyl)-4,5,6,7-tetrahydro-l-benzothien-2-yl)- l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate Ethyl 7-bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3- quinolonecarboxylate and Example 43B were processed as described in Example IE to provide the desired product. MS (DCI/NH3) m/z 568 (M+H)+;
1H NMR (300 MHz, CDCI3) 8.63 (s, IH), 8.20 (d, IH), 7.62 (d, IH), 7.29 (s, IH), 4.40 (q, 2H), 3.97 (m, IH), 3.65 (s, 3H), 3.63 (d, 2H), 2.96-2.75 (m, 3H), 2.41-2.30 (m, IH), 2.11- 1.95 (m, 2H), 1.63-1.51 (m, IH), 1.41 (t, 3H), 1.18 (m, 2H), 0.97 (m, 2H), 0.93 (s, 9H), 0.08 (s, 6H).
Example 43D ethyl l-cyclopropyl-7-(5-(hydroxymethyl)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylate Example 43C was processed as described in Example 35E to provide the desired product.
MS (DCI/NH3) m/z 454 (M+H)+;
1H NMR (300 MHz, CDCI3) 8.63 (s, IH), 8.21 (d, IH), 7.62 (d, IH), 7.29 (s, IH), 4.40 (q, 2H), 3.97 ( , IH), 3.69 (m, 2H), 3.65 (s, 3H), 2.98-2.78 (m, 3H), 2.39 (m, IH), 2.17-2.01 (m, 2H), 1.66-1.54 (m, IH), 1.41 (t, 3H), 1.19 (m, 2H), 0.98 (m, 2H).
Example 43E l-cvclopropyl-7-(5-(hvdroxymethyl)-4.5,6,7-tetrahvdro-l-benzothien-2-yl)-8-methoxy-4- oxo-l,4-dihvdro-3-quinolinecarboxylic acid Example 43C was processed as described in Example 2B to provide the desired product, mp 218-219 °C; MS (ESI(+)) m/z 412 (M+H)+;
Η NMR (300 MHz, DMSO-d6) 14.95 (s, IH), 8.78 (s, IH), 8.09 (d, IH), 7.99 (d, IH), 7.57 (s, IH), 4.59 (t, IH), 4.25 (m, IH), 3.68 (s, 3H), 3.42 (t, 2H), 2.92-2.71 ( , 3H), 2.33- 2.24 (m, IH), 2.02 (m, IH), 1.86 (m, IH), 1.45 (m, IH), 1.16 (m, 2H), 1.04 (m, 2H).
Example 44 l-cvclopropyl-7-(5-(hvdroxymethyl)-6,7-dihvdro-l-benzothien-2-yl)-8-methoxy-4-oxo-
1 ,4-dihydro-3-quinoIinecarboxylic acid
Example 44B tert-butyl(dimethyl)((2-(tributylstannyl)-6,7-dihydro-l-benzothien-5-yl)methoxy)silane Example 44A was processed as described in Example ID to provide the desired product.
MS (DCI/NH3) m/z 571 (M+H)+; 1H NMR (300 MHz, CDC13) 6.88 (s, IH), 6.45 (m, IH), 4.22 (br s, 2H), 2.93 (t, 2H), 2.35 (t, 2H), 1.55-0.90 (m, 36H), 0.10 (s, 6H).
Example 44C ethyl 7-(5-(((tert-butvI(dimethyl)silyl)oxy)methyl)-6,7-dihydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate
Ethyl 7-bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3- quinolonecarboxylate and Example 44B were processed as described in Example 314729E to provide the desired product. MS (DCI/NH3) m/z 566 (M+H)+; 1H NMR (300 MHz, CDC13) 8.63 (s, IH), 8.21 (d, IH), 7.63 (d, IH), 7.36 (s, IH), 6.46
(m, IH), 4.40 (q, 2H), 4.25 (br s, 2H), 3.98 (m, IH), 3.64 (s, 3H), 2.97 (t, 2H), 2.41 (t, 2H), 1.41 (t, 3H), 1.19 (m, 2H), 0.97 (m, 2H), 0.95 (s, 9H), 0.12 (s, 6H).
Example 44D ethyl l-cyclopropyl-7-(5-(hydroxymethyl)-6,7-dihydro-l-benzothien-2-yl)-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxylate Example 44C was processed as described in Example 35E to provide the desired product.
MS (DCI/NH3) m/z 452 (M+H)+;
Η NMR (300 MHz, CDCI3) 8.63 (s, IH), 8.22 (d, IH), 7.62 (d, IH), 7.36 (s, IH), 6.49 (m, IH), 4.85 (d, IH), 4.40 (q, 2H), 4.26 (d, 2H), 3.97 (m, IH), 3.64 (s, 3H), 2.99 (t, 2H), 2.49 (t, 2H), 1.42 (t, 3H), 1.19 (m, 2H), 0.98 (m, 2H).
Example 44E l-cvclopropyl-7-(5-(hvdroxymethyl)-6,7-dihydro-l-benzothien-2-yl)-8-methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid
Example 44D was processed as described in Example 2B to provide the desired product, mp 205-206 °C; MS (ESI(+)) m/z 424 (M+H)+; 1H NMR (300 MHz, CDCI3) 8.90 (s, IH), 8.23 (d, IH), 7.76 (d, IH), 7.42 (s, IH), 6.51 (m, IH), 4.86 (s, IH), 4.27 (s, 2H), 4.11 (m, IH), 3.68 (s, 3H), 3.01 (t, 2H), 2.50 (t, 2H), 1.28 (m, 2H), 1.06 (m, 2H).
Example 45 l-cvclopropyl-7-(5-hvdroxy-5,6-dihvdro-4H-cvclopentarblthien-2-yl)-8-methoxy-4-oxo-
1 ,4-dihvdro-3-quinolinecarboxylic acid
Example 45A l-diazo-3-(2-thienyl)acetone A solution of 2-(2-thiophenyl)-acetic acid (13.56 g, 84.4 mmol) and 3 drops of
DMF in 1: 1 dichloromethane-hexanes (340 mL) was treated dropwise over 20 minutes with oxalyl chloride (9.20 mL, 105.5 mmol), stirred at ambient temperature for 3 hours, and concentrated to provide 4.2 g (ca. 100%) of the acid chloride as a brown oil. A solution of the acid chloride in diethyl ether (200 mL) was treated with a solution of diazomethane.(ca. 240 mmol) in ether (500 mL) (Generated according to the method of Hudlic y, J. Org. Chem. 1980, 45, 5377 from Diazald (51.7 g, 241.1 mmol) and KOH (20g, 314 mmol)). The solution sat with occasional swirling for 30 minutes then was treated with several drops of acetic acid to decompose the excess diazomethane, washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with hexanes then with 10% ethyl acetate in hexanes to provide 11.0 g (78%) of the desired product as an off- white solid. MS (ESI(+)) m/z 167 (M+H)+ and 184 (M+NH4)+;
Η NMR (300 MHz, CDC13) 7.24 (dd, IH), 6.99 (dd, IH), 6.92 (m, IH), 5.25 (br s, IH),
3.81 (br s, 2H).
Example 45B
4,6-dihvdro-5H-cvclopentarblthiophen-5-one A solution of Example 45A (11.0 g, 66.21 mmol) in dichloromethane (1.55 mL) at room temperature was treated with dirhodium tetraacetate (125 mg), stirred for 3 hours, and concentrated. The residue was purified by flash column chromatography on silica gel with hexanes then 5% ethyl acetate in hexanes to provide 2.83 g (31%) of the desired product as a white solid. 1H NMR (300 MHz, CDCI3) 7.26 (ddd, IH), 6.97 (d, IH), 3.54 (s, 2H), 3.42 (s, 2H).
Example 45C 5,6-dihydro-4H-cyclopenta[blthiophen-5-ol
A solution of Example 45B (1.69 g, 12.23 mmol) in THF (61 mL) at 0 °C was treated dropwise over 10 minutes with IM solution of lithium aluminum hydride in THF
(6.1 mL, 6.1 mmol), stirred for 30 minutes, warmed to room temperature, recooled to
0 °C, treated sequentially with ethyl acetate (50 mL) saturated sodium potassium tartrate (75 mL), and ethyl acetate. The layers were separated, and the organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated to provide 1.6 lg (94%) of the desired product as a tan solid.
MS (DCI NH3) m/z 141 (M+H)+ and 158 (M+NH4)+;
Η NMR (300 MHz, CDCI3) 7.19 (dd, IH), 6.83 (d, IH), 4.99 (m, IH), 3.26 (dd, IH), 3.12 (dd, IH), 2.86 (ddd, IH), 2.71 (dd, IH).
Example 45D tert-butyl(5,6-dihydro-4H-cyclopentarblthien-5-yloxy)dimethylsilane A solution of Example 45C (2.15 g, 15.34 mmol), N, N-diisopropylethylamine (3.97 g, 30.68 mmol), and 4-(N, N-dimethylamino)pyridine (0.469 g, 3.83 mmol) in dichloromethane (51 mL) at room temperature was treated with the tert- butyldimethylchlorosilane (2.78 g, 18.40 mmol), stirring for 24 hours, diluted with dichloromethane, extracted with water, saturated ammonium chloride solution, and saturated sodium bicarbonate solution, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with hexanes then with ethyl acetate in hexanes to provide 3.8g (97%) of the desired product as a colorless
MS (ESI(+)) m/z 252 (M+H)+ and 272 (M+NH4)+;
Η NMR (300 MHz, CDC13) 7.14 (dt, IH), 6.78 (d, IH), 4.98 (m, IH), 3.07 (dd, IH), 3.04 (ddd, IH), 2.72 (dddd, IH), 2.67 (dddd, IH), 0.91 (s, 9H), 0 10 (s, 6H).
Example 45E tert-butyl(dιmethyl)((2-(trιbutylstannyl)-5,6-dιhvdro-4H-cyclopenta|'blthιen-5- yl)oxy)sιlane Example 45D was processed as descπbed in Example ID to provide the desired product.
Η NMR (300 MHz, CDC13) 6 84 (s, IH), 5.00 ( , IH), 3.20 (dd, IH), 3 05 (dd, IH), 2.83 (dddd, IH), 2.68 (dddd, IH), 1.58 (m, 6H), 1 37 (m, 6H), 1.24 (m, 6H), 0.92 (m, 18H), 0.10 (s, 6H).
Example 45F ethyl 7-(5-((tert-butyl(dιmethyl)sιlyl)oxy)-5,6-dιhvdro-4H-cyclopentarblthιen-2-yl)-l- cvclopropyl-8-methoxy-4-oxo-l,4-dιhydro-3-quιnolιnecarboxyIate Ethyl 7-bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dιhydro-3- quinolonecarboxylate and Example 45E were processed as descπbed in Example IE to provide the desired product. MS (ESI(+)) m/z 540 (M+H)+;
Η NMR (300 MHz, CDC13) 8.18 (d, IH), 7.58 (d, IH), 7.31 (s, IH), 5.00 (m, IH), 4.37 (q, 2H), 3.95 (m, IH), 3.61 (s, 3H), 3.23 (dd, IH), 3.08 (dd, IH), 2.88 (dd, IH), 2.72 (dd, IH), 1.39 (t, 3H), 1.16 (m, 2H), 0.95 (m, 2H), 0.90 (s, 9H), 0.10 (s, 6H).
Example 45G ethyl l-cvclopropyl-7-(5-hydroxy-5,6-dιhydro-4H-cyclopenta[blthιen-2-yl)-8-methoxy-4- oxo-l,4-dιhydro-3-quιnolιnecarboxylate A solution of Example 45F (0.777 g, 1.43 mmol) in THF (30 mL) at 0 °C was treated with pyπdinium hydrofluonde (15 mL) portionwise over 1 hour, warmed to room temperature diluted with water and ethyl acetate. The layers were separated, and the organic layer was washed with water and saturated sodium bicarbonate solution, dπed (Na2SO4), filtered, and concentrated. The residue was puπfied by flash column chromatography on silica gel with hexanes then with ethyl acetate in hexanes to provide 472 mg (77%) of the desired product as an off-white solid mp 161- 163 °C; MS (ESI(+)) m/z 426 (M+H)+;
Η NMR (300 MHz, CDC13) 8.63 (s, IH), 8.20 (d, IH), 7.59 (d, IH), 7.37 (s, IH), 5.05 (m, IH), 4.40 (q, 2H), 3.97 (m, IH), 3.64 (s, 3H), 3.34 (dd, IH), 3.18 (dd, IH), 2.96 (dd, IH), 2.70 (dd, IH), 2.10 (br d, IH), 1.41 (t, 3H), 1.19 (m, 2H), 0.98 (m, 2H).
Example 45H l-cvclopropyl-7-(5-hydroxy-5,6-dihydro-4H-cyclopentarblthien-2-yl)-8-methoxy-4-oxo-
1 ,4-dihvdro-3-quinolinecarboxylic acid Example 45G was processed as described in Example 2B to provide the desired product. mp 254-255 °C; MS (ESI(+)) m/z 398 (M+H)+;
Η NMR (300 MHz, CDC13) 14.75 (s, IH), 8.90 (s, IH), 8.22 (d, IH), 7.74 (d, IH), 7.44 (s, IH), 5.06 (m, IH), 4.11 (m, IH), 3.67 (s, 3H), 3.36 (dd, IH), 3.21 (dd, IH), 2.98 (dd, IH), 2.81 (dd, IH), 1.26 (m, 2H), 1.06 (m, 2H).
Example 46 l-cyclopropyl-8-methoxy-7-(4-methoxy-5,6-dihydro-4H-cvclopentarblthien-2-yl)-4-oxo-
1 ,4-dihydro-3-quinolinecarboxylic acid
Example 46A 4-methoxy-5,6-dihydro-4H-cycIopentarblthiophene A solution of 5,6-dihydrocyclopenta[b]thiophene-4-one (1.25 g, 9.06 mmol, prepared by the method of Balenkova, E. S., et al Tetrahedron Lett. 1996, 37, 4199) in methanol at 0 °C was treated portionwise with NaBHi, stirred at room temperature for 45 minutes, quenched with IM HCI, and extracted 3 times with ethyl acetate. The combined extracts were dried (Na2SO4), filtered, and concentrated to provide an oil which was purified by flash column chromatography on silica gel with 10% ethyl acetate in hexanes to provide 0.84 g (60%) of the desired product as a clear oil. MS (DCI/NH3) m/z 172 (M+NH4)+;
1H NMR (300 MHz, DMSO-d6) δ 7.38 (d, IH), 7.00 (d, IH), 4.69 (dd, IH), 3.25 (s, 3H), 3.05-2.85 (br m, IH), 2.82-2.60 (br m, 2H), 2.35-2.22 (br m, IH).
Example 46B methyl 2-(tributylstannyl)-5,6-dihydro-4H-cyclopentafblthien-4-yl ether Example 46A was processed as described in Example ID to provide the desired product.
MS (DCI/NH3) m/z 412 (M-CH3OH)+;
Η NMR (300 MHz, CDCI3) 6.99 (s, IH), 4.76 (m, IH), 3.38 (s, 3H), 3.05 (m, IH), 2.78 (m, 2H), 2.48 (m, IH), 1.55 ( , 6H), 1.33 (m, 6H), 1.07 ( , 6H), 0.89 (t, 9H).
Example 46C l-cyclopropyl-8-methoxy-7-(4-methoxy-5,6-dihvdro-4H-cycIopenta[blthien-2-yl)-4-oxo-
1 ,4-dihydro-3-quinolinecarboxylic acid Ethyl 7-bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3- quinolonecarboxylate and Example 46B were processed as described in Example IE to provide the desired product. MS (DCI/NH3) m/z 412 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 14.92 (br s, IH), 8.80 (s, IH), 8.12 (d, IH), 8.04 (d, IH), 7.80 (s, IH), 4.79 (dd, IH), 4.30-4.20 (m, IH), 3.69 (s, 3H), 3.14-3.00 (m, IH), 2.95- 2.80 (m, IH), 2.78-2.62 (m, IH), 2.38-2.34 (m, IH), 1.20-1.00 (br m, 4H).
Example 47 l-cyclopropyl-7-(6-hvdroxy-4,5,6,7-tetrahydro-l-benzothien-2-y1)-8-methoxy-4-oxo-l,4- dihvdro-3-quinolinecarboxylic acid
Example 47A tert-butyl(dimethyl)(4,5,6,7-tetrahydro-l-benzothien-6-vIoxy)silane 4,5-Dihydrobenzo[b]thiophene-6(7H)-one (prepared by the method of Padwa, A., et al. J. Org. Chem. 1989, 54, 299) was processed according to Example 35A to provide the desired product. MS (DCI/NH3) m/z 269 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 7.13 (d, IH), 6.68 (d, IH), 4.13-4.03 (m, IH), 2.89 (dd,
IH), 2.67-2.43 (m, 3H), 1.81-1.54 (m, 2H), 0.90 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H).
Example 47B tert-butyl(dimethyl)((2-(tributylstannyl)-4,5,6,7-tetrahydro-l-benzothien-6-yl)oxy)silane Example 47A was processed as described in Example ID to provide the desired product. Η NMR (300 MHz, DMSO-d6) δ 6.79 (s, IH), 4.18-4.10 ( , IH), 3.05-2.93 (m, IH),
2.80-2.53 (m, 3H), 1.90-1.60 (m, 2H), 1.60-1.45 (m, 6H), 1.40-1.20 (m, 6H), 1.10-0.97 (m, 6H), 0.99 (s, 3H), 0.90-0.80 ( , 18H), 0.10 (s, 3H). Example 47C 7-(6-((tert-butyl(dimethyl)silyl)oxyV4.5.6,7-tetrahydro-l-benzothien-2-yl)-l-cvclopropyl- 8-methoxy-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid Ethyl 7-bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3- quinolonecarboxylate and Example 47B were processed as described in Example IE to provide the desired product. MS (DCI/NH3) m/z 526 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 14.83 (s, IH), 8.68 (s, IH), 8.00 (d, IH), 7.87 (d, IH), 7.46 (s, IH), 4.20-4.08 (m, 2H), 3.95 (dd, IH), 3.57 (s, 3H), 2.70-2.53 (m, 5H), 1.85-1.60 (m, 4H), 1.10-0.86 (m, 4H), 0.99 (s, 3H), 0.77 (s, 9H), 0.10 (s, 3H).
Example 47D l-cvclopropyl-7-(6-hydroxy-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8-methoxy-4-oxo-l,4- dihydro-3-quinolinecarboxylic acid
Example 47C was processed as described in Example 35E to provide the desired product.
MS (DCI/NH3) m/z 412 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 8.78 (s, IH), 8.09 (d, IH), 7.96 (d, IH), 7.55 (s, IH), 4.93 (d, IH), 4.30-4.19 (m, IH), 4.10-3.97 (m, IH), 3.67 (s, 3H), 3.03 (dd, IH), 2.85-2.55 (m, 3H), 1.95-1.83 (m, IH), 1.80-1.68 (m, IH), 1.20-1.00 (m, 4H).
Example 48 l-cyclopropyl-6-fluoro-4-oxo-7-(4-oxo-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l,4- dihydrori,81naphthyridine-3-carboxylic acid
Example 48A tert-butyl(6,7-dihydro-l-benzothien-4-yloxy)dimethylsilane A solution of 1.0M lithium bis(trimethylsilyl)amide in THF (26.4 mL, 26.4 mmol) at -40 °C was treated dropwise with a solution of 4-keto-4,5,6,7-tetrahydrothianaphthene (3.64 g, 24.0 mmol) in THE (30 mL), stirred for 2 hours, and treated dropwise with a solution of t-butyldimethylsilyl chloride (3.72 g, 24.8 mmol) in THF (30 mL). After 1 hour at -40 °C, the reaction mixture warmed to room temperature, stirred for 18 hours, poured into cold 10% aqueous NH4CI. The layers were separated, and the aqueous layer was extracted with dichloromethane. The combined extracts were dried (Na2SO4) filtered, and concentrated to provide 6.07 g (95%) of the desired product as an oil. MS (APCI(+)) m/z 267 (M+H)+; Η NMR (300 MHz, CDC13) 7.02 (d, IH), 6.97 (d, IH), 4.85 (dd, IH), 2.80 (dd, 2H), 2.62 (m, 2H), 1.00 (s, 9H), 0.20 (s, 6H).
Example 48B tert-butyl(dimethyl)((2-(tributylstannyl)-6,7-dihydro-l-benzothien-4-yl)oxy)silane
Example 48B was processed as described in Example ID to provide the desired product.
MS (APCI(+)) m/z 556 (M+H)+;
Η NMR (CDCI3) 7.10 (s, IH), 5.83 (dd, IH), 2.82 (dd, 2H), 2.40 (m, 2H), 1.50-1.02 (m, 18H), 1.00 (s, 9H), 0.90 (t, 9H), 0.20 (s, 6H).
Example 48C ethyl 1 -cyclopropyl-6-fluoro-4-oxo-7-(4-oxo-4,5 ,6,7-tetrahydro- 1 -benzothien-2-yl)- 1 ,4- dihydrori,81naphthyridine-3-carboxylate Ethyl 7-chloro-l-cyclopropyl-6-fluoro-4-oxo-l,4-dihydro[l,8]napthyridine-3- carboxylate and Example 48B were processed as described in Example IE to provide the desired product.
MS (APCI(+)) m/z 426 (M+H)+;
1H NMR (300 MHz, CDC13) 8.68 (s, IH), 8.43 (d, IH), 8.25 (d, IH), 4.41 (q, 2H), 3.68 (m, IH), 3.12 (dd, 2H), 2.63 (dd, 2H), 2.29 (m, 2H), 1.41 (t, 3H), 1.10 (m, 2H), 0.90 (m, 2H).
Example 48D l-cvclopropyl-6-fluoro-4-oxo-7-(4-oxo-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l,4- dihydro|T,81naphthyridine-3-carboxylic acid
A solution of Example 48C (0.155 g, 0.37 mmol) in ethanol (3 mL) was treated with IM HCI (3.7 mL, 3.7 mmol), heated at 90 °C for 5 hours, and concentrated. The residue was dissolved in dichloromethane, washed with water, dried (Na2SO4), filtered, and concentrated to provide 0.065 g (44%) of the desired product as a pale yellow solid. mp 298-299 °C (decomp.);
MS (APCI(+)) m/z 399 (M+H)+;
1H NMR (300 MHz, CDC13) 8.90 (s, IH), 8.46 (d, IH), 8.32 (d, IH), 3.82 (dt, IH), 3.13
(dd, 2H), 2.62 (dd, 2H), 2.30 (dt, 2H), 1.42 (m, 2H), 1.15 (m, 2H).
Example 49 l-cvclopropyl-6-fluoro-7-((4E)-4-(hvdroxyimino -4,5,6,7-tetrahydro-l-benzothien-2-yl)-4- oxo-l,4-dihydrorL81naphthyridine-3-carboxylic acid Example 48D (0.250 g, 0.62 mmol) was suspended in 2:1 ethanol/THF (8 mL), and treated with hydroxylamine hydrochloride (0.161 g, 2.50 mmol) and sodium bicarbonate (0.218 g, 2.60 mmol) in water (3 mL), heated at 75 °C for 24 hours, cooled to room temperature, and diluted with to form a precipitate. The precipitate was collected by filtration, triturated in iso-propanol, filtered, and dried to provide 0.220 g (85%) of the desired product as an off-white solid, mp >300 °C; MS (APCI(-)) m/z 412 (M-H)";
1H NMR (300 MHz, DMSO-d6) 13.5 (br s, IH), 11.60 (s, IH), 8.65 (s, IH), 8.35 (d, IH), 8.05 (d, IH), 3.70 (m, IH), 2.93 (dd, 2H), 2.67 (dd, 2H), 1.98 (m, 2H), 1.28 (m, 2H), 1.08 (m, 2H).
Example 50 l-cvclopropyl-8-methoxy-4-oxo-7-(4-oxo-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l,4- dihvdro-3-quinolinecarboxylic acid
Example 50A ethyl l-cyclopropyl-8-methoxy-4-oxo-7-(4-oxo-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l,4- dihvdro-3-quinolinecarboxylate Ethyl 7-bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3- quinolonecarboxylate and Example 48B were processed as described in Example IE to provide the desired product. MS (APCI(+)) m/z 438 (M+H)+;
Η NMR (300 MHz, CDC13) 8.65 (s, IH), 8.36 (d, IH), 7.90 (s, IH), 7.63 (d, IH), 4.40 (q, 2H), 3.97 (m, IH), 3.63 (s, 3H), 3.10 (dd, 2H), 2.62 (dd, 2H), 2.28 (m, 2H), 1.41 (t, 3H), 1.20 (m, 2H), 0.98 (m, 2H).
Example 50B l-cvclopropyl-8-methoxy-4-oxo-7-(4-oxo-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l,4- dihydro-3-quinolinecarboxylic acid Example 50A was processed as described in Example 48D to provide the desired product. mp 266-267 °C;
MS (APCI(+)) m/z 410 (M+H)+; MS (APCI(-)) 408 (M-H)"; Η NMR (300 MHz, CDC13) 14.65 (s, IH), 8.92 (s, IH), 8.27 (d, IH), 7.95 (s, IH), 7.77 (d, IH), 4.10 (m, IH), 3.68 (s, 3H), 3.12 (dd, 2H), 2.63 (dd, 2H), 2.30 (m, 2H), 1.30 (m, 2H), 1.04 (m, 2H).
Example 51 l-cvclopropyl-7-((4E)-4-(hydroxyimino)-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid Example 50B was processed as described in Example 49 to provide the desired product. mp 296-297 °C;
MS (APCI(+)) m/z 425 (M+H)+;
Η NMR (300 MHz, DMSO-d6) 12.25 (s, IH), 10.85 (s, IH), 8.80 (s, IH), 8.13 (d, IH), 8.00 (d, IH), 7.91 (s, IH), 4.25 (m, IH), 3.68 (s, 3H), 2.90 (dd, 2H), 2.67 (dd, 2H), 1.93 (m, 2H), 1.16 (m, 2H), 1.05 (m, 2H).
Example 52 l-cyclopropyl-8-diflouromethoxy-7-(7-methyl-4,5,6,7-tetrahvdrotheino(2,3-c)pyrindin-2- yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride Ethyl 7-bromo-l-cyclopropyl-8-difluoromethoxy-4-oxo-l,4-dihydro-3- quinolinecarboxylate and Example 2 ID were processed as described in Example IE to provide the desired product, mp 222-225 °C;
MS (DCI/NH3) m/z 447 (M+H)+; lH NMR (300 MHz, CD3OD) δ 9.01 (s, IH), 8.40 (d, IH), 7.90 (d, IH), 7.55 (s, IH), 6.62 (dd, IH), 4.86 (m, IH), 4.27 (m, IH), 3.74 (m, IH), 3.52 (m, IH), 3.10 (m, 2H), 1.76 (d, 3H), 1.32 (m, 2H), 1.07 (m, 2H).
Example 53 l-cvclopropyl-8-methoxy-4-oxo-7-(5-oxo-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l,4- dihydro-3-quinolinecarboxylic acid
Figure imgf000104_0001
Example 53A A solution of 5-keto-4,5,6,7-tetrahydrothianapthene (prepared by the method of Padwa, et al. J. Org. Chem. 1989, 54, 299-308.) (3.00g, 19.7 mmol), ethylene glycol (2.50g, 40.0 mmol), and p-toluenesulfonic acid (0.380g, 2.00 mmol) in toluene was heated to 100°C overnight. After cooling, the mixture was partitioned between ethyl acetate and water. The organic phase was washed with saturated aqueous sodium bicarbonate, water, and brine, dried (Na2SO4), and concentrated. The resulting residue was purified by chromatography on silica gel eluting with 10% ethyl acetate in hexane to provide the desired product (3.44g, 89%) as a yellow oil.
Figure imgf000105_0001
Example 53B The desired product was prepared by substituting example 53A for examplelC in example ID.
Figure imgf000105_0002
Example 53C
The desired product was prepared by substituting example 53B and ethyl 7-bromo- l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate for example ID and ethyl 7-bromo-l-cyclopropyl-4-oxo-l,4-dihydro-3-quinolinecarboxylate, respectively in example IE.
Example 53D l-cyclopropyI-8-methoxy-4-oxo-7-(5-oxo-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l,4- dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting example 53C for example 48C in example 48D.
MS (APCI) m/z 410 (M+l)+;
1H NMR (300 MHz, CDC13) δ 14.68 (s, IH), 8.92 (s, IH), 8.26 (d, IH), 7.76 (d, IH), 7.37 (s, IH), 4.10 (m, IH), 3.69 (s, 3H), 3.57 (s, 2H), 3.24 (t, 2H), 2.78 (t, 2H), 1.32-1.23 (m, 2H), 1.09-1.03 (m, 2H).
Example 54 7-r5-(azidomethyl)-4,5,6,7-tetrahvdro-l-benzothien-2-yll-l-cyclopropyl-8-methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid A solution of 70A (0.040 g, 0 084mmol) and aqueous sodium hydroxide (1 mL of a 1 M solution) in ethanol (1 L) was heated to 40°C for 16 h. The mixture was cooled to room temperature and acidified with 6 N HCI (0.2 mL) then extracted with ethyl acetate, dried (MgSO4), and concentrated. The resulting acid was was puπfied by chromatography on silica gel eluting with 70% acetone in hexane with 0.5% acetic acid then 85% acetone in hexane with 0.5% acetic acid to provide the desired product (0.015 g, 40% yield). MS (ESI) m/z 449 (M-H) ;
1H NMR (300 MHz, CDC13) δ 8.90 (s, IH), 8.23 (d, IH), 7.75 (d, IH), 7.35 (s, IH), 4.10 (m, IH), 3.67 (s, 3H), 3.39 (d, 2H), 2.90 (m, 3H), 2.42 (m, IH), 2 11 (m, 2H), 1.66 (m, IH), 1.27 (m, 2H), 1.05 (m, 2H).
Example 55 l-cvclopropyl-7-((5E/Z)-5-(hydroxyιmιno)-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-8- methoxy-4-oxo-l,4-dιhydro-3-quιnolιnecarboxylιc acid
The desired product was prepared by substituting example 53D for example 48D in example 49.
MS (ESI) m/z 425 (M+H)+;
Η NMR (300 MHz, CDC13) δ 8.92 (s, IH), 8.22 (d, IH), 7.79 (d, IH), 7.43 (s, IH), 4.16 (m, IH), 3.78 (s, IH), 3.69 (s, 3H), 3.53 (s, IH), 3.37 (m, 2H), 3.00 (m, 2H), 2.70 (m, IH), 1.31 (m, 2H), 1.08 (m, IH).
Example 56 l-cyclopropyl-8-methoxy-7-((5E/Z)-5-(methoxyιmιno)-4,5,6,7-tetrahydro-l-benzothιen-2- yl)-4-oxo-l,4-dιhydro-3-quιnoIιnecarboxylιc acid
The desired product was prepared by substituting example 53D for example 48D and methoxyamine hydrochloπde for hydroxylamine hydrochloπde in example 49. MS (ESI) m/z 439 (M+H)+;
Η NMR (300 MHz, DMSO-rf6) δ 8.79 (s, IH), 8.12 (d, IH), 7.99 (d, IH), 7.65 (s, IH), 4.25 (m, IH), 4.10 (s, IH), 3.81 (s, 3H major), 3.79 (s, 3H minor), 3.68 (s, 3H), 3.65 (s, IH), 2 97 (m, 2H), 2 80 (t, IH), 2.60 (t, IH), 1.15 ( , 2H), 1.04 (m, 2H).
Example 57 l-cyclopropyl-7-(5-methyl-4,5.6.7-tetrahvdrothieno[2,3-clpyndin-2-yl)-4-oxo-l,4- dιhydro|T,81naphthyπdιne-3-carboxylιc acid hydrobromide
Example 57A N-methylene-l-(3-thιenyl)-2-propanamιne The desired product was prepared by substituting 3-(2-amιnopropyl)-thιophene (prepared by the method of Anne-Archard, et al. Eur. Pat. Appl. 82-401132) for 2- thiophenethylamine in example 1-A
Figure imgf000107_0001
Example 57B The desired product was prepared by substituting example 57 A for example 1 A in example IB
Figure imgf000107_0002
Example 57C The desired product was prepared by substituting example 57B for example 1 IB in example l lC.
Figure imgf000107_0003
Example 57D The desired product was prepared by substituting example 57C for example 218B in example 218C
Example 57E ethyl 7-{6-r(benzyloxy)carbonyll-5-methyl-4,5,6,7-tetrahydrothieno[2,3-clpyridin-2-yl }-l- cyclopropyl-8-methoxy-4-oxo-l,4-dιhydro-3-quιnolιnecarboxylate The desired product was prepared by substituting example 57D and ethyl 7-bromo- l-cyclopropyl-8-methoxy-4-oxo-l,4-dιhydro-3-quιnohnecarboxylate and a reaction time of 4 hours for example ID and 7-bromo-l-cyclopropyl-4-oxo-l,4-dιhydro-3- quinohnecarboxylate and a reaction time of 24 hours, respectively in example IE. Example 57F 7-{ 6-r(benzyloxy)carbonyll-5-methyl-4,5,6,7-tetrahvdrothienof2,3-clpyridin-2-yl }-l- cyclopropyl-8-methoxy-4-oxo-L4-dihvdro-3-quinolinecarboxylic acid The desired product was prepared by substituting example 57E for example 2A in example 2B.
Example 57G l-cvclopropyl-7-(5-methyl-4,5,6,7-tetrahydrothienor2,3-clpyridin-2-yl)-4-oxo-l,4- dihvdro|T,81naphthyridine-3-carboxylic acid hydrobromide The desired product was prepared by substituting example 57F for example 40B in example 40C. mp 156-157° C; MS (APCI) m/z 367 (M+H)+;
Η NMR (300 MHz, OMSO-d6) δ 9.40 (br s, 2H), 9.10 (br s, IH), 8.83 (s, IH), 8.67 (d, IH), 8.17 (d, IH), 8.04 (s, IH), 4.45 (s, 2H), 3.80 (m, IH), 3.20 (m, IH), 2.60 (m, 2H), 1.40 (d, 3H), 1.15 (m, 2H), 1.07 (m, 2H).
Example 58 7-(5-bromo-4-oxo-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4-oxo-
1 ,4-dihydro-3-quinolinecarboxylic acid
Figure imgf000108_0001
Example 58A
The desired product was prepared by substituting example 48B and ethyl 7-bromo- l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate for example ID and ethyl 7-bromo-l-cyclopropyl-4-oxo-l,4-dihydro-3-quinolinecarboxylate in example IE.
Figure imgf000108_0002
A solution of example 58A (1.64 g, 3.0 mmol) in dichloromethane (40 mL) was treated with 4-(dimethylamino)pyridinium tribromide (1.45 g, 4.0 mmol) and stirred at room temperature for 3 hours. The reaction mixture was partitioned between water and dichloromethane, dried (Na2SO4) and concentrated. The resulting mixture was separated by silica gel chromatography eluting with 1% methanol in dichloromethane to give example 58B (0.1 lg, 8%) and example 62A .
For example 58B:
MS (DC17NH3) m/z (M+H)+;
Η NMR (300 MHz, CDC13) δ 8.93 (s, IH), 8.30 (d, IH), 7.98 (s, IH), 7.78 (d, IH), 4.68
(m, IH), 4.10 (m, IH), 3.69 (s, 3H), 3.38 ( , IH), 3.13 (m, IH), 2.63 (m, 2H), 1.30
(m,2H), (m, 2H).
Example 59 1 -cyclopropyl-8-methoxy-4-oxo-7-(6-oxo-4, 5 ,6,7-tetrahydro- 1 -benzothien-2-yl)- 1 ,4- dihydro-3-quinolinecarboxylic acid
Figure imgf000109_0001
Example 59A The desired product was prepared by substituting example 47B and ethyl 7-bromo- l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate for example ID and ethyl 7-bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate, respectively in example IE and was purified by chromatography on silica gel eluting with 20% ethyl acetate in hexanes.
Figure imgf000109_0002
Example 59B The desired product was prepared by substituting example 59A for example 35D in example 35E and was purified by chromatography on silica gel eluting with 50% ethyl acetate in hexane.
Figure imgf000110_0001
Example 59C The desired product was prepared by substituting example 59B for example 41C in example 324511A and was used without further purification.
Example 59D l-cyclopropyl-8-methoxy-4-oxo-7-(6-oxo-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l,4- dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting example 59C and THF as reaction solvent for example 59C and EtOH as reaction solvent, respectively in example 59D.
MS (DCI/NH3) m z 410 (M+H)+;
Η-NMR (300 MHz, d6-DMSO) δ 8.79 (s, IH), 8.12 (d, IH), 8.03 (d, IH), 7.70 (s, IH), 4.25 (m, IH), 3.72 (s, 2H), 3.70 (s, 3H), 3.03 (dd, 2H), 2.64 (dd, 2H), 1.2-1.05 (m, 4H).
Example 60 l-cyclopropyl-7-((6E/Z)-6-(hydroxyimino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinoIinecarboxylic acid
The desired product was prepared by substituting example 59D for example 59D in example 49 and the product isolated by partitioning the reaction mixture between ethyl acetate and water, the organic phase dried (Na2SO4), and the concentrated residue triturated with hexanes to afford a white solid. MS (DCI/NH3) m/z 425 (M+H)+;
Η-NMR (300 MHz, d6-DMSO) δ 14.90 (s, IH), 8.78 (s, IH), 8.10 (d, IH), 7.97 (d, IH), 7.63 (s, IH), 4.25 (m, IH), 3.80 (s, 2H), 3.69 (s, 3H), 3.67-3.5 (m, 2H), 2.78 (m, 2H), 2.56 (m, IH), 1.3-1.00 (m, 4H).
Example 61 l-cvclopropyl-8-methoxy-4-oxo-7-(7-oxo-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l,4- dihydro-3-quinolinecarboxylic acid
Figure imgf000111_0001
Example 61 A
A solution of example 4 IC (0.05 g, 0.1 Immol) in CH2C12 (20 mL) was cooled to 0°C, treated with Dess-Martin periodinane (0.06 g, 0.14 mmol), allowed to come to room temperature and stir for 4 hour. The reaction mixture was partitioned between water and dichloromethane, the organic phase washed with sat. Na2S2O6j 10% K2CO3 , brine, and dried (Na2SO ). Concentration gave a dark oil that was purified by silica gel chromatography eluting with hexane:acetone:methanol (55:45:5) to hexane:acetone:methanol (40:50: 10) to provide the desired product (0.028 g , 53 % yield) as a tan solid.
Example 6 IB l-cyclopropyl-8-methoxy-4-oxo-7-(7-oxo-4,5,6,7-tetrahydro- l-benzothien-2-yl)-l,4- dihvdro-3-quinolinecarboxylic acid The desired product was prepared by substituting example 61A for example 2A in example 2B.
MS (APCI) m/z 410 (M+H+)+
1H NMR (300 MHz, DMSO-d6) δ 8.82 (s, IH), 8.17 (d, IH ), 8.10 (d,lH), 7.87 (s,lH), 4.27 (m, IH), 3.71 (s, 3H), 2.93 (t, 2H), 2.60 (t, 2H), 2.14 (m, 2H), 1.17 (s, 2H), 1.06 (s, 2H).
Example 62 7-(5-azido-4-oxo-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l-cvclopropyl-8-methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid
Figure imgf000112_0001
A solution of example 58 A (1.64 g, 3.0 mmol) in dichloromethane (40 mL) was treated with 4-(dimethylamino)pyridinium tri bromide (1.45 g, 4.0 mmol) and stirred at room temperature for 3 hours. The reaction mixture was partitioned between water and dichloromethane, dried (Na2SO ) and concentrated. The resulting mixture was separated by silica gel chromatography eluting with 1% methanol in dichloromethane to give example 58B (0.1 lg, 8%) and example 62A . For example 58: MS (DCI NH m/z (M+H)+;
Η NMR (300 MHz, CDC13) δ 8.93 (s, IH), 8.30 (d, IH), 7.98 (s, IH), 7.78 (d, IH), 4.68 (m, IH), 4.10 (m, IH), 3.69 (s, 3H), 3.38 (m, IH), 3.13 (m, IH), 2.63 (m, 2H), 1.30
Figure imgf000112_0002
Example 62B A solution of example 62A (0.10 g, 0.19 mmol) in DMSO (5 mL) was treated with sodium azide (0.015 g, 0.23 mmol) and stirred at room temperature for 2 hours. The reaction mixture was partitioned between water and dichloromethane, the aqueous layer extracted with dichloromethane, the combined organic layers washed with brine, dried (Na2SO4), and concentrated to yield the desired product (0.054 g, 58%).
Example 62C 7-(5-azido-4-oxo-4,5,6 7-tetrahvdro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4-oxo-
1 ,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting example 62B for example 48C in example 48D.
MS (DCI/NH3) m/z 451 (M+H)+;
Η NMR (300 MHz, CDC13) δ 8.93 (s, IH), 8.30 (d, IH), 7.96 (s, IH), 7.77 (d, IH), 4.26 (dd, IH), 4.10 (m, IH), 3.68 (s, 3H), 3.22 (m, 2H), 2.31 (m, 2H), 2.48 (m, 2H), 1.29 (m, 2H), 1.06 (m, 2H).
Example 63 l-cyclopropyl-8-methoxy-7-((7E/Z)-7-(methoxyιmιno)-4,5,6,7-tetrahvdro-l-benzothιen-2- yl)-4-oxo-l,4-dιhvdro-3-quιnolιnecarboxylιc acid The desired product was prepared by substituting example 61B for example 48D in example 49. MS (ESI) m/z 408 (M-OCH3 +H)"
Η NMR (300 MHz, DMSO-d6) δ 8.73 (s, IH), 8.12 (d, IH), 7.96 (d, IH), 7.82 (s, IH), 4.17 (m,lH), 4.02 (s, 3H), 3.68 (s, 3H), 2.92 (t, 2H), 2.59 (t, 2H), 2.12 (m, 2H), 1.14 (d, 2H), 0 95 (s, 2H).
Example 64 l-cyclopropyl-8-methoxy-7-((4E/Z)-4-(methoxyimιno)-4,5,6,7-tetrahydro-l-benzothιen-2- yl)-4-oxo-l,4-dιhydro-3-quιnolιnecarboxylιc acid A solution of example 50 (0.120 g, 0.3 mmol) was suspended in 4 mL of MeOH and treated with NaOAc (0.125 g, 1.5 mmol) and methoxylamine hydrochloπde (0.218 g, 1.6 mmol) The reaction mixture was heated at 90° C for 18 hours. The solvent was removed and 20 mL of 10% NH C1 was added. The product was isolated by suction filtration and was dπed under vacuum giving the desired product as a white solid (0.100 g, 76%). mp 232-233° C;
MS (APCI) m/z 439 (M+H)+;
Η NMR (300 MHz, OMSO-d6) δ 8.80 (s, 0.85H), 8.41 (s, 0.15H), 8.13 (d, 0.15H), 8.11 (d, 0.85H), 8.02 (d, 0.85H), 7.98 (d, 0.15H), 7.89 (s, IH), 4.27 (m, IH), 3.92 (s, 0.45H), 3.90 (s, 2.55H), 3.70 (s, 3H), 3.30 (s, IH), 3.01 (dd, 0.3H), 2.91 (dd, 1.70H), 2.81 (dd, 0.3H), 2 68 (dd, 1.70H), 2.01 (m, 0.3H), 1.97 (m, 1.7H), 1.18 (m, 2H), 1.05 (m, 2H).
Example 65 l-cyclopropyl-7-((4E/Z)-4-(ethoxyιmιno)-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-8- methoxy-4-oxo-L4-dιhvdro-3-quιnolιnecarboxylιc acid
The desired product was prepared by substituting O- ethylhydroxylamine hydrochloπde for hydroxylamine hydrochloride in example 49. mp 208-210° C; MS (APCI) m/z 453 (M+H)+; Η NMR (300MHz, DMSO-cf6) δ 8.82 (s, IH), 8.13 (d, IH), 8.05 (d, IH), 7.88 (s, IH), 4.27 (m, IH), 4.15 (q, 2H), 3.69 (s, 3H), 3.30(s, IH), 2.90 (dd, 2H), 2.67 (dd, 2H), 1.92 (m, 2H), 1.28 (t, 3H), 1.15 ( , 2H), 1.05 (m, 2H). Example 66 l-cvclopropyl-8-methoxy-7-((6E/Z)-6-(methoxyimino)-4,5,6,7-tetrahvdro-l-benzothien-2- yl)-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid
The desired product was prepared by substituting example 59D and O- methylhydroxylamine for example 59D and hydroxylamine hydorchloride, respectively in example 49 and the product isolated by partitioning the reaction mixture between ethyl acetate and water, the organic phase dried (Na2SO4), and the concentrated residue triturated with hexanes to afford a white solid. MS (DCI/NH3) m/z 439 (M+H)+;
1H-NMR (300 MHz, d6-DMSO) δ 8.79 (s, IH), 8.10 (d, IH), 8.00 (d, IH), 7.63 (s, IH), 4.25 (m, 2H), 3.83 (s, 3H), 3.68 (s, 3H), 2.80-2.68 (m, IH), 2.60-2.45 (m, 2H), 1.30 (m, 2H), 1.15 (m, 2H), 1.05 (m, 2H).
Example 67 l-cyclopropyl-7-(6,7-dihydro-l-benzothien-2-yl)-8-methoxy-4-oxo-l,4-dihydro-3- quinolinecarboxylic acid
Figure imgf000114_0001
Example 67A
A solution of p-toluenesulfonic anhydride (13.7g, 42.0 mmol) in CH2C12 (70mL) was added dropwise to a solution of example 198A (5.33g, 35.0 mmol) and 4- dimethylaminopyridine (5.50g, 45.5 mmol) in CH2C12 at 0 °C. The reaction mixture was slowly warmed to room temperature overnight, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, saturated aqueous ammonium chloride, dried
(Na2SO ) and concentrated. The resulting oil was purified by chromatography on silica gel eluting with 10% ethyl acetate in hexane to provide the desired product (3.25 g, 68%) as a pale yellow oil.
Figure imgf000114_0002
Example 67B The desired product was prepared by substituting example 67A for example IC in example ID.
Figure imgf000115_0001
Example 67C The desired product was prepared by substituting example 67B and ethyl 7-bromo- l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate for example ID and ethyl 7-bromo-l-cyclopropyl-4-oxo-l,4-dihydro-3-quinolinecarboxylate, respectively in example IE.
Example 67D l-cvclopropyl-7-(6,7-dihydro-l-benzothien-2-yl)-8-methoxy-4-oxo-l,4-dihydro-3- quinolinecarboxylic acid The desired product was prepared by substituting example 67C for example 2A in example 2B. MS (DCI NH3) m/z 394 (M+l )+;
'H NMR (300 MHz, DMSO-J6) d 8.79 (s, IH), 8.11 (d, IH), 8.00 (d, IH), 7.68 (s, IH), 6.54 (dt, IH), 5.92 (dt, IH), 4.25 (m, IH), 3.69 (s, 3H), 2.92 (t, 2H), 2.46 (m, 2H), 1.17- 1.03 (m, 4H).
Example 68 l-cyclopropyl-8-methoxy-7-((4E/Z)-4-(4-mo holinylimino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting N-aminomorpholine and a reaction time of 48 hours for 1-aminopyrrolidine hydrochloride and a reaction time of 24 hours in example 74. mp 118-120° C; MS (APCI) m/z 494 (M+H)+;
Η NMR (300MHz, CDC13) δ 14.70 (br s, IH), 8.90 (s, IH), 8.25 (d, IH), 7.87 (d, IH), 7.38 (s, IH), 4.10 (m, IH), 3.85 (m, 4H), 3.67 (s, 3H), 3.10 (m, 2H), 2.94 (m, 2H), 2.82 (m, 4H), 2.05 (m, 2H), 1.28 ( , 2H)m 1.04 (m, 2H). Example 69 l-cyclopropyl-7-(4,5-dιhydroxy-4,5,6,7-tetrahvdro-l-benzothιen-2-yl)-8-methoxy-4-oxo-
1 ,4-dιh vdro-3-quιnolιnecarboxylιc acid
Figure imgf000116_0001
Example 69A A solution of example 67C (0.130g, 0.30mmol) in 1: 1:1 t-butanol acetone:H2O was treated with 4-methyl moφhohne N-oxide (0 060g, 0.51 mmol) and osmium tetraoxide ( 0.005g, 0.02 mmol). The mixture was stirred at 0°C for 7 h Sodium sulfite (0.400g) was added, the reaction was warmed to 25°C, stirred for 1 h, and partitioned between CH2C12 and water. The layers were separated, and the aqueous layer was extracted 3 times with CH2C12. The combined organic layers were dried (Νa2SO4),and concentrated The residue was puπfied by chromatography on silica gel eluting with CH C12 then 5% MeOH in CH2C12 to provide the desired product as an off-white solid (0.085g, 62%).
Example 69B l-cvclopropyl-7-(4,5-dιhvdroxy-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-8-methoxy-4-oxo- 1 ,4-dιhydro-3-qumolιnecarboxylιc acid
The desired product was prepared by substituting example 69A for example 2A in example 2B
MS (DCI NH3) m/z 428 (M+l)+;
Η NMR (300 MHz, OMSO-d6) δ 8.79 (s, IH), 8.12 (d, IH), 7.99 (d, IH), 7.70 (s, IH), 4.92, (m, IH), 4 56 (m, IH), 4.52 (m, IH), 4.25 (m, IH), 3.72 (m, IH), 3.68 (s, 3H), 2.95- 2.70 (m, 2H), 2 15-1.70 (m, 2H), 1 20-1 03 ( , 4H)
Example 70 7-(5-(amιnomethyl)-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-l-cyclopropyl-8-methoxy-4- oxo-l,4-dιhydro-3-quιnolιnecarboxylιc acid hydrochlonde
Figure imgf000117_0001
Example 70A The desired product was prepared by substituting example 43D for example 37A and DMF at 65°C for toluene:dichloromethane at room temperature in example 37B.
Figure imgf000117_0002
Example 70B The desired product was prepared by substituting example 70A for example 20 IC in example 201D.
Figure imgf000117_0003
Example 70C
A solution of example 70B (0.660 g, 1.2 mmol) in ethanol (3 mL) was treated with aqueous sodium hydroxide (3 mL of a 1 M solution) for 17 h at room temperature. The mixture was acidified with acetic acid (8mL) then concentrated. The resulting acid was purified by chromatography on silica gel eluting with 30% acetone in hexane with 0.5% acetic acid then 40% acetone in hexane with 0.5% acetic acid to provide the desired product (0.590 g, 94%) as an off white solid.
Example 70D 7-(5-(aminomethyl)-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride
The desired product was prepared by substituting example 70C for example 40B in example 40C. MS (ESI) m/z 425 (M+H)+; Η NMR (300 MHz, OMSO-d6) δ 8.80 (s, IH), 8.11 (d, IH), 8.01 (d, IH), 7 94 (br s, 2H), 7 58 (s, IH), 4.25 (m, IH), 3.68 (s, 3H), 2.93-2 74 (m, 5H), 2.38 (m, IH), 2.07 (m, 2H), 1.52 (m, IH), 1 15 (m, 2H), 1.03 (m, 2H)
Example 71
7-(6-amιno-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4- dιhydro-3-quιnolιnecarboxylιc acid, tnfluoroactic acid salt
Figure imgf000118_0001
Example 71 A A solution of example 59C (0.061 g, 0.139 mmol) in MeOH (6 ml) was treated with 3 A molecular sieves, ammonium acetate (0 107 g, 1.39 mmol) and sodium cyanoborohydπde (0.009 g, 0.139mmol) and was stirred at room temperature for 2 hours. The reaction mixture was treated with 2 drops AcOH followed by di-tert-butyldicarbonate (0.303 g, 1.39 mmol), stirred for an additional 2 hours and partitioned between saturated aqueous NH4C1 and ethyl acetate. The aqueous layer was extracted with ethyl acetate, the combined organic layers washed with water, brine, dπed (MgSO4) and concentrated. The resulting residue was puπfied by column chromatography on silica gel eluting with 97:3 / CH2C12:MeOH to give the desired product (0.069 g, 93%).
Figure imgf000118_0002
Example 7 IB The desired product was prepared by substituting example 71 A for example 2 A in example 2B.
Example 71C
7-(6-amιno-4,5,6,7-tetrahvdro-l-benzothιen-2-yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4- dιhydro-3-quιnolιnecarboxylιc acid, tnfluoroactic acid salt The desired product was prepared by substituting example 7 IB for example 40B in example 40C.
MS (APCI) m/z 411 (M+H)+;
Η NMR (300 MHz, DMSO-J6) δ 8.80 (s, IH), 8.12 (d, IH), 8.05 (br s, 3H), 8.00 (d, IH), 7.62 (s, IH), 4.26 (m, IH), 3.68 (s, 3H), 3.60 (m, IH), 3.21 (m, 2H), 2.89-2.65 ( , 2H), 2.12 (m, IH), 1.83 (m, IH), 1.15 (m, 2H), 1.03 (m, 2H).
Example 72 7-((4E/Z)-4-(tert-butoxyimino)-4,5,6 -tetrahydro-l-benzothien-2-yI)-l-cyclopropyl-8- methoxy-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting O-t-butylhydroxylamine hydrochloride for hydroxylamine in example 49. mp 238-240° C; MS (APCI) m/z 481 (M+H)+;
Η NMR (300MHz, CDC13) δ 14.73 (br s, IH), 8.91 (s, IH), 8.26 (d, IH), 7.90 (s, IH), 7.87 (d, IH), 4.10 (m, IH), 3.69 (s, 3H), 2.90 (dd, 2H), 2.74 (dd, 2H), 2.00 (dd, 2H), 1.35 (s, 9H), 1.28 (m, 2H), 1.05 (m, 2H).
Example 73 7-((4E/Z)-4-((benzyloxy)imino)-4,5,6 -tetrahvdro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting O-benzylhydroxylamine hydrochloride and a reaction time of 9 hours for hydroxylamine hydrochloride and a reaction time of 5hours, respectively in example 49. mpl05-107° C; MS (APCI) m/z 515 (M+H)+;
Η NMR (300MHz,
Figure imgf000119_0001
δ 14.70 (s, 0.7H), 14.60 (s, 0.3H), 8.90 (s, 0.7H), 8.88 (s, 0.3h), 8.25 (d, 0.7H), 8.20 (d, 0.3H), 7.94 (s, 0.3H), 7.88 (s. 0.7H), 7.82 (d, 0.7H), 7.38 (m, 5H), 7.28 (d, 0.3H), 5.22 (s 1.4H), 5.17 (s, 0.6H), 4.10 (m, IH), 3.67 (s, 2.1H), 3.57 (s, 0.9H), 3.11 (dd, 0.6H), 3.00 (dd, 0.6H), 2.90 (dd, 1.4H), 2.80 (dd, 1.4H), 2.10(dd, 0.6H), 2.00 (dd, 1.4H), 1.30 ( , 2H), 1.05 (m, 2H).
Example 74 l-cyclopropyl-8-methoxy-4-oxo-7-((4E/Z)-4-(l-pyrrolιdιnylιmιno)-4,5,6,7-tetrahvdro-l- benzothιen-2-yl)-l,4-dιhvdro-3-quιnolιnecarboxylιc acid A solution of example 48C (0.180 g, 0.41 mmol) in absolute EtOH (6 mL) under a positive N2 atmosphere was treated with 1-amιnopyrrolιdιne hydrochloπde (0.151 g, 1.23 mmol) and Et3N (210 μL, 1.50 mmol). The reaction mixture was heated at 75° C for 24 hours the solvent removed and the residue dissolved in CH2C12 , washed with water, dπed (Na2SO4), and concentrated.
A solution of the resulting solid (0.180 g, 0.35 mmol) in THF (5 mL) was treated with LιOH-H2O( 0.147 g, 3.5 mmol) in water (7 0 mL) at 25° C for 4 hours. The solution wasd adjusted to pH 7 with 10% NH4CI and IM H3PO4 extracted with CH2C12, the combined organic phases dπed (Na2SO ) and concentrated to give the desired product as a solid (0.130 g, 77%). mp 90-91° C;
MS (APCI) m/z 478 (M+H)+; 1H NMR (300MHz, CDC13) δ 14.75 (br s, IH), 8.89 (s, IH), 8.22 (d, IH), 7 93 (s, IH), 7.88 (d, IH), 4.12 (m, IH), 3.68 (s, 3H), 3.10 (m, 4H), 2.90 (dd, 2H), 2.72 (dd, 2H), 2 08 (m, 2H), 1.88 (m, 4H), 1.35 (m, 2H), 1.07 (m, 2H).
Example 75
7-(4-amιno-4,5,6,7-tetrahydro-l-benzothιen-3-yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4- dιhydro-3-quιnolιnecarboxylιc acid
Figure imgf000120_0001
Example 75A
A solution of example 260C (2.98 g, 8.6 mmol) in diethyl ether (18 mL) at -65°C was treated dropwise with n-butylhthium (3.96 mL of a 2.5 M solution in hexane, 9.89 mmol) and was stirred at -65°C for 30 min The mixture was treated dropwise with chlorotπbutylstannane (2.33 mL, 8.6 mmol) then allowed to warm to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with brine, dπed (Na SO4) and concentrated to provide the desired product as an orange oil (4.78 g, quantitative yield).
Figure imgf000121_0001
Example 75B The desired product was prepared by substituting example 75A, and ethyl 7- bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dιhydro-3-quιnohnecarboxylate for example ID and ethyl 7-bromo-l-cyclopropyl-4-oxo-l,4-dιhydro-3-quιnolιne-3-carboxylate respectively in example IE and the resulting ethyl ester was purified by chromatography on silica gel eluting with 10% acetone in hexane
Figure imgf000121_0002
Example 75C The desired product was prepared by substituting example 75B for example 35D in example 35E and the resulting alcohol was puπfied by chromatography on silica gel eluting with 30% acetone in hexane.
Figure imgf000121_0003
Example 75D
The desired product was prepared by substituting example 75C for example 37A in example 37B and the resulting azide was puπfied by chromatography on silica gel eluting with 20% acetone in hexane.
Figure imgf000121_0004
Example 75E The desired product was prepared by substituting example 75D for example 20 IC in example 201D and the resulting alcohol was puπfied by chromatography on silica gel eluting with 20% acetone in hexane.
Figure imgf000122_0001
Example 75F The desired product was prepared by substituting example 75E and a reaction time of 4 h for example 2A and a reaction time of 2 h in example 2B. The resulting acid was purified by chromatography on silica gel eluting with 30% acetone in hexane.
Example 75G 7-(4-amino-4,5,6,7-tetrahvdro-l-benzothien-3-yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4- dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting example 75F for example 40B in example 40C. MS (ESI) m/z 411 (M+H)+;
1H NMR (300 MHZ, OMSO-d6) δ 8.84 (s, IH), 8.20 (d, IH), 7.84 (br s, 2H), 7.61 (s, IH), 7.58 (d, IH), 4.56 (s, IH), 4.24 (m, IH), 3.41 (s, 3H), 2.94 (m, 2H), 2.16 (m, IH), 1.96 (m, 3H), 1.26 (m, 2H), 1.10 (m, 2H).
Example 76 7-(5-amino-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4- dihydro-3-quinolinecarboxylic acid hydrochloride
Figure imgf000122_0002
Example 76A
The desired product was prepared by substituting example 42B, ethyl 7-bromo-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate and a reaction time of 4 h for example ID, ethyl 7-bromo-l-cyclopropyl-4-oxo-l,4-dihydro-3-quinolinecarboxylate and a reaction time of 24h in example IE.
Figure imgf000123_0001
Example 76B The desired product was prepared by substituting example 76A for example 35D in example 35 E and the resulting alcohol was puπfied by chromatography on silica gel eluting with CH2C12 then 3% MeOH in CH2C12
Figure imgf000123_0002
Example 76C The desired product was prepared by substituting example 76B for example 45G in example 249A
Figure imgf000123_0003
Example 76D The desired product was prepared by substituting example 76C for example 249A in example 249B.
Figure imgf000123_0004
Example 76E The desired product was prepared by substituting example 76D for example 201 A in example 201B
Figure imgf000124_0001
Example 76F The desired product was prepared by substituting example 76E for example 2A in example 2B
Figure imgf000124_0002
Example 76G 7-(5-amιno-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-l-cyclopropyl-8-methoxy-4-oxo-L4- dιhydro-3-quιnolιnecarboxyhc acid hydrochloπde The desired product was prepared by substituting example 76F for example 40B in example 40C.
MS (DCI/NH3) m/z 411 (M+l)+;
Η NMR (300 MHz, MeOH-d4) δ 8.95 (s, IH), 8.20 (d, IH), 7.90 (d, IH), 7.51 (s, IH), 4.29 (m, IH), 3 70 (m, 4H), 3.20 (m, IH), 3.05 (m, 2H), 2.25 (m, IH), 2.32 (m, IH) 2.01 (m, IH), 1 30-1.23 (m, 2H), 1.09-1.04 (m, 2H).
Example 77 l-cvclopropyl-8-methoxy-7-r4-(methylamino)-4,5,6,7-tetrahydro-l-benzothien-2-yll-4-
Figure imgf000124_0003
Example 77A A solution of example 40A (0.44 g, 0.82 mmol) in tetrahydrofuran (5 mL) was added dropwise to a solution of 1.0M sodium bis(tnmethylsilyl)amide (1 48 mL, 1.47 mmol) in tetrahydrofuran (20 mL) at -70°C. This mixture was stirred for 2 hours then treated with iodomethane (0.20 mL, 3.28 mmol) and stirred at 10°C for 16 hours. The reaction mixture was partitioned between 10% NHtCl and dichloromethane, dried (Na2SO4), concentrated, and purified by silica gel column eluting with 10% hexane in ethyl acetate to yield the desired p
Figure imgf000125_0001
Example 77B The desired product was prepared by substituting example 77A for example 2A in example 2B.
Example 77C l-cyclopropyl-8-methoxy-7-r4-(methylamino)-4,5,6,7-tetrahydro-l-benzothien-2-yll-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride The desired product was prepared by substituting example 77B for example 40B in example 40C. MS (DCI/NH3) m/z 425 (M+H)+;
Η NMR (300 MHz, CD3OD) δ 8.97 (s, IH), 8.23 (d, IH), 7.93 (d, IH), 7.78 (s, IH), 4.47 (m, IH), 4.29 (m, IH), 3.72 (s, 3H), 2.98 (m, 2H), 2.82 (s, 3H), 2.01-2.29 (m, 4H), 1.28 (m, 2H), 1.08 (m, 2H).
Example 78 l-cyclopropyl-7-((5E/Z)-5-(ethoxyimino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)- methoxy-4-oxo- 1 ,4-dihvdro-3-quinolinecarboxylic acid
Figure imgf000125_0002
Example 78A The desired product was prepared by substituting example 76B for example 41C in example 61 A.
Figure imgf000126_0001
Example 78B The desired product was prepared by substituting example 78A for example 48D, ethoxyamine hydrochloride for hydroxylamine hydrochloride, and a reaction time of 17 h at room temperature for 24 h at 75°C in example 61A.
Example 78C l-cvclopropyl-7-((5E/Z)-5-(ethoxyimino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolιnecarboxylic acid The desired product was prepared by substituting example 78B for example 2A in example 2B.
MS (ESI) m/z 453 (M+H)+;
Η NMR (300 MHz, DMSO-rf6) δ 8.79 (s, IH), 8.11 (d, IH), 7.98 (d, IH), 7.52 (s, IH), 4.25 (m, IH), 4.07 (q, 2H), 3.69 (s, 3H), 3.63 (m, 2H), 2.96 (m, 2H), 2.81 (m, IH), 2.61 (m, IH), 1.22 (t, 3H), 1.04 (m, 2H), 0.86 (m, 2H).
Example 79 7-((5E/Z)-5-((benzyloxy)imino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid
Figure imgf000126_0002
Example 79A The desired product was prepared by substituting example 78A for example 48D, O-benzylhydroxylamine hydrochloride for hydroxylamine hydrochloride, and a reaction time of 17 h at room temperature for 24 h at 75°C in example 61A.
Example 79B 7-((5E/Z)-5-((benzyloxy)ιmιno)-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dιhydro-3-quιnolιnecarboxylιc acid The desired product was prepared by substituting example 79A for example 2A in example 2B. MS (ESI) m/z 515 (M+H)+;
Η NMR (300 MHz, DMSO-rf6) δ 8.79 (s, IH), 8.1 1 (d, IH), 7.97 (d, IH), 7.66 (s, IH), 7.37 (m, 5H), 5.10 (s, 2H), 4.26 (m, IH), 3.78 (m, 2H), 3.68 (s, 3H), 3.46 (m, IH), 2.98 (M, 2H), 2.66 (M, IH), 1.16 (m, 2H), 1.04 (M, 2H).
Example 80 7-((4E/Z)-4-((amιnocarbonyl)hvdrazono)-4,5,6,7-tetrahvdro-l-benzothιen-2-yI)l- cvclopropyl-8-methoxy-4-oxo-l,4-dιhvdro-3-quιnolmecarboxylιc acid The desired product was prepared by substituting semicarbazide hydrochloπde and a reaction time of 48 hours for 1-amιnopyrrohdιne hydrochloπde and a reaction time of 24 hours in example 74. mp 243-244° C; MS (APCI) m/z 467 (M+H)+;
Η NMR (300 MHz, OMSO-d6) δ 9.28 (br s, IH), 8.80 (s, IH), 8.40 (s, IH), 8.23 (d, IH), 8 13 (d, IH), 7.30 (br s, 2H), 6.60 (br s, IH), 4.26 (m, IH), 3.71 (s, 3H), 2.89 (dd, 2H), 2 57 (dd, 2H), 1.95 (m, 2H), 1.20 (m, 2H), 1.03 (m, 2H).
Example 83 l-cyclopropyl-7-(4-(dιmethylamιno)-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-8-methoxy-4- oxo-l,4-dιhydro-3-quιnolιnecarboxylιc acid hydrochlonde
Figure imgf000127_0001
Example 83A The desired product was prepared by substituting example 40A for example 40B in example 40C and the crude reaction mixture partitioned between water and dichloromethane. The aqueous layer was adjusted to pH 9 with sodium hydroxide, extracted with dichloromethane, dried (Na2SO ), filtered, and concentrated to give a yellow solid that was used without further purification
Figure imgf000128_0001
Example 83B A solution of Example 83A (0.24 g, 0.55 mmol) in tetrahydrofuran (2 mL) was added to a cooled solution (-70°C) of 1.0M sodium bis(tirmethylsilyl)amide (1.37 mL, 1.38 mmol) and stirred for 2 hours. Iodomethane (0.14 g, 2.20 mmol) was added and the mixture was warmed to room temperature and stired for 3 hours. The reaction mixture was partitioned between 10% NFI CI and dichloromethane, dried (Na2SO4), concentrated, and purified by silica gel column eluting with a gradient of 1% to 6% methanol in dichloromethane to yield (0.055g, 22%) of the desired product.
Example 83C l-cvclopropyl-7-(4-(dimethylamino)-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-8-methoxy-4- oxo-l,4-dihydro-3-quinoIinecarboxylic acid hydrochloride The desired product was prepared by substituting example 83B for example 2A in example 2B followed by treatment with 4M HCI in dioxane and filtration provide the solid product.
MS (DCI/NH3) m/z 439 (M+H)+;
Η NMR (300 MHz, CD3OD) δ 8.97 (s, IH), 8.24 (d, IH), 7.93 (d, IH), 7.81 (, IH), 4.74 (m, IH), 4.29 (m, IH), 3.72 (s, 3H), 2.97 (m, 2H), 2.92 (d, 3H), 2.17 ( , 2H), 1.99 (m, 2H), 1.28 (m, 2H), 1.08 (m, 2H).
Example 84 7-((4E/Z)-4-r(aminocarbothioyl)hydrazono)-4, 5 ,6,7-tetrahydro- 1 -benzothien-2-yl)- 1 - cvclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid
The desired product was prepared by substituting thiosemicarbazide and a for 1- aminopyrrolidine hydrochloride and a reaction time of 24 hours in example 331536 and was purified by silica gel chromatography eluting with 3.5 % MeOH in dichloromethane. mp 235-236° C; MS (APCI) m/z 481 (M-H)", 483 (M+H)+;
Η NMR (300 MHz, OMSO-d6) δ 8.70 (s, IH), 8.50 (s, IH), 8.32 (d, IH), 8.12 (d, IH), 4.28 (m, IH), 3.72 (s, 3H), 3.30 (m, 4H), 2.91 (dd, 2H), 2.69 (dd, 2H), 1.96 (dd, 2H), 1.20 (m, 2H), 1.07 (m, 2H). Example 85 l-cvclopropyl-8-methoxy-7-((4E/Z)-4-(((methylamino)carbothioyl)hydrazono)-4, 5,6,7- tetrahvdro-l-benzothien-2-yl)-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid The desired product was prepared by substituting 4-methyl-3-thiosemicarbazide, a reaction time of 48 hours and a reaction temperature of 100° C for 1-aminopyrrolidine hydrochloride, a reaction time of 24 hours and a reaction temperature of 75° C in example 331536. mp 272-273° C; MS (APCI) m/z 495 (M-H)", 497 (M+H)+;
1H NMR (300 MHz, OMSO-d6) δ 8,80 (s, IH), 8.53 (d, IH), 8.40 (s, IH), 8.16 (d, IH), 4.25 (m, IH), 3.72 (s, 3H), 3.30 (m, 3H), 3.08 (d, 3H), 2.90 (dd, 2H), 2.68 (dd, 2H), 1.97 (dd, 2H), 1.20 (m, 2H), 1.08 (m, 2H).
Example 86 l-cvclopropyl-8-methoxy-7-(5-methylene-4-oxo-4,5,6,7-tetrahydro-l-benzothien-2-yl)-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid
Example 86A ethyl l-cyclopropyl-8-methoxy-7-(5-methylene-4-oxo-4,5,6,7-tetrahvdro-l-benzothien-2- yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylate
A mechanically stirred solution of dimethylamine hydrochloride (3.70 g, 0.045 mol), paraformaldehyde (1.30 g, 0.045 mol), and 10 mL cone. HCI in (4:1) DME:dichloroethane. (125 mL) was heat to 90°C for 10 minutes, treated dropwise with a solution of example 50A (1.0 g, 0.0023 mol) in DME (35 mL) and heated to 110-125°C for 4.5 hour. The reaction mixture was cooled, filtered, and the filtrate concentrated. The residue was dissolved in CH2C1 , washed with sat. NaHCO3, brine, and dried (Na2SO ). The concentrated residue was triturated in ethyl ether and filtered to give the desired product as a yellow solid (0.72 g, 70 %).
Example 86B l-cyclopropyl-8-methoxy-7-(5-methylene-4-oxo-4,5,6,7-tetrahydro-l-benzothien-2-yl)-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting example 86A for example 2A in example 2B.
MS (APCI) m/z 421 (M+H)+
Η NMR (300 MHz, CDC13) δ 14.6 (s, IH), 8.92 (s, IH), 8.28 (d, IH), 8.02 (s, IH), 7.80 (d, IH), 6.23 (s, IH), 5.52 (s, IH), 4.10 (m.lH), 3.68 (s, 3H), 3.17 (t, 2H), 3.02 (t, 2H), 1.30 (d, 2H), 1.06 (s, 2H).
Example 88 l-cyclopropyI-8-methoxy-7-(4-((methylsulfonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-
2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid A solution of example 83 A (0.065 g, 0.148 mmol) in CH2C12 (5 ml) was cooled to 0 °C, treated with diisopropylethylamine (0.029 g, 0.222 mmol) followed by methanesulfonyl chloride (0.022 g, 0.192 mmol) and stirred for 2 hours. The reaction mixture was partitioned between brine and CH2C12, the layers separated and the aqueous layer extracted with CH2C12. The combined organic phases were washed with brine and concentrated. The resulting residue was dissolved in 4:1 THF:water (5 ml), treated with LiOH-H2O (0.031 g, 0.740 mmol) and stirred at room temperature for 2 hours. The mixture was diluted with saturated aqueous NH4C1, brought to pH 5-6 with 10 % H3PO4 and extracted several times with ethyl acetate. The combined organic phases were washed with brine, dried (Na2SO4), concentrated and the residue triturated in 25 % acetone in hexanes. Filtration gave the desired product as a tan solid (0.031 g, 43%). MS (DCI/NH3) m/z 489 (M+H)+; 1H NMR (300 MHz, DMSO-J6) δ 8.79 (s, IH), 8.14 (d, IH), 7.98 (d, IH), 7.69 (s, IH), 7.51 (d, IH), 4.49 (m, IH), 4.25 (m, IH), 3.69 (s, 3H), 3.08 (s, 3H), 2.77 (m, 2H), 2.10- 1.98 (m, 2H), 1.87-1.74 (m, 2H), 1.15 (m, 2H), 1.04 (m, 2H).
Example 89 l-cvclopropyl-8-methoxy-4-oxo-7-(4-(lH-pyrrol-l-yl)-4,5,6,7-tetrahydro-l-benzothien-2- yl)-l,4-dihvdro-3-quinolinecarboxylic acid A solution of example 40 (0.07g, 0.16 mmol), sodium acetate (0.07g, 0.94 mmol) and 2,5-dimethoxytetrahydrofuran (0.22 mL, 1.56 mmol) in acetic acid (1 mL) was heated at 80°C for 2 hours. The reaction mixture was diluted with water (30 mL), filtered, and oven dried to yield (0.07g, 97%) of the desired compound. MS (DCI/NH3) m/z 461 (M+H)+;
Η NMR (300 MHz, CD3OD) δ 8.93 (s, IH), 8.15 (d, IH), 7.78 (d, IH), 7.23 (s, IH), 6.72 (m, 2H), 6.09 (m, 2H), 5.33 (m, IH), 4.26 (m, IH), 3.65 (s, 3H), 2.95 (m, 2H), 2.25 (m, 2H), 2.04 (m, 2H), 1.24 (m, 2H), 1.05 (m, 2H).
Example 90 l-cvclopropyl-7-((4E/Z)-4-(((ethylamino)carbothioyl)hvdrazono)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-8-methoxy-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid
The desired product was prepared by substituting 4-ethyl-3-thiocarbazide, a reaction time of 48 hours and a reaction temperature of 100° C for 1-aminopyrrolidine hydrochloride, a reaction time of 24 hours and a reaction temperature of 75° C in example 74. mp 265-266° C;
MS (APCI) m/z 511 (M+H)+;
Η NMR (300 MHz, OMSO-d6) δ 14.90 (s, IH), 10.15 (s, IH), 8.80 (s, IH), 8.57 (dd, IH), 8.48 (s, IH), 8.15 (dd, IH), 4.26 (m, IH), 3.71 (s, 3H), 3.65 (q, 2H), 3.40 (s, IH), 2.90 (dd, 2H), 2.70 (dd, 2H), 2.03 (dd, 2H), 1.18 (m, 2H), 1.16 (t, 3H), 1.06 (m, 2H).
Example 91 7-((4E/Z)-4-((amino(oxo)acetyl)hydrazono)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cycIopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting oxamic hydrazide, a reaction time of 18 hours and a reaction temperature of 100° C in the absence of Et3N for 1- aminopyrrolidine hydrochloride, a reaction time of 24 hours and a reaction temperature of 75° C in example 74. mp 298-300° C; MS (APCI) m/z 493 (M-H)", 495 (M+H)+;
1H NMR (300 MHz, DMSO-*) δ 8.70 (s, IH), 8.29 (br s, 2H), 8.13 (d, IH), 8.05 (d, IH), 8.01 (s, IH), 7.96 (br s, 2H), 4.26 (m, IH), 3.70 (s, 3H), 3.35 (s, IH), 3.00 (dd, 2H), 2.71 (dd, 2H), 1.18 (m, 2H), 1.08 (m, 2H).
Example 92 l-cvclopropyl-8-methoxy-7-((4E/Z)-4-((4-methyl-l-piperazinyl)imino)-4,5,6,7-tetrahydro- l-benzothien-2-yl)-4-oxo-L4-dihvdro-3-quinolinecarboxylic acid
Example 92A
A solution of example 50A (0.065g, 0.15 mmol) and l-amino-4-methylpiperazine (0.13g, 1.2 mmol) in absolute ethanol (15 mL) was refluxed over 4A molecular sieves for 48 hour. The reaction mixture was concentrated and the residue purified by silica gel chromatography eluting with a gradient from CH2Cl2:CH3OH (98:2) to CH2Cl2:CH3OH (88:12) to provide the desired product (0.05 g, 63 %).
Figure imgf000132_0001
Example 92B l-cvclopropyl-8-methoxy-7-((4E/Z)-4-((4-methyl-l-piperazinyl)imino)-4,5,6,7-tetrahydro- l-benzothien-2-yl)-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid
A solution of example 92A (0.20 g, 0.35 mmol) in of 3:1 THF:H2O (10 mL) was treated with LiOH-H2O (0.028 g, 0.070 mmol) and stirred overnight at room temperature. The reaction mixture was brought to pH ~ 5 with 10% HCI, was extracted with ethyl acetate, and the combined organic phases washed with brine, dried (Na2SO ) and concentrated to give the desired product (0.013 g, 68 %).
MS (APCI) m/z 507 (M+H)+
Η NMR (300 MHz, CDC13), δ 8.85 (s, IH) 8.18(d, IH), 7.91 (s, IH), 7.86 (d, IH), 4.06 (m, IH), 3.61 (s, 3H), 2.91-2.84 (m, 5H), 2.74-2.60 (m, 5H), 2.56 (m, 2H), 2.0 (t, 2H), 1.21 (d, 2H), 1.15 (s, 3H), 1.02 (s, 2H).
Example 94 l-cvclopropyl-8-methoxy-4-oxo-7-(4-((3-pyridinylmethyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-l,4-dihvdro-3-quinolinecarboxylic acid dihydrochloride
Figure imgf000133_0001
Example 94A A solution of example 83A (0.12g, 0.27 mmol) in dichloromethane (5 mL) was treated with acetic acid (1 drop), 3-pyridine carboxaldehyde (0.039 mL, 0.41 mmol), and sodium cyanoborohydride (0.021g, 0.32 mmol) and stirred at room temperature for 2 hours. The reaction mixture was partitioned between 10% sodium bicarbonate solution and dichloromethane, dried (Na2SO4), concentrated and the residue purified by silica gel chromatography eluting with a gradient of 1% to 4% methanol in dichloromethane to yield (0.09g, 62%) of the desired compound.
Example 94B l-cvclopropyl-8-methoxy-4-oxo-7-(4-((3-pyridinylmethyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid di hydrochloride The desired product was prepared by substituting example 94A for example 2A in example 2B followed by treatment with 4M HCI in dioxane and filtration of the solid product.
MS (DCI/NH3) m/z 502 (M+H)+;
Η NMR (300 MHz, CDC13) δ 8.90 (s, IH), 8.67 (m, IH), 8.53 (m, IH), 8.23 (d, IH), 7.88 (d, IH), 7.57 (s, IH), 6.58 (m, IH), 4.11 (m, IH), 3.96 (d, 2H), 3.87 (m, IH), 3.66 (s, 3H0, 2.85 (m, 2H), 2.07 (m, 2H), 1.85 (m, 2H), 1.28 (m, 2H), 1.05 (m, 2H).
Example 96 7-((4E/Z)-4-(acetylhydrazono)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyI-8- methoxy-4-oxo- 1 ,4-dihvdro-3-quinolinecarboxylic acid
The desired product was prepared by substituting acetic hydrazide, a reaction time of 60 hours and a reaction temperature of 100° C in the absence of Et3N for 1- aminopyrrolidine hydrochloride, a reaction time of 24 hours and a reaction temperature of 75° C in example 74. mp 281-282° C;
MS (APCI) m/z 466 (M+H)+;
Η NMR (300 MHz, DMSO-J6) δ 8.80 (s, IH), 8.14 (d, IH), 8.00 (s, IH), 7.95 (br s, IH), 4.27 (m, IH), 3.70 (s, 3H), 3.30 (s, IH), 2.90 (m, 2H), 2.61 (m, 2H), 2.25 (s, 3H), 2.00 (m, 2H), 1.16 (m, 2H), 1.07 (m, 2H). Example 97 7-(4-(benzylamino)-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4- oxo-l,4-dihvdro-3-quinolinecarboxylic acid hydrochloride
Figure imgf000134_0001
Example 97A The desired product was prepared by substituting example 83A and benzaldehyde for example 83A and 3-pyridine carboxaldehyde, respectively in example 94A.
Example 97B 7-(4-(benzylamino)-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride The desired product was prepared by substituting example 97A for example 94A in example 94B
MS (DCI/NH3) m/z 501 (M+H)+;
Η NMR (300 MHz, DMSO-*) δ 8.80 (s, IH), 8.17 (d, IH), 8.13 (s, IH), 7.97 (d, IH), 7.65 (m, 2H), 7.44 (m, 3H), 4.51 (m, IH), 4.26 (m, 3H), 3.70 (s, 3H), 2.89 (m, 2H), 2.15 (m, 2H), 1.86 (m, 2H), 1.17 (m, 2H), 1.04 (m, 2H).
Example 98 l-cyclopropyl-7-(4-(ethvIamino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8-methoxy-4-oxo- L4-dihvdro-3-quinolinecarboxylic acid hydrochloride
Figure imgf000134_0002
Example 98 A The desired product was prepared by substituting iodoethane for iodomethane in example 77A.
Figure imgf000135_0001
Example 98B The desired product was prepared by substituting example 98A for example 2A in example 2B.
Example 98C l-cvclopropyl-7-(4-(ethylamino)-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-8-methoxy-4-oxo- l,4-dihydro-3-quinolinecarboxylic acid hydrochloride The desired product was prepared by substituting example 98B for example 40B in example 40C.
MS (DCI/NH3) m/z 439 (M+H)+;
Η NMR (300 MHz, CD3OD) δ 8.98 (s, IH), 8.24 (d, IH), 7.95 (d, IH), 7.81 (s, IH), 4.52 (m, IH), 4.30 (m, IH), 3.72 (s, 3H), 3.26 (m, 2H), 2.98 (m, 2H), 2.00-2.24 (m, 4H), 1.40 (t, 3H), 1.28 (m, 2H), 1.08 (m, 2H).
Example 99 l-cyclopropyl-8-(difluoromethoxy)-7-(4-hydroxy-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-4- oxo-l,4-dihydro-3-quinoIinecarboxylic acid
Figure imgf000135_0002
Example 99A A solution of ethyl l-cyclopropyl-7-bromo-8-difluoromethoxy-4-oxo-l,4- dihydroquinoline-3-carboxylate (1.50 g, 3.73 mmol) and example 38B (3.12 g, 5.59 mmol) in toluene (40 ml) was treated with PdC12(PPh3)2 (0.261 g, 0.373 mmol) and heated at 90 oC for 10 hours. The reaction mixture was allowed to cool, was poured into a mixture of 200 ml ethyl acetate and 300 ml saturated KF solution and stirred vigorously for 30 min. The biphasic mixture was filered through celite, the layers separated, the aqueous layer extracted with ethyl acetate, the compined organic phases washed with brine, dried (MgSO4). Concentration gave a residue that was passed through a plug of silica gel eluting with 25% acetone in hexanes and the filtrate and concentrated to give a mixture of carboxylate acid and ethyl ester.
A solution of this mixture in 1:1 MeOH:THF (30 ml) was treated with trimethylsilyldiazomethane (9.3 ml of a 2M solution in hexanes, 18.6 mmol)) and stirred at room temperature for 72 hours. The reaction mixture was partitioned between ethyl acetate and saturated NH4C1 solution, the organic phase washed with brine, dried (MgSO4) and concentrated to give the crude methyl ester as a yellow solid (1.80 g).
A solution of the crude product in THF (50 ml) was cooled to OoC, treated with TBAF (11.1 ml of a IM solution in THF, 11.1 mmol) and stirred for 2.5 hours. The reaction mixture was partitioned between ethyl acetate and saturated NH4C1 solution, the organic phase washed with brine, dried (MgSO4) and concentrated. The crude residue was purified by silica gel chromatography eluting with a gradient from 30% to 50% acetone in hexanes to give the desired product (0.83 g, 48%) as a yellow foam.
Example 99B l-cyclopropyl-8-(difluoromethoxy)-7-(4-hydroxy-4,5,6,7-tetrahydro-l-benzothien-2-yl)-4- oxo-l,4-dihvdro-3-quinolinecarboxylic acid The desired product was prepared by substituting example 99A for example 2A in example 2B. The crude residue was triturated in 33% acetone in hexanes, filtered and washed with hexanes to give a yellow solid.
MS (APCI) m/z 482 (M+H)+;
1H NMR (300 MHz, DMSO-*) δ 14.67 (s, IH), 8.85 (s, IH), 8.27 (d, IH), 7.95 (d, IH),
7.69 (s, IH), 6.94 (t, IH), 5.19 (d, IH), 4.62 (m, IH), 4.15 (m, IH), 2.85-2.65 (m, 2H),
2.05-1.86 (m, 2H), 1.83-1.61 (m, 2H), 1.20 (m, 2H), 1.03 (m, 2H).
Example 100 l-cyclopropyl-7-((4E/Z)-4-(4,5-dihydro-lH-imidazol-2-ylhydrazono)-4,5,6,7-tetrahydro-l- benzothien-2-v])-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting 2-hydrazino-2-imidazoline hyrdobromide, NaOAc and a reaction time of 48 hours for 1-aminopyrrolidine hydrochloride, Et3N and a reaction time of 24 hours in example 74. mp 237-238° C;
MS (APCI) m/z 492 (M+Η)+; Η NMR (300 MHz, DMSO-*) δ 9.25 (br s, IH), 8.81 (s, 0.5H), 8.80 (s, 0.5H), 8.32 (s,
IH), 8.15 (d, 0.5H), 8.10 (d, 0.5H), 8.07 (d, 0.5H), 8.02 (d, 0.5H), 4.27 (m, IH), 3.70 (d, 3H), 3.60 (m, 2H), 3.40 (m, 2H), 3.30 (s, IH), 2.95 (dd, IH), 2.90 (dd, IH), 2.55 (dd, IH), 2.00 (m, 2H), 1.28 (m, 2H), 1.04 (m, 2H).
Example 101
7-(4-amino-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8-(difluoromethoxy)-4- oxo-l,4-dihvdro-3-quinolinecarboxylic acid hydrochloride
Figure imgf000137_0001
Example 101A
The desired product was prepared by substituting example 99A for example 37A in example 37B and the crude product purified by silica gel chromatography eluting with a gradient from 25% to 50% acetone in hexanes.
Figure imgf000137_0002
Example 10 IB The desired product was prepared by substituting example 101A for example 201C in example 201C and the crude product triturated in hot 25% acetone in hexanes and filtered.
Figure imgf000137_0003
Example 101C
The desired product was prepared by substituting example 101B for example 2A in example 2B.
Example 101D
7-(4-amino-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8-(difluoromethoxy)-4- oxo-l,4-dihydro-3-quinolinecarboxyιic acid hydrochloride The desired product was prepared by substituting example 101C for example 40B in example 40C. MS (APCI) m/z 481 (M+Cl)";
Η NMR (300 MHz, DMSO-*) δ 8.87 (s, IH), 8.52 (br s, 3H), 8.34 (d, IH), 8.01 (s, IH), 7.88 (d, IH), 7.02 (t, IH), 4.42 (m, IH), 4.15 (m, IH), 2.86 (m, 2H), 2.09-1.97 (m, 2H), 1.93-1.77 (m, 2H), 1.20 (m, 2H), 1.04 (m, 2H).
Example 102 l-cvclopropyl-7-(4-hydroxy-2-methyl-l,l-dioxido-3,4-dihvdro-2H-thienor3,2- el T 1 ,21thiazin-6-yl)-8-methoxy-4-oxo- 1 ,4-dihvdro-3-quinolinecarboxylic acid
Figure imgf000138_0001
Example 102A
The desired product was prepared by substituting 4-Ηydroxy-3,4-dihydro-2- methyl-2H-thieno[3,2-e]l,2-thiazine 1,1-dioxide (prepared by the method of DuPriest, et.al. J. Org. Chem. 1997, 62, 9372-75) for the intermediate alcohol in example 218B.
Figure imgf000138_0002
Example 102B A solution of diisopropyl amine (0.412 g, 4.08 mmol) in THF (50 mL) was cooled to 0 °C, treated dropwise with rc-BuLi (1.5 mL of a 2.5 M solution in hexanes, 3.75 mmol), stirred for 30 minutes and cooled to -50 °C. This solution was treated dropwise with a solution of example 102A (0.543 g, 1.63 mmol) in THF (10 mL), stirred for 1 hour at 0 °C, recooled to -50 °C, treated with chlorotributylstannane (0.584 g, 1.79 mmol) and allowed to warm to room temperature overnight. The reaction mixture was partitioned between water and ethyl acetate, the aqueous phase extracted with ethyl acetate, the combined organic phases washed with water, brine, dried (Na SO4) and concentrated to provide the desired product that was used without purification.
Figure imgf000138_0003
Example 102C A solution of example 102B (0.37 g, 0.60 mmol), ethyl 7-bromo-l-cyclopropyl-8- methoxy-4-oxo-l ,4-dihydro-3-quinolinecarboxylate (0.220 g, 0.60 mmol) and PdC12(PPh3)2 (0.042 g, 0.06 mmol) in toluene (2 ml) was heated to 85 oC for 6 hours. The reaction mixture was allowed to cool, concentrated, suspended in ethyl acetate and filtered. The filtrate was concentrated and purified by silica gel chromatography eluting with 20% acetone in hexanes to give the desired product (0.173 g, 47%) as a colorless solid.
Figure imgf000139_0001
Example 102D The desired product was prepared by substituting example 102C for example 35D in example 35E and the crude residue purified by silica gel chromatography eluting with 30% then 50% acetone in hexanes.
Example 102E l-cvclopropyl-7-(4-hvdroxy-2-methyl-l,l-dioxido-3,4-dihydro-2H-thienor3,2- el T 1 ,21thiazin-6-yl)-8-methoxy-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting example 102D for example 48C in example 48D. MS (DCI/NΗ3) m/z 477 (M+H)+; Η NMR (300 MHz, DMSO-*) δ 14.77(s, IH), 8.83 (s, IH), 8.20 (d, IH), 8.14 (d, IH), 7.97 (s, IH), 6.05 (d, IH), 4.92 (q, IH), 4.27 (m, IH), 3.94 (dd, IH), 3.77 (s, 3H), 3.73 (dd, IH), 2.97 (s, 3H), 1.18 (m, 2H), 1.05 (m, 2H).
Example 104
1 -cyclopropyl -7-(4-((3-fluorobenzyl)amino)-4, 5, 6,7-tetrahydro-l -benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride
Figure imgf000139_0002
Example 104 A
The desired product was prepared by substituting example 3-fluorobenzaldehyde for 3-pyridine carboxaldehyde in example 94.
Figure imgf000140_0001
Example 104B l-cyclopropyI-7-(4-((3-fluorobenzyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihvdro-3-quinoIinecarboxylic acid hydrochloride The desired product was prepared by substituting example 104A for example 94A in example 94B.
MS (DCI/NH3) m/z 519 (M+H)+;
1HNMR (300MHz, CD3OD) δ 8.97 (s, IH), 8.23 (d, IH), 7.93 (d, IH), 7.85 (s, IH), 7.51 (m, IH), 7.48 (m, 2H), 7.22 (m, IH), 467 (m, IH), 4.43 (m, 2H), 4.29 (m, IH), 3.72 (s, 3H), 3.01 (m,2H), 2.00-2.32 (m, 4H), 1.28 (m, 2H), 1.08 (m, 2H).
Example 105 7-((4E/Z)-4-[(aminocarbothioyl)(methyl)hvdrazono)-4,5,6,7-tetrahydro-l-benzothien-2- yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid
The desired product was prepared by substituting 2-methylthiocarbazide, a reaction time of 60 hours and a reaction temperature of 100° C for 1-aminopyrrolidine hydrochloride, a reaction time of 24 hours and a reaction temperature of 75° C in example 74. mp 176-178° C;
MS (APCI) m/z 497 (M+H)+;
1H NMR (300 MHz, DMSO-*) δ 8.65 (s, IH), 8.25 (d, IH), 7.90 (s, IH), 7.62 (d, IH), 4.26 (m, IH), 4.00 (s, 2H), 3.70 (s, 3H), 3.30 (s, IH), 3.00 (dd, 2H), 2.62 (dd, 2H), 2.00 (m, 2H), 1.40 (s, 3H), 1.18 (m, 2H), 1.03 (m, 2H).
Example 106 l-cvclopropyl-8-methoxy-7-(5-methyl-4-oxo-4,5,6,7-tetrahydro-l-benzothien-2-yl)-4-oxo- l,4-dihydro-3-quinolinecarboxylic acid
Figure imgf000141_0001
Example 106 A
A solution of example 86A (0.50 g, 0.0011 mol) in ethanol (80 mL) in a Paar apparatus was treated with 10 % Pd/C (0.050 g, 10 wt%), pressurized to 60 psi and heated to 65°C. When the reaction was determined complete based upon H2 consumption, the mixture was allowed to cool, was filtered through celite and concentrated to give the desired product (0.50 g, 92 %) as a solid which was used without further purification.
Example 106B l-cvclopropyI-8-methoxy-7-(5-methyl-4-oxo-4,5,6,7-tetrahydro-l-benzothien-2-yI)-4-oxo-
1 ,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting example 106A for example 2A in example 2B to give the desired product.
MS (APCI) m/z 424 (M+H)
1H NMR (300 MHz, CDC13) δ 14.66 (s, IH), 8.93 (s, IH), 8.29 (d, IH), 7.94 (s, IH), 7.79 (d, IH), 4.11 (m, IH), 3.68 (s, 3H), 3.18-3.12 (m, 2H), 2.63 (m, IH), 2.39-2.28 (m, IH), 2.05 (m, IH), 1.31 (d, 3H), 1.08 (s, 2H), 0.86 (s, 2H).
Example 107 l-cyclopropyl-8-(difluoromethoxy)-7-(4-(methylamino)-4,5,6,7-tetrahvdro-l-benzothien- 2-yl)-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid hydrochloride
Figure imgf000141_0002
Example 107 A
The desired product was prepared by substituting Example 210B and ethyl 7- bromo-l-cyclopropyl-8-difluoromethoxy-4-oxo-l ,4-dihydro-3-quinolinecarboxylate and a reaction time of 3 hours for example ID, ethyl 7-bromo-l-cyclopropyl-4-oxo-l,4-dihydro- 3-quinolinecarboxylate and a reaction time of 24 hours in example IE.
Figure imgf000142_0001
Example 107B The desired product was prepared by substituting example 107A for example 2A in example 2B.
Figure imgf000142_0002
Example 107C l-cvclopropyl-8-(difluoromethoxy)-7-(4-(methyIamino)-4,5,6,7-tetrahvdro-l-benzothien- 2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride
The desired product was prepared by substituting example 107B for example 40B in example 40C.
MS (DCI/NH3) m/z 461 (M+H)+;
1H NMR (300 MHz, CD3OD) δ 8.98 (s, IH), 8.40 (d, IH), 7.87 (d, IH), 7.72 (s, IH), 6.62 (t, IH), 4.45 (m, IH), 4.26 (m, IH), 2.99 (m, 2H), 2.80 (s, 3H), 2.00-2,27 (m, 4H), 1.32 (m, 2H), 1.07 (m, 2H).
Example 108 l-cyclopropyl-6-fluoro-7-(4-(methylamino)-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-4-oxo- l,4-dihvdro|T,81naphthyridine-3-carboxylic acid hydrochloride
Figure imgf000142_0003
Example 108 A The desired product was prepared by substituting Example 210B, ethyl 1- cyclopropyl-7-chloro-4-oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylate and a reaction time of 3 hours for example ID, ethyl 7-bromo- l-cyclopropyl-4-oxo-l,4-dihydro-3- quinolinecarboxylate and a reaction time of 24 hours in example IE.
Figure imgf000143_0001
Example 108B The desired product was prepared by substituting example 108A for example 2A in example 2B.
Figure imgf000143_0002
Example 108C l-cvclopropyl-6-fluoro-7-(4-(methylamino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-4-oxo- l,4-dιhydrori,81naphthyridine-3-carboxylic acid hydrochloride The desired product was prepared by substituting example 108B for example 40B in example 40C.
MS (DCI/NH3) m/z 414 (M+H)+;
Η NMR (300 MHz, CD3OD) δ 8.96 (s, IH), 8.49 (d, IH), 8.13 (s, IH), 4.50 (m, IH), 3.87 (m, IH), 3.02 (m, 2H), 2.82 (s, 3H), 1.98-2.30 (m, 4H), 1.41 (m, 2H), 1.20 (m, 2H).
Example 109 7-(4-amino-2-meth yl- 1 , 1 -dioxido-3 ,4-dihvdro-2H-thienor3,2-el \ 1 ,21thiazιn-6-vD- 1 - cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride
Figure imgf000143_0003
Example 109 A The desired product was prepared by substituting example 102D for example 206E in example 206F and the crude residue purified by silica gel chromatography eluting with 30% then 50% acetone in hexanes.
Figure imgf000143_0004
The desired product was prepared by substituting example 109A for example 201C in example 201C and the crude residue purified by Silica gel chromatography eluting with 30% acetone in hexanes.
Example 109C
7-(4-amino-2-methyl- 1 , 1 -dioxido-3 ,4-dih vdro-2H-thienor3 ,2-el f 1.21 thiazin-6- yl)- 1 - cyclopropyl-8-methoxy-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid hydrochloride The desired product was prepared by substituting example 109B for example 48C in example 48D. MS (DCI/NΗ3) m/z 476 (M+H)+;
Η NMR (300 MHz, DMSO-*) δ 8.85(s, IH), 8.35 (s, IH), 8.29 (d, IH), 7.95 (m, IH), 4.96 (dd, IH), 4.28 (m, IH), 4.03 (m, 2H), 3.79 s, 3H), 2.97 (s, 3H), 1.18 (m, 2H), 1.04 (m, 2H).
Example 110
1 -cyclopropyl -7-(4-(hydroxymethyl)-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-8-methoxy-4- oxo-l,4-dihvdro-3-quinolinecarboxylic acid
Figure imgf000144_0001
Example 110A To a stirring suspension of (methoxymethyl)triphenylphosphonium chloride (26.105 g, 76.15 mmol) in diethyl ether at 0° was added phenyl lithium (76.15 mmol) dropwise from an addition funnel over 15 minutes. The resulting orange suspension was stirred at 0° for 1 hour before cooling to -78° and adding a solution of the 4-keto-4,5,6,7- tetrahydrothianaphthene ( 11.04 g, 72.53 mmol) in diethyl ether dropwise over 35 minutes. The reaction mixture was stirred overnight while gradually warming to room temperature. The reaction was quenched with water and extracted into 3x CH C12, the combined organic layers dried (Na2SO4), concentrated to give a colorless oil (12.36 g, 95% yield) as a mixture of geometric isomers.
Figure imgf000145_0001
Example HOB A solution of example 110A (6.02 g, 33.40 mmol) in formic acid (100 mL) was stirred at room temperature for 3.5 hours. The reaction mixture was poured over sat. NaHCO3, neutralized by the addition of solid NaHCO3 , partitioned with CH2C12 and the organic phase dried (MgSO4). Concentration gave an oil that was used without further purification.
Figure imgf000145_0002
Example HOC The desired product was prepared by substituting example HOB for example 218A in example 218B and was purified by silica gel chromatography eluting with hexane to 5% ether in hexane step gradient.
Figure imgf000145_0003
Example HOD The desired product was prepared by substituting example 110C for example 218B in example 218C.
Figure imgf000145_0004
Example HOE The desired product was prepared by substituting example 110D and ethyl 7- bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate for example ID and 7-bromo-l-cyclopropyl-4-oxo-l,4-dihydro-3-quinolinecarboxylate, respectively in example IE.
Figure imgf000146_0001
Example 11 OF The desired product was prepared by substituting example 110E for example 2A in example 2B.
Example HOG l-cvclopropyl-7-(4-(hydroxymethyl)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8-methoxy-4- oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting example 110F for example 35D in example35E and was purified by silica gel chromatography eluting with 20%-50% acetone in hexanes. The resulting yellow solid was dissolved in a minimum of CH C12, triturated with Et2O, filtered, washed with Et2O and dried under vacuum to give a white solid.
MS (DCI/NH3) m/z 426 (M+H)+; 1H-NMR (300 MHz, d6-DMSO) δ 14.05 (s, IH), 8.78 (s, IH), 8.10 (d, IH), 8.00 (d, IH), 4.75 (dd, IH), 4.25 (m, IH), 3.70 (m, IH), 3.67 (s, 3H), 3.49 (m, IH), 2.77 (m, 3H), 1.97- 1.63 (m, 5H), 1.15 (m, 2H), 1.04 (m, 2H).
Example 111 l-cyclopropyl-8-methoxy-4-oxo-7-(4-(l-pyrrolidinylmethyl)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid
Figure imgf000147_0001
Example 111A The desired product was prepared by substituting example HOE for example 35D in example 35E and was used without further purification.
Figure imgf000147_0002
Example 11 IB The desired product was prepared by substituting example 111 A for example 45G in example342124A and was used without further purification.
Example 11 IC l-cyclopropyl-8-methoxy-4-oxo-7-(4-(l-pyrrolidinylmethyl)-4,5,6,7-tetrahvdro-l- benzothien-2-vD-l ,4-dihydro-3 -quinohnecarboxylic acid A solution of example 11 IB (0.050 g, 0.094 mmol), pyrrolidine (85 uL, 0.94 mmol) in THF (2 mL) was heated at 50° overnight in a sealed vial. The reaction mixture was partitioned between ethyl acetate and 1 N HCI and the organic phase was removed. The aqueous phase was adjusted to pH=7.5 with IN NaOH, was extracted with ethyl acetate, the combined organic phases dried (Na2SO4) and concentrated to give the intermediate ester a colorless solid (0.039 g, 82% yield) A solution of the ester above in IN HCI (5 mL) was heated at 80° for 4 hours, cooled to room temperature and concentrated. The residue was triturated in methanol and with diethyl ether, filtered and the solid product washed with diethyl ether and dried under vacuum to give the desired product (0.023 g, 65% yield) as a white solid. MS (DCI/NH- m/z 479 (M+H)+; Η-NMR (300 MHz, d6-DMSO) δ 9.35 (br s, IH), 8.79 (s, IH), 8.13 (d, IH), 7.97 (d, IH), 7.70 (s, IH), 4.25 ( , IH), 3.68 (s, 3H), 3.50-3.00 (m, 10H), 2.80 (m, IH), 2.20-1.70 (m, 6H), 1.15 (m, 2H), 1.03 (m, 2H). Example 112 l-cvclopropyl-8-methoxy-4-oxo-7-(4-((2-pyrrolidinylmethyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid dihydrochloride
Figure imgf000148_0001
Example 112A The desired product was prepared by substituting N-(tert-Butoxycarbonyl)-prolinal for 3-pyridine carboxaldehyde in
Figure imgf000148_0002
Example 112B The desired product was prepared by substituting example 112A for example 2 A in example 2B.
Example 112C l-cvclopropyl-8-methoxy-4-oxo-7-(4-((2-pyrro1idinylmethyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxyIic acid dihydrochloride The desired product was prepared by substituting example 112B for example 40B in example 40C.
MS (DCI/ΝH3) m/z 494 (M+H)+;
Η NMR (300 MHz, CD3OD) δ 8.97 (s, IH), 8.23 (d, IH), 8.08 (s IH), 8.02 (d, IH), 4.67 (m, IH), 4.29 (m, IH), 4.02 (m, IH), 3.72 (s, 3H), 3.61 ( , IH), 3.43 (m, 2H0, 3.32 (m, 2H), 3.00 (m, 2H), 2.40 (m, IH), 2.03-2.28 (m, 6H), 1.93 ( , IH), 1.28 (m, 2H), 1.07 (m, 2H).
Example 113 7-(4-(acetylamino)-4,5,6,7-tetrahydro-l-benzothien-2-vI)-l-cyclopropyI-8-methoxy-4-oxo- l,4-dihydro-3-quinolinecarboxylic acid An Argonaut Quest 210 synthesizer was equipped with 5 ml reaction tubes. One tube was charged with lml of 1: 1 / dichloromethane:dimethylacetamide, N- cyclohexylcarbodiimide, N'-methyl polystyrene HL (NovaBiochem, 200-400 mesh, 2% DVB, 1.52 mmol/g loading) (0.151 g, 0.23 mmol), 1-hydroxybenzotriazole hydrate (0.003 g, 0.019 mmol) and acetic acid (0.01 ml, 0.17 mmol) and the mixture was agitated for 30 min. A solution of Example 83A (0.050 g, 0.114 mmol) in 1ml of 1:1 / dichloromethane:dimethylacetamide was added and the mixture was stirred for 48 h at room temperature. PS-Trisamine resin (Argonaut, 100-200 mesh, 1% DVB, 4.06 mmol/g loading) (0.135 g, 0.55 mmol) was added and the mixture was agitated for 2 h. The mixture was filtered through the Quest reaction tube and the residual resin was washed with dichloromethane (2 x 2 ml). The combined filtrates were concentrated and eluted through an Extract-Clean Silica Tube (Alltech, 2 g, 12 ml) with 2% methanol in dichloromethane. The product fraction was collected, concentrated to a volume of ca. 2 ml and was washed with 2N aqueous sodium hydroxide solution (1 x 2 ml). The layers were separated and the organic layer was evaporated to dryness. The residue was redissolved in 1 : 1 / tetrahydrofuran :methanol (2 ml), 2N aqueous sodium hydroxide solution (0.83 ml, 1.66 mmol) was added and the mixture was shaken at ambient temperature over night. The mixture was neutralized with 4M hydrochloric acid in dioxane and was concentrated to dryness The residue was taken up in 1:1 / dichloromethane:methanol (2 ml), filtered and the filtrate was evaporated to dryness. The residue was purified by preparative reverse phase HPLC (Waters Prep Nova-Pak HR C18 column, 25 x 100 mm, 6 μm, 60 A, 0.01% trifluoroacetic acid in wateπacetonitrile) to give the desired product (0.045 g, 89%) as an off-white solid.
MS (DCI/NH3) m/z 453 (M+H)+;
Η NMR (300 MHz, DMSO dβ) δ 8.78 (s, IH), 8.25 (d, IH), 7.98 (d, IH), 7.56 (s, IH), 4.92 (m, IH), 4.26 (m, IH), 3.68 (s, 3H), 2.78 (m, 2H), 1.94 (m, IH), 1.88 (s, 3H), 1.82 (m, IH), 1.67 (m, 2H), 1.16 (m, 2H), 1.10 (m, 2H).
Example 114 l-cyclopropyl-8-methoxy-4-oxo-7-(4-(propionylamino)-4,5,6,7-tetrahydro-l-benzothien-2- yl)-l,4-dihvdro-3-quinolinecarboxylic acid The desired product was prepared by substituting propionic acid for acetic acid in
Example 113.
MS (DCI/NH3) m/z 467 (M+H)+;
Η NMR (300 MHz, DMS.O-d6) δ 8.78 (s, IH), 8.18 (d, IH), 8.10 (d, IH), 7.95 (d, IH), 7.54 (s, IH), 4.94 (m, IH), 4.25 (m, IH), 3.68 (s, 3H), 2.80 (m, 2H), 2.16 (q, 2H), 1.92 (m, 2H), 1.81 (m, IH), 1.66 (m, IH), 1.15 (m, 2H), 1.05 (t, 2H), 1.04 ( , 3H). Example 115 l-cyclopropyl-8-methoxy-7-(4-((methoxyacetyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2- yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting 2-methoxyacetic acid for acetic acid in Example 113. MS (DCI/NH3) m/z 483 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 8.78 (s, IH), 8.10 (d, IH), 9.06 (d, IH), 7.96 (d, IH), 7.52 (s, IH), 5.02 (m, IH), 4.25 (m, IH), 3.88 (s, 2H), 3.68 (s, 3H), 3.32 (s, 3H), 2.80 (m, 2H), 1.71-2.30 (m, 4H), 1.16 ( , 2H), 1.03 (m, 2H).
Example 116 l-cvclopropyl-8-methoxy-4-oxo-7-(4-((tetrahvdrofuranyl-2-carbonyl)amino)-4, 5,6,7- tetrahvdro-l-benzothien-2-yl)-l,4-dihvdro-3-quinolinecarboxylic acid The desired product was prepared by substituting 2-tetrahydrofuroic acid for acetic acid in Example 113.
MS (DCI/NH3) m/z 509 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 8.78 (s, IH), 8.10 q, IH), 7.94 (d, IH), 4.96 (m, IH), 4.22-4.43 (m, 2H), 3.90 (m, IH), 3.70-3.82 (m, 2H), 3.68 (d, 2H), 3.64 (s, 3H),2.80 (m, 2H), 2.16 (m, IH), 1.25-2.03 (m, 6H), 1.15 (m, 2H), 1.04 (m, 2H).
Example 117 l-cvclopropyl-8-methoxy-4-oxo-7-(4-((tetrahydrofuranyl-3-carbonyl)amino)-4, 5,6,7- tetrahydro-l-benzothien-2-yl)-l,4-dihvdro-3-quinolinecarboxylic acid The desired product was prepared by substituting 3-tetrahydrofuroic acid for acetic acid in Example 1 13. MS (DCI/NH3) m/z 509 (M+H)+;
Η NMR (300 MHz, DMSO-dό) δ 8.79 (s, IH), 8.36 (d, IH), 8.10 (dd, IH), 7.92 (dd, IH), 7.53 (d, IH), 4.96 (m, IH), 4.26 (m, IH), 3.61-3.91 (m, 7H), 2.81 (m, 2H), 1.90-2.13 (m, 3H), 1.84 (m, IH), 1.68 (m, IH), 1.18 (m, 2H), 1.04 (m, 2H).
(346829) Example 1 18 l-cvclopropyl-8-methoxy-7-(4-((4-mo holinylacetyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid
The desired product was prepared by substituting 2-morpholinoacetic acid for acetic acid in Example 1 13. MS (DCI/NH3) m/z 538 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 9.11 (d, IH), 8.79 (s, IH), 8.11 (d, IH), 8.04 (d, IH), 7.64 (s, IH), 5.02 (m, IH), 4.26 (m, IH), 4.04 (s, 2H), 3.86-3.98 (m, 6H), 3.68 (s, 2H), 3.49 (m, 2H), 3.28 (m, 2H), 2.82 (m, 2H), 2.00 (m, 2H), 1.86 (m, IH), 1.74 (m, IH), 1.17 (m, 2H), 1.03 (m, 2H).
Example 119 l-cyclopropyl-8-methoxy-7-(4-((3-(4-moφholinyl)propanoyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid
The desired product was prepared by substituting 3-moφholinopropionic acid for acetic acid in Example 113.
MS (DCI/NH3) m/z 552 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 11.41 (br s, IH), 8.79 (s, IH), 8.59 (d, IH), 8.11 (d, IH), 7.99 d, IH), 7.59 (s, IH), 4.96 (m, IH), 4.25 (m, IH), 3.78-3.99 (m, 4H), 3.68 (s,
3H), 3.48 (m, 4H), 3.08 (m, 2H), 2.79 (m, 2H), 1.94 (m, 2H), 1.84 (m, IH), 1.70 (m, IH),
1.16 (m, 2H), 1.03 (m, 2H).
Example 120 l-cyclopropyl-8-methoxy-4-oxo-7-(4-((lH-pyrrol-2-yIcarbonyl)amino)-4,5,6,7-tetrahydro- l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting pyrrole-2-carboxylic acid for acetic acid in Example 113. MS (DCI/NΗ3) m/z 504 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 11.49 (br s, IH), 8.77 (s, IH), 8.30 (d, IH), 8.08 (d, IH), 7.93 (d, IH), 7.56 (s, IH), 6.87 (m, 2H), 6.07 (m, IH), 5.18 (m, IH), 4.24 (m, IH), 3.68 (s, 3H), 2.82 (m, 2H), 1.75-2.10 (m, 4H), 1.15 (m, 2H), 1.02 (m, 2H).
Example 121 l-cvclopropyl-8-methoxy-4-oxo-7-(4-((3-pyridinylacetyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting 3-pyridyl-acetic acid for acetic acid in Example 113.
MS (DCI/NH3) m/z 530 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.93 (s, IH), 8.8 (d, IH), 8.83 (d, IH), 8.79 (s, IH), 8.59 (d, IH), 8.10 (d, IH), 8.09 (dd, IH), 7.94 (d, IH), 7.54 (s, IH), 4.96 (m, IH), 4.28 (m, IH), 3.88 (d, IH), 3.68 (s, 3H), 2.82 (m, IH), 1.84 (m, 2H), 1.72 (m. IH), 1.17 (m, 2H), 1.02 (m, 2H).
Example 122 l-cvclopropyl-8-methoxy-4-oxo-7-(4-((3-pyridazinylcarbonyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)- 1 ,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting pyridazine-3-carboxylic acid for acetic acid in Example 113.
MS (DCI/NH3) m/z 517 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 9.43 (dd, IH), 9.31 (d, IH), 8.77 (s, IH), 8.31 (dd, IH), 8.05 (d, IH), 7.99 (dd, IH), 7.93 (d, IH), 7.63 (s, IH), 5.28 (m, IH), 4.25 (m, IH), 3.68 (s, 3H), 2.86 (m, 2H), 1.83-2.14 (m, 4H), 1.15 (m, 2H), 1.04 (m, 2H).
Example 123 l-cyclopropyl-7-(4-((lH-imidazol-2-ylcarbonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2- yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting imidazole-2-carboxylic acid for acetic acid in Example 113. MS (DCI/NΗ- m/z 505 (M+Η)+;
Η NMR (300 MHz, DMSO-d6) δ 9.80 (d, IH), 8.78 (s, IH), 8.08 (d, IH), 7.98 (d, IH), 7.80 (s, 2H), 7.70 (s, IH), 5.70 (m, IH), 4.25 (m, IH), 3.69 (s, 3H), 2.85 (m, 2H), 1.84- 2.16 (m, 4H), 1.16 (m, 2H), 1.03 (m, 2H).
Example 124 l-cyclopropyl-8-methoxy-4-oxo-7-(4-((l,3-thiazol-2-ylcarbonyl)amino)-4,5,6,7- tetrahvdro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid
The desired product was prepared by substituting thiazole-2-carboxylic acid for acetic acid in Example 113. MS (DCI/NH3) m/z 522 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 9.01 (d, IH), 8.80 (s, IH), 7.96-8.08 (m, 4H), 7.60 (s, IH), 5.18 (m, IH), 4.24 ( , IH), 3.67 (s, 3H), 2.83 (m, 2H), 1.80-2.15 (m, 4H), 1.17 (m, 2H), 1.02 (m, 2H). Example 125 l-cvclopropyl-8-methoxy-7-(5-(methylamino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-4- oxo-l,4-dihvdro-3-quinolinecarboxylic acid hydrochloride
Figure imgf000153_0001
Example 125 A The desired product was prepared by substituting example 76E for example 40A in example 77A.
Figure imgf000153_0002
Example 125B The desired product was prepared by substituting example 125 A for example 2A in example 2B.
Example 125C l-cyc1opropyl-8-methoxy-7-(5-(methylamino)-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride The desired product was prepared by substituting example 125B for example 40B in example 40C.
MS (DCI/NH3) m/z 425 (M+l)+;
Η NMR (300 MHz, DMSO-*) δ 8.96 (s, IH), 8.21 (d, IH), 7.91(d, IH), 7.53 (s, IH), 4.29 (m, IH) 3.70 (s, 3H), 3.59, (m, IH), 3.28 (m, IH), 3.05 (m, 2H), 2.83 (s, 3H), 2.77 (m, IH), 2.40 (m, IH), 2.14 (m, IH), 1.31-1.03 (m, 4H). Example 126 l-cvclopropyl-8-methoxy-7-(4-(4-moφholinylmethyl)-4,5,6,7-tetrahvdro-l-benzothien-2- yl)-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid
The desired product was prepared by substituting moφholine for pyrolidine in example 11 IC .
MS (DCI/NH3) m/z 495 (M+H)+;
Η-NMR (300 MHz, d6-DMSO) δ 14.95 (br s, IH), 8.78 (s, IH), 8.11 (d, IH), 7.97 (d, IH), 7.86 (s, IH), 4.25 (m, IH), 3.65 (m, 7H), 2.96 (m, IH), 2.76 (m, 2H), 2.60-2.38 (m, 6H), 1.95 (m, 4H), 1.15 (m, 2H), 1.03 (m, 2H).
Example 127 l-cyclopropyl-7-(4-((dimethylamino)methyl)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting N,N-dimethylamine for pyrolidine in example 1 1 IC. MS (DCI/NH3) m/z 453 (M+H)+; Η-NMR (300 MHz, d6-DMSO) δ 8.73 (s, IH), 8.07 (d, IH), 7.92 (d, IH), 7.72 (s, IH), 4.20 (m, IH), 3.65 (s, 3H), 2.87 (m, IH), 2.75 (m, 2H), 2.47 (dd, IH), 2.30 (dd, IH), 2.21 (s, 6H), 1.90-1.60 (m, 4H), 1.13 (m, 2H), 0.99 (m, 2H).
Example 128 l-cvclopropyl-7-(4-(((dimethylamino)acetyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-
8-methox V-4-QXQ- 1 ,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting N,N-dimethylaminoacetic acid for acetic acid in Example 113. MS (DCI7NH3) m/z 496 (M+H)+.
Example 129 l-cyclopropyl-8-methoxy-4-oxo-7-(4-((2-pyridinylacetyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-l,4-dihvdro-3-quinolinecarboxylic acid The desired product was prepared by substituting 2-pyridyl -acetic acid for acetic acid in Example 113. MS (DCI NH3) m/z 530 (M+H)+. Example 130
7-(4-(aminomethyl)-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l-cvclopropyl-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid
Figure imgf000155_0001
Example 130 A A solution of example 111A (0.300 g, 0.564 mmol) and sodium azide (0.110 g, 1.695 mmol) in DMF (4 mL) was heated for 6 hours at 60°, cooled to room temperature and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (Na2SO4), and the crude product purified by silica gel chromatography eluting with 20% acetone in hexanes followed by 2% methanol in dichloromethane to give the desired product (0.232 g, 86% yield) as a yellow solid.
Figure imgf000155_0002
Example 130B The desired product was prepared by substituting example 130A for example 20 IC in example 20 ID and was purified by silica gel chromatography eluting with a gradient from 20-50% acetone in hexanes.
Figure imgf000155_0003
Example 130C
The desired product was prepared by substituting example 130B for example 2A in example 2B.
Figure imgf000156_0001
Example 130D
7-(4-(aminomethyl)-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4- oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting example 130C for example 59C in example 59D. MS (DC17NH3) m/z 425 (M+H)+;
1H-NMR (300 MHz, ck-DMSO) δ 8.80 (s, IH), 8.11 (d, IH), 8.08 (br s, 2H), 8.05 (d, IH), 7.80 (s, IH), 4.25 (m, IH), 3.68 (s, 3H), 3.10 (m, IH), 2.92 (m, IH), 2.80 (m, IH), 1.95 (m, 2H), 1.80-1.60 (m, 2H), 1.15 (m, 2H), 1.03 (m, 2H).
Example 131 l-cyclopropyl-8-methoxy-4-oxo-7-((4E/Z)-4-((4-pyridinylmethoxy)imino)-4,5,6,7- tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid
Figure imgf000156_0002
Example 131 A
The desired product was obtained by substituting example 48C for example 50 in example 61A.
Example 13 IB l-cvclopropyl-8-methoxy-4-oxo-7-((4E/Z)-4-((4-pyridinylmethoxy)imino)-4,5,6,7- tetrahydro-l-benzothien-2-vI)-l,4-dihvdro-3-quinolinecarboxylic acid A solution of example 131 A (0.150 g, 0.33 mmol) in THF (6 ml) under positive N2 atmosphere and was treated with Et3N (183 μL, 1.32 mmol) and 4-picolylchloride hydrochloride (0.054 g, 0.33 mmol) and was heated at 50° C for 12 hours. The reaction mixture was poured into 30 mL 10% NHtCl and extracted with CH2C12, dried (Na2SO ), filtered and concentrated to give the ethyl ester intermediate.
The desired product was obtained by substituting the ethyl ester intermediate above for example 2A in example 2B. mp 108-110° C;
MS (APCI) m/z 516 (M+H)+;
1H NMR (300 MHz, DMSO-*) δ 8.80 (s, IH), 8.55 (m, 2H), 8.10 (d, IH), 8.05 (d, IH),
7.82 (s, IH), 7.40 (m, 2H), 5.25 (s, 2H), 4.25 (m, IH), 3.68 (s, 3H), 3.30 (s, IH), 2.90 (dd, 2H), 2.80 (dd, 2H), 1.98 (dd, 2H), 1.20 (m, 2H), 1.07 (m, 2H).
Example 132 7-(4-((2-aminoethyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid dihydrochloride
Figure imgf000157_0001
Example 132A The desired product was prepared by substituting tert-butyl N-(2- oxoethyl)carbamate for 3-pyridine carboxaldehyde in example 94A.
Figure imgf000157_0002
Example 132B The desired product was prepared by substituting example 132A for example 2A in example 2B.
Example 132C 7-(4-((2-aminoethyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid dihydrochloride The desired product was prepared by substituting example 132B for example 40B in example 40C. MS (DCI/ΝH3) m/z 454 (M+H)+; Η NMR (300 MHz, CD3OD) δ 8.97 (s, IH), 8.23 (m, 1H0, 8.02 (m, 2H0, 4.65 (m, IH), 4.28 (m, IH), 3.73 (s, 3H), 3.56 (m, 2H), 3.42 (m, 2H), 3.00 (m, 2H), 2.02-2.28 (m, 4H), 1.28 (m, 2H), 1.07 (m, 2H).
Example 133 l-cvclopropyl-8-methoxy-7-(4-((l-methyl-4-piperidinyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid dihydrochloride
Figure imgf000158_0001
Example 133 A The desired product was prepared by substituting l-methyl-4-piperi done and a reaction time of 24 hours for 3-pyridine carboxaldehyde and a reaction time of 2 hours in example 94A.
Figure imgf000158_0002
Example 133B A solution of example 133A (0.18 g, 0.35 mmol) in acetonitrile (12 mL) was treated with di-tert-butyl dicarbonate and a catalytic amount of dimethylaminopyridine at room temperature for 20 hours. The reaction mixture was partitioned between water and dichloromethane, dried (Na2SO ), filtered, concentrated and purified by silica gel chromatography eluting with 1% methanol in dichloromethane to yield 0.15g (71%) of the desired compound.
Figure imgf000158_0003
Example 133C
The desired product was prepared by substituting example 133B for example 2A in example 2B. Example 133D l-cyclopropyl-8-methoxy-7-(4-((l-methyl-4-piperidinyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid dihydrochloride The desired product was prepared by substituting example 133C for example 40B in example 40C.
MS (DCI/NH3) m/z 508 (M+H)+;
Η NMR (300 MHz, CD3OD) δ 8.96 (s, 1H0, 8.22 (m, IH), 8.03 (m, 2H), 4.76 (m, IH), 4.29 (m, IH), 3.83 (m, IH), 3.73 (s, 3H), 3.66 (m, IH), 3.83 (m, IH), 3.73 (s, 3H), 3.66 (m, IH), 3.25 (m, 2H), 3.00 (m, 4H), 2.93 (s, 3H), 2.02-2.58 (m, 6H), 1.28 (m, 2H), 1.08 ( , 2H).
Example 134 l-cyclopropyl-7-((4E/Z)-4-(hvdroxyimino)-5-methyl-4,5,6,7-tetrahydro-l-benzothien-2- yl)-8-methoxy-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid
Figure imgf000159_0001
Example 134 A The desired product was prepared by substituting example 106A and hydroxylamine hydrochloride for example 50 and methoxylamine hydrochloride in example 64.
Figure imgf000159_0002
Example 134B l-cvclopropyl-7-((4E/Z)-4-(hvdroxyimino)-5-methyl-4,5,6,7-tetrahvdro-l-benzothien-2- yl)-8-methoxy-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting example 134A for example 2A in example 2B. mp 239-240° C; MS (APCI) m/z 439 (M+H)+;
Η NMR (300 MHz, DMSO-*) δ 8.82 (s, 0.15H), 8.80 (s, 0.85H), 8.20 (d, 0.15H), 8.13 (d, 0.85H), 8.00 (d, 0.85H) 7.95 (d, 0.15H), 7.89 (s, IH), 4.25 (m, IH), 3.72 (s, 0.45H), 3.70 (s, 2.55H), 3.50 (m, IH), 3.40 (s, IH), 3.00 (d, 2H), 2.70 (m, 2H), 1.90 (m, IH), 1.25 (m, 2H), 1.15 (d, 3H), 1.07 (m, 2H).
Example 135 l-cvclopropyl-7-(4-hvdroxy-7,7-dioxido-5,6-dihydro-4H-thienof2,3-tjlthiopyran-2-yl)-8- methoxy-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid
Figure imgf000160_0001
Example 135 A A solution of example 36C (1.00 g, 1.75 mmol) and ethyl 7-bromo-l -cyclopropyl - 8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate (0.581 g, 1.58 mmol) in toluene (30 ml) was heated to 85 oC for 2 hour, allowed to cool to room temperature and was concentrated. The resulting brown oil was dissolved in MeOΗ (20 ml), cooled to 0 °C and treated with trimethylsilyldiazomethane (2.61 ml of a 2M solution in hexanes, 5.22 mmol). The reaction mixture was allowed to warm to room temperature, stir for 72 hours and concentrated. The crude residue was purified by silica gel chromatography eluting with 15% acetone in hexanes to give the desired product (0.530 g, 68%) as a yellow foam.
Figure imgf000160_0002
A solution of example 135B (0.480 g, 0.72 mmol) in CH2C12 (15 ml) was cooled to 0 oC and treated portionwise with m-chloroperbenzoic acid (0.355 g, 1.43 mmol) and stirred for 3 hours. The reaction mixture was partitioned between saturated NaHCO3 and CH C12 , the organic layer washed with 10% Na2S O3, saturated NaHCU3, brine and dried (MgSO4). The crude residue was purified by silica gel chromatography eluting with 35% acetone in hexanes to give the desired product (0.275 g, 65%) as a yellow foam.
Figure imgf000161_0001
Example 135C The desired product was prepared by substituting example 135B for example 35D in example 35E and the crude residue purified by silica gel chromatography eluting with 3% MeOH in CH2C12.
Example 135D l-cyclopropyl-7-(4-hydroxy-7,7-dioxido-5,6-dihydro-4H-thieno[2,3-blthiopyran-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid
The desired product was prepared by substituting example 135C for example 48C in example 48D to give the desired product. MS (APCI) m/z 496 (M+Cl)";
1H NMR (300 MHz, DMSO-*) δ 8.83 (s, IH), 8.19 (d, IH), 8.14 (d, IH), 7.92 (s, IH), 5.92 (d, IH), 4.87 (m, IH), 4.27 (m, IH), 3.75 (s, 3H), 3.67 (m, 2H), 2.54 (m, IH), 2.37 (m, IH), 1.19 (m, 2H), 1.04 (m, 2H).
Example 136 7-(4-(((5-chloro-l,3-dimethyl-lH-pyrazol-4-yl)sulfonyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-l-cvclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid, bis (trifluoroacetic acid salt)) The Argonaut Quest 210 synthesizer was equipped with 5 ml reaction tubes. One tube was charged with PS-DIEA resin (Argonaut, 22-165 mesh, 1% DVB, 3.75mmol/g loading) (0.060 g, 0.225 mmol). A solution of Example 83 A (0.050 g, 0.114 mmol) and 4- (dimethylamino)pyridine (0.010 g, 0.08 mmol) in 3 ml of 5: 1 / dichloromethane:dimethylacetamide was added. Then 5-chloro-1.3-dimethyl-lH- pyrazole-4-sulfonyl chloride (0.031 g, 0.137 mmol) was added and the mixture was shaken at room temperature overnight. PS-Trisamine resin (Argonaut, 100-200 mesh, 1% DVB, 4.06 mmol/g loading) (0.135 g, 0.55 mmol) was added and the mixture was shaken for 1 h. The mixture was filtered through the Quest reaction tube and the residual resin was washed with dichloromethane (2 x 2 ml). The combined filtrates were concentrated to dryness. The residue was dissolved in 3 ml of 1 : 1 / tetrahydrofuran:methanol, 2N aqueous sodium hydroxide solution (1 ml, 2.0 mmol) was added and the mixture was shaken overnight. The mixture was neutralized with 4M hydrochloric acid in dioxane and concentrated to dryness. The residue was suspended in 1: 1 / dichloromethane:methanol (2 ml) and filtered to remove any inorganics. The resulting clear solution was concentrated to dryness and was purified by preparative reverse phase HPLC (Waters Prep Nova-Pak HR C18 column, 25 x 100 mm, 6 μm, 60 A, 0.01% trifluoroacetic acid in wateπacetonitrile) to give the desired product (0.008 g, 12%) as an off-white solid. MS (DCI/NH3) m/z 604 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 8.79 (s, IH), 8.34 (d, IH), 8.16 (d, IH), 7.78 (d, IH), 7.26 (s, IH), 4.33 (m, IH), 4.25 (m, 2H), 3.80 (s, 3H), 3.66 (s, 3H), 2.75 (m, 2H), 2.35 (s, 3H), 1.62-2.02 (m, 4H), 1.18 (m, 2H), 1.05 (m, 2H).
Example 137 7-(4-(((4-cyanophenyl)sulfonv1)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid
The desired product was prepared by substituting 4-cyanophenylsulphonyl chloride for 5-chloro-1.3-dimethyl-lH-pyrazole-4-sulfonyl chloride in Example 136. MS (DCI/NΗ3) m/z 576 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 8.79 (s, IH), 8.53 (d, IH), 8.17 (t, 2H), 8.10 (d, 2H), 7.63 (d, IH), 6.97 (s, IH), 4.46 (m, IH), 4.23 (m, IH), 3.64 (s, 3H), 2.74 (m, 2H), 1.58- 1.96 (m, 4H), 1.15 (m, 2H), 1.02 (m, 2H).
Example 138 l-cyclopropyI-8-methoxy-4-oxo-7-(4-((phenylsuIfonyl)amino)-4,5,6,7-tetrahvdro-l- benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting phenylsulphonyl chloride for 5- chloro-1.3-dimethyl-lH-pyrazole-4-sulfonyl chloride in Example 136. MS (DCI/NΗ3) m/z 551 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.79 (s, IH), 8.20 (d, IH), 8.13 (d, IH), 7.95 (dd, 2H), 7.73 ( , 3H), 7.60 (d, IH), 6.93 (s, IH), 4.38 (m, IH), 4.24 (m, IH), 3.62 (s, 3H), 2.72 (m, 2H), 1.88 ( , IH), 1.74 (m, 2H) 1.63 (m, IH), 1.16 (m, 2H), 1.02 (m, 2H). Example 139 7-(4-(((2-cvanophenyl)sulfonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oχo-l,4-dihvdro-3-quinolinecarboxylic acid
The desired product was prepared by substituting 2-cyanophenylsulphonyl chloride for 5-chloro-1.3-dimethyl-lH-pyrazole-4-sulfonyl chloride in Example 136. MS (DCI/NΗ3) m/z 576 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, IH), 8.74 (d, IH), 8.13-8.24 (m, 2H), 7.86-7.99 (m, 2H), 7.66 (d, H), 4.52 (m, IH), 4.35 (m, IH), 3.64 (s, 3H), 2.74 (m, 2H), 2.44 (m, 2H), 2.28 (m, IH), 1.74 (m, IH), 1.16 (m, 2H), 1.04 (m, 2H).
Example 140 ' l-cyclopropyl-8-methoxy-7-(4-(((4-methoxyphenyl)sulfonyI)amino)-4,5,6,7-tetrahvdro-l- benzothien-2-yl)-4-oxo- 1 ,4-dihvdro-3-quinolinecarbox ylic acid The desired product was prepared by substituting 4-methoxyphenylsulphonyl chloride for 5-chloro-1.3-dimethyl-lH-pyrazole-4-sulfonyl chloride in Example 136. MS (DCI/NΗ3) m/z 581 (M+H)+; Η NMR (300 MHz, DMSO-d6) δ 8.78 (s, IH), 8.10 (d, IH), 8.03 (d, IH), 7.86 (d, IH), 7.60 (d, IH), 7.19 (d, IH), 6.93 (s, IH), 4.33 (m, IH), 4.24 (m, IH), 3.86(s, 3H), 3.63 (s, 3H), 2.72 (m, 2H), 1.62-1.93 (m, 4H), 1.14 (m, 2H), 1.02 (m, 2H).
Example 141 l-cvclopropyl-8-methoxy-7-(4-(((3-nitrophenyl)sulfonyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxyIic acid The desired product was prepared by substituting 3-nitrophenylsulphonyl chloride for 5-chloro-1.3-dimethyl-lH-pyrazole-4-sulfonyl chloride in Example 136. MS (DCI/NΗ3) m/z 596 (M+H)+;
Η NMR (300 MHz, DMSO-αV) δ 8.79 (s, IH), 8.65 (t, IH), 8.56 (d, IH), 8.54 (m, IH), 8.36(m, IH), 8.11 (d, IH), 7.97 (t, IH), 7.65 (d, IH), 7.09 (s, IH), 4.47 (m, IH), 4.23 (m, IH), 3.63 (s, 3H), 2.74 (m, 2H), 1.60-1.93 (m, 4H), 1.15 (m, 2H), 1.03 (m, 2H).
Example 142 l-cvclopropyl-8-methoxy-4-oxo-7-(5-((2-pyrrolιdιnylmethyl)amιno)-4,5,6,7-tetrahydro-l- benzothιen-2-yl)-l,4-dιhydro-3-qυιnolιnecarboxylιc acid dihydrochlonde
Figure imgf000164_0001
Example 142A The desired product was prepared by substituting example 76E for example 40A in example 83A.
Figure imgf000164_0002
Example 142B The desired product was prepared by substituting example 142A and Nftert- butoxycarbonyl)-prolιnal for example 83A and 3-pyπdme carboxaldehyde in example 94A.
Example 142C l-cvclopropyl-8-methoxy-4-oxo-7-(5-((2-pyrrolιdιnylmethyl)amιno)-4,5,6,7-tetrahvdro-l- benzothιen-2-yO- 1 ,4-dιh vdro-3-quιnohnecarboxylιc acid dihydrochloride The desired product was prepared by substituting example 142B for example 2A in example 2B followed by treatment with 4.0 N HCI in dioxane. MS (APCI/NH3) m/z 494 (M+l)+; 1H NMR (300 MHz, DMSO-*) δ 8.80 (s, IH), 8.13 (d, IH), 8.01 (s, IH), 7.64 (s, IH), 4.25 (m, IH), 3 93 (m, IH), 3.69 (s, 3H), 3 45 (m, 2H), 3.10-2 80 (m, 3H,) 2 40-1 70 (m, 8H), 1.20-1 00 (m, 4H).
Example 143 7-(4-amιno-7,7-dιoxιdo-5,6-dιhydro-4H-thιeno[2,3-t lthιopyran-2-yl)-l-cyclopropyl-8- methox v-4-oxo- 1 ,4-dιhydro-3-quιnolιnecarbox yhc acid hydrochlonde
Figure imgf000165_0001
Example 143 A The desired product was prepared by substituting example 135C for example 37 A in example 37B and the crude residue purified by silica gel chromatography eluting with 50% acetone in hexanes.
Figure imgf000165_0002
Example 143B The desired product was prepared by substituting example 143A for example 20 IC in example 201C and the crude residue purified by silica gel chromatography eluting with 40% acetone in hexanes.
Example 143C 7-(4-amino-7,7-dioxido-5,6-dihvdro-4H-thienor2,3- ?lthiopyran-2-y1)-l-cvclopropyl-8- methoxy-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid hydrochloride The desired product was prepared by substituting example 143B for example 48C in example 48D. MS (DCTJNH3) m/z 461 (M+H)+;
Η NMR (300 MHz, DMSO-*) δ 8.85 (s, IH), 8.28 (d, IH), 8.26 (d, IH), 7.98 (s, IH), 4.78 (m, IH), 4.28 (m, IH), 3.86 (m, IH), 3.77 (s, 3H), 2.78 (m, IH), 2.63 (m, IH), 1.21 (m, 2H), 1.06 (m, 2H).
Example 144 l-cvclopropyl-7-(4-(((3,5-dimethyl-4-isoxazolyl)sulfonyl)amino)-4,5,6,7-tetrahvdro-l- benzothien-2-yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid, trifluoroacetic acid salt
The desired product was prepared by substituting 3,5-dimethylisoxazole-4- sulphonyl chloride for 5-chloro-1.3-dimethyl-lH-pyrazole-4-sulfonyl chloride in Example 136. MS (DCI/NΗ3) m/z 570 (M+H)+; Η NMR (300 MHz, DMSO-d6) δ 8.79 (s, IH), 8.56 (d, IH), 8.14 (d, IH), 7.81 (d, IH), 7.31 (s, IH), 4.48 (m, IH), 4.36 (m, IH), 3.65 (s, 3H), 2.76 (m, 2H), 2.65 (s, 3H), 2.39 (s, 3H), 1.64-1.98 (m, 4H), 1.18 (m, 2H), 1.05 (m, 2H).
Example 145 7-(4-((2,l,3-benzoxadiazol-4-ylsulfonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid, bis(trifluoroacetic acid salt) The desired product was prepared by substituting 2,l,3-benzoxadiazole-4- sulphonyl chloride for 5-chloro-1.3-dimethyl-lH-pyrazole-4-sulfonyl chloride in Example 136.
MS (DCI/NΗ3) m/z 593 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 8.86 (d, IH), 8.78 (s, IH), 8.44 (d, IH), 8.20 (d, IH), 8.11 (d, IH), 7.81 (dd, IH), 7.53 (d, IH), 7.05 (s, IH), 4.65 (m, IH), 4.22 (m, IH), 3.59 (s, 3H), 2.72(m, 2H), 1.63-1.98 (m, 4H), 1.15 (m, 2H), 1.03 (m, 2H).
Example 146 l-cyclopropyl-7-(4-(((dimethylamino)sulfonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2- yl)-8-methoxy-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid The desired product was prepared by substituting N,N-dimethylsulphamoyl chloride for 5-chloro-1.3-dimethyl-lH-pyrazole-4-sulfonyl chloride in Example 136. MS (DCI/NΗ3) m/z 518 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.79 (s, IH), 8.15 (d, IH), 7.92 (d, IH), 7.70 (s, IH), 7.63 (d, IH), 4.38 (m, IH), 4.27 (m, IH), 3.69 (s, 3H), 2.75 (s, 6H), 2.02 (m, 2H), 1.84 (m, 2H), 1.16 (m, 2H), 1.04 (m, 2H).
Example 147 l-cyclopropyl-8-methoxy-4-oxo-7-(4-((2-thienylsulfonyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting thiophene-2-sulphonyl chloride for 5-chloro-1.3-dimethyl-lH-pyrazole-4-sulfonyl chloride in Example 136. MS (DCI/NΗ3) m/z 557 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.79 (s, IH), 8.40 (d, IH), 8.16 (d, IH), 8.04 (dd, IH), 7.75 (dd, IH), 7.69 (d, IH), 7.28 (dd, IH), 6.97 (s, IH), 4.44 (m, IH), 4.24 (m, IH), 3.64 (s, 3H), 2.74 (m, 2H), 1.03-1.96 (m, 4H), 1.16 (m, 2H), 1.04 (m, 2H).
Example 148 7-(4-(((3-cvanophenyl)sulfonyl)amino)-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l- cvclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting 3-cyanophenylsulphonyl chloride for 5-chloro-1.3-dimethyl-lH-pyrazole-4-sulfonyl chloride in Example 136. MS (DCI/NΗ m/z 576 (M+Η)+;
1H NMR (300 MHz, DMSO-d6) δ 8.79 (s, IH), 8.44 (d, IH), 8.36 (m, IH), 8.23 (m, 2H), 8.15 (d, IH), 7.90 (t, IH), 7.65 (d, IH), 7.00 (s, IH), 4.48 (m, IH), 4.24 (m, IH), 3.64 (s, 3H), 2.75 (m, 2H), 1.60-1.94 (m, 4H), 1.16 (m, 2H), 1.03 (m, 2H).
Example 149 7-(4-(((4-(acetylamino)phenyI)sulfonyl)amino)-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l- cvclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting 4-acetamidobenzenesulphonyl chloride for 5-chloro-1.3-dimethyl-lH-pyrazole-4-sulfonyl chloride in Example 136. MS (DCI/NΗ3) m/z 608 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 10.43 (br s, IH), 8.78 (s, IH), 8.08 (t, 2H), 7.86 (s, 4H), 7.46 (d, IH), 6.65 (s, IH), 4.35 (m, IH), 4.22 (m, 2H), 3.62 (s, 3H), 2.72 (m, 2H), 2.15 (s, 3H), 1.65-1.95 (m, 4H), 1.12 (m, 2H), 1.01 (m, 2H).
Example 150 7-(4-((2,l,3-benzothiadiazol-4-ylsulfonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cvclopropyl-8-methoxy-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid bisQrifluoroacetic acid salt) The desired product was prepared by substituting 2,l,3-benzothiadiazole-4- sulphonyl chloride for 5-chloro-1.3-dimethyl-lH-pyrazole-4-sulfonyl chloride in Example 136. . MS (DCI/NΗ3) m/z 609 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.78 (s, IH), 8.48 (dd, 2H), 8.32 (d, IH), 8.11 (d, IH), 7.92 (dd, IH), 7.38 (d, IH), 6.86 (s, IH), 4.76 (m, IH), 4.21 (m, IH), 3.57 (s, 3H), 2.72 (m, 2H), 1.59-1.97 (m, 4H), 1.24 ( , 2H), 1.14 (m, 2H), 1.01 (m, 2H).
Example 151 l-cvclopropyl-7-(4-(((5-(3-isoxazolyl)-2-thienyl)sulfonyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-8-methoxy-4-oxo-L4-dihvdro-3-quinolinecarboxylic acid, trifluoroacetic acid salt The desired product was prepared by substituting 5-isoxazole-3-ylthiophene-2- sulphonyl chloride for 5-chloro-1.3-dimethyl-lH-pyrazole-4-sulfonyl chloride in Example 136.
MS (DCI/NΗ3) m/z 624 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 8.79 (s, IH), 8.14 (d, IH), 8.03 (d, IH), 7.86 (d, IH), 7.78 (d, IH), 7.29 (s, IH), 4.78 (s, IH), 4.52 (m, IH), 4.24 (m, IH), 3.66 (s, 3H), 2.74 (m, 2H), 1.62-1.98 (m, 4H), 1.15 (m, 2H), 1.02 (m, 2H).
Example 152 l-cvclopropyl-7-(4-(((4-fluorophenyl)sulfonyl)amino)-4,5,6,7-tetrahvdro-l-benzothien-2- yl)-8-methoxy-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid The desired product was prepared by substituting 4-fluorophenylsulphonyl chloride for 5-chloro-1.3-dimethyl-lH-pyrazole-4-sulfonyl chloride in Example 136. MS (DCI/NΗ3) m/z 569 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.79 (s, IH), 8.24 (d, IH), 8.13 (d, IH), 7.99 (dd, 2H), 7.65 (d, IH), 7.55 (dd, 2H), 7.01 (s, IH), 4.40 (m, IH), 4.24 (m, IH), 3.64 (s, 3H), 2.72 (m, 2H), 1.57-1.94 (m, 4H), 1.16 (m, 2H), 1.03 (m, 2H).
Example 153
7-(4-(((6-chloroimidazor2,l-b1[l,31thiazol-5-yl)sulfonyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihvdro-3-quinoIinecarboxylic acid bis(trifluoroacetic acid salt) The desired product was prepared by substituting 6-chloroimidazo[2,l-b]thiazole- 5-sulphonyl chloride for 5-chloro-1.3-dimethyl-lH-pyrazole-4-sulfonyl chloride in Example 136. MS (DCI/NH3) m/z 632 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 8.96 (d, IH), 8.80 (s, IH), 8.14 (d, IH), 8.03 (d, IH), 7.69 (d, IH), 7.56 (d, IH), 6.90 (s, IH), 4.45 (m, IH), 4.23 (m, IH), 3.62 (s, 3H), 2.76 (m, 2H), 1.68-1.96 ( , 4H), 1.17 (m, 2H), 1.03 (m, 2H).
Example 154 l-cyclopropyl-8-methoxy-4-oxo-7-(4-((4-pyridinylacetyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxyIic acid The desired product was prepared by substituting 4-pyridyl-acetic acid for acetic acid in Example 113. MS (DCI/NH3) m/z 530 (M+H)+.
Example 155 l-cyclopropyl-7-(4-((2-hvdroxyethyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihvdro-3-quinoIinecarboxylic acid hydrochloride
Figure imgf000169_0001
Example 155 A
The desired product was prepared by substituting (tert-butyldimethylsilyloxy)- acetaldehyde and a reation temperature of 0°C for 3-pyridine carboxaldehyde and an ambient reation temperature, resp .
Figure imgf000169_0002
Example 155B
The desired product was prepared by substituting example 155A for example 133A in example 133B.
Figure imgf000170_0001
Example 155C The desired product was prepared by substituting example 155B for example 35D in example 35E.
Figure imgf000170_0002
Example 155D The desired product was prepared by substituting example 155C for example 2A in example 2B.
Example 155E l-cvclopropyl-7-(4-((2-hydroxyethyl)amino)-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid hydrochloride The desired product was prepared by substituting example 155D for example 40B in example 40C. MS (DCI/NH3) m/z 455 (M+H)+;
IH NMR (300 MHz, CD3OD) δ 8.97 (s.lHO, 8.24 (d, IH), 7.94 (m, IH), 7.87 (m, IH). 4.62 (m, IH), 4.28 (m, IH), 3.88 (m, 2H), 3.72 (s, 3H), 3.26 (m, 2H), 2.99 (m, 2H), 1.94- 2.27 (m, 4H), 1.28 (m, 2H), 1.08 (m, 2H).
Example 156
7-(4-amino-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-6-fluoro-4-oxo-l,4- dihydro|T,81naphthyridine-3-carboxylic acid hydrochloride
Figure imgf000170_0003
Example 156A The desired product was prepared by substituting example 35C for example 35D in example 35E and was used without further purification.
Figure imgf000171_0001
Example 156B The desired product was prepared by substituting example for example 37A in example 37B and the crude product puπfied by silica gel chromatography eluting with 50% ethyl acetate in hexanes
Figure imgf000171_0002
Example 156C The desired product was prepared by substituting example 156B for 201C in example 201C and the crude product recrystahzed from ethyl acetate.
Figure imgf000171_0003
Example 15 D 7-(4-amιno-4,5,6,7-tetrahvdro-l-benzothιen-2-yl)-l-cyclopropyl-6-fluoro-4-oxo-l,4- dihvdro[T,81naphthyndine-3-carboxyhc acid hydrochlonde
A solution of example 156C (0.134 g, 0.247 mmol) in THF (10 ml) was treated with 1 N HCI (10 ml) and heated to 80 °C for 14 hours. The resulting heterogeneous mixture was filtered and the white solid obtained suspended in CH2C12 (5 ml) and treated with HCI (5 ml of a 4N solution in dioxane). After stirπng for 4 hours, the mixture was filtered to give the desired product (0.079 g, 80%) as a yellow solid. MS (APCI) m/z 383 (M-NH2)+;
1H NMR (300 MHz, DMSO-*) δ 8.82 (s, IH), 8.57 (d, IH), 8.51 (br s, 3H), 8.28 (d, IH), 4.46 (m, IH), 3.83 (m, IH), 2.89 (m, 2H), 2 20-1.97 ( , 2H), 1.93-1.77 (m, 2H), 1.31 (m, 2H), 1 18 (m, 2H)
Example 157
7-(4-((gIycyl)amιno)-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-l-cyclopropyl-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid, trifluoroacetic acid salt The Argonaut Quest 210 synthesizer was equipped with 5 ml reaction tubes. One tube was charged with 1 ml 1 : 1 / dichloromethane:dimethylacetamide, N- cyclohexylcarbodiimide, N' -methyl polystyrene HL (NovaBiochem, 200-400 mesh, 2% DVB, 1.52 mmol/g loading) (0.151 g, 0.23 mmol), 1-hydroxybenzotriazole hydrate (0.003 g, 0.019 mmol) and N-(9-fluorenylmethoxycarbonyl)-glycine (0.051 g, 0.171 mmol). The mixture was stirred for 30 min before a solution of Example 83 A (0.05 g, 0.114 mmol) in 1 ml of 1:1 / dichloromethane:dimethylacetamide was added. The mixture was stirred 48 h at room temperature. PS-Trisamine resin (Argonaut, 100-200 mesh, 1% DVB, 4.06 mmol/g loading) (0.135 g, 0.55 mmol) was added and the mixture was agitated for 2 h. Piperidinomethyl polystyrene HL resin (NovaBiochem, 200-400 mesh, 2% DVB, 3.5 mmol/g loading) (0.244 g, 0.855 mmol) was added and the mixture was shaken for 7 days. The mixture was filtered through the Quest reaction tube and the residual resin was washed with dichloromethane (2 x 2 ml). The filtrate was concentrated to dryness and the residue was redissolved in 3 ml of 1:1 / tetrahydrofuran: methanol. 2N aqueous sodium hydroxide solution (1 ml) was added and the mixture was shaken overnight. The mixture was neutralized with 4M hydrochloric acid in dioxane and concentrated to dryness. The residue was suspended in 1:1 / dichloromethane:methanol (2 ml) and was filtered to remove any inorganics. The resulting clear solution was concentrated to dryness and was purified by preparative reverse phase HPLC (Waters Prep Nova-Pak HR C18 column, 25 x 100 mm, 6 μm, 60 A, 0.01 % trifluoroacetic acid in water: acetonitrile) to give the desired product (0.005 g, 12%) as an off-white solid. MS-(DCI/NH3) z 468 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 14.97 (br s, IH), 8.80 (s, IH), 8.72 (d, IH), 8.12 (d, IH), 7.96 (d, IH), 7.78 (d, IH), 7.58 (s, IH), 5.01 (m, 2H), 4.26 (m, IH), 3.70 (s, 3H), 2.84 (m, 2H), 1.98 (m, 2H), 1.79 (m, IH), 1.71 (m, IH), 1.18 (m, 2H), 1.04 (m, 2H).
Example 158 7-(4-((D-aIanyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid, trifluoroacetic acid salt
The desired product was prepared by substituting N-(9-fluorenylmethoxycarbonyl)- L-alanine for N-(9-fluorenylmethoxycarbonyl)-glycine in Example 157. MS (DCI/NH3) m/z 482 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 8.79 (s, IH), 8.75 (dd, IH), 8.12 (d, IH), 7.93 (dd, IH), 7.52 (d, IH), 4.98 (m, IH), 4.26 (m, IH), 3.84 (m, IH), 3.70 (d, 3H), 2.83 (m, 2H), 1.98 (m, 2H), 1.88 (m, IH), 1.72 (m, IH), 1.40 (dd, 3H), 1.18 (m, 2H), 1.04 (m, 2H). Example 159 l-cvclopropyl-8-methoxy-4-oxo-7-(4-((D-prolyl)amino)-4,5,6,7-tetrahydro-l-benzothien- 2-vπ-l,4-dihydro-3-quinolinecarboxylic acid, trifluoroacetic acid salt The desired product was prepared by substituting N-(9-fluorenylmethoxycarbonyl)-
L-proline for N-(9-fluorenylmethoxycarbonyl)-glycine in Example 157. MS (DC17NH3) m/z 508 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 9.70 (br s, IH), 9.51 (br s, IH), 8.91 (dd, IH), 8.79 (s, IH), 7.95 (dd, IH), 7.59 (d, IH), 5.0 (m, IH), 4.26 (m, IH), 4.20 (m, IH), 3.70 (d, 3H), 3.60 (m, 2H), 2.84 (m, 2H), 2.32 (m, IH), 1.95 (m, 5H), 1.88 (m, IH), 1.73 (m, IH), 1.18 (m, 2H), 1.04 (m, 2H).
Example 160 7-(4-(((2R)-2-amino-3-(lH-imidazol-5-yl)propanoyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid bis(trifluoroacetic acid salt) The desired product was prepared by substituting N-α-(9- fluorenylmethoxycarbonyl)-N-trityl-L-histidine for N-(9-fluorenylmethoxycarbonyl)- glycine in Example 157.
MS (DCI/NΗ3) m/z 548 (M+Η)+;
Η NMR (300 MHz, DMSO-d6) δ 14.90 (br s, IH), 8.96 (d, IH), 8.81 (dt, IH), 8.79 (d, IH), 8.15 (dd, IH), 7.90 (dd, IH), 7.47 (dd, IH), 4.95 (m, IH), 4.25 (m, IH), 4.11 (m, 2H), 3.68 (d, 3H), 3.22 (m, 2H), 2.80 (m, 2H), 1.97 (m, IH), 1.86 (m, IH), 1.80 (m, 2H), 1.50 (m, IH), 1.17 (m, 2H), 1.03 (m, 2H).
Example 161 7-(4-((leucyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4- oxo-l,4-dihvdro-3-quinolinecarboxylic acid, trifluoroacetic acid salt
The desired product was prepared by substituting N-(9-fluorenylmethoxycarbonyl)- D-leucine for N-(9-fluorenylmethoxycarbonyl)-glycine in Example 157. MS (DCI/NH3) m/z 524 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 8.86 (dd, IH), 8.80 (d, IH), 8.14 (dd, IH), 7.90 (dd, IH), 7.53 (d, IH), 4.99 (m, IH), 4.25 (m, IH), 3.68 (d, 3H), 2.84 (m, 2H), 2.72 ( , IH), 1.55-2.04 (m, 7H), 1.16 (m, 2H), 1.04 (m, 2H). Example 162
7-(4-((D-tyrosyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cvclopropyl-8-methoxy- 4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid trifluoroacetate The desired product was prepared by substituting N-(9-fluorenylmethoxycarbonyl)-
4-(diethylphosphono)-L-tyrosine for N-(9-fluorenylmethoxycarbonyl)-glycine in Example
157.
MS (DCI/NH3) m/z 574 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 14.89 (br s, IH), 8.79 (d, IH), 8.68 (dd, IH), 8.30 (m, IH), 8.25 (m, IH), 7.00-7.24 (m, 4H), 6.72 (d, 1H0, 4.90 (m, IH), 4.24 (m, IH), 3.95 ( ,
IH), 3.90 (m, IH), 3.67 (d, 3H0, 3.00 (m, IH), 2.75 (m, 2H), 1.92 (m, IH), 1.86 ( , IH),
1.75 (m, 2H), 1.44 (m, IH), 1.16 (m, 2H), 1.05 (m, 2H).
Example 163
7-(4-((O-methyl-D-tyrosyl)amino)-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid, trifluoroacetic acid salt The desired product was prepared by substituting N-(9-fluorenylmethoxycarbonyl)- O-methyl-L-tyrosine for N-(9-fluorenylmethoxycarbonyl)-glycine in Example 157. MS (DCI/NH3) m/z 588 (M+H)+;
1H NMR (300 MHz, DMSO- L.) δ 8.79 (d, IH), 8.66 (dt, IH), 8.13 (dd, IH), 7.85 (dd, IH), 7.17 (dt, 2H), 6.87 (dd, 2H), 4.91 (m, IH), 4.26 (m, IH), 3.78 (s, 3H), 3.68 (d, 3H), 3.52 (s, 2H), 3.00 (m, 2H), 2.78 (m, 2H), 1.66-2.00 (m, 4H), 1.17 (m, 2H), 1.02 (m, 2H).
Example 164 7-(4-((D-methionyl)amino)-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l-cvclopropyl-8- methoxy-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid trifluoroacetate The desired product was prepared by substituting N-(9-fluorenylmethoxycarbonyl)- L-methionine for N-(9-fluorenylmethoxycarbonyl)-glycine in Example 157. MS (DCI/NH3) m/z 542 (M+H)+;
'H NMR (300 MHz, DMSO-d6) δ 8.86 (d, IH), 8.79 (s, IH), 8.10 (d, IH), 7.88 (d, IH), 7.54 (s, IH), 5.00 (m, IH), 4.26 (m, IH), 3.70-3.89 (m, 4H), 3.69 (d, 3H), 2.82 (m, 2H), 2.46-2.50 (m, 3H), 1.94-2.10 (m, 3H), 1.89 (m, IH), 1.79 (m, IH), 1.17 (m, 2H), 1.03 (m, 2H). Example 165
7-(4-(((2R)-2-amino-3-(3-pyridinyl)propanoyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2- yl)-l-cvclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid bis(trifluoroacetic acid salt) The desired product was prepared by substituting N-(9-fluorenylmethoxycarbonyl)-
L-3-pyridylalanine for N-(9-fluorenylmethoxycarbonyl)-glycine in Example 157. MS (DCI/NH3) m/z 558 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 8.80 (dt, IH), 8.59 (dt, 2H), 8.50 (d, 2H), 8.16 (dd, IH), 7.90 (dd, IH), 7.55 (m, IH), 4.90 (m, IH), 4.25 (m, IH), 3.68 (d, 3H), 3.15 (m, 2H), 2.78 (m, 2H), 2.52 (s, 2H), 2.50 (m, IH), 1.66-2.00 (m, 4H), 1.40 (m, IH), 1.17 (m, 2H), 1.02 (m, 2H).
Example 166 l-cvclopropyl-8-methoxy-4-oxo-7-(4-(((2/?)-piperidinylcarbonyl)amino)-4, 5,6,7- tetrahvdro-l-benzothien-2-yl)-l,4-dihvdro-3-quinolinecarboxylic acid, trifluoroacetic acid salt The desired product was prepared by substituting N-(9-fluorenylmethoxycarbonyl)- L-pipecholinic acid for N-(9-fluorenylmethoxycarbonyl)-glycine in Example 157. MS (DCI/NH3) m/z 522 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 9.19 (dd, IH), 8.82 (dd, IH), 8.72 (m, IH), 8.11 (dd, IH), 7.93 (dd, IH), 7.52 (d, IH), 4.99 (m, IH), 4.26 (m, IH), 4.10 (m, 2H), 3.78 (m, IH), 3.68 (d, 3H), 3.29 (m, IH), 2.96 (m, IH), 2.82 (m, 2H), 2.12 (m, IH), 1.98 (m, 2H), 1.42- 1.81 (m, 4H), 1.18 (m, 2H), 1.03 (m, 2H).
Example 167 l-cyclopropyl-8-methoxy-4-oxo-7-(4-((4-pyrimidinylcarbonyl)amino)-4,5,6,7-tetrahydro- l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid bis(trifluoroacetic acid salt) The desired product was prepared by substituting pyrimidine-4-carboxylic acid for acetic acid in Example 113. MS (DCI/NH3) m/z 517 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δl4.90 (br s, IH), 9.31 (d, IH), 9.08 (d, 2H), 8.78 (s, IH), 8.10 (dd, IH), 8.02 (dd, 2H), 7.60 (s, IH), 5.22 (m, IH), 4.24 (m, IH), 3.72 (s, 3H), 2.85 (m, 2H), 1.72-2.10 ( , 4H), 1.15 (m, 2H), 1.02 (m, 2H).
Example 169 l-cyclopropyl-8-methoxy-4-oxo-7-(4-((phenylacetyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting phenylacetic acid for acetic acid in Example 113.
MS (DCI/NH3) m/z 529 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 14.92 (br s, IH), 8.79 (s, IH), 8.49 (d, IH), 8.10 (d, IH), 7.76 (d, IH), 7.3 (s, IH), 7.32 (m, 3H), 7.25 (m, IH), 4.92 (m, IH), 4.24 (m, IH), 4.01 (s, 3H), 3.64 (s, 2H), 3.47 (d, 2H), 2.80 (m, 2H), 1.95 (m, 2H), 1.82 (m, IH), 1.68 (m, IH), 1.15 (m, 2H), 1.03 (m, 2H).
Example 170 l-cvclopropyl-7-(4-(3-furoylamino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting 3-furoic acid for acetic acid in Example 113.
MS (DCI/NH3) m/z 505 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 8.79 (s, IH), 8.48 (d, IH), 8.24 (d, IH), 8.09 (d, IH), 7.98 (d, IH), 7.71 (d, IH), 7.58 (s, IH), 6.91 (d, IH), 5.18 (m, IH), 4.25 (m, IH), 3.68 (s, 3H), 2.83 (m, 2H), 2.03 (m, 2H), 1.87 (m, IH), 1.78 ( , IH), 1.15 (m, IH), 1.02 (m, 2H).
Example 171 l-cvclopropyl-8-methoxy-4-oxo-7-(4-((2-pyridinylcarbonyl)amino)-4,5,6,7-tetrahvdro-l- benzothien-2-yl)-l,4-dihvdro-3-quinolinecarboxylic acid, trifluoroacetic acid salt The desired product was prepared by substituting pyridine-2-carboxylic acid for acetic acid in Example 113. MS (DCI/NH3) m/z 516 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 8.74 (d, IH), 8.62 (d, IH), 8.54 (s, IH), 8.13 (m, IH), 8.03 (m, IH), 7.92 (d, IH), 7.75 (d, IH), 7.61 (m, IH), 7.59 (s, IH), 5.20 (m, IH), 4.06 (m, IH), 3.65 (s, 3H), 2.84 (m, 2H), 1.83-2.08 (m, 4H), 1.09 (m, 2H), 0.92 (m, 2H).
Example 172 l-cvclopropyl-8-methoxy-4-oxo-7-(4-((lH-pyrazol-4-ylcarbonyl)amino)-4,5,6,7- tetrahvdro-l-benzothien-2-yl)-l ,4-dihvdro-3-quinolinecarboxylic acid bis(trifluoroacetic acid salt) The desired product was prepared by substituting pyrazole-4-carboxylic acid for acetic acid in Example 113. MS (DCI/NH3) m/z 505 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 8.79 (s, IH), 8.33 (d, IH), 8.10 (m, IH), 8.09 (d, IH), 7.95 (d, IH), 7.58 (s, IH), 5.18 (m, IH), 4.23 (m, IH), 3.64 (s, 3H), 2.82 (m, 2H), 1.66- 2.10 (m, 4H), 1.15 (m, 2H), 1.02 (m, 2H).
Example 173 7-(4-((D-aspartyl)amino)-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy- 4-oxo-l,4-dihydro-3-quinolinecarboxylic acid, trifluoroacetic acid salt The desired product was obtained as a by-product from Example 180. MS (DCI/NH3) m/z 526 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 8.79 (s, IH), 8.18 (d, IH), 7.98 (m, IH), 7.44 (d, IH), 4.96 (m, IH), 4.08 (m, IH), 3.76 (s, 3H), 3.60 (m, 2H), 2.82 (m, 2H),m 1.98 (m, 2H), 1.86 (m, IH), 1.72 (m, IH), 1.14 (m, 2H), 1.00 (m, 2H).
Example 174 l-cvclopropyl-8-methoxy-7-(4-((N-methyl-D-leucyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid, trifluoroacetic acid salt The desired products were prepared by substituting N-(9- fluorenylmethoxycarbonyl)-N-methyl-L-leucine for N-(9-fluorenylmethoxycarbonyl)- glycine in Example 157.
4 ?-isomer:
MS (DCI/NH3) m/z 538 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 14.98 (br s, IH), 9.08 (d, IH), 8.94 m, IH), 8.80 (s,
IH), 8.11 (d, IH), 7.83 (d, IH), 7.47 (s, IH), 5.03 (m, IH), 4.25 (m, IH), 3.68 (s, 3H), 2.83 (m, 2H), 1.54-2.07 (m, 8H), 1.18 (m, 2H), 1.06 (m, 2H), 0.92 (m, 6H).
45-isomer:
MS (DCI/NH3) m/z 538 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 14.97 (br s, IH), 9.09 (d, IH), 8.80 (s, IH), 8.12 (d,
IH), 7.93 (d, IH), 7.62 (s, IH), 5.05 (m, IH), 4.25 (m, IH), 3.71 (m, IH), 3.69 (s, 3H), 3.03 (m, 2H), 2.59 (s, 3H), 1.92 (m, 3H), 1.72 (m, 3H), 1.60 (m, 2H), 1.17 (m, 2H), 1.02
(m, 2H), 0.91 (m, 6H). Example 175 7-(4-((D-norleucyl)amino)-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid, trifluoroacetic acid salt The desired products were prepared by substituting and N-(9- fluorenylmethoxycarbonyl)-L-norleucine for N-(9-fluorenylmethoxycarbonyl)-glycine in Example 157. 4R-isomer: MS (DCI/NH3) m/z 524 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 14.98 (br s, IH), 8.79 (s, IH), 8.10 (d, IH), 7.85 (d, IH), 7.69 (s, IH), 5.01 (m, IH), 4.25 (m, IH), 3.72 (m, IH), 3.69 (s, 3H), 2.85 (m, 2H), 1.98 (m, 2H), 1.89 (m, IH), 1.76 (m, 3H), 1.32 (m, 4H), 1.17 (m, 2H), 1.05 (m, 2H), 0.82 (m, 3H). 45-isomer:
MS (DCI/NH3) m/z 540 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 14.98 (br s, IH), 8.82 (d, IH), 8.79 (s, IH), 7.94 (d, IH), 7.57 (s, IH), 5.01 (m, IH), 4.26 (m, IH), 3.77 (m, IH), 3.70 (s, 3H), 2.84 (m, 2H), 1/97 (m, 2H), 1.87 (m, IH), 1.71 (m, 3H), 1.32 (m, 4H), 1.18 (m, 2H), 1.03 (m, 2H), 0.88 (m, 3H).
Example 180 7-(4-((β-O-methyl-D-aspartyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yI)-l- cvclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid, trifluoroacetic acid salt The desired product was prepared by substituting N-(9-fluorenylmefhoxycarbonyl)- L-aspartic acid β-methyl ester for N-(9-fluorenylmethoxycarbonyl)-glycine in Example 157. Example 173 was isolated as a by-product. MS (DCI/NH3) m/z 540 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 14.98 (br s, IH), 8.78 (s, IH), 8.12 (dd, IH), 7.97 (dd, IH), 7.55 (dd, IH), 4.98 (m, IH), 4.26 (m, IH), 4.12 (m, IH), 3.68 (m, 6H), 2.95 (m, IH), 2.82 (m, 2H), 1.98 (m, 2H), 1.88 (m, IH), 1.70 (m, IH), 1.12 (m, 2H), 0.98 (m, 2H).
Example 182 l-cvclopropyl-8-methoxy-4-oxo-7-((4E)-4-((3-pyridinylmethoxy)imino)-4,5,6,7- tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid The desired product was obtained by substituting 3-picolylchloride hydrochloride, a reaction temperature of 70° C and a reaction time of 7 hours for 4-picolylchloride hydrochloride, a reaction temperature of 50° C and a reaction time of 12 hours, respectively in examplel31B. . mp 181-183° C; MS (APCI) m/z 516 (M+H)+;
Η NMR (300 MHz, DMSO-*) δ 14.90 (s, IH), 8.80 (s, IH), 8.65 (m, IH), 8.52 (m, IH), 8.15 (m, IH), 8.05 (d, IH), 7.88 (s, IH), 7.86 (m, IH), 7.42 (dd, IH), 5.23 (s, 2H), 4.25 (m, IH), 3.70 (s, 3H), 2.40 (m, 2H), 2.30 (m, 2H), 1.95 (m, 2H), 1.15 (m, 2H), 1.07 (m, 2H).
Example 183 l-cyclopropyl-8-methoxy-4-oxo-7-((4E)-4-((2-pyridinylmethoxy)imino)-4.5,6,7- tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid The desired product was obtained by substituting 2-picolylchloride hydrochloride and a reaction time of 8 hours for 4-picolylchloride hydrochloride and a reaction time of 12 hours, respectively in examplel31B. mp 178-179° C; MS (APCI) m/z 516 (M+H)+;
Η NMR (300 MHz, DMSO-*) δ 8.80 (s, IH), 8.55 (d, IH), 8.10 (d, IH), 8.05 (d, IH), 7.83 (s, IH), 7.80 (dd, IH), 7.40 (d, IH), 7.32 (dd, IH), 5.28 (s, 2H), 4.25 (m, IH), 3.68 (s, 3H), 3.30 (s, IH), 2.92 (dd, 2H), 2.80 (dd, 2H), 1.95 (m, 2H), 1.18 (m, 2H), 1.07 (m, 2H).
Example 185 l-cyclopropyl-7-(4-hydroxy-5-methyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid
Figure imgf000179_0001
A mechanically stirred solution of 2-acetylthιophene (20.0 g, 0.160 mol) in 9: 1 CH2Cl2:CH3OH (400 ml) was treated with 4.0 mL cone. HCI followed by portionwise addition of 4-dιmethylamιnopyπdιnιum tnbromide (20.0 g, 0.170 mol). The resulting red orange solution was stirred 4 hours, concentrated, the residue slurπed in diethyl ether and filtered. The filtrate was washed with water, bπne, and dried (Na2SO4). Concetration gave the desired product (20 g, 63 %) as an oil.
Figure imgf000180_0001
Example 185B
A mechanically stirred suspension of NaH (6.88 g of a 60 % mineral oil suspension, 0.170 mol) in THF (70 ml) was cooled to 0°C, treated dropwise with diethyl methylmalonate (30.0 g, 0.170 mole), stirred for 20 minutes and treated dropwise with a solution of example 185A (33 7 gm, 0.160 mol) in THF (110 ml). The resulting mixtue was allowed to warm to room temperature, stir 2 hours, was treated with water (20 ml), concentrated and partitioned between water and ethyl ether. The organic phase was washed with water, bπne, and dπed (Na2SO4).
A solution of the crude product above in 10 % KOH (400 ml ) and EtOH (200 ml) was heated to reflux for 1 hour and allowed to stir overnight at room temperature. The reaction mixture was poured into ice cold 6N HCI, the pH adjusted to 4.0 with cone. HCI, and extracted several times with ether. The combined organic layers were washed with water, brine, and dπed (Na SO ) After concentration, the desired product was obtained by crystallization from petroleum ether and ethyl ether (15.0 g, 40 %) as a light brown solid.
Figure imgf000180_0002
Example 185C
A solution of example 185B (28.0 g, 0.115 mol) in diethylene glycol (100 mL) was heated at 175-180°C. for 20 minutes, allowed to cool to room temperature and was poured into ice/water containing a 5 mL of acetic acid. A brown tan precipitate was collected by filtration and recrystalhzed from hot water and ethanol to give the desired product (17.0 g, 75 %) as white crystals.
Figure imgf000181_0001
Example 185D
A solution of potassium hydroxide (16.4 g, 0.300 mol) in diethylene glycol (90 mL) was treated portionwise with example 185C (16.1 g, 0.081 mol) followed by hydrazine monohydrate (8.20 g, 0.160 mol) and the resulting mixture heated to 200°C for 2.5 hours. The reaction mixture was cooled to room temperature and partitioned between water and ethyl ether. The organic phase was washed with water, brine, dried (Na2SO4) and concentrated. The oily residue was distilled under reduced pressure (135-145° C, 0.2 torr) to give the desired product (13.8 g, 92 %).
Figure imgf000181_0002
Example 185E
Neat polyphosphoric acid (100 g) was mechanically stirred, warmed to 70°C, and treated dropwise with a solution of example 185D (9.70 g, 0.052 mol) in ethyl ether (10 ml). The reaction mixture was heated to 120°C for 3 hours and poured into a mixture of ice and cone. HCI (40 mL). The resulting mixture was extracted with ethyl ether the organic phase washed with water, brine, and dried over (Na2SO4) and the crude residue purified by silica gel chromatography eluting with hexane/ethyl acetate (4:1) to give the desired product (3.0 g, 34 %) as a clear oil.
Figure imgf000181_0003
Example 185F
A solution of example 185E (4.10 g, 0.025 mol) in EtOH (40 mL) was cooled to 0°C and treated with NaBHi (2.50 g, 0.067 mol) and stirred for 2.5 hour at room temperature. The reaction was partitioned between 2 % acetic acid and methylene chloride. The organic phase was washed with sat. NaHCO3, brine, dried (Na2SO4) and concentrated to give the desired product as a yellow oil (3.75 g, 90 %) which was used without further purification.
Figure imgf000182_0001
A solution of example 185F (3.75 g, 0.022 mol), imidazole (3.0 g, 0.044 mol), and
0.020 g of N,N-dimethylaminopyridine in DMF (40 mL)was cooled to 0°C and treated with tert-butyldimethylchlorosilane (6.7 g, 0.45 mol), warmed to room temperature, stirred for 20 hours, poured into 10 % NH4C1, and extracted 2X with ethyl ether. The organic phase was washed with water, brine, dried (Na2SO4), and concentrated. The resulting residue was purified by silica gel chromatography eluting with hexane:ethyl acetate (7:1) to give the desired compound (6.1 g, 96 %) as a yellow oil.
Figure imgf000182_0002
Example 185H
The desired product was prepared by substituting example 185G for example 218B in example 218C and was used without further purification.
Example 1851 ethyl 7-(4-((tert-butyl(dimethyl)silyl)oxy)-5-methyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)- l-cvclopropyl-8-methoxy-4-oxo-l,4-dihvdro-3-quinolinecarboxyIate
The desired product was prepared by substituting example 185H and ethyl-7- bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate for ethyl -7 - bromo-l-cyclopropyl-4-oxo-l,4-dihydro-3-quinolinecarboxylate and example ID, respectively in example IE and was purified by silica gel chromatography eluting with methylene chloride and then with a 3:97 methanol: methylene chloride gradient to give a yellow foam.
Figure imgf000183_0001
Example 185J The desired product was prepared by substituting example 1851 for example 35D in example 35E and was used without further purification.
Example 185K l-cvclopropyl-7-(4-hydroxy-5-methyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8-methoxy-4- oxo-L4-dihydro-3-quinolinecarboxylic acid
The desired product was prepared by substituting example 185J for example 2A in example 2B and was purified by chromatography on silica gel eluting with hexane:acetone:methanol (50:45:5) to give light yellow solid.
MS (ESI) m/z 426 (M+H)+; Η NMR (300 MHz, DMSO-d6) δ 14.9 (br s, IH), 8.79 (s, IH), 8.12 (d, IH,), 7.97 ( t,lH, maj, min ), 7.73 (s,lH, maj ), 7.69 (s, IH, min ), 5.22 (d, IH, maj), 4.87 (d, IH, min), 4.46
(m, IH, min ), 4.25 (m, 2H, maj, min), 4.14 (t, IH, maj ), 3.60 (s, 3H), 2.82-2.78 (m, 2H, maj, min), 1.96-1.92 (m, IH , min) 1.70-1.58 ( m, 2H, maj, min), 1.14 (d, 3H, min), 1.06
(d, 3H, maj),1.02 ( s, 2H, maj, min), 0.87 (t, 2H, maj, min).
Example 186 l-cyclopropyl-8-methoxy-7-(4-(((methylanilino)carbonyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid The Argonaut Quest 210 synthesizer was equipped with 5 ml reaction tubes. One tube was charged with PS-DIEA resin (Argonaut, 22-165 mesh, 1% DVB, 3.75 mmol/g loading) (0.072 g, 0.27 mmol) and a solution of Example 83A (0.040 g, 0.09mmol) and 4- (dimethylamino)pyridine (0.010 g, 0.08 mmol) in 3ml of 1:1 / dichloromethane:dimethylacetamide was added. N-Methyl-N-phenylcarbamoyl chloride (0.018 mg, 0.108 mmol) was added and the mixture was shaken overnight at ambient temperature. PS-Trisamine resin (Argonaut, 100-200 mesh, 1% DVB, 4.06 mmol/g loading) (0.135 g, 0.55 mmol) was added and the mixture was shaken for 1 h. The mixture was filtered and washed with dichloromethane (2 x 2 ml). The resulting solution was concentrated to dryness and the residue was redissolved in 3 ml of 1:1 / tetrahydrofuran:methanol. 2N aqueous sodium hydroxide solution (1 ml, 2.0 mmol) was added and the mixture was shaken overnight. The mixture was then neutralized with 4M hydrochloric acid in dioxane and concentrated to dryness. The residue was suspended in 1: 1 / dichloromethane:methanol (2 ml) and was filtered to remove any inorganics. The resulting clear solution was concentrated to dryness and was purified by preparative reverse phase HPLC (Waters Prep Nova-Pak HR C18 column, 25 x 100 mm, 6 μm, 60 A, 0.01% trifluoroacetic acid in water: acetonitrile) to give the desired product (0.014 g, 28%) as an off-white solid. MS (DCI/NH3) m/z 544 (M+H)+; Η NMR (300 MHz, DMSO-d6) δ 8.79 (s, IH), 8.14 (d, IH), 7.98 (d, IH), 7.63 (s, IH), 7.38 (s, IH), 6.15 (d, IH), 4.82 (m, IH), 4.26 (m, IH), 3.78 (s, 3H), 3.26 (s. 3H), 2.76 (m, 2H), 1.95 (m, 2H), 1.75 (m, 2H), 1.18 (m, 2H), 1.05 (m, 2H).
Example 187 l-cvclopropyl-7-(4-(((diethylamino)carbonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2- yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting N,N-diethylcarbamoyl chloride for N-methyl-N-phenylcarbamoyl chloride in Example 186. MS (DCI/NH3) m/z 510 (M+H)+; Η NMR (300 MHz, DMSO-dβ) δ 8.78 (s, IH), 8.10 (d, IH), 7.90 (d, IH), 7.56 (s, IH), 6.40 (d, IH), 4.86 (m, IH), 4.24 (m, IH), 3.68 (s, 3H), 3.28 (m, 4H), 2.80 (m, 2H), 1.63- 2.06 (m, 4H), 1.15 (m, 2H), 1.05 (m, 8H).
Example 188 l-cvclopropyl-7-(4-(((diisopropylamino)carbonyl)amino)-4,5,6,7-tetrahydro-l-benzothien- 2-yl)-8-methoxy-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid The desired product was prepared by substituting N,N-diisopropylcarbamoyl chloride for N-methyl-N-phenylcarbamoyl chloride in Example 186. MS (DCI/NH3) m/z 538 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.78 (s, IH), 8.10 (d, IH), 7.84 (d, IH), 7.58 (s, IH), 6.18 (d, IH), 4.86 (m, IH), 4.24 (m, 2H), 3.75 (m, 2H), 3.68 (s, 3H), 2.80 (m, 2H), 2.05 (m, IH), 1.93 (m, IH), 1.78 (m, 2H), 1.22 (t, 6H), 1.14 (m, 2H), 1.04 (m, 2H).
Example 189 l-cvclopropyl-8-methoxy-7-(4-((4-moφholinylcarbonyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid The desired product was prepared by substituting moφholine-4-carbanoyl chloride for N-methyl-N-phenylcarbamoyl chloride in Example 186. MS (DCI/NH3) m/z 524 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 8.78 (s, IH), 8.11 (d, IH), 7.96 (d, IH), 7.56 (s, IH), 6.79 (d, IH), 4.87 (m, IH), 4.69 (m, IH), 4.75 ( , 2H), 4.05 (m, 2H), 3.70 (m, IH), 3.68 (s, 3H), 3.56 (m, IH), 2.78 (m, 2H), 1.65-2.03 (m, 4H), 1.16 (m, 2H), 1.03 (m, 2H).
Example 190 l-cvclopropyl-8-methoxy-7-(4-((methoxycarbonyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting methyl chloroformate for N- methyl-N-phenylcarbamoyl chloride in Example 186. MS (DCI7NH3) m/z 469 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 8.79 (s, IH), 8.11 (d, IH), 7.99 (d, IH), 7.59 (s, IH), 4.68 (m, IH), 4.25 ( , IH), 3.68 (s, 3H), 3.59 (s, 3H), 2.78 (m, 2H), 1.64-2.02 (m, 4H), 1.17 (m, 2H), 1.03 (m, 2H).
Example 191 7-(4-(((benzyloxy)carbonyl)amino)-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid
The desired product was prepared by substituting benzyl choroformate for N- methyl-N-phenylcarbamoyl chloride in Example 186. MS (DCI/NH3) m/z 545 (M+H)+;
1H NMR (300 MHz, DMSO-ds) δ 8.78 (s, IH), 8.10 (d, IH), 7.90 (d, IH), 7.72 (d, IH), 7.55 (s, IH), 7.49 (m, 3H), 7.45 (m, IH), 5.11 (dd, 2H), 4.71 (m, IH), 4.25 (m, 2H), 3.67 (s, 3H), 2/79 ( , 2H), 1.64-2.02 (m, 4H), 1.15 ( , 2H), 1.02 (m, 2H). Example 192 l-cyclopropyl-7-(4-((isobutoxycarbonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid
The desired product was prepared by substituting isobutyl chloroformate for N- methyl-N-phenylcarbamoyl chloride in Example 186. MS (DCI/NH3) m/z 511 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 8.78 (s, IH), 8.10 (d, IH), 7.94 (d, IH), 7.58 (s, IH), 7.54 (d, IH), 4.68 (m, IH), 4.26 (m, IH), 3.82 (m, 2H), 3.68 (s, 3H), 2.78 (m, 2H), 1.63- 2.04 (m, 5H), 1.16 (m, 2H), 1.04 (m, 2H), 0.91 (d, 6H).
Example 193 l-cvclopropyl-7-(4-((ethoxycarbonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting ethyl chloroformate for N- methyl-N-phenylcarbamoyl chloride in Example 186. MS (DCI/NH3) m/z 483 (M+H)+; Η NMR (300 MHz, DMSO-ds) δ 8.78 (s, IH), 8.10 (d, IH), 7.96 (d, IH), 7.59 (s, IH),
7.52 (d, IH), 4.68 (m, IH), 4.26 (m, IH), 4.05 (q. 2H), 3.68 (s, 3H), 2.78 (m, 2H), 1.98 (m, 2H), 1.80 (m, IH), 1.70 (m, IH), 1.21 (t, 3H), 1.15 (m, 2H), 1.02 (m, 2H).
Example 194
7-(4-((butoxycarbonyl)amino)-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting n-butyl chloroformate for N- methyl-N-phenylcarbamoyl chloride in Example 186. MS (DCI/NH3) m/z 511 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 14.92 (br s, IH), 8.78 (s, IH), 8.10 (d, IH), 7.96 (d, IH), 7.58 (s, IH), 7.52 (d, IH), 4.68 (m, IH), 4.23 (m, IH), 4.02 (m, 2H), 3.68 (s, 3H), 2.78 (m, 2H), 1.97 (m, 2H), 1.80 (m, IH), 1.70 (m, IH), 1.56 (m, 2H), 1.46 (m, 2H), 1.15 (m, 2H), 1.03 (m, 2H), 0.90 (t, 3H).
Example 195 7-(4-(((4-chlorobutoxy)carbonyl)amino)-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting 4-chlorobutyl chloroformate for N-methyl-N-phenylcarbamoyl chloride in Example 186. MS (DCI/NH3) m/z 546 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 8.79 (s, IH), 8.12 (d, IH), 7.96 (d, IH), 7.59 (s, IH), 6.79 (d, IH), 4.87 (m, IH), 4.25 (m, IH), 3.68 (s, 3H), 3.55 (m, 4H), 2.80 (m, 2H), 1.64- 2.06 (m, 4H), 1.18 (m, 2H), 1.03 (m, 2H).
Example 196 l-cycIopropyl-7-((5E/Z)-5-(hvdroxymethylene)-4-oxo-4,5,6,7-tetrahydro-l-benzothien-2- yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid A solution of sodium methoxide (0.30 g, 5.6 mmol) and ethyl formate (0.45 mL, 5.6 mmol) in toluene (10 mL) at 0°C was treated with example 50A (0.82 g, 1.9 mmol). The reaction mixture was stirred at 0°C for 3 hours then at room temperature for 2 hours and partitioned between IM sodium hydroxide and dichloromethane. The aqueous layer was acidified with IM hydrochloric acid and the product extracted into dichloromethane, dried (Na2SO4), filtered, and concentrated to yield (0.10 g, 12%) of the desired compound. MS (DCI/NH3) m/z 438 (M+H)+;
Η NRM (300 MHz, CDC13) δ 8.93 (s, IH), 8.28 (d, IH), 7.98 (s, IH), 7.82 (d, IH), 7.51 (m, IH), 4.14 (m, IH), 3.70 (s, 3H), 3.10 (t, 2H), 2.77 (m, 2H), 1.31 (m, 2H), 1.08 (m, 2H).
Example 198 l-cvclopropyl-7-(4-(3-hydroxy-l-azetidinyl)-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid hydrochloride
Figure imgf000187_0001
Example 198A A solution of 4-keto-4,5,6,7-tetrahydrothianaphthene (5.0 g, 32.85 mmol) in methanol (100 mL) at 0°C was treated with sodium borohydride (2.3 g, 60.80 mmol) and stirred 2 hours. The reaction mixture was partitioned between dichloromethane and water, the aqueous layer extracted with dichloromethane, the combined organic layers dried (Na2SO ) and concentrated to yield the desired compound (5.06 g, 100%).
Figure imgf000188_0001
Example 198B The desired product was prepared by substituting example 198A and dichloromethane as the reaction solvent for example 37A and 1:1 toluene:dichloromethane as reaction solvent, respectively in example 37B and was used without further purification.
Figure imgf000188_0002
Example 198C
The desired product was prepared by substituting example 198B for example 201C example 20 ID.
Figure imgf000188_0003
Example 198D A solution of example 198C (2.64 g, 10.4 mmol) in dichloromethane (20 mL) was treated with 4M HCI in dioxane (5.2 mL) at room temperature for 4 hours. The resulting precipitate was filtered, rinsed with diethyl ether, suspended in a 1 : 1 mixture of dichloromethane and methanol (50 mL) and treated with Amberlite IRA-400 (OH) ion exchange resin at room temperature for 2 hours. The resin was filtered and the filtrate concentrated to yield the desired product (0.72 g, 45%).
Figure imgf000188_0004
Example 198E A solution of example 198D (0.72 g, 4.7 mmol) in isopropanol (20 mL) was treated with epichlorohydrin (0.48 mL, 6.1 mmol) and heated to 75°C for 26 hours. The reaction mixture was partitioned between 5% sodium bicarbonate solution and dichloromethane, the organic phase dried (Na2SO ) and concentrated to yield the desired compound (0.47 g, 48%).
Figure imgf000189_0001
Example 198F A solution of example 198E (0.47 g, 2.2mmol) in dichloromethane (30 mL) was cooled to 0°C, treated with tert-butyldimethylsilyl chloride (2.5 mL of a 1.0M solution in dichloromethane, 2.5mmol) and imidazole (0.28 g, 4.0 mmol), and stirred for 3 hours at this temperature followed by 20 hours at room temperature. The reaction mixture was partitioned between water and dichloromethane, dried (Na2SO4) and the concentrated residue purified by silica gel chromatography eluting with 2% methanol in dichloromethane to yield the desired compound (0.58 g, 80%).
Figure imgf000189_0002
Example 198G The desired product was prepared by substituting example 198F for example 218B in example 218C.
Figure imgf000189_0003
Example 198H
The desired product was prepared by substituting example 198G, ethyl 7-bromo-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate and a reaction time of 3 hours for example ID, ethyl 7-bromo-l-cyclopropyl-4-oxo-l,4-dihydro-3- quinolinecarboxylate and a reaction time of 24 hours, respectively in example IE. Example 1981 l-cvclopropyl-7-(4-(3-hydroxy-l-azetidinyl)-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride The desired product was prepared by substituting example 198H for example 35D in example 35E and the crude product treated with 4M HCI in dioxane. MS (DCI/NH3) m/z 467 (M+H)+;
1H NMR (300 MHz, CD3OD) δ 8.96 (s, IH), 8.23 (d, 1H0, 7.95 (d, IH), 7.74 (s, IH), 4.60 (m, IH), 4.40 (m, 2H), 4.28 (m, 2H), 4.13 (m, IH), 3.94 (m, 2H), 3.72 (s, 3H), 2.97 (m, 2H), 2.03 (m, 4H), 1.28 (m, 2H), 1.06 (m, 2H).
Example 199 k
7-(4-amino-5-methyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride
Figure imgf000190_0001
Example 199 A The desired product was prepared by substituting example 185J for example 37A in example 37B and was purified by chromatography on silica gel eluting with CH2Cl2:CH3OH (98:2) to give a yellow solid.
Figure imgf000190_0002
Example 199B The desired product was prepared by substituting example 199 A for example 20 IC in example 201D and was purified by chromatography on silica gel eluting with CH2Cl2:CH3OH (96:4) to give a yellow oil.
Figure imgf000191_0001
Example 199C The desired product was prepared by substituting example 199B for example 2A in example 2B.
Example 199D 7-(4-amino-5-methyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cvclopropyl-8-methoxy-4- oxo-l,4-dihydro-3-quinoIinecarboxylic acid hydrochloride The desired product was prepared by substituting example 199C for example 40B in example 40C.
MS (ESI) m/z 425 (M+H+)+; Η NMR (300 MHz, DMSO-de) δ 8.80 (s, IH), 8.5 (br s, 2H, maj, min), 8.49 (br s, IH, maj, min), 8.17 (d, IH, maj, min), 8.11 (s, IH, maj), 7.96 (s, IH, min), 7.91 (d, IH, maj, min), 4.40 (br s, IH, min), 4.26 (m, 2H, maj, min), 4.09 ( t, IH, maj), 3.74 (s, 3H, min), 3.70 (s, 3H, maj), 2.92-2.84 (m, 2H, maj, min), 2.10-2.08 (m, 2H, maj, min), 1.86-1.84 (m, IH, min), 1.72-1.68 (m, IH, maj), 1.14 (d, 3H, maj, min), 1.08 (d, 2H, maj, min), 1.02 (br s, 2H).
Example 200 7-(4-amino-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l-cvclopropyl-4-oxo-l,4-
Figure imgf000191_0002
Example 200A The desired product was prepared by substituting example 38B and ethyl 1- cylopropyl-7-chloro-4-oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylate for example ID and ethyl l-cyclopropyl-7-bromo-8-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylate, respectively in example IE and the crude material purified by silica gel chromatography eluting with 2: 1 hexane:acetone.
Figure imgf000192_0001
Example 200B The desired product was prepared by substituting example 200A for example 35Dιn example 35E to give a yellow solid that was used without further punfication.
Figure imgf000192_0002
Example 200C The desired product was prepared by substituting example 200B and 1:10 THF/dichloromethane as reaction solvent for example 37A for 1:1 toluene/dichloromethane as reaction solvent, respectively in example 37B.
Figure imgf000192_0003
Example 200D The desired product was prepared by substituting example 200C for example 201C in example 201D and the crude product tπturated in 3:1 hexane/acetone and filtered to provide a cream colored solid.
Example 200E 7-(4-amιno-4,5,6,7-tetrahvdro-l-benzothιen-2-yl)-l-cyclopropyl-4-oxo-l,4- dιhydrori,81naphthyndιne-3-carboxylιc acid hydrochlonde The desired product was prepared by substituting example 200D for example 48C and THF for EtOH in example 48D and the reaction mixture filtered to provide a yellow solid. MS (APCI ) m/z 382 (M+H)+;
IH NMR (300 MHz, DMSO-*) δ 14.75 (bs, IH), 8.80 (s, IH), 8.73 (d, IH), 8.64 (s, 3H), 8.33 (s, IH), 7.92 (d, IH), 4.41 ( , IH), 3.82 (m, IH), 2.86 (m, 2H), 2.12 (m, 2H), 1.86 (m, 2H), 1.31 (m, 2H), 1.15 (m, 2H) Example 201
7-(7-amino-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cvclopropyl-8-methoxy-4-oxo-l,4- dihydro-3-quinolinecarboxylic acid hydrochloride
Figure imgf000193_0001
Example 201 A The desired product was prepared by substituting example 41B and ethyl 7-bromo- l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate for example ID and ethyl 7-bromo-l -cyclopropyl -4-oxo-l,4-dihydro-3-quinolinecarboxylate, respectively in example IE followed by substituting the resulting crude product for example 38C in example 39A.
Figure imgf000193_0002
Example 20 IB
The desired product was prepared by substituting example 201 A for example 35D in example 35E and was purified by silica gel chromatography eluting with hexane then
50% acetone in hexane to provide the desired product.
Figure imgf000193_0003
Example 20 IC The desired product was prepared by substituting example 201B for example 37A in example 37B and was purified by silica gel chromatography eluting with hexane then
50% acetone in hexane to provide the desired product.
Figure imgf000194_0001
Example 20 ID
A solution of example 201C (0.751 g, 1.70 mmol), palladium hydroxide (0.075 g), and di-t-butyl dicarbonate (1.85 g, 8.50 mmol) in ethanol (20mL) was treated with tπethyl silane (1.1 mL, 6.80 mmol) and stirred overnight. The reaction mixture was filtered. The filtrate was partitioned between CH2C12 and water. The aqueous phase was extracted with CH2C12, the combined organic phases washed with water, bπne, dπed (Na2SO4), and concentrated. The residue was puπfied by silica gel chromatography eluting with a gradient of hexane to 50% acetone in hexane to provide the desired product (0.540 g, 1.00 mmol) as a yellow solid.
Figure imgf000194_0002
Example 201E
The desired product was prepared by substituting example 20 ID for example 2A in example 2B
Example 20 IF 7-(7-amιno-4,5,6,7-tetrahvdro-l-benzothιen-2-yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4- dιhvdro-3-quιnolιnecarboxylιc acid hydrochlonde The desired product was prepared by substituting example 201E for example 40B in example 40C Mp 174-178°C, MS (DCI/NH3) m/z 411 (M+l)+, Η NMR (300 MHz, DMSO-*) δ 14.86 (br s, IH), 8.82 (s, IH), 8.46 (br s, 2H), 8.15 (d, IH), 8.04 (d, IH), 7.67 (s, IH), 4.62 (m, IH), 4.27 (m, IH), 3.71 (s, 3H), 2.72 (m, 2H), 2.14-1.82 (m, 4H), 1.16-1.04 (m, 4H); 13C NMR (75 MHz, DMSO-*) δ 177.2, 165.6, 151.7, 147.0, 139.6, 136.3, 136.0, 134.5, 132.8, 128.7, 126.5, 125.8, 121.6, 107.8, 66.4, 62.9, 45.1, 27.8, 24.8, 18.3, 9.2, 9.1; IR (mic) 3420 (COOH), 1730 (C=O) cm"1; Anal, calcd for C22H23N2O4SC1 0.5 H2O: C, 57.95; H, 5.30; N, 6.14; found: C, 57.95; H, 5.25; N, 6.25.
Example 202 l-cyclopropyl-7-(7-hydroxy-4,5,6,7-tetrahydrothieno[3,2-elpyridin-2-yl)-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxyIic acid
Figure imgf000195_0001
Example 202A
A solution of 7-hydroxy-4,5,6,7-tetrahydrothieno(3,2-c)pyridine (prepared by the method of Maffrand, et. al.; .Heterocycl.Chem. 13; 1976; 1347-1349) (2.10 g, 13.50 mmol) in CH C12 (20 mL) and di-tert-butyldicarbonate (3.54 g, 16.2 mmol) was stirred overnight at ambient temperature. The reaction mixture was poured over water, extracted with diethyl ether and the combined organic phases dried (Na2SO4) and the crude product purified by silica gel chromatography eluting with 15% Et2O in hexanes to afford the desired product (1.03 g, 31% yield) as a clear oil.
Figure imgf000195_0002
Example 202B The desired product was prepared by substituting example 202A for example 185F in example 185G.
Figure imgf000196_0001
Example 202C The desired product was prepared by substituting example 202B for example 11C in examplel lD.
Figure imgf000196_0002
Example 202D The desired product was prepared by substituting example 202C and ethyl 7- bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate for example ID and 7-bromo-l-cyclopropyl-4-oxo-l,4-dihydro-3-quinolinecarboxylate, respectively in example IE and was purified by silica gel chromatography eluting with a gradient from 20-50% acetone in hexanes.
Figure imgf000196_0003
Example 202E The desired product was prepared by substituting example 202D for example 35D in example 35E and was purified by silica gel chromatography eluting with 25% acetone in hexanes followed by 4% methanol in CH2C12.
Example 202F l-cyclopropyl-7-(7-hydroxy-4,5,6,7-tetrahydrothienor3,2-clpyridin-2-yl)-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid
The desired product was prepared by substituting example 202E for example 59C in example 59D to give the product as a colorless solid. MS (DCI/NH3) m/z 413 (M+H)+; Η-NMR (300 MHz, d6-DMSO) δ 9.75 (br s, IH), 9.40 (br s, IH), 8.80 (s, IH), 8.15 (d, IH), 7.95 (d, IH), 7.69 (s, IH), 5.05 (t, IH), 4.25 (m, 3H), 3.70 (s, 3H), 3.60-3.20 (br m, 2H), 1.17 (m, 2H), 1.05 (m, 2H).
Example 203 l-cvclopropyl-8-methoxy-4-oxo-7-(7-oxo-4,5,6,7-tetrahydrothienof3,2-clpyridin-2-yl)-l,4- dihydro-3-quinolinecarboxylic acid hydrochloride
Figure imgf000197_0001
Example 203A The desired product was prepared by substituting example 202D for example 41C in example 324511A and was purified by silica gel chromatography eluting with a gradient from 20-30% acetone in hexanes step.
Example 203B l-cyclopropyl-8-methoxy-4-oxo-7-(7-oxo-4,5,6,7-tetrahvdrothieno[3,2-clpyridin-2-yl)-l,4- dihydro-3-quinolinecarboxylic acid hydrochloride The desired product was prepared by substituting example 203A for example 59C in example 59D.
MS (DCI/NH3) m/z 411 (M+H)+;
1H-NMR (300 MHz, d6-DMSO) δ 10.26 (br s, IH), 8.83 (s, IH), 8.23 (d, IH), 8.11 (d, IH), 8.03 (s, IH), 4.58 (s, 2H), 4.28 (m, IH), 4.12 (s, 2H), 3.75 (s, 3H), 1.18 (m, 2H), 1.08 (m, 2H).
Example 204 l-cyclopropyl-7-(5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting example 206E for example 2A in example 2B and the resulting crude product triturated in hot 33% acetone in hexanes and filtered to give a buff solid. MS (APCI) m/z 448 (M+H)+;
Η NMR (300 MHz, DMSO-*) δ 8.80 (s, IH), 8.13 (d, IH), 8.02 (d, IH), 7.73 (s, IH), 6.13 ( , IH), 4.71 (m, IH), 4.27 (m, IH), 3.69 (s, 3H), 3.04-2.90 (m, 2H), 2.50-2.21 (m, 2H), 1.15 (m, 2H), 1.04 (m, 2H).
Example 206
7-(4-amino-5,5-difluoro-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-
4-oxo-l,4-dihydro-3-quinolinecarboxylic acid
Example 206A
A solution of 4-keto-4,5,6,7-tetrahydrothianapthene (3.16 g, 20.8 mmol) in THF (150 ml) was treated with N-fluorobenzenesulfonamide (15.06 g, 47.8 mmol), cooled to - 78 °C, treated dropwise with lithium bis(trimethylsilyl)amide (52.0 ml of a IM THF solution, 51.9 mmol), stirred 1 hour at this temperature and allowed to come to room temperature and stir for 14 hours. The resulting reaction mixture was treated with water (2 ml) and partitioned between saturated aqueous ammonium chloride and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic layers washed with saturated aqueous NaHCO3, water, brine and dried (MgSO4). After concentration, the crude residue was purified by column chromatography on silica gel eluting with 10% then 20% ethyl acetate in hexanes to give the desired product (2.96 g, 76%) as an amber oil.
Figure imgf000198_0002
Example 206B
The desired product was prepared by substituting example 206 A for example 218A in example 218B and the crude residue purified by silica gel chromatography eluting with 10 % ethyl acetate in hexanes.
Figure imgf000198_0003
Example 206C
The desired product was prepared by substituting example 206B for example 218B in example 218C and was used without further purification.
Figure imgf000199_0001
Example 206D
The desired product was prepared by substituting example 206C and ethyl 7-bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate for example ID and 7-bromo-l-cyclopropyl-4-oxo-l,4-dihydro-3-quinolinecarboxylate, respectively in example IE and the crude residue purified by silica gel chromatography eluting with hexanes, 20% acetone in hexanes, 25% acetone in hexanes then 33% acetone in hexanes.
Figure imgf000199_0002
Example 206E
The desired product was prepared by substituting example 206D for example 35D in example 35E and the crude alcohol carried on without purification.
Figure imgf000199_0003
A solution of example 204E (1.41 g, 2.97 mmol) in CH2C12 (50 ml) was treated with diphenylphosphorylazide (2.45 g, 8.91 mmol) followed by DBU (1.36 g, 8.91 mmol) and stirred at room temperature for 16 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous NH4CI and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with 10% H3PO4, water, brine and dried (MgSO4). Concentration gave the phosphonate as a thick amber oil that was carried on without purification.
A solution of the above phosphonate in DMSO (50 ml) was treated with sodium azide (1.93 g, 29.7 mmol) and heated to 85 °C for 14h. The reaction mixture was poured into 700 ml water, diluted with 200 ml ethyl acetate and NaCl added slowly to the stirred mixture until the layers resolved. The layers were separated and the aqueous phase extracted with ethyl acetate and the combined organic layers washed with water, brine and dried (MgSO ). The concentrated residue was purified by silica gel chromatography eluting with a gradient from 25% to 33% acetone in hexanes to give the desired product (0.527 g, 36%) as a tan foam.
Figure imgf000200_0001
Example 206G
The desired product was prepared by substituting example 206F for example 201C in example 201C and the crude product purified by silica gel chromatography eluting with 33% acetone in hexanes.
Figure imgf000200_0002
The desired product was prepared by substituting example 206G for example 2A in example 2B and the crude product purified by silica gel chromatography eluting with 3% methanol in CH2C12.
Figure imgf000200_0003
Example 2061 7-(4-amino-5,5-difluoro-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy- 4-oxo-l,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting example 206H for example 40B in example 40C. MS (ESI) m/z 447 (M+H)+;
Η NMR (300 MHz, DMSO-*) δ 9.17 (br s, 3H), 8.81 (s, IH), 8.22 (d, IH), 8.09 (s, IH), 7.87 (d, IH), 5.03 (m, IH), 4.27 (m, IH), 3.71 (s, 3H), 3.12 (m, 2H), 2.75-2.50 ( , 2H), 1.16 (m, 2H), 1.05 (m, 2H). Example 207 l-cyclopropyl-7-(5-(hvdroxymethyl)-5-methyl-4-oxo-4,5,6,7-tetrahydro-l-benzothien-2- yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid
Figure imgf000201_0001
Example 207A
The desired product was prepared by substituting 4-Keto-4, 5,6,7- tetrahydrothianaphthene for example 5 le 196A.
Figure imgf000201_0002
Example 207B A solution of example 207A (1.73 g, 9.6 mmol) in acetone (100 mL) was treated with potassium carbonate (3.97g, 28.8 mmol) and methyl iodide (0.78 mL, 12.5 mmol) at room temperature for 28 hours. The reaction mixture was partitioned between water and dichloromethane, dried (Na2SO4), filtered, concentrated, and purified by silica gel chromatography eluting with 1% methanol in dichloromethane to yield 1.05 g (56%) of the desired compound.
Figure imgf000201_0003
Example 207C A solution of example 207B (1.03 g, 5.3 mmol) in dichloromethane (40 mL) was treated with acetic acid (2 drops) and sodium cyanoborohydride (0.30 g, 6.1 mmol) at room temperature for 3 hours. The reaction mixture was partitioned between dichloromethane and water, dried (Na2SO ), concentrated and purified by silica gel chromatography eluting with a gradient of 1% to 4% methanol in dichloromethane to yield (0.26 g, 13%) of the desired compound.
Figure imgf000201_0004
Example 207D The desired product was prepared by substituting example 207C for example 198E in example 198F.
Figure imgf000202_0001
Example 207E The desired product was prepared by substituting example 207D for example 218B in example 218C.
Figure imgf000202_0002
Example 207F The desired product was prepared by substituting example 207E, ethyl 7-bromo- l- cyclopropyl-8-methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylate and a reaction time of 4 hours for example ID, ethyl 7-bromo-l -cyclopropyl -4-oxo-l, 4-dihydro-3- quinolinecarboxylate and a reaction time of 24 hours in example IE.
Example 207G l-cvclopropyl-7-(5-(hvdroxymethyl)-5-methyl-4-oxo-4,5,6,7-tetrahydro-l-benzothien-2- yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting example 207F for example 35D in example 35E and the crude product triturated with 1: 1 diethyl etheπethanol. MS (ESI+) m/z 454 (M+H)+; Η NMR (300 MHz, DMSO-*) δ 8.81 (s, IH), 8.11 (d, IH), 7.96 (d, IH), 7.51 (s, IH), 4.27 (m, IH), 4.00 (s, 2H), 3.70 (s, 3H), 3.17 (m, 2H), 2.35 (m, 2H), 1.96 (m, 2H), 1.17 (m, 2H), 1.05 (m, 2H), 0.81 (s, 3H).
Example 208
7-(7-amino-4,5,6,7-tetrahvdrothieno[3,2-c1pyridin-2-vI)-l-cyclopropyl-8-methoxy-4-oxo- l,4-dihvdro-3-quinolinecarboxylic acid
Figure imgf000203_0001
Example 208A The desired product was prepared by substituting example 202E for example 37A in example 37B and was punfied by silica gel chromatography eluting with 20% acetone in hexanes.
Figure imgf000203_0002
Example 208B The desired product was prepared by substituting example 208A for example 353365C in example 353365D and was puπfied by silica gel chromatography using 20% acetone in hexanes.
Example 208C 7-(7-amιno-4,5,6,7-tetrahvdrothιenor3,2-clpyndιn-2-yl)-l-cvclopropyl-8-methoxy-4-oxo- l,4-dιhydro-3-quιnolιnecarboxyIιc acid The desired product was prepared by substituting example 208B for example 59C in example 59D and was puπfied by tπturation in methanol / Et2O and filtered to give the solid product.
MS (DCIVNH3) m/z 412 (M+H)+;
Η-NMR (300 MHz, d6-DMSO) δ 10.25 (br s, IH), 9.07 (br s, 2H), 8.82 (s, IH), 8.18 (d, IH), 8.04 (d, IH), 7.78 (s, IH), 5 00 (m, IH), 4.45-4.20 (m, 3H), 3.80-3.60 (m, 5H), 1.20- 1.00 (m, 4H).
Example 209 l-cyclopropyl-7-(4-hvdroxy-4,5,6,7-tetrahydrothιeno[2,3-clpyπdιn-2-yl)-8-methoxy-4- oxo-l,4-dιhydro-3-quιnolιnecarboxylιc acid
Figure imgf000204_0001
Example 209A The desired product was prepared by substituting 4-hydroxy-4,5,6,7- tetrahydrothieno(2,3-c)pyridine was (prepared by the method of Maffrand, et.al.; Heterocycles; 1980, 14; 321-324) for 7-hydroxy-4,5,6,7-tetrahydrothieno(3,2-c)pyridine in example 202A.
Figure imgf000204_0002
Example 209B The desired product was prepared by substituting example 209A for example 202A in example 202B.
Figure imgf000204_0003
Example 209C The desired product was prepared by substituting example 209B for example 202B in example 202C.
Figure imgf000204_0004
Example 209D The desired product was prepared by substituting example 209C and ethyl 7- bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate for example ID and 7-bromo-l-cyclopropyl-4-oxo-l,4-dihydro-3-quinolinecarboxylate, respectively in example IE.
Figure imgf000205_0001
Example 209E The desired product was prepared by substituting example 209D for example 35D in example 35E.
Figure imgf000205_0002
Example 209F l-cycIopropyl-7-(4-hydroxy-4,5,6,7-tetrahvdrothienor2,3-c'1pyridin-2-yl)-8-methoxy-4- oxo-l,4-dihvdro-3-quinolinecarboxylic acid The desired product was prepared by substituting example 209E for example 59C in example 59D.
MS (DCI/NH3) m/z 413 (M+H)+;
1H-NMR (300 MHz, dό-DMSO) δ 9.90 (br s, IH), 9.42 (br s, IH), 8.80 (s, IH), 8.15 (d, IH), 8.03 (d, IH), 7.83 (s, IH), 4.92 (t, IH), 4.55-4.30 (m, 2H), 4.25 (m,lH), 3.68 (s, 3H), 3.40 (m, 2H), 1.15 (m, 2H), 1.05 (m,2H).
Example 210 l-cvclopropyl-6-fluoro-8-methoxy-7-(4-(methylamino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinoIinecarboxylic acid hydrochloride
Figure imgf000205_0003
Example 210A The desired product was prepared by substituting 4-keto4,5,6,7- tetrahydrothianaphthene for 7-keto4,5,6,7-tetrahydrothianaphthene in example 216A.
Figure imgf000206_0001
Example 21 OB The desired product was prepared by substituting example 210A for example 218B in example 218C.
Figure imgf000206_0002
Example 2 IOC
The desired product was prepared by substituting example 21 OB, ethyl-7-bromo-l- cyclopropyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate.and a reaction time of 3 hours for example ID and ethyl-7-bromo-l-cyclopropyl-4-oxo-l,4-dihydro-3- quinolinecarboxylate and a reaction time of 24 hours in example aand was purified by chromatography on silica gel with 1% HO Ac in ethyl acetate.
Figure imgf000206_0003
Example 210D The desired product was prepared by substituting example 210C for example 2A in example 2B.
Example 210E l-cvclopropyl-6-fluoro-8-methoxy-7-(4-(methylamino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride The desired product was prepared by substituting example 210D for example 40B in example 40C. MS (ESI) m/z 443 (M+H )+ Η NMR ( 300MHz,DMSO-*) 9.10 (br,lH),7.96 ( d,lH),7.85 ( d,lH),4.43
(m,lH),4.22(m,lH),4.02(s,lH),3.65(s,3H),2.90(m,2H),262(s,3H),2.15-
1.97(m,3H),1.86(m,lH),1.15(m,2H),1.10(m,2H).
Example 211 l-cvclopropyl-8-methoxy-4-oxo-7-(4-oxo-4,5,6,7-tetrahvdrothienor2,3-clpyridin-2-yl)-l,4- dihydro-3-quinolinecarboxyIic acid hydrochloride
Figure imgf000207_0001
Example 211 A The desired product was prepared by substituting example 209E for example 41C in example 324511 A and was purified by silica gel chromatography eluting with a gradient from 20-30% acetone in hexanes.
Example 21 IB l-cyclopropyl-8-methoxy-4-oxo-7-(4-oxo-4,5,6,7-tetrahydrothienor2,3-clpyridin-2-yl)-l,4- dihydro-3-quinolinecarboxylic acid hydrochloride The desired product was prepared by substituting example 211 A for example 59C in example 59D.
MS (DCI NH3) m/z 411 (M+H)+;
Η-NMR (300 MHz, d6-DMSO) δ 10.30 (br s, IH), 8.82 (s, IH), 8.20 (d, IH), 8.17 (s, IH), 8.16 (d, IH), 4.77 (s, 2H), 4.26 (m, IH), 4.06 (s, 2H), 3.71 (s, 3H), 1.15 (m, 2H), 1.05 (m, 2H).
Example 212
7-[4-(3-amino-l-azetidinyl)-4,5,6,7-tetrahydro-l-benzothien-2-yll-l-cycIopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinoIinecarboxylic acid dihydrochloride
Figure imgf000208_0001
Example212A A solution of example 83A (1.26 g, 2 9 mmol) in isopropanol (25 mL) was treated with epichlorohydπn (0.27 mL, 3.7 mmol) at 75°C for 65 hours. The reaction mixture was partitioned between water and dichloromethane, dπed (Na2SO4), and the concentrated residue purified by silica gel chromatography eluting with a gradient of 1% to 6% methanol in dichloromethane to y e desired compound.
Figure imgf000208_0002
Example 212B The desired product was prepared by substituting example 212A for example
358696E in example 358696F and was used without further puπfication.
Figure imgf000208_0003
Example 212C The desired product was prepared by substituting example 212B for example 201C in example 201D and the crude product puπfied by silica gel chromatography eluting with a gradient of 1% to 3% methanol in dichloromethane to.
Example 212D 7-r4-(3-amιno-l-azetιdιnvI)-4,5,6,7-tetrahydro-l-benzothιen-2-yll-l-cyclopropyl-8- methoxy-4-oxo-l,4-dιhvdro-3-quιnolmecarboxyIιc acid dihydrochlonde
The desired product was prepared by substituting example 212C and tetrahydrofuran as the reation solvent for example 48C and ethanol as the reaction solvent in example 48D. MS (ESI+) m/z 466 (M+H)+; Η NMR (300 MHz, CD3OD) δ 8.97 (s, IH), 8 23 (d, IH), 7.99 (d, IH), 7.83 (s, IH), 4 48- 4.74 (m, 4H), 4.37 (m, IH), 4 28 (m, IH), 3 72 (s, 3H), 2.86-3.14 (m, 2H), 2 00-2.20 ( , 4H), 1 28 (m, 2H), 1.06 (m, 2H) Example 213 l-cyclopropyl-7-(4-hydroxy-5,5-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methox V-4-QXQ- 1 ,4-dih vdro-3-quinolinecarboxylic acid
Figure imgf000209_0001
Example 213 A An oven-dried system under positive N2 atmosphere was charged with 60%
NaH/mineral oil (2.20 g, 56.2 mmol), which was washed twice with hexane to remove the mineral oil. Added 40 mL dry DMF and cooled in an ice bath. To this was added 4-keto- 4,5,6,7-tetrahydrothianaphthene (3.37 g, 22.0 mmol) in 40 mL of dry DMF dropwise with stirring. After 30 minutes Mel (5.75 L, 92.5 mmol) was added dropwise with stirring. After 30 minutes the reaction was warmed to 25° C and stirred for 22 hours. The reaction was quenched by pouring into 250 mL 10% NH4CI. Extracted twice with CH C12. The combined organic layers were washed five times with water, dried (Na2SO4), filtered and concentrated. The entire procedure was repeated a second time to give complete dialkylation. The product was purified by silica gel chromatography eluting with CH C1 to give the desired product as a colorless oil (3.22 g, 82%).
Figure imgf000209_0002
Example 213B The desired product was prepared by substituting example 213 A for example 218 A in example 218B.
Figure imgf000209_0003
Example 213C The desired product was prepared by substituting example 213B for example 218B in example 218C.
Figure imgf000210_0001
Example 213D The desired product was prepared by substituting example 213C and ethyl 7- bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate and a reaction time of 6 hours for example ID and 7-bromo-l-cyclopropyl-4-oxo-l,4-dihydro-3- quinolinecarboxylate and a reaction time of 24 hours, respectively in example IE
Figure imgf000210_0002
Example 213E The desired product was prepared by substituting example 213D for example 35D in example 35E.
Example 213F l-cvclopropyl-7-(4-hvdroxy-5,5-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting example 213E for example 2 A in example 2B. mp 93-94° C;
MS (APCI) m/z 440 (M+H)+;
1H NMR (300 MHz, DMSO-*) δ 14.94 (br s, IH), 8.78 (s, IH), 8.12 (d, IH), 7.95 (d, IH), 7.70 (s, IH), 5.10 (d, IH), 4.25 (m, IH), 4.18 (d, IH), 3.70 (s, 3H), 2.70 (m, 2H), 1.60 (m, 2H), 1.18 (m, 2H), 1.07 (m, 2H), 0.95 (s, 3H), 0.90 (s, 3H).
Example 216 l-cyclopropyl-8-methoxy-7-(7-(methylamino)-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-4- oxo-l,4-dihvdro-3-quinolinecarboxylic acid hydrochloride
Figure imgf000211_0001
Example 216A
A solution of 7-keto-4,5,6,7-tetrahydrothienanapthene (prepared by the method of Caubere, et al. Eur. J. Med. Chem. 1998, 867-77) (1.819g, 12.0 mmol) and N-methyl ammonium acetate (14.32g, 157 mmol) in methanol (25 L) was cooled to 0°C and treated with sodium cyanoborohydride (0.530g, 8.40 mmol). The mixture was allowed to warm to room temperature and stirred for seven days. Water (5 mL) was added, the mixture was partitioned between 10% HCI and ethyl acetate. The aqueous phase was made basic with 1 Ν ΝaOH and extracted with ethyl acetate. The organic phase was washed with water and brine, dried (Νa2SO4), and concentrated. The resulting crude amine (1.081g, 6.50mmol) was dissolved in CH2C1 (15 mL) and treated with di-tert-butyl dicarbonate (1.53 g, 7.01mmol) and stirred overnight. The reaction mixture was diluted with CH2C12 and washed with water and brine, dried (Na SO4), and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of hexane to 25% ethyl acetate in hexane to provide the desired product (1.735 g, 54%) as an orange oil.
Figure imgf000211_0002
Example 216B
The desired product was prepared by substituting example 216A for example 218B in example 218C.
Figure imgf000212_0001
Example 216C The desired product was prepared by substituting example 216B and ethyl 7- bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate for example ID and ethyl 7-bromo-l-cyclopropyl-4-oxo-l,4-dihydro-3-quinolinecarboxylate, respectively in example IE.
Figure imgf000212_0002
Example 216D The desired product was prepared by substituting example 216C for example 2 A in example 2B.
Figure imgf000212_0003
Example 216E l-cvclopropyl-8-methoxy-7-(7-(methylamino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-4- oxo-l,4-dihvdro-3-quinolinecarboxylic acid hydrochloride The desired product was prepared by substituting example 216D for example 40B in example 40C. MS (DCI/NH3) m/z 425 (M+l)+; 'H NMR (300 MHz, DMSO-*) δ 8.82 (s, IH), 8.16 (d, IH), 8.05 (d, IH), 7.71 (s, IH), 4.58 (m, IH), 4.29 (m, IH), 3.71 (s, 3H), 2.87-2.67 (m, 5H), 2.20-1.75 (m, 4H), 1.17-1.05 (m, 4H).
Example 218 l-cyclopropyl-7-(7-hvdroxy-4,4-dimethyl-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid
Figure imgf000213_0001
Example 218A A solution 4,4-dimethyl-4,5,6,7-tetrahydrobenzo[b]thiophene (7.7 g, 46.3 mmol, prepared by the method of Reetz, et. al. Chem. Ber. 1985, 118, 1050-1057) in 250 mL of 1: 1 acetic acid/water at -15 °C was treated dropwise with a solution of Ce(SO )2 (74 g, 400 mmol) dissolved in 400 mL of water. The mixture was stirred for 16 hours, diluted with 500 mL of water and extracted 3 x 200 mL with Et2O. The extracts were combined, washed consecutively with IN NaOH, water, brine, dried (MgSO4), concentrated and the residue purified by flash chromatography on silica gel eluting with 10% EtOAc in hexane to give the desired compound (3.6 g, 43%) as a yellow oil.
Figure imgf000213_0002
Example 218B A solution of example 218A (4.17 g, 23.2 mmol) in EtOH (75 ml) was treated with NaBHt (880 mg, 23.2 mmol), heated at 50 °C for 2 hours, cooled, poured into 200 mL of iced water and extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4) and concentrated to give the crude alcohol which was used without purification. A solution of the crude alcohol (4.2 g, 23.2 mmol) and imidazole (1.9 g, 28 mmol) in methylene chloride (50 ml) at 0 °C was treated with tert-butyldimethylchlorosilane (3.85 g, 25.5 mmol), warmed to ambient temperature, stirred for 16 hours and partitioned between water and dichloromethane. The dichloromethane layer was separated, washed with brine, dried (MgSO ) and concentrated. The resulting residue was purified by flash chromatography on silica gel eluting with 10% EtOAc in hexane to give the desired compound (6.3 g, 92%) as a yellow oil.
Figure imgf000214_0001
Example 218C
A solution of diisopropyl amine (3.6 mL, 25.5 mmol) in THF (50 mL) was cooled to 0 °C, treated dropwise with n-BuLi (11.1 mL of a 2.5 M solution in hexanes, 27.7 mmol), stirred for 30 minutes and cooled to -50 °C. This solution was treated dropwise with a solution of example 218B (6.3 g, 21.3 mmol) in THF (10 mL), stirred for 1 hour at 0 °C, recooled to -50 °C, treated with chlorotributylstannane (9.0 g, 27.7 mmol) and allowed to warm to room temperature overnight. The reaction mixture was partitioned between water and ethyl acetate, the aqueous phase extracted with ethyl acetate, the combined organic phases washed with water, brine, dried (Na2SO4) and concentrated to provide the desired product that was used without further purification.
Figure imgf000214_0002
Example 218D The desired product was prepared by substituting example 218C and ethyl 1- cyclopropyl -7-bromo-8-methoxy-4-oxo- 1 ,4-dihydroquinoline-3-carboxylate for example ID and ethyl l-cyclopropyl-7-bromo-4-oxo-l,4-dihydroquinoline-3-carboxylate, respectively in Example IE and purified by silica gel chromatography eluting with 2:1 hexane:acetone.
Figure imgf000214_0003
Example 218E The desired product was prepared by substituting example 218D for example 35D in example 35E and was used without further purification. Example 218F l-cyclopropyl-7-(7-hydroxy-4,4-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid The desired product was prepared by substituting example 218E for example 2A in example 2B and the crude product purified by chromatography on silica gel eluting with 97:3 methylene chloride/methanol. MS (APCI ) m/z 440 (M+H)+;
IH NMR (300 MHz, DMSO- *) δ 14.95 (s, IH), 8.79 (s, IH), 8.10 (d, IH), 8.07 (d, IH), 7.76 (s, IH), 5.51 (d, IH), 4.71 (m, IH), 4.26 (m, IH), 3.69 (s, 3H), 2.01 (m, IH), 1.81- 1.55 (m, 3H), 1.27 (s, 3H), 1.26 (s, 3H), 1.15 (m, 2H), 1.03 (m, 2H).
Example 222 7-(7-amino-4,4-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy- 4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid hydrochloride
Figure imgf000215_0001
Example 222A The desired product was prepared by substituting example 218E for example 37 A in example 37B and was purified by silica gel chromatography eluting with 2:1 hexane:acetone.
Figure imgf000215_0002
Example 222B The desired product was prepared by substituting example 222A for example 201C in example 201D and separating the components by silica gel chromatography eluting with 3: 1 hexane:acetone. Example 227A was also isolated as a by-product.
Figure imgf000215_0003
Example 222C The desired product was prepared by substituting example 222B for example 2A in Example 2B.
Example 222D
7-(7-amino-4,4-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cvclopropyl-8-methoxy- 4-oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride The desired product was prepared by substituting example 222C for example 40B in example 40C. MS (APCI ) m/z 439 (M+H)+;
IH NMR (300 MHz, DMSO- *) δ 8.82 (s, IH), 8.52 (bs, 3H), 8.16 (d, IH), 8.13 (d, IH), 7.91 (s, IH), 4.56 (m, IH), 4.27 (m, IH), 3.72 (s, 3H), 2.20-1.60 (m, 4H), 1.35 (s, 3H), 1.26 (s, 3H), 1.15-1.00 (m, 4H).
Example 224
7-(4-amino-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-6-fluoro-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride
Figure imgf000216_0001
Example 224A
The desired product was prepared by substituting example 38B and ethyl-7-bromo- l-cyclopropyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate for example
IDand ethyl-7-bromo-l-cyclopropyl-4-oxo-l,4-dihydro-3-quinolinecarboxylate IE and was purified by silica gel c hyl acetate.
Figure imgf000216_0002
Example 224B The desired product was prepared by substituting example 224A for example 38C in example 39A.
Figure imgf000217_0001
Example 224C The desired product was prepared by substituting example 224B for example 35D in example 35E.
Figure imgf000217_0002
Example 224D The desired product was prepared by substituting example 224C for example 37A in example 37B.
Figure imgf000217_0003
Example 224E The desired product was prepared by substituting example 224D for example 20 IC in example 20 ID.
Figure imgf000217_0004
Example 224F The desired product was prepared by substituting example 224E for example 2A in example 2B.
Example 224G 7-(4-amino-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l-cyclopropyl-6-fluoro-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride The desired product was prepared by substituting example 224F for example 40B in example 40C. MS(ESI) m/z 429 (M+H)+; Η NMR (300MHz,DMSO-*)-δ
8.80(s,lH),8.53(br,2H),7.95(d,lH),7.87(d,lH),4.43(m,lH),4.23(m,lH),3.66(s,3H),2.86(m, 2H),2.20-2.00(m,2H), 1.87(m,2H), 1.17(m,2H), 1.08(m,2H).
Example 225 7-(4-amino-4,5,6,7-tetrahvdrothieno[2,3-clpyridin-2-yl)-l-cycIopropyl-8-methoxy-4-oxo-
1 ,4-dihydro-3-quinoIinecarboxyIic acid
Figure imgf000218_0001
Example 225A The desired product was prepared by substituting example 209E for example 37A in example 37B and was purified by silica gel chromatography eluting with 20% acetone in hexanes.
Figure imgf000218_0002
Example 225B The desired product was prepared by substituting example 225A for example 353365C in example 353365D and was purified by silica gel chromatography eluting with 20% acetone in hexanes.
Example 225C 7-(4-amino-4,5,6,7-tetrahydrothieno[2,3-clpyridin-2-yl)-l-cyclopropyl-8-methoxy-4-oxo-
1 ,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting example 225B for example 48C in example 48D and the crude solid product was triturated in methanol / Et2O, filtered and dried under vacuum. MS (DCI/NH3) m/z 412 (M+H)+;
Η-NMR (300 MHz, d6-DMSO) δ 10.30 (br s, IH), 9.10 (br s, 2H), 8.80 (s, IH), 8.20 (d, IH), 8.15 (s, IH), 7.90 (d, IH), 4.80 (m, IH), 4.52 (dd, 2H), 4.27 (m, IH), 3.72 (s, 3H), 3.80-3.58 (m, IH), 3.40 (br m, 3H), 1.15 (m, 2H), 1.05 (m, 2H).
Example 226
7-(7-azido-4,5,6,7-tetrahydrothienof3,2-clpyridin-2-yl)-l-cyclopropyI-8-methoxy-4-oxo-
1 ,4-dihydro-3-quinolinecarboxylic acid
The desired product was prepared by substituting example 208A for example 59C in example 59D.
MS (DCI7NH3) m/z 438 (M+H)+;
Η-NMR (300 MHz, d6-DMSO) δ 10.20 (br s, IH), 9.50 (br s, IH), 8.80 (s, IH), 8.18 (d,
IH), 8.02 (d, IH), 7.78 (s, IH), 5.48 (dd, IH), 4.25 (m, 3H), 3.72 (s, 3H), 3.72-3.50 (m,
2H), 1.17 (m, 2H), 1.07 (m, 2H).
Example 227 l-cvclopropyl-7-(4,4-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8-methoxy-4-oxo-
Figure imgf000219_0001
Example 227A The desired product was obtained as a by-product from Example 222B and was separated by silica gel chromatography eluting with 3: 1 hexane:acetone.
Example 227B l-cyclopropyl-7-(4,4-dimethyl-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-8-methoxy-4-oxo-
1 ,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting example 227A for example 2A in example 2B and was used without further purification. MS (APCI ) m/z 424 (M+H)+;
IH NMR (300 MHz, DMSO- *) δ 14.96 (s, IH), 8.79 (s, IH), 8.10 (d, IH), 8.08 (d, IH), 7.81 (s, IH), 4.25 (m, IH), 3.68 (s, 3H), 2.76 (t, 2H), 1.85 (m, 2H), 1.61 (m, 2H), 1.27 (s, 6H), 1.14 (m, 2H), 1.02 (m, 2H).
Example 228
7-(7-amino-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-6-fluoro-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride
Figure imgf000220_0001
Example 228A The desired product was prepared by substituting example 41B and ethyl 7-bromo- l-cyclopropyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate for example ID and ethyl 7-bromo-l-cyclopropyl-4-oxo-l,4-dihydro-3-quinolinecarboxylate, respectively in example IE.
Figure imgf000220_0002
Example 228B
The desired product was prepared by substituting example 228A for example 35D in example 35E and was purified by silica gel chromatography eluting with hexane then
50% acetone in hexane to provide the desired product.
Figure imgf000220_0003
Example 228C The desired product was prepared by substituting example 228B for example 37A in example 37B.
Figure imgf000221_0001
Example 228D The desired product was prepared by substituting example 228C for example 20 IC in example 201D.
Figure imgf000221_0002
Example 228E The desired product was prepared by substituting example 228D for example 2A in example 2B.
Example 228F 7-(7-amino-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-6-fluoro-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride
The desired product was prepared by substituting example 228E for example 40B in example 40C.
Mp 148-153°C (dec); MS (APCI) m/z 429 (M+l) +;
Η NMR (300 MHz, DMSO-*) δ 8.81 (s, IH), 8.59 (br s, 2H), 7.95 (d, IH), 7.42 (d, IH), 4.63 (m, IH), 4.26 (m, IH), 3.57 (s, 3H), 2.80-2.63 (m, 2H), 2.16-1.82 (m, 4H), 1.20-1.06 (m, 4H); 13C NMR (75 MHz, DMSO-*) δ 176.3 (d), 165.5, 156.7 (d), 151.5, 150.2 (d), 139.5, 134.6, 133.1, 131.28 (d), 128.9, 126.9 (d), 123.1 (d), 107.2, 106.5 (d), 66.4, 63.0, 45.1, 27.9, 24.8, 18.3, 9.1, 9.0; IR (mic) 3420 (COOH), 1740 (C=O), cm'1; Anal, calcd for C22H22N2O4SFC1 0.25 H2O: C, 56.28; H, 4.83; N, 5.96; found: C, 56.29; H, 4.55; N, 5.62.
Example 229
7-(5-acetyl-7-amino-4,5,6,7-tetrahydrothieno[3,2-clpyridin-2-yl)-l-cvclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid
Figure imgf000222_0001
Example 229A To a solution of 208A (0.100 mg, 0.177 mmol) in CH2C12 (2 mL) was added TFA (1 mL) at room temperature. After 30 minutes the reaction mixture was concentrated in vacuo. and triturated with Et2O. The mixture was filtered, the solid washed with Et2O and dried under high vacuum to give the desired product ( 0.078 g, 95%yield).
Figure imgf000222_0002
Example 229B
To a solution of example 229A (250 mg, 0.537 mmol) in CH2C12 was added acetic anhydride (101 uL, 1.074 mmol) and triethyl amine (262 uL, 1.88 mmol). The reaction mixture was stirred overnight at room temperature, diluted with CH2C12 and washed sequentially with IN HCI, sat. NaHCQ3, brine, dried (Na2SO4), and concentrated to give the desired product (0.264 g, 97% yield) that was used without further purification.
Figure imgf000222_0003
Example 229C The desired product was prepared by substituting example 229B for example 201C in example 201D.
Figure imgf000223_0001
Example 229C The desired product was prepared by substituting example 229B for example 2A in example 2B.
Figure imgf000223_0002
Example 229D 7-(5-acetyl-7-amino-4,5,6,7-tetrahydrothienor3,2-clpyridin-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting example 229C for example 59C in example 59D.
MS (DCI/NH3) m/z 454 (M+H)+;
Η-NMR (500 MHz, 90°, d6-DMSO) δ 8.80 (s, IH), 8.60 (br s, 2H), 8.18 (d, IH), 7.90 (d, IH), 7.65 (s, IH), 4.95 (m, 2H), 4.68 (m, 2H), 4.43 (m, 2H), 4.28 (m, IH), 3.71 (s, 3H), 2.16 (s, 3H), 1.16 (m, 2H), 1.07 (m, 2H).
Example 230
7-(7-amino-5-(methylsulfonyl)-4,5,6,7-tetrahydrothienor3,2-clpyridin-2-yl)-l-cyclopropyl-
8-methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid
Figure imgf000223_0003
Example 230A A solution of example 229A (250 mg, 0.537 mmol) in CH2C12 (10 ml) was treated with triethylamine (224 uL, 1.611 mmol) and methanesulfonyl chloride (62 uL, 0.806 mmol) and the resulting mixture stirred overnight at ambient temperature. The reaction mixture was partitioned between CH2C12 and IN HCI, the organic layer washed with sat. NaHCO3, brine and dried (Na2SO ). The concentrated residue product was purified by silica gel chromatography eluting with 2% MeOH in CH C12 to give the desired product (0.277 g, 95% yield).
Figure imgf000224_0001
Example 230B The desired product was prepared by substituting example 230A for example 353365C in example 353365D.
Figure imgf000224_0002
Example 230C The desired product was prepared by substituting example 230B for example 2A in example 2B.
Figure imgf000224_0003
Example 230D 7-(7-amino-5-(methylsulfonyl)-4,5,6,7-tetrahvdrothienor3,2-clpyridin-2-yl)-l-cvclopropyl- 8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting example 230C for example 40B in example 40C.
MS (DCI/NH3) m/z 490 (M+H)+;
Η-NMR (300 MHz, d6-DMSO) δ 8.82 (s, IH), 8.70 (br s, 2H), 8.17 (d, IH), 8.04 (d, IH), 7.79 (s, IH), 4.80 (m, IH), 4.57 (d, IH), 4.29 (m, 2H), 3.95 (dd, IH), 3.72 (s, 3H), 3.60- 3.45 (m, 3H), 3.10 (s, 3H), 1.20-1.00 (m, 4H).
Example 232 7-(4-amino-3-methyl-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4- oxo-l,4-dihydro-3-quinoIinecarboxylic acid hydrochloride
Figure imgf000225_0001
Example 232A A solution of example 260C (2.00 g, 5.78 mmol) in Et2O (20 mL) was treated with methyl magnesium bromide (2 L of a 3.0 M solution in diethyl ether, 6.00 mmol) and [l,3-bis(diphenylphosphino)-propane]dichloronickel (0.050g, 0.10 mmol) and stirred at 35°C overnight. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (Na2SO4), and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of hexane to 2% ethyl acetate in hexane to provide the desired product (0.701g, 43%) as an orange oil.
Figure imgf000225_0002
Example 232B The desired product was prepared by substituting example 232A for example 218B in example 218C.
Figure imgf000225_0003
Example 232C The desired product was prepared by substituting example 232B and ethyl 7- bromo-l-cyclopropyl-8-methoxy-4-oxo-l ,4-dihydro-3-quinolinecarboxylate for example ID and ethyl 7-bromo-l-cyclopropyl-4-oxo-l,4-dihydro-3-quinolinecarboxylate, respectively in example IE.
Figure imgf000225_0004
Example 232C The desired product was prepared by substituting example 232B for example 38C in example 39A.
Figure imgf000226_0001
Example 232D
The desired product was prepared by substituting example 232C for example
35Din example 35E and was purified by silica gel chromatography eluting with hexane then 50% acetone in hexane to provide the desired product.
Figure imgf000226_0002
Example 232E The desired product was prepared by substituting example 232D for example 37A in example 37B and was purified by silica gel chromatography eluting with hexane then 50% acetone in hexane to provide the desired product.
Figure imgf000226_0003
Example 232F The desired product was prepared by substituting example 232E for example 201C in example 201D.
Figure imgf000226_0004
Example 232G The desired product was prepared by substituting example 232F for example 2A in example 2B. Example 232H 7-(4-amino-3-methyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cvclopropyl-8-methoxy-4- oxo-l,4-dihvdro-3-quinolinecarboxylic acid hydrochloride The desired product was prepared by substituting example 232G for example 40B in example 40C. MS (APCI) m/z 408 (M-18+l)+;
Η NMR (300 MHz, DMSO-*) δ 8.82 (s, IH), 8.16 (m, 3H), 7.51 (d, IH), 4.48 (m, IH), 4.25 (m, IH), 3.57, (s, 3H), 3.47 (s, 3H), 3.03-2.70 (m, 2H), 2.10-1.88 (m, 4H), 1:18-1.09 (m, 4H).
Example 233 l-cyclopropyl-7-((4E/Z)-4-(hydroxyimino)-5,5-dimethyl-4,5,6,7-tetrahydro-l-benzothien-
2-yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid
Figure imgf000227_0001
Example 233A The desired product was prepared by substituting example 213E for example 41C in example 61 A.
Figure imgf000227_0002
Example 233B
The desired product was prepared by substituting example 233A, a reaction temperature of 60° C and a reaction time of 48 hours for example 50, a reaction temperature of 90° C and a reaction time of 18 hours, respectively in example 64.
Figure imgf000227_0003
Example 233C l-cvclopropyl-7-((4E/Z)-4-(hydroxyimino)-5,5-dimethyl-4,5,6,7-tetrahvdro-l-benzothien- 2-yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting example 233B for example 2A in example 2B. mp 135-138° C; MS (APCI) m/z 453 (M+H)+;
Η NMR (300 MHz, CDC13) δ 8.90 (s, IH), 8.61 (s, IH), 8.25 (d, IH), 7.82 (d, IH), 4.10 (m, IH), 3.68 (s, 3H), 3.03 (dd, 2H), 1.95 (dd, 2H), 1.60 (br s, 2H), 1.20 (m, 2H), 1.18 (s, 6H), 1.06 (m, 2H).
Example 234 l-cvclopropyl-7-(4-hydroxy-6,6-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid
Figure imgf000228_0001
Example 234A The desired product was prepared by substituting 6,7-Dihydro-6,6- dimethylbenzo[b]thiophen-4-one (prepared by the method of Sen, et al. Indian J. Chem 1999, 38B, 648-656.) and a reaction temperature of 0°C for example 218A and a reaction temperature of 50 °C in example 218B.
Figure imgf000228_0002
Example 234B
The desired product was prepared by substituting example 234A for example 218B in example 218C.
Figure imgf000228_0003
Example 234C Example 238A The desired products were prepared by substituting example 234B, ethyl 7-bromo- l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate and a reaction time of 4 hours for example ID, ethyl 7-bromo-l-cyclopropyl-4-oxo-l,4-dihydro-3- quinolinecarboxylate and a reaction time of 24 hours, respectively in example IE and the resulting mixture separated by silica gel chromatography. Example 238A was isolated as a by-product.
Example 234D l-cyclopropyl-7-(4-hydroxy-6,6-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting example 234C for example 35D in example 35E and the crude product triturated in 1:1 diethyl ether: ethanol and filtered to give the desired solid. MS (DC17NH3) m/z 440 (M+H)+;
1H NMR (300 MHz, CD3OD) δ 8.94 (s, IH), 8.20 (d, IH), 7.99 (d, IH), 7.74 (s, IH), 4.76 (m, IH), 4.28 (m, IH), 3.70 (s, 3H), 2.65 (m, 2H), 1.95 (m, IH), 1.58 (m, IH), 1.27 (m, 2H0, 1.17 (s, 3H), 1.06 (m, 2H), 1.03 (s, 3H).
Example 235
7-(7-amino-6-methyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4- oxo-l,4-dihvdro-3-quinolinecarboxyIic acid hydrochloride
Figure imgf000229_0001
Example 235 A A solution of 7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene (8.0 g, 52.6 mmol, prepared by the method of Cagniant, et. al. 7et. Lett. 1975, 2885) in anhydrous THF (200 mL) at -78 °C was treated dropwise with lithium bis(trimethylsilyl)amide (58 mL of a IM solution in hexanes, 58 mmol), stirred for 1 hour, treated with methyl iodide (22.4 g, 158 mmol), warmed to ambient temperature and partitoned between saturated ammonium chloride and EtOAc. The organic phase was washed with brine, dried (MgSO4), concentrated and the residue purified by flash chromatography on silica gel eluting with 10% EtOAc in hexane to give the desired compound (5.9 g, 68%) as a colorless oil.
Figure imgf000230_0001
Example 242A Example 235B
The desired product was prepared by substituting example 235 A for example 218A in example 218B and separating the diastereomers by silica gel chromatography eluting with hexanes. [Example 242A (cis) Rf = 0.55; Example 235B (trans) Rf = 0.42].
Figure imgf000230_0002
Example 235C The desired product was prepared by substituting example 235B for example 218B in example 218C and was used without further purification.
Figure imgf000230_0003
Example 235D The desired product was prepared by substituting example 235C, ethyl 1- cyclopropyl-7-bromo-8-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylate and a reation time of 5 hours for example ID, ethyl l-cyclopropyl-7-bromo-4-oxo-l,4-dihydroquinoline- 3-carboxylate and a reaction time of 24 hours, respectively in Example IE and purifying by chromatography on silica elu e.
Figure imgf000230_0004
Example 235E
The desired product was prepared by substituting example 235D for example 35D in example 35E and was use without further purification.
Figure imgf000230_0005
The desired product was prepared by substituting example 235E for example 37A in example 37B and was purified by chromatography on silica eluting with 2: 1 hexane/acetone to give an inseparable mixture of diastereomers.
Figure imgf000231_0001
Example 235G The desired product was prepared by substituting example 235F for example 201C in example 201D.
Figure imgf000231_0002
Example 235H
The desired product was prepared by substituting example 235G for example 2A in example 2B.
Example 2351
7-(7-amino-6-methyl-4,5,6,7-tetrahvdro-l-benzothien-2-yI)-l-cyclopropyl-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride The desired product was prepared as a 2:1 mixture (trans/cis) of diastereomers by substituting example 235H for example 40B in example 40C. MS (APCI ) m/z 425 (M+H)+;
Major (trans): IH NMR (300 MHz, DMSO- *) δ 8.82 (s, IH), 8.49 (bs, 3H), 8.14 (d, IH), 8.05 (d, IH), 7.68 (s, IH), 4.28 (m, IH), 4.26 (m, IH), 3.72 (s, 3H), 2.70 (t, 2H), 2.25 (m, IH), 2.03 (m, IH), 1.64 (m, IH), 1.20-0.98 (m, 4H), 1.05 (s, 3H).
Minor (cis): IH NMR (300 MHz, DMSO- *) δ 8.82 (s, IH), 8.32 (bs, 3H), 8.14 (d, IH), 8.05 (d, IH), 7.67 (s, IH), 4.57 (m, IH), 4.26 (m, IH), 3.72 (s, 3H), 2.67 (m, 2H), 2.22 (m, IH), 1.90-1.72 (m, 2H), 1.20-0.98 ( , 4H), 1.10 (s, 3H).
Example 238 7-(4-amino-6,6-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cvclopropyl-8-methoxy- 4-oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride
Figure imgf000232_0001
Example 238B The desired product was prepared by substituting example 238A in example 234C for example 35D in example 35E and was used without purification.
Figure imgf000232_0002
Example 238C The desired product was prepared by substituting example 238B and dichloromethane as reaction solvent for example 37A and 1: 1 toluene:dichloromethane as reaction solvent in example 37B.
Figure imgf000232_0003
Example 238D Example 236A
The desired products were prepared by substituting example 238C for example 201C in example 201D and the resulting mixture separated by silica gel chromatography eluting with a gradient of 0% to 2% methanol in dichloromethane. Example 236A was isolated as a by-product.
Figure imgf000232_0004
Example 238E The desired products were prepared by substituting example 238D for example 2A in example 2B.
Figure imgf000232_0005
Example 238F
7-(4-amino-6,6-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-
4-oxo-l,4-dihvdro-3-quinolinecarboxyIic acid hydrochloride The desired products were prepared by substituting example 238E for example 40B in example 40C.
MS (DCI/NH3) m/z 439 (M+H)+;
Η NMR (300 MHz, CD3OD) δ 8.98 (s, IH), 8.24 (d, IH), 7.90 (d, IH), 7.82 (s, IH), 4.49 (m, IH), 4.29 (m, IH), 3.72 (s, 3H), 2.77 (m, 2H), 2.09 (dd, IH), 1.68 (dd, IH), 1.28 (m, 2H), 1.24 (s, 3H), 1.08 (m, 2H), 1.05 (s, 3H).
Example 236 l-cyclopropyI-7-(6,6-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8-methoxy-4-oxo- l,4-dihvdro-3-quinolinecarboxylic acid The desired products were prepared by substituting example 236A in example 238D for example 40B in example 40C. MS (DCI/NH3) m/z 424 (M+H)+; Η NMR (300 MHz, CD3OD) δ 8.94 (s, IH), 8.28 (d, IH), 7.89 (d, IH), 7.47 (s, IH), 4.28 (m, IH), 3.70 (s, 3H), 2.72 (t, 2H), 2.61 (s, 2H), 1.64 (t, 2H) 1.27 (m, 2H), 1.06 (m, 2H), 1.04 (s, 6H).
Example 237
7-(7-amino-6-fluoro-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4- oxo-l,4-dihvdro-3-quinolinecarboxylic acid hydrochloride
Figure imgf000233_0001
The desired product was prepared by substituting example 240E for example 35D in example 35E and was purified by silica gel chromatography eluting with hexane then
50% acetone in hexane to provide the desired product.
Figure imgf000234_0001
Example 237B
The desired product was prepared by substituting.example 237A for example 37A in example 37B and was purified by silica gel chromatography eluting with hexane then
50% acetone in hexane to provide the desired product.
Figure imgf000234_0002
Example 237C The desired product was prepared by substituting example 237B for example 20 IC in example 201D.
Figure imgf000234_0003
Example 237D The desired product was prepared by substituting example 237C for example 2A in example 2B.
Example 237E 7-(7-amino-6-fluoro-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cvclopropyl-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride The desired product was prepared by substituting example 237D for example 40B in example 40C and was obtained as a 4: 1 (tran.ι>: '.-?)mixture of diastereomers. MS (DC17NH3) m/z 429 (M+l)+;
Η NMR (500 MHz, DMSO-*) δ 8.79 (s, IH), 8.10 (d, IH), 7.91 (d, IH), 7.57 (s, IH), 5.43-5.18 (m, IH), 5.86 (dd, 0.2H), 5.71 (dd, 0.8H), 5.25 (m, IH), 3.67 (s, 3H), 2.82-2.72 (m, 2H), 2.57-1.98 (m, 2H), 1.19-0.95 (m, 4H).
Example 239 l-cvclopropyl-8-methoxy-4-oxo-7-(7-oxo-4,5,6,7-tetrahydro-l,3-benzothiazol-2-yl)-l,4- dihvdro-3-quinolinecarboxylic acid
Figure imgf000235_0001
Example 239A A mixture of Ethyl 7-bromo-l-cyclopropyl-4-oxo-l,4-dihydro-3-quinoline-3- carboxylate (5.0 g, 13.66 mmol), cuprous cyanide (1.6 g, 17.8 mmol) and dimethylformamide was heated to 140 °C for 8 hours. The hot reaction-mixture was poured into a mixture of ice-water (100 mL), and con. NHtOH ( 15 mL) and the resulting off-white solid in a dark blue colored solution is filtered. The solid was washed with water and extracted with methylene chloride. The organic layer was washed with brine, dried (Na2SO ), filtered, and evaporated in vacuo and the residue triturated with ethyl acetate to provide 2.03 g ( 48 %) of the desired product as white solid. M.p. 200-201 °C MS (APCI+) m/z 313 (M+H)+; Η NMR (300 MHz, DMSO-*) δ 8.57 (s, 1 H), 8.06 (d, 1 H), 7.79 (d, 1 H), 4.24 (q, 2 H), 4.06 (m, 1 H), 4.06 (s, 3 H), 1.28 (t, 3 H), 1.13 (m, 2 H), 1.04 (m, 2 H).
Figure imgf000235_0002
Example 239B
Hydrogen sulfide was passed through a suspension of example 239A (1.5 g, 4.8 mmol), triethyl amine (2 mL, 15 mmol) and pyridine ( 30 mL) for 0.5 hour. To this dark suspension methylene chloride ( 10 mL) is added and the resulting dark green solution is heated to 50 °C for 12 hours in a sealed tube. After removing the solvents in vacuo, the residue is washed with water, ether and ethanol to afford the desired product as a off-white solid. (0.61 g, 36%).
M.p. 224-225 °C
MS (APCI+) m/z 347 (M+l)+;
Η NMR (300 MHz, DMSO-*) 10.27 (s, 1 H), 9.70 (s, 1 H), 8.55 (s, 1 H), 7.94 (d, 1 H),
7.41 (d, 1 H), 4.23 (q, 2 H), 4.05 (m, 1 H), 3.86 (s, 3 H), 1.28 (t, 3 H), 1.11 (m, 2 H), 1.00
(m, 2 H).
Figure imgf000236_0001
Example 239C
A mixture of example 239B (0.347 g, 1 mmol) and 2-bromo-3-hydroxycyclohex-2- en-l-one (0.286 g, 1.5 mmol), (prepared by the method described by Shepard and White
JCS Perkin 1987, 1, 2153-2155,) in DMF (2 mL) was heated to 50 °C for 3 hours in a sealed tube. The resulting solution was diluted with water, the aqueous layer extracted with methylene chloride, the combined organic phases washed with brine, dried (Na2SO4), concentrated, and purified by silica gel chromatography eluting with 2 % methanol in methylene chloride to provide the desired product (0.106 g, 24 % yield) as a off-white solid. MS ((APCI+)) m/z 439 (M+H)+;
1H NMR (300 MHz, DMSO-*) δ 8.60 (s, 1 H), 8.33 (d, 1 H), 8.11 (d, 1 H), 4.25 (q, 2 H), 4.14 (m, 1 H), 3.84 (s, 3 H), 3.10 (t, 2 H), 2.64 (t, 2 H), 2.20 (m, 2 H), 1.29 (t, 3 H), 1.12 (m, 2 H), 0.94 (m, 2 H).
Example 239D l-cyclopropyl-8-methoxy-4-oxo-7-(7-oxo-4,5,6,7-tetrahydro-l,3-benzothiazol-2-yl)-l,4- dihydro-3-quinolinecarboxylic acid A solution of example 239C (0.043 g, 0.1 mmol) was suspended in THF (0.5 mL) and IM HCI ( 0.5 mL) and was heated to 100 °C for 10 hours in a sealed tube. Solvent was concentrated in vacuo, and the resulting precipitate that formed filtered and washed with ethyl acetate to give the desired product (0.019 g, 46 %) as a tan solid. MS (APCI+) m/z 411 (M+H)+; IH NMR (300 MHz, DMSO-*) δ 14.69 (s, 1 H), 8.86 (s, 1 H), 8.50 (d, 1 H), 8.26 (d, 1 H), 4.32 ( , 1 H), 3.87 (s, 3 H), 3.12 (t, 2 H), 2.65 (t, 2 H), 2.20 (m, 2 H), 1.18 (m, 2 H), 1.04 (m, 2 H).
Example 240 l-cvclopropyl-7-(6-fluoro-7-hvdroxy-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8-methoxy-4- oxo- 1 ,4-dihvdro-3-quinolinecarboxylic acid
Figure imgf000237_0001
Example 240A A solution of 7-keto-4,5,6,7-tetrahydrothienanapthene (2.812g, 18.5 mmol, prepared by the method of Caubere, et al. Eur. J. Med. Chem. 1998, 867-77) and N- fluorosulfonimide (10.21 g, 32.4 mmol) in THF (35 mL) was cooled to -78°C, lithum (bistrimethylsilyl)amide (32.4 mL of a 1.0 M solution in THF, 32.4 mmol) was added dropwise, and the mixture was allowed to warm to room temperature overnight. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (Νa2SO4), and concentrated. The resulting residue was purified by silica gel chromatography eluting with a gradient of hexane to 20% ethyl acetate in hexane to provide the desired product (2.218g, 70.0%) as a white solid.
Figure imgf000237_0002
Example 240B The desired product was prepared by substituting example 240A for example 218A in example 218B to give a 3: 1 (cis:trans) mixture of diastereomers.
F-Q OTBCS snBU3
Example 240C The desired product was prepared by substituting example 240B for example 218B in example 218C.
Figure imgf000238_0001
The desired products were prepared by substituting example 240C and ethyl 7- bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate for example
ID and ethyl 7-bromo-l-cyclopropyl-4-oxo-l,4-dihydro-3-quinolinecarboxylate, respectively in example IE and the crude product substituted for example 38C in example
39A. The resulting mixture of the methyl and ethyl esters was separated by silica gel chromatography eluting with a gradient of hexane to 50% acetone in hexane.
Figure imgf000238_0002
Example 240F The desired product was prepared by substituting example 240D for example 35D in example 35E and was purified by silica gel chromatography eluting with hexane then 50% acetone in hexane.
Example 240G l-cyclopropyl-7-(6-fluoro-7-hydroxy-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxyIic acid The desired product was prepared by substituting example 240F for example 2A in example 2B
MS (DCI/NH3) m/z 430(M+1)+;
Η NMR (300 MHz, CDC13) δ 14.8 (br s, IH), 8.79 (s, IH), 8.12, (d, IH), 7.98 (d, IH), 7.58 (s, 0.75H), 7.56 (s, 0.25H), 5.05-4.70 (m, 2H), 4.25 (m, IH), 3.64 (s, 3H), 2.8-2.64 (m, 2H), 2.31- 1.90 (m, 2H), 1.20-1.00 (m, 4H).
Example 241 l-cvclopropyl-7-(7-hvdroxy-6,6-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-1.4-dihydro-3-quinolinecarboxylic acid
Figure imgf000239_0001
Example 241 A
A solution of example 235A (2.0 g, 12.0 mmol) in anhydrous THF (50 mL)at -78 °C was treated dropwise with lithium bis(trimethylsilyl)amide (13.2 mL of a IM solution in hexanes, 13.2 mmol), stirred for 30 minutes, treated with methyl iodide (3.4 g, 24.0 mmol), warmed to ambient temperature and partitioned between saturated ammonium chloride and EtOAc. The organic phase was washed with brine, dried (MgSO ) and concentrated to give the desired compound (2.1 g, 97%) as a yellow oil.
Figure imgf000239_0002
Example 241B The desired product was prepared by substituting example 241A for example 218A in example 218B.
>Q ^snBU3
OTBS
Example 24 IC The desired product was prepared by substituting example 241B for example 218B in example 218C.
Figure imgf000239_0003
Example 24 ID The desired product was prepared by substituting example 241C, ethyl 1- cyclopropyl-7-bromo-8-methoxy-4-oxo-l ,4-dihydroquinoline-3-carboxylate and a reaction time of 4 hours for example ID, ethyl l-cyclopropyl-7-bromo-4-oxo-l,4-dihydroquinoline- 3-carboxylate and a reaction time of 24 hours, respectively in example IE and was purified by chromatography on silica gel eluting with 2: 1 hexane:acetone to provide an off-white solid.
Figure imgf000240_0001
Example 24 IE The desired product was prepared by substituting example 241D for example 35D in example 35E and was purified by chromatography on silica eluting with 95:5 dichloromethane:methanol.
Figure imgf000240_0002
Example 241F l-cyclopropyl-7-(7-hydroxy-6,6-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yI)-8- methoxy-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid
The desired product was prepared by substituting example 241E for example 2A in example 2B and the crude material triturated with 4: 1 Et2O:hexane (25 mL)and the solid collected by filtration. MS (APCI ) m/z 440 (M+H)+; IH NMR (300 MHz, DMSO- *) δ 14.94 (s, IH), 8.79 (s, IH), 8.10 (d, IH), 7.99 (d, IH), 7.55 (s, IH), 5.49 (d, IH), 4.36 (d, IH), 4.26 (m, IH), 3.69 (s, 3H), 2.60 (m, 2H), 1.74- 1.54 (m, 2H), 1.15 (m, 2H), 1.04 (m, 2H), 1.01 (s, 3H), 0.88 (s, 3H).
Example 242 l-cvclopropyl-7-((61S,7S)-7-hydroxy-6-methyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid
jC snBu3
OTBS Example 242B
The desired product was prepared by substituting example 242A in example 235B for example 218B in example 218C.
Figure imgf000241_0001
Example 242C The desired product was prepared by substituting example 242B, ethyl 1- cyclopropyl-7-bromo-8-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylate and a reaction time of 2 hours for example ID, ethyl l-cyclopropyl-7-bromo-4-oxo-l,4-dihydroquinoline- 3-carboxylate and a reaction time of 24 hours, respectively in example IE and purified by chromatography on silica eluting with 2:1 hexane/acetone.
Figure imgf000241_0002
Example 242D
The desired product was prepared by substituting example 242C for example 35D in example 35E and was used without further purification.
Figure imgf000241_0003
Example 242E l-cyclopropyl-7-((65,7 )-7-hydroxy-6-methyl-4,5,6,7-tetrahvdro-l-benzothien-2-yI)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting example 242D for example 2A in example 2B and the crude material purified by triturating with 4:1 Et2O:hexanes (25 mL) and collecting the solid product by filtration. MS (APCI) m/z 426 (M+H)+;
IH NMR (300 MHz, DMSO- *) δ 8.79 (s, IH), 8.11 (d, IH), 8.00 (d, IH), 7.55 (s, IH), 5.21 (d, IH), 4.60 (dd, IH), 4.26 (m, IH), 3.68 (s, 3H), 2.74-2.55 (m, 2H), 1.95 (m, IH), 1.76-1.62 (m, 2H), 1.14 (m, 2H), 1.03 (m, 2H), 1.01 (d, 3H). Example 243 l-cvclopropyl-8-methoxy-4-oxo-7-(4,5,6,7-tetrahvdro-l-benzothιen-2-yl)-l,4-dιhydro-3- quinolinecarboxylic acid
Figure imgf000242_0001
Example 243A The desired product was prepared by substituting 4,5,6,7-tetrahydrothιenanapthene (prepared by the method of Caubere, et al. Eur. J. Med. Chem. 1998, 867-77) for example 218B in example 218C.
Figure imgf000242_0002
Example 243B The desired product was prepared by substituting example 243A and ethyl 7- bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dιhydro-3-qumolιnecarboxylate for example ID and ethyl 7-bromo-l -cyclopropyl -4-oxo-l,4-dihydro-3-qumolmecarboxylate, rspectively in example IE.
Example 243C l-cvclopropyl-8-methoxy-4-oxo-7-(4,5,6,7-tetrahydro-l-benzothιen-2-yl)-l,4-dιhydro-3- quinohnecarboxylic acid
The desired product was prepared by substituting example 243A for example 2A in example 2B.
MS (DCI/NH3) m/z 396(M+1)+;
1H NMR (300 MHz, DMSO-*) δ 8.78 (s, IH), 8.10 (d, IH), 7.98 (d, IH), 7.56 (s, IH), 4.27-4.22 (m, IH), 3.67 (s, 3H), 2.79 (t, 2H), 2.64 (t, 2H), 1.80-1.74 (m, 4H), 1.17-1.03 (m, 4H).
Example 244 7-(7-amιno-6,6-dιfluoro-4,5,6,7-tetrahvdro-l-benzothιen-2-yl)-l-cvclopropyl-8-methoxy- 4-oxo-l,4-dιhydro-3-quιnolιnecarboxylιc acid hydrochlonde
Figure imgf000243_0001
Example 244A The desired product was prepared by substituting 7-keto-4,5,6,7- tetrahydrothienanapthene (prepared by the method of Caubere, et al. Eur. J. Med. Chem. 1998, 867-77) for 4-keto-4,5,6,7-tetrahydrothienanapthene in example 358696A.
Figure imgf000243_0002
Example 244B
The desired product was prepared by substituting example 244A for example 218 A and room temperature for heating to 50°C in example 218B.
Figure imgf000243_0003
Example 244C
The desired product was prepared by substituting example 244B for example IC in example ID.
Figure imgf000243_0004
* Example 244D
The desired product was prepared by substituting example 244C, ethyl 7-bromo-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate, and a reaction time of 10 h for example ID, ethyl 7-bromo-l-cyclopropyl-4-oxo-l,4-dihydro-3-quinoline-3- carboxylate and a reaction time of 24 h respectively in example IE.
Figure imgf000244_0001
Example 244E
The desired product was prepared by substituting example 244B for example 35D in example 35E and the resulting alcohol was carried on without further purification.
Figure imgf000244_0002
Example 244F
The desired product was prepared by substituting example 244E for example 37A in example 37B and the resulting azide was purified by chromatography on silica gel eluting with 10% acetone in hexane then 20% acetone in hexane.
Figure imgf000244_0003
Example 244G The desired product was prepared by substituting example 244F for example 20 IC in example 201D.
Figure imgf000244_0004
Example 244H The desired product was prepared by substituting example 244G for example 2A in example 2B. Example 2441 7-(7-amino-6,6-difluoro-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l-cyclopropyI-8-methoxy- 4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid hydrochloride The desired product was prepared by substituting example 244H for example 40B in example 40C. MS (ESI) m/z 447 (M+H)+;
Η NMR (300 MHz, DMSO-*) δ 9.20 (br s, 2H), 8.82 (s, IH), 8.17 (d, IH), 8.05 (d, IH), 7.74 (s, IH), 5.22 (m, IH), 4.28 (m, IH), 4.00 (m, 2H), 3.73 (s, 3H), 2.94 (t, 2H), 1.10 (m, 4H).
Example 245 7-(7-amino-6,6-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy- 4-oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride
Figure imgf000245_0001
Example 245A The desired product was prepared by substituting example 24 IE for example 37 A in example 37B and purified by chromatography on silica eluting with 2: 1 hexanes:acetone.
Figure imgf000245_0002
Example 245B
The desired product was prepared by substituting example 245 A for example 20 IC in example 20 ID.
Figure imgf000246_0001
Example 245C The desired product was prepared by substituting example 245B for example 2A in example 2B.
Example 245D 7-(7-amino-6,6-dimethyl-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy- 4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid hydrochloride The desired product was prepared by substituting example 245C for example 40B in example 40C. MS (APCI ) m/z 439 (M+H)+;
IH NMR (300 MHz, DMSO- *) δ 8.81 (s, IH), 8.42 (bs, 3H), 8.15 (d, IH), 8.04 (d, IH), 7.68 (s, IH), 4.27 (m, 2H), 3.73 (s, 3H), 2.68 (m, 2H), 1.87 (m, IH), 1.63 (m, IH), 1.20- 0.95 (m, 4H), 1.08 (s, 6H).
Example 246 l-cyclopropyl-6-fluoro-8-methoxy-7-(7-(methyIamino)-4,5,6,7-tetrahvdro-l-benzothien-2- yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride
Figure imgf000246_0002
Example 246A The desired product was prepared by substituting example 216B and ethyl 7- bromo-l-cyclopropyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate for example ID and ethyl 7-bromo-l-cyclopropyl-6-fluoro-4-oxo-l,4-dihydro-3- quinolinecarboxylate, respectively in example IE.
Figure imgf000247_0001
Example 246B The desired product was prepared by substituting example 246A for example 2A in example 2B.
Example 246C l-cvclopropyl-6-fluoro-8-methoxy-7-(7-(methylamino)-4,5,6,7-tetrahydro-l-benzothien-2- yl)-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid hydrochloride
The desired product was prepared by substituting example 246B for example 40B in example 40C. MS (DCI/NH3) m/z 443 (M+l)+;
1H NMR (300 MHz, MeOH-*) δ 8.95 (s, IH), 7.98 (d, IH), 7.48 (d, IH), 4.64 (t, IH), 4.26 (m, IH), 3.68 (s, 3H), 2.95- 2.74 (m, 5H), 2.30-2.24 (m, 2H), 2.06-1.99 (m, 2H), 1.52-1.10 (m, 4H).
Example 247 l-cvclopropyl-8-methoxy-4-oxo-7-(5-oxo-5,6-dihvdro-4H-cyclopentar&lthien-2-yl)-l,4- dihydro-3-quinolinecarboxylic acid
Example 247A A solution of Example 45G (0.500 g, 1.18 mmol) in dichloromethane (12 mL) was treated with the Dess-Martin periodinane (798mg, 1.88 mmol) followed by stirring at ambient temperature for 3 h. The solution was diluted with dichloromethane and added to a solution of sodium thiosulfate (3.50g, 14.10 mmol) in saturated sodium bicarbonate solution (60mL). The mixture was stirred for 30 min and the layers separated. The aqueous phase was extracted with dichloromethane, and the combined organic layers were dried over Na2SO . Concentration in vacuo afforded a beige solid which was purified by chromatography on silica gel eluting with chloroform and then with methanol in chloroform to afford the desired material (0.399 g, 80%) as a white solid.
Example 247B l-cyclopropyl-8-methoxy-4-oxo-7-(5-oxo-5,6-dihvdro-4H-cyclopenta[ ?1thien-2-yl)-l,4- dihydiO-3-quinolinecarboxylic acid A solution of Example 247A (0.129 g, 0.30 mmol) in 3mL TΗF and ImL ethanol was treated with 0.91mL 1.0 N HC1 solution followed by warming at reflux for 5h. The solution was cooled and concentrated in vacuo with ethanol to remove water. The purple solid was triturated with 2:1 ethanol-water, collected by filtration, and washed with ether. The solid was dried in a vacuum oven (50°C/10mm Hg) for 18 h to afford the desired product (0.086g, 72%) as a purple solid. MS (ESI) m/z 396 (M+H)+; Η ΝMR (DMSO-*, 300 MHz) δ 8.80 (s, 1 H), 8.13 (d, 1 H), 8.05 (d, 1 H), 7.81 (s, 1 H), 4.26 (m, 1 H), 3.70 (s, 3 H), 3.65 (br s, 2 H), 3.48 (br s, 2 H), 1.16 (m, 2 H), 1.06 (m, 2 H).
Example 248 l-cyclopropyl-8-methoxy-7-((5E/Z)-5-(methoxyimino)-5,6-dihydro-4H- cyclopentaffr1thien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid
The desired compound was prepared by substituting Example 247B for Example 50 in Example 325004 to give a purple solid. MS (ESI) m/z 425 (M+Η)+;
Η ΝMR (DMSO-*, 300 MHz) δ 14.82 (br s, 1 H), 8.79 (s, 1 H), 8.11 (d, 1 H), 8.00 (d, 1 H), 7.73, 7.71 (s, 1 H), 4.25 (br m, 1 H), 3.85 (s, 3 H), 3.80 (d, 2 H), 3.69 (s, 3 H), 3.61 (d, 2 H), 1.16 (m, 2 H), 1.04 (m, 2 H).
Example 249 7-(5-amino-5,6-dihvdro-4H-cyclopenta[ ->lthien-2-yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4- dihydro-3-quinolinecarboxylic acid hydrochloride
Figure imgf000248_0001
Example 249A
A solution of Example 45G (0.504g, 1.30 mmol), and triethylamine (0.9mL, 6.50 mmol) in dichloromethane (6.5mL) at 0°C was treated dropwise with methanesulfonyl chloride (0.25mL, 2.20 mmol), followed by stirring for 30 min. The solution was warmed to ambient temperature, diluted with dichloromethane (30mL) and extracted with water
(2x), 1.0 M citric acid, and saturated sodium bicarbonate. Drying (Na2SO4) and concentration in vacuo afforded the desired product (0.666g, 100%) as an off-white foam.
Figure imgf000249_0001
Example 249B A solution of Example 249A (0.655g, 1.30mmol) and sodium azide (0.846g, 13.0 mmol) in DMF (16mL) was warmed at 60°C for 45 min, followed by cooling to ambient temperature for 18 h. The solution was diluted with ethyl acetate (lOOmL) and washed with water (5 x 20mL) and then with saturated NaCl solution. Drying (Na2SO4) and concentration in vacuo afforded the desired product (0.530g, 90%) as a buff-colored solid.
Figure imgf000249_0002
Example 249C The desired compound was prepared by substituting Example 324124B for Example 201C in Example 201D.
Example 249D
7-(5-amino-5,6-dihvdro-4H-cvclopenta[fc1thien-2-yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4- dihydro-3-quinolinecarboxylic acid hydrochloride A solution of Example 249C (0.067g, 0.13mmol) in TΗF (5 mL) and 1.0 N ΗC1 solution (4 mL) was warmed at reflux for 5 h. The solution was cooled to ambient temperature and concentrated in vacuo. The residue was suspended in ethanol and concentrated in vacuo twice. The material was suspended in dichloromethane and treated with 5 mL of 4.0 N ΗC1 in dioxane, followed by stirring at ambient temperature for 1 h.
The solid was collected by filtration and washed with ether. These procedures afforded the desired product (0.043g, 86%) as an orange solid. MS (ESI) m/z 397 (M+Η)+; Η NMR (DMSO-*, 300 MHz) δ 8.79 (s, 1 H), 8.49 (br s, 1 H), 8.11 (d, 1 H), 7.98 (d, 1 H), 7.69 (s, 1 H), 4.34 (br m, 1 H), 4.27 (m, 1 H), 3.69 (s, 3 H), 3.40 (dd, 1 H), 3.21 (dd, 1 H), 3.06 (dd, 1 H), 2.87 (dd, 1 H), 1.16 (m, 2 H), 1.04 (m, 2 H).
Example 250 l-cvcIopropyl-7-(5-((ethoxycarbonyl)amino)-5,6-dihvdro-4H-cyclopentarblthien-2-yl)-8- methoxy-4-oxo-l ,4-dihvdro-3-quinolinecarboxylic acid The desired product was prepared by substituting ethyl chloroformate for methyl chloroformate in Example 251. MS (ESI) m/z 469 (M+Η)+;
Η NMR (CDC13, 300 MHz) δ 14.73 (s, 1 H), 8.91 (s, 1 H), 8.23 (d, IH), 7.73 (d, 1 H), 7.41 (s, 1 H), 4.80 (br m, 1 H), 4.12 (om, 3 H), 3.67 (s, 3 H), 3.42 (dd, 1 H), 3.26 (dd, 1 H), 2.87 (dd, 1 H), 2.70 (dd, 1 H), 1.26 (om, 5 H), 1.11 (m, 2 H).
Example 251 l-cvclopropyl-8-methoxy-7-(5-((methoxycarbonyl)amino)-5,6-dihvdro-4H- cvclopentarfrlthien-2-yl)-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid A solution of Example 249 (0.041 mg, 0.10 mmol) in 3 mL acetone and 1 mL saturated sodium bicarbonate solution was treated with methyl chloroformate (12 μL, 0.16 mmol) followed by stirring at ambient temperature for 2 h. The mixture was adjusted to pΗ 2 by addition of 1.0 N ΗC1 solution. The mixture was adsorbed onto a Varian Chem- Elut CE1010 cartridge, and after equilibration for 5 min, the product was eluted with methanol in dichloromethane. The material was purified by preparative reverse-phase ΗPLC. These procedures afforded the desired product (21mg, 45%) as a light yellow solid.
MS (ESI) m/z 455 (M+Η)+; Η ΝMR (CDC13, 300 MHz) δ 14.73 (s, 1 H), 8.91 (s, 1 H), 8.23 (d, 1 H), 7.73 (d, 1 H), 4.89 (br m, 1 H), 4.11 (m, IH), 3.71 (br s, 3 H), 3.67 (s, 3 H), 3.43 (dd, 1 H), 3.26 (dd, 1 H), 2.87 (dd, 1 H), 2.69 (dd, 1 H), 1.28 (m, 2 H), 1.06 (m, 2 H).
Example 252 7-(5-(acetylamino)-5,6-dihvdro-4H-cvclopentarblthien-2-yl)-l-cyclopropyl-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid A solution of Example 249 (0.015 g, 0.04 mmol), 1 mL triethylamine, and 3 mg N, N-dimethylaminopyridine in dichloromethane (2 mL) was treated with acetic anhydride (250 μL). The solution was stirred at ambient temperature for 2 h. The solution was diluted with dichloromethane and filtered through a Varian Chem-Elut CE1010 (which had been pretreated with 2 mL water and 2 mL 1 N HCI solution), eluting with dichloromethane. The filtrate was concentrated in vacuo to afford a yellow solid which was purified by preparative HPLC to give the desired product (0.011 g, 64%) as a yellow solid.
MS (ESI) m/z 439 (M+H)+; Η NMR (CDC13, 300 MHz) δ 14.73 (s, 1 H), 8.88 (s, 1 H), 8.20 (d, IH), 7.71 (s, 1 H), 5.98 (br d, IH), 5.11 (m, 1 H), 4.10 (m, 1 H), 3.67 (s, 3 H), 3.45 (dd, 1 H), 3.28 (dd, 1 H), 2.85 (dd, 1 H), 2.69 (dd, 1 H), 2.02 (s, 3 H), 1.28 (m, 2 H), 1.07 (m, 2 H).
Example 253 l-cyclopropyl-8-methoxy-7-(5-(((4-methylphenyI)sulfonyl)amino)-5,6-dihvdro-4H- cyclopentarfrlthien-2-yl)-4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid A solution of Example 249 (0.041 g, 0.10 mmol) and triethylamine (36 μL, 0.26 mmol) in 3 mL dichloromethane was treated with p-toluenesulfonyl chloride (0.030 g, 0.16 mmol) followed by stirring at ambient temperature for 2 h. The solution was diluted with dichloromethane and filtered through a Varian Chem-Elut CE1010 cartridge (which had been pretreated with 2 mL water and 2 mL 1 N ΗC1 solution) eluting with methanol in dichloromethane. The filtrate was concentrated in vacuo to afford a yellow solid, which was purified by preparative ΗPLCto give the desired compound (0.0081 g, 14%) as an off- white solid.
MS (ESI) m/z 551 (M+Η)+;
1H NMR (CDCI3, 300 MHz) δ 14.72 (s, 1 H), 8.89 (s, 1 H), 8.20 (d, 1 H), 7.82 (d, 2 H), 7.68 (d, 1 H), 7.34 (d, 2 H), 5.04 (br d, 1 H), 4.51 (m, 1 H), 4.08 (m, 1 H), 3.64 (s, 3 H), 3.25 (dd, 1 H), 3.09 (dd, 1 H), 2.83 (dd, 1 H), 2.65 (dd, 1 H), 2.47 (s, 3 H), 1.27 (m, 2 H), 1.03 (m, 2H).
Example 254 l-cyclopropyl-8-methoxy-7-(5-((methylsulfonyl)amino)-5,6-dihydro-4H- cyclopentarblthien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid
A solution of Example 249 (0.039 g, 0.10 mmol) and triethylamine (35 μL, 0.25 mmol) in 3 L dichloromethane was treated with methanesulfonyl chloride (12 μL, 0.15 mmol) followed by stirring at ambient temperature for 2 h. The solution was diluted with dichloromethane and filtered through a Varian Chem-Elut CE1010 cartridge (which had been pretreated with 2 mL water and 2 mL 1 NHC1 solution) eluting with dichloromethane. The filtrate was concentrated in vacuo to afford a yellow solid which was purified by preparative HPLC to give the desired product (0.013g, 27%) as a beige solid.
MS (ESI) m/z 475 (M+H)+;
Η ΝMR (CDC13, 300 MHz) δ 14.72 (s, 1 H), 8.90 (s, 1 H), 8.23 (d, 1 H), 7.72 (d, 1 H), 7.41 (s, 1 H), 4.83 (br d, 1 H), 4.68 (m, 1 H), 4.09 (m, 1 H), 3.67 (s, 3 H), 3.48 (dd, 1 H), 3.33 (dd, 1 H), 3.06 (s, 3 H), 3.02 (dd, 1 H), 2.82 (dd, 1 H), 1.28 (m, 2 H), 1.06 (m, 2 H).
Example 255
7-((5E/Z)-5-((benzyloxy)imino)-5,6-dihvdro-4H-cyclopentarfelthien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid
The desired compound was prepared by substituting Example 247B and O- benzylhydroxylamine hydrochloride for Example 50 and methoxylamine hydrochloride, respectively in Example 64.
MS (ESI) m/z 501 (M+Η)+; Η ΝMR (DMSO-*, 300 MHz) δ 14.91 (s, 1 H), 8.79 (s, 1 H), 8.11 (d, 1 H), 7.73, 7.71
(s, 1 H), 7.35 (om, 5 H), 5.13 (s, 2 H), 4.25 (m, 1 H), 3.84 (d, 2 H), 3.69 (s, 3 H), 3.64 (d. 2
H), 1.15 (m, 2 H), 1.05 (m, 2 H).
Example 256 l-cvclopropyl-7-((5E/Z)-5-(hvdroxyimino)-5,6-dihydro-4H-cyclopentarblthien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid The desired compound was prepared by substituting Example 247B and hydroxylamine hydrochloride for Example 50 and methoxylamine hydrochloride, respectively in Example 325004. MS (ESI) m/z 411 (M+Η)+;
Η ΝMR (DMSO-*, 300 MHz) δ 14.91 (s, 1 H), 10.82, 10.81 (s, 1 H), 8.79 (s, 1 H), 8.1 1 (d, 1 H), 8.01 (d, 1 H), 7.74, 7.73 (s, 1 H), 4.26 (m, 1 H), 3.77 (d, 2 H), 3.69 (s, 3 H), 3.58 (d, 2 H), 1.16 (m, 2 H), 1.05 (m, 2 H).
Example 257 7-(4-amino-4-methyl-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid
Figure imgf000253_0001
Example 257 A
A solution of 4-keto-4,5,6,7-tetrahydrothianapthene (8.0g, 52.58 mmol) and 2,6-di- tert-butyl-4-methylpyridine (11.87g, 57.83 mmol) in dichloromethane (210 mL) at 0°C was treated dropwise with triflic anhydride (10.7 mL, 63.62 mmol). The mixture was stirred at 0°C for 10 min, followed by warming to ambient temperature for 30 min. The mixture was concentrated in vacuo and the residue was slurried in 1 : 1 ethyl acetate- hexane. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The oil obtained was purified by silica gel chromatography eluting with hexane and then with ethyl acetate in hexane to give the desired product (10.9g, 73%) as a dark red oil.
Figure imgf000253_0002
Example 257B
A solution of Example 257a (10.86g, 38.21 mmol), triethyl amine (10.9 mL), methanol (65.6 mL), palladium acetate (514mg, 2.29 mmol), and triphenylphosphine
(1.20g, 4.58 mmol) in DMF (190 mL) was warmed at 50°C under an atmosphere of carbon monoxide (4 atmospheres pressure) for 2 h. The solution was cooled to ambient temperature and vented to the atmosphere. The DMF was removed by short path vacuum distillation (oil bath temperature 55°C, 0.4 mm Hg). The residue was dissolved in 250 mL ethyl acetate and extracted with water (2 x lOOmL) and saturated sodium bicarbonate solution (lOOmL). Drying (Na2SO4) and concentration in vacuo afforded a brown oil which was purified by silica gel chromatography eluting with hexane and then with ethyl acetate in hexane to give the desired c , 67%) as a colorless oil.
Figure imgf000253_0003
Example 257C A solution of Example 257B (3.0g, 15.44 mmol) in anhydrous methanol (37 mL) was treated with magnesium turnings (863 mg, 35.53 mmol) followed by stirring at ambient temperature for 18 h. The solution was treated with saturated ammonium chloride solution (30 mL) followed by dilution with water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried (Na2SO4). Concentration in vacuo afforded an amber oil which was purifed by silica gel chromatography eluting with hexane and then with ethyl acetate in hexane to give the desired product (2.36g, 78%) as a colorless oil.
Figure imgf000254_0001
Example 257D A solution of Example 257C (2.36g, 12.02 mmol) in 1.0 N NaOH solution (47 mL) was warmed at reflux for 3 h. The solution was cooled to 0°C and adjusted to pH 2 by addition of 6 N HCI solution. The mixture was extracted with ethyl acetate (3 x 75 mL) and the combined organic layers were dried (Νa2SO4) and concentrated in vacuo to afford the desired compound (2.14g, 98%) as a light amber solid.
Figure imgf000254_0002
Example 257E A solution of Example 257D (2.14g, 11.75 mmol) in dichloromethane (40 mL) was treated with a solution of oxalyl chloride in dichloromethane (6.5 mL, 2.0 M, 12.90 mmol) followed by stirring at ambient temperature for 2.5 h. The solution was concentrated in vacuo to approximately one third original volume and the concentrate was diluted with dichlormethane (30 mL). The solution was cooled to 0°C, and treated sequentially with triethylamine (4.1 mL, 29.36 mmol) and N, N-dimethylaminopyridine (360 mg, 2.94 mmol). The solution was then treated with 2-(trimethylsilyl)ethanol (2.10 mL, 14.68 mmol) followed by stirring at 0°C for 30 min, and then warming to ambient temperature for 1 h. The solution was diluted with dichloromethane and extracted with water (3x). Drying (Na2SO4) and concentration in vacuo afforded an orange oil which was purified by silica gel chromatography eluting with hexane and then with ethyl acetate in hexane. These procedures afforded the as a colorless oil.
Figure imgf000254_0003
Example 257F A solution of Example 257E (3.02g, 10.69 mmol) in THF (43 mL) at -78°C was treated dropwise over 10 min with a solution of lithium hexamethyldisilylazide (15.0 mL, 14.97 mmol) followed by stirring at -78°C for 1 h. The solution was treated with a solution of methyl iodide in methyl-tert-butyl ether (10.7 mL, 21.38 mmol) followed by warming to 0°C for 1 h, and then warming to ambient temperature for 18 h. The solution was treated with saturated ammonium chloride solution (5 mL), followed by dilution with water and ethyl acetate. The organic layer was extracted with water (2x) and saturated sodium chloride solution. Drying (Na2SO4) and concentration in vacuo afforded an amber oil which was purified by silica gel chromatography eluting with hexane and then with
Figure imgf000255_0001
Example 257G
A solution of 2,2,6,6-tetramethylpiperidine (0.24 mL, 1.43 mmol) in THF (6 mL) at -78°C was treated with a solution of n-butyllithium in hexane (0.53 mL, 2.5 M, 1.32 mmol) followed by warming at -15°C for 4 min, and cooling again to -78°C. To this solution was added via cannula a cold (-78°C) solution of Example 257F (0.327g, 1.10 mmol) in 4 mL THF. The orange solution was stirred at -78°C for 2 h. The solution was treated with tri-n-butylchlorostannane (0.36 mL, 1.32 mmol) dropwise followed by stirring at -78°C for 15 min, warming to -40°C for 30 min, and then to 0°C and finally ambient temperature. The solution was stirred at ambient temperature for 30 min and was added to cold (0°C) saturated ammonium chloride solution followed by dilution with ethyl acetate and water. The organic layer was extracted with saturated ammonium chloride solution
(2x) and saturated sodium chloride solution. Drying (Na2SO4) and concentration in vacuo afforded the desired product (0.729g, ca. 100%) as a colorless oil.
Figure imgf000255_0002
Example 257H A solution of Example 257G (0.646mg, 1.10 mmol), ethyl 7-bromo-l-cyclopropyl-
8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate (0.202 g, 0.55 mmol), bis(triphenylphosphine)palladium (II) chloride (0.040g, 0.06 mmol) in 6 mL toluene was degassed by alternate evacuation and purging with nitrogen. The solution was warmed at 95°C for 3 h, followed by cooling to ambient temperature. The solution was diluted with ethyl acetate and extracted with saturated ammonium chloride solution. The mixture was filtered through a pad of celite and the layers of the filtrate were separated. The organic phase was extracted with saturated ammonium chloride solution (2x) and with saturated sodium chloride solution. Drying (Na2SO4) and concentration in vacuo afforded a brown oil which was dissolved in dichloromethane and treated with an excess of diazoethane (prepared from N-ethyl-N-nitrosourea in dichloromethane by the method of Marshall: Marshall, J. A.; Partridge, J. J. J. Org. Chem. 1968, 33, 4090) followed by allowing the resulting solution to stand at ambient temperature for 18 h. The solution was dried (MgSO4) and concentrated in vacuo to afford an amber oil. This material was purified by silica gel chromatography, eluting with ethyl acetate in hexane to give the desired product (0.106 g, 33%) as an off-white solid.
Figure imgf000256_0001
Example 2571
A solution of Example 257h (0.099 g, 0.17 mmol) in THF (2.0 mL) was treated with a solution of tetrabuylammonium fluoride (0.34 mL, 1.0 M, 0.34 mmol) followed by stirring at ambient temperature for 30 min. The solution was diluted with dichloromethane and extracted with water (3x). The solution was dried (Na2SO4) and concentrated in vacuo to afford the desired product (0.081 mg, 100%) as an off-white solid.
Figure imgf000256_0002
Example 257J A solution of Example 2571 (0.081 g, 0.17 mmol) and triethylamine (28 μL, 0.20 mmol) in toluene (1.5 mL) was treated with diphenylphosphoroyl azide (37 μL, 0.17 mmol) followed by warming at 80°C for 3 h. The solution was cooled to ambient temperature and treated with 2-(trimethylsilyl)ethanol (73 μL, 0.51 mmol) followed by warming at 60°C for 2 h. The solution was cooled to ambient temperature, diluted with dichloromethane and extracted with water (3x). Drying (Na2SO4) and concentration in vacuo afforded an oil which was purified by silica gel chromatography eluting with ethyl acetate in hexane to give the desired product (0.053g, 52%) as an oil. Example 257K 7-(4-amino-4-methyl-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l-cvclopropyl-8-methoxy-4- oxo-l,4-dihvdro-3-quinolinecarboxylic acid A solution of Example 257J (0.047 g, 0.08 mmol) in THF (1.0 mL) was treated with a solution of tetrabutylammonium fluoride (0.16 mL, 1.0 M, 0.16 mmol) followed by warming at 70°C for 1 h. The solution was cooled to ambient temperature and diluted with chloroform, followed by extraction with water (2x). Drying (Na2SO ) and concentration in vacuo afforded an oil. This material was dissolved in THF (1.0 mL) and water (0.5 mL) and treated with lithium hydroxide monohydrate (17 mg, 0.39 mmol) followed by stirring at ambient temperature for 1 h. The mixture was concentrated in vacuo and the residue was dissolved in water (5 mL). The solution was adjusted to pH 7 by addition of 1 N HCI solution, followed by extraction with dichloromethane (5x). The organic phase was dried (Νa2SO ) and concentrated in vacuo to afford, after trituration with chlorform-hexane, the desired product (0.018 g, 54%) as a buff-colored solid. MS (ESI) m/z 425 (M+H)+;
1H NMR (DMSO-*, 300 MHz) δ 8.78 (s, 1 H), 8.11 (d, 1 H), 8.01 (d, 1 H), 7.93 (s, 1 H), 4.24 (m, 1 H), 3.68 (s, 3 H), 2.75 (t, 2 H), 1.93 (m, 1 H), 1.82 (m, 1 H), 1.71 (m, 2 H), 1.33 (s, 3 H), 1.24 (m, IH), 1.15 (m, 2 H), 1.03 (m, 2 H).
Example 258 l-cyclopropyl-7-(5-(dimethylamino)-5,6-dihvdro-4H-cyclopenta[blthien-2-yl)-8-methoxy-
4-oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride
Figure imgf000257_0001
Example 258 A
The desired product was prepared by substituting Example 45F for Example 38C in Example 39A and was used without further purification.
Figure imgf000257_0002
Example 258B The desired product was prepared by substituting Example 258A for Example 45F in Example 45G.
Figure imgf000258_0001
Example 258C The desired product was prepared by substituting Example 258B for Example 45G in Example 249A.
Figure imgf000258_0002
Example 258D The desired product was prepared by substituting Example 258C for Example249A in Example 249B.
Figure imgf000258_0003
Example 258E The desired product was prepared by substituting Example 258D and 10: 1 dichloromethane:DMF as reaction solvent for Example 201C and dichloromethane as reaction solvent, respectively in Example 35366D.
Figure imgf000258_0004
Example 258F The desired product was prepared by substituting Example 258E for Example 40B in Example 40C.
Example 258G l-cvclopropyl-7-(5-(dimethylamino)-5,6-dihydro-4H-cyclopenta[b1thien-2-yl)-8-methoxy- 4-oxo-l,4-dihvdro-3-quinolinecarboxylic acid hydrochloride A solution of Example 258F (0.096g, 0.22 mmol) in 6.42 mL of 37% formaldehyde solution was treated with 1.6 mL of 88% formic acid, followed by warming at 90°C for 24 h. The solution was cooled to ambient temperature and concentrated in vacuo, removing the last traces of water by azeotroping with ethanol. The residue was suspended in dichloromethane and filtered through a pad of celite to remove insoluble materials. The filtrate was treated with 4 N ΗC1 in dioxane. The precipitate was collected by filtration and washed with ether to give the desired product (0.050g, 51%) as a yellow solid.
MS (ESI) m/z 425 (M+Η)+;
Η ΝMR (CDC13, 300 MHz) δ 8.91 (s, 1 H), 8.32 (s, 1 H), 8.24 (d, 1 H), 7.72 (d, 1 H), 7.40 (s, 1 H), 4.18 (m, 1 H), 4.11 (m, IH), 3.66 (s, 3H), 3.37 (d, 2 H), 3.19 (d, 2H), 2.71 (s, 6 H), 1.28 (m, 2 H), 1.06 (m, 2 H).
Example 259
7-(4-azido-5,5-dimethyl-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-
4-oxo-l,4-dihydro-3-quinolinecarboxylic acid
Figure imgf000259_0001
Example 259 The desired product was prepared by substituting example 213E for example 45G in example 249A.
Figure imgf000259_0002
Example 259B The desired product was prepared by substituting example 259A and DMSO as reaction solvent for example 249A and DMF as reaction solvent in example 249B. Example 259C 7-(4-azido-5,5-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy- 4-oxo-l,4-dihydro-3-quinolinecarboxylic acid
The desired product was prepared by substituting example 259B for example 2A in example 2B. mp 89-90° C;
MS (APCI) m/z 465 (M+H)+; 1H NMR (300 MHz, DMSO-*) δ 8.90 (s, IH), 8.24 (d, IH), 7.75 (d, IH), 7.53 (s, IH), 4.13 (m, 2H), 3.68 (s, 3H), 2.90 (m, 2H), 1.90 (m, 2H), 1.53 (br s, IH), 1.28 (m, 2H), 1.13 (s, 3H), 1.09 (s, 3H), 1.07 (m, 2H).
Example 260
7-(7-amino-4,5,6,7-tetrahvdro-l-benzothien-3-yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4- dihydro-3-quinolinecarboxylic acid
Figure imgf000260_0001
Example 260A A solution of 7-keto-4,5,6,7-tetrahydrothienanapthene (4.00g, 26.3 mmol, prepared by the method of Caubere, et al. Eur. J. Med. Chem. 1998, 867-77) in 50% aqueous acetic acid was cooled to 0°C and treated dropwise with a solution of bromine (6 mL, 103 mmol) in 50% aqueous acetic acid. The mixture was allowed to warm to room temperature and stirred overnight. Saturated aqueous sodium acetate (50 mL) was added. The precipitate was filtered, washed with water and dried under vacuum to provide the desired product (8.07g, 99%) as a white solid.
Figure imgf000260_0002
Example 260B
The desired product was prepared by substituting example 260A for example 218A in example 218B.
Figure imgf000261_0001
Example 260C A solution of example 260B in diethyl ether was cooled to -78°C and treated dropwise with n-butyl lithium (2.2 mL of a 2.5 M solution in hexanes, 5.5mmol). The reaction mixture was stirred at -78°C for 1 h. Water (10 mL) was added and the mixture was allowed to warm to room temperature over 2 h. The layers were separated. The organic layer was washed with brine, dried (Na2SO ), and concentrated. The resulting residue was purified by silica gel chromatography eluting with 10% ethyl acetate in hexane to provide the desired product (1.735 g, 100%) as an orange oil.
Figure imgf000261_0002
Example 260D
A solution of example 260C (1.73 g, 4.99 mmol) in diethyl ether (10 mL) was cooled to -50°C, treated dropwise with n-butyl lithium (2.5 mL of a 2.5 M solution in hexanes, 6.25 mmol), stirred at -50°C for 1.5 h. After cooling to -78°C the reaction mixture was treated dropwise with a solution of chlorotributylstannane (1.65 L, 5.1 mmol), allowed to warm to room temperature, and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (Na2SO4), and concentrated to give the desired product as a yellow oil that was used without further purification.
Figure imgf000261_0003
Example 260E The desired product was prepared by substituting example 260D and ethyl 7- bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate for example ID and ethyl 7-bromo-l-cyclopropyl-4-oxo-l,4-dihydro-3-quinolinecarboxylate, resxpectively in example IE.
Figure imgf000262_0001
Example 260F
The desired product was prepared by substituting example 260E for example 35D in example 35E and was purified by silica gel chromatography eluting with hexane then
50% acetone in hexane to provide the desired product.
Figure imgf000262_0002
Example 260G The desired product was prepared by substituting example 260F for example 37 A example 37B.
Figure imgf000262_0003
Example 260H The desired product was prepared by substituting example 260G for example 201C in example 201D.
Figure imgf000262_0004
Example 2601 The desired product was prepared by substituting example 260H for example 2A in example 2B.
Example 2601 7-(7-amino-4,5,6,7-tetrahydro-l-benzothien-3-yl)-l-cvclopropyl-8-methoxy-4-oxo-l,4- dihvdro-3-quinolinecarboxylic acid The desired product was prepared by substituting example 2601 for example 40B in example 40C.
MS (APCI) m/z 445 (M+Cl)";
Η NMR (300 MHz, DMSO-*) δ 8.82 (s, IH), 8.38 (br s, 2 H), 8.17 (d, IH), 7.79 (s, IH), 7.48 (d, IH), 4.63 (m, IH), 4.23 (m, IH), 3.42 (s, 3H), 3.15 (m, 2H), 2.25-1.75 (m, 4H), 1.17-1.10 (m, 4H).
Example 261
7-(7-amino-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8-(difluoromethoxy)-4- oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid
Figure imgf000263_0001
Example 261 A
The desired product was prepared by substituting example 41B and ethyl 7-bromo- l-cyclopropyl-8-difluoromethoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate for example
ID and ethyl 7-bromo-l-cyclopropyl-4-oxo-l,4-dihydro-3-quinolinecarboxylate, respectively in example IE followed by substituting the crude product for example 38C in example 39A.
Figure imgf000263_0002
Example 26 IB The desired product was prepared by substituting example 261 A for example 35D in example 35E and was puπfied by silica gel chromatography eluting with hexane then
50% acetone in hexane to provide the desired product.
Figure imgf000264_0001
Example 26 IC The desired product was prepared by substituting example 26 IB for example 37A
Figure imgf000264_0002
Example 26 ID The desired product was prepared by substituting example 26 IC for example 20 IC in example 201D.
Figure imgf000264_0003
Example 26 IE The desired product was prepared by substituting example 26 ID for example 2A in example 2B.
Example 261F
7-(7-amιno-4,5,6,7-tetrahydro-l-benzothιen-2-yl)-l-cvclopropyl-8-(dιfluoromethoxy)-4- oxo-l,4-dιhvdro-3-quιnolιnecarboxylιc acid The desired product was prepared by substituting example 261E for example 40B in example 40C. MS (DC17NH3) m/z 447(M+1)+;
Η NMR (300 MHz, DMSO-*) δ 14.58 (s, IH), 8.88 (s, IH), 8.49 (br s, 2H), 8.32 (d, IH), 7.60 (s, IH), 6.99 (dd, IH), 4.63 (m, IH), 4.15 (m, IH), 2.68, (m, 2H) 2.14-1.82 (m 4H), 1.21-1.03 (m, 4H).
Example 262 l-cvclopropyl-7-(7-hydroxy-5,5-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid
Figure imgf000265_0001
Example 262A
The desired product was prepared by substituting Example 213A for Example 185C in Example 185D.
Figure imgf000265_0002
Example 262B The desired product was prepared by substituting 262A for 4,4-dimethyl-4, 5,6,7- tetrahydrobenzo[b]thiophene in Example 218 A and was purified by silica gel chromatography eluting with CH2C12.
Figure imgf000265_0003
Example 262C The desired product was prepared by substituting Example 262B for Example 218A in Example 218B
Figure imgf000266_0001
Example 262D The desired product was prepared by substituting Example 262C for Example 218B in Example 218C.
Figure imgf000266_0002
Example 262E The desired product was prepared by substituting Example 262D, ethyl 7- bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate and a reaction time of 8.5hours for Example ID, ethyl 7-bromo-l-cyclopropyl-4-oxo-l,4-dihydro-3- quinoline-3-carboxylate and a reaction time of 8.5 hours, respectively in Example IE.
Figure imgf000266_0003
Example 262F
The desired product was prepared by substituting Example 262E for Example 35D in Example 35E and was purified by silica gel chromatography eluting with 3.5% MeOH in CH2C12.
Example 262G l-cvclopropyl-7-(7-hvdroxy-5,5-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting Example 262F for Example 2A in Example 2B. mp 182-183° C; MS (APCI) m/z 440 (M+H)+;
Η NMR (300MHz, CDCl 3) δ 14.72 (br s, IH), 8.91 (s, IH), 8.23 (d, IH), 7.78 (d, IH), 7.33 (s, IH), 5.00 (br m, IH), 4.10 (m, IH), 3.67 (s, 3H), 2.50 (dd, 2H), 2.04 (dd, 2H), 1.55 (br s, IH), 1.25 (m, 2H), 1.15 (s, 3H), 1.08 (m, 2H), 1.02 (s, 3H).
Example 263
7-(7-amino-5,5-dimethyl-4,5,6,7-tetrahvdro-l-benzothien-2-yl)-l-cvclopropyl-8-methoxy-
4-oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride
Figure imgf000267_0001
Example 263 A
The desired product was prepared by substituting Example 262F for Example 37A in Example 37B and was purified by silica gel chromatography eluting with 2% MeOH in
CH2C12.
Figure imgf000267_0002
Example 263B
The desired product was prepared by substituting 263A for 201C in Example 201D and was purified by silica gel chromatography eluting with 2% MeOH in CH2C12.
Figure imgf000268_0001
Example 263C The desired product was prepared by substituting Example 263B for 2A in Example 2B.
Example 263D
7-(7-amino-5,5-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy- 4-oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride The desired product was prepared by substituting Example 263C for Example 40B in Example 40C. mp 194-195° C;
MS (APCI) m/z 439 (M+H)+;
Η NMR (300MHz, CDCl 3) δ 8.83 (s, IH), 8.52 (br s, 3H), 8.15 (d, IH), 8.06 (d, IH), 7.68 (s, IH), 4.53 (m, IH), 4.28 (m, IH), 3.73 (s, 3H), 3.30 (s, IH), 2.45 (m, 2H), 2.03 (,
2H), 1.16 (s, 3H), 1.12 (m, 2H), 1.08 (m, 2H), 0.94 (s, 3H).
Example 264 l-cvclopropyl-7-(4-hvdroxy-4,5,6,7-tetrahydro-l-benzofuran-2-yl)-8-methoxy-4-oxo-l ,4- dihydro-3-quinolinecarboxylic acid
Figure imgf000268_0002
Example 264A The desired product was prepared by substituting 4-hydroxy-4, 5,6,7- tetrahydrobenzofuran (prepared by the method of L. Mase, et.al. Tetrahedron. 1996, 52, 8169-8180) for Example 185F in Example 185G.
Figure imgf000269_0001
Example 264B The desired product was prepared by substituting Example 264A for Example
218B in Example 218C.
Figure imgf000269_0002
Example 264C The desired product was prepared by substituting Example 264B and ethyl-7- bromo-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate for Example ID and ethyl-7-bromo- 1 -cyclopropyl-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylate, respectively in Example IE.
Figure imgf000269_0003
Example 264D The desired product was prepared by substituting Example 264C for Example 35D in Example 35E. Example 264E l-cvclopropyl-7-(4-hvdroxy-4,5,6,7-tetrahydro-l-benzofuran-2-yl)-8-methoxy-4-oxo-l,4- dihydro-3-quinolinecarboxylic acid The desired product was prepared by substituting Example 264D for Example 2A in Example 2B. MS (ESI) m/z 430 (M+Cl")" ;
Η NMR (300 MHz, DMSO-d6) δ 14.94 (s, IH), 8.78 (d,lH), 7.97(d, IH), 7.26(s,lH), 5.05 (br s, 5.05), 4.62(m,lH), 4.26 (m,lH), 3.75 (s, IH), 2.68-2.59(m, 2H), 1.98 (m,lH), 1.88 (m, lH), 1.75 (m,lH), 1.67 (m, IH), 1.17 (d, 2H), 1.04 (s, 2H).
Example 265
7-(4-amino-4,5,6,7-tetrahydro-l-benzofuran-2-yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4- dihydro-3-quinolinecarboxylic acid hydrochloride
Figure imgf000270_0001
Example 265A The desired product was prepared by substituting Example 264D for Example 37A in Example 37B and was purified by chromatography on silica gel eluting with CH2Cl2:CH3OH (96:4).
Figure imgf000270_0002
Example 265B The desired product was prepared by substituting Example 265A for
Example 20 IC in Example 20 ID and was purified by chromatography on silica gel eluting with CH2Cl2:CH3OH (96:4).
Figure imgf000271_0001
Example 265C The desired product was prepared by substituting Example 265B for Example 2A in Example 2B.
Example 265D 7-(4-amino-4,5,6,7-tetrahydro-l-benzofuran-2-yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4- dihydro-3-quinolinecarboxylic acid hydrochloride
The desired product was prepared by substituting Example 265C for Example 40B in Example 40C. MS (ESI) m/z 395 (M+H+)+;
Η NMR (300 MHz, CD3OD) δ 8.96 (s, IH), 8.23 (d, IH), 7.47 (s, IH), 4.48 (m, IH), 4.32 (m, IH), 3.81 (s, 3H), 2.82 ( , 2H), 2.82-2.13 (m, 2H), 2.04-1.90 (m, 2H), 1.24 (d, 2H), 1.07 (s, 2H).
Using the schemes and experimentals discussed hereinabove, the following compounds were prepared. The MIC data for the compounds is presented in Table 1 or Table 2.

Claims

WHAT IS CLAIMED IS
1. A compound selected from the group consisting of compounds of formula (I)
Figure imgf000272_0001
(I), or pharmaceutically acceptable salts or prodrugs thereof, wherein
Figure imgf000272_0002
A is nitrogen or j wherein W is selected from the group consisting (1) hydrogen and (2) optionally substituted alkyl;
2
A is selected from the group consisting of
(1) -S-,
(2) -O-, and
7 7
(3) -N(R )-, wherein R is hydrogen or Cι-C6 alkyl;
R is selected from the group consisting of
(1) hydrogen, (2) halide, and
(3) optionally protected amino;
2 ?
Z is nitrogen or R , wherein R is selected from the group consisting of (1) hydrogen,
(2) halide,
(3) optionally protected hydroxyl,
(4) -OR8, and (5) -S(O)nR , wherein n is zero, one, or two, and wherein R in (4) and (5) is selected from the group consisting of (a) C3-C6 alkenyl, (b) C,-C6 alkyl, and
(c) C3-C6 alkynyl, wherein (a)-(c) can be optionally substituted with one, two, or three substituents independently selected from the group consisting of (i) alkoxy, (ii) aryl,
(iii) C3-C6 cycloalkyl, (iv) azido, (v) cyano, (vi) halide, (vii) optionally protected amino,
(viii) optionally protected carboxyl, and
(ix) optionally protected hydroxyl;
3 R is selected from the group consisting of
(1) C3-C6 alkenyl,
(2) d-C6 alkyl,
(3) C3-C6 alkynyl, wherein (l)-(3) can be optionally substituted with one, two, or three substutuents independently selected from the group consisting of
(a) Cj-C6 alkanoyloxy,
(b) Cι-C6 alkoxy,
(c) aryl,
(d) azido, (e) cyano,
(f) C3-C6 cycloalkyl,
(g) halide,
(h) optionally protected amino, (i) optionally protected carboxyl, (j) optionally protected hydroxyl,
(k) oxo, (1) Cι-C6 perfluoroalkoxy, (m) C- -C6 perfluorothioalkoxy, and (n) thioxo,
(4) aryl,
(5) C3-C6 cycloalkyl, and
(6) heterocycle, wherein (4)-(6) can be optionally substituted with one, two, or three substituents independently selected from the group consisting of
(a) C--C6 alkanoyloxy,
(b) Ci-C6 alkoxy,
(c) C2-C6 alkenyl, (d) Cι-C6 alkyl,
(e) C2-C6 alkynyl,
(0 aryl,
(g) azido,
(h) cyano, (i) C3-C6 cycloalkyl,
(j) halide,
(k) optionally protected amino
(1) optionally protected carboxyl,
(m) optionally protected hydroxyl, (n) -Cό perfluoroalkoxy, and
(o) Cι-C6 perfluorothioalkoxy;
or
2 3 R and R together are selected from the group consisting of
Figure imgf000274_0001
Figure imgf000275_0001
and
Figure imgf000275_0002
and
9 10 wherein one of R or R in (l)-(5) is hydrogen and the other is selected from the group consisting of (1) hydrogen,
(2) C,-C6 alkyl,
(3) Cι-C6 haloalkyl, and
(4) optionally protected hydroxyl, or
9 10 wherein R and R together are alkylidene or C3-C6 spiroalkyl;
R is hydrogen or -OR , wherein R is hydrogen or a carboxyl protecting group;
and
R and R together are a carbocyclic or a heterocyclic ring, wherein the carbocyclic ring and the heterocyclic ring can be optionally substituted with one, two, or three substituents independently selected from the group consisting of
(I) optionally substituted aryl, (2) azido,
(3) carboxaldehyde,
(4) cyano,
(5) halide,
(6) nitro, (7) optionally substituted Cι-C6 alkyl,
(8) optionally substituted C3-C6 alkenyl,
(9) optionally substituted C3-C6 alkynyl,
(10) optionally protected amino,
(I I) optionally protected hydroxyl, (12) optionally protected carboxyl,
(13) optionally substituted C--C6 alkanoyloxy, (14 ) optionally substituted Cj-C6 alkoxy,
(15 ) optionally substituted aryl,
(16 ) optionally substituted C3-C6 cycloalkyl,
135 (17 ) optionally substituted heterocycle,
(18 ) oxo,
(19 ) C--C6 perfluoroalkoxy,
(20 ) Cι-C6 perfluorothioalkoxy,
(21 ) optionally substituted Cι-C6 thioalkoxy,
140 (22 ) thioxo,
(23 ) a nitrogen protecting group,
(24 ) heterocycle,
(25 ) -C(O)N(R12)2,
(26 ) -C(O)SR12,
145 (27 ) -N(R12)2
(28 ) =N-,
(29 ) -OC(O)N(R12)2,
(30 ) =N-N(R12)2,
(31 ) =N(R12)-N(R12)2,
150 (32 ) -N(R12)-C(=NR12)-N(R12)2,
(33; ) =NOR12,
(34 ) =NN(R12)C(O)N(R12)2,
(35 ) -N(R12)C(O)N(R12)2,
(36; ) -C(O)R12,
155 (37; ) -OC(O)R12,
(38, ) -N(R12)C(O)R12,
(39; ) -N(R12)S(O)nR12,
(4o; ) -OR12,
(4r l -S(O)nR12,
160 (42; 1 -SC(O)R12,
(43; 1 -OC(O)OR12,
(44; 1 =N(R12)OR12,
(45; -OC(=N(R12))R12,
(46; 1 -N(R12)C(=NR12)R12,
165 (47; l -C(O)OC(O)R12,
(48; =N-N(R ' 2)-C(O)C(O)N(R ' 2)2,
(49; =NN(R12)C(S)N(R12)2, (50) =C(R12)OR12,
(51) alkylidene,
170 (52) optionally substituted spiroheterocycle, and
(53) =N-N(RI 3)(R14),
12 wherein R in (25)-(50) is independently selected from the group consisting of (1) hydrogen, 175 (2) opti on al 1 y s ubstituted ary 1 ,
(3) optionally substituted Cι-C6 alkyl,
(4) optionally substituted C3-C6 alkenyl,
(5) optionally substituted aryl, and
180 (6) optionally substituted heterocycle, and
13 14 wherein R and R in (53) together with the nitrogen atom to which they are attached from a heterocycle selected form the group consisting of pyrrolidinyl, piperidinyl, imidazolidinyl, pyrazolidinyl, piperazinyl, morpholinyl, and
185 thiomorpholinyl,
13 14 wherein the heterocycle defined by R and R together can be optionally substituted with optionally substituted alkyl.
2. A compound according to Claim 1 wherein A is methine.
2 3. A compound according to Claim 1 wherein A is -S-
4. A compound according to Claim 1 wherein R is hydrogen.
5. A compound according to Claim 1 wherein R is fluoride.
l 2
6. A compound according to Claim 1 wherein Z is R and R is methoxy.
l 2
7. A compound according to Claim 1 wherein Z is ■ and R is difluoromethoxy.
8. A compound according to Claim 1 wherein R is cyclopropyl.
9. A compound according to Claim 1 wherein R and R together are an optionally substituted carbocyclic ring.
1 2 1
10. A compound according to Claim 1 wherein A is methine, A is -S-, R is T l 2 hydrogen, Z is R and R is methoxy, R is cyclopropyl, R is hydrogen, R and R together are an optionally substituted carbocyclic ring and the substituent is amino.
11. A compound according to Claim 1 wherein R and R together are an optionally substituted heterocyclic ring.
12. A method for preparing a compound of formula (la), the method comprising
(a) reacting compounds of formula (la)
Figure imgf000278_0001
((llaa), wherein R , R , R , and Z are defined in Claim 1, and Q is a first covalent bond precursor, with compounds of formula (II)
wherein A
Figure imgf000278_0002
is a second covalent bond precursor, in the presence of a catalyst, to provide a first product; and (b) optionally hydrolyzing the first product.
13. The method according to Claim 12, wherein Q is selected from chloride, bromide, iodide, methanesulfonate, or trifluoromethanesulfonate. 2
14. The method according to Claim 12, wherein Q is a trialkylstannane, boronic acid, boronic ester, magnesium halide, zinc halide, or -silyl(alkyl)cyclobutane.
15. The method according to Claim 12 wherein the catalyst is selected from tetrakis(triphenylphosphine)palladium(0), palladium(II) chloride(dibenzylidine acetone), or palladium(IT) chloride bis(triphenylphosphine).
16. The method according to Claim 13, wherein Q is bromide.
2
17. The method according to Claim 14, wherein Q is a trialkylstannane.
18. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Claim 1 in combination with a pharmaceutically acceptable carrier.
19. A method of inhibiting the growth of bacteria which comprises contacting the bacteria with an pharmaceutically effective amount of a compound of Claim 1.
20. A compound selected from the group consisting of l-cyclopropyl-4-oxo-7-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-l,4-dihydro-3- quinolinecarboxylic acid, l-cyclopropyl-8-methoxy-4-oxo-7-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)- l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-4-oxo-7-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-l,4- dihydrof l ,8]naphthyridine-3-carboxylic acid, l-cyclopropyl-6-fluoro-4-oxo-7-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-l,4- dihydro[l,8]naphthyridine-3-carboxylic acid, l-cyclopropyl-8-(difluoromethoxy)-4-oxo-7-(4,5,6,7-tetrahydrothieno[3,2- c]pyridin-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-4-oxo-7-(4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-l,4-dihydro-3- quinolinecarboxylic acid, l-cyclopropyl-8-methoxy-4-oxo-7-(4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)- l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-4-oxo-7-(4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-l,4- dihydro[l,8]naphthyridine-3-carboxylic acid, l-cyclopropyl-6-fluoro-4-oxo-7-(4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-l,4- dihydro[l,8]naphthyridine-3-carboxylic acid, l-cyclopropyl-8-(difluoromethoxy)-4-oxo-7-(4,5,6,7-tetrahydrothieno[2,3- c]pyridin-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-4-oxo-l,4- dihydro[l,8]naphthyridine-3-carboxylic acid, l-cyclopropyl-6-fluoro-7-(6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-4- oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylic acid, l-cyclopropyl-7-(6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-4-oxo-l,4- dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-8-(difluoromethoxy)-7-(6-methyl-4,5,6,7-tetrahydrothieno[3,2- c]pyridin-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-8-methoxy-7-(6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-
4-oxo-l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-4-oxo-l,4- dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-4-oxo-l,4- dihydro[l,8]naphthyridine-3-carboxylic acid, l-cyclopropyl-6-fluoro-7-(4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-4- oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylic acid, l-cyclopropyl-8-methoxy-7-(4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)- 4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-8-(difluoromethoxy)-7-(4-methyl-4,5,6,7-tetrahydrothieno[3,2- c]pyridin-2-yl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-4-oxo-l,4- dihydro[l,8]naphthyridine-3-carboxylic acid, l-cyclopropyl-6-fluoro-7-(7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-4- oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylic acid, l-cyclopropyl-8-methoxy-7-(7-methyl-4,5,6,7-tetrahydrotheino[2,3-c]pyrindin-2- yl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-4-oxo- l,4-dihydro[l,8]naphthyridine-3-carboxylic acid, l-cyclopropyl-7-(7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-4-oxo- l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-6- fluoro-4-oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylic acid, l-cyclopropyl-8-(difluoromethoxy)-7-(7,7-dimethyl-4,5,6,7-tetrahydrothιeno[3,2- c]pyridin-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(4-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-4-oxo-l,4- dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-8-methoxy-7-(4-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-
4-oxo-l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-8-(difluoromethoxy)-7-(4-methyl-4,5,6,7-tetrahydrothieno[2,3- c]pyridin-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(4-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-4-oxo-l,4- dihydro[l,8]naphthyridine-3-carboxylic acid, l-cyclopropyl-6-fluoro-7-(4-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-4- oxo- 1 ,4-dihydro[ 1 ,8]naphthyridine-3-carboxylic acid, l-cyclopropyl-7-(4,4-dimethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-6-fluoro-7-(4-hydroxy-4,5,6,7-tetrahydro-l-benzothien-2-yl)-4-oxo- l,4-dihydro[l,8]naphthyridine-3-carboxylic acid, l-cyclopropyl-7-(4-hydroxy-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid,
7-(4-amino-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(4-hydroxy-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid,
7-(4-azido-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid, 7-(4-amino-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4-oxo-
1 ,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(7-hydroxy-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(5-hydroxy-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(5-(hydroxymethyl)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(5-(hydroxymethyl)-6,7-dihydro-l-benzothien-2-yl)-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(5-hydroxy-5,6-dihydro-4H-cyclopenta[b]thien-2-yl)-8-methoxy-
4-oxo-l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-8-methoxy-7-(4-methoxy-5,6-dihydro-4H-cyclopenta[b]thien-2-yl)- 4-oxo-l,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-7-(6-hydroxy-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8-methoxy-4- 95 oxo-l ,4-dihydro-3-quinolinecarboxylic acid, l-cyclopropyl-6-fluoro-4-oxo-7-(4-oxo-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l,4- dihydro[l ,8]naphthyridine-3-carboxylic acid, l-cyclopropyl-6-fluoro-7-((4E/Z)-4-(hydroxyimino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l ,4-dihydro(l,8)naphthyridine-3-carboxylic acid; 100 l-cyclopropyl-8-methoxy-4-oxo-7-(4-oxo-4,5,6,7-tetrahydro-l-benzothien-2-yl)- l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-((4E/Z)-4-(hydroxyimino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)- 8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-diflouromethoxy-7-(7-methyl-4,5,6,7-tetrahydrotheino(2,3- 105 c)pyrindin-2-yl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(5-oxo-4,5,6,7-tetrahydro-l-benzothien-2-yl)- l,4-dihydro-3-quinolinecarboxylic acid;
7-[5-(azidomethyl)-4,5,6,7-tetrahydro-l-benzothien-2-yl]-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; 110 l-cyclopropyl-7-((5E/Z)-5-(hydroxyimino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-
8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-((5E/Z)-5-(methoxyimino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(5-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-4-oxo-l,4- 115 dihydro[l ,8]naphthyridine-3-carboxylic acid;
7-(5-bromo-4-oxo-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy- 4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(6-oxo-4,5,6,7-tetrahydro-l-benzothien-2-yl)- 1 ,4-dihydro-3-quinolinecarboxylic acid; 120 l-cyclopropyl-7-((6E/Z)-6-(hydroxyimino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-
8-methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(7-oxo-4,5,6,7-tetrahydro-l-benzothien-2-yl)- l,4-dihydro-3-quinolinecarboxylic acid;
7-(5-azido-4-oxo-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy- 125 4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-((7E/Z)-7-(methoxyimino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-((4E/Z)-4-(methoxyimino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; 130 l-cyclopropyl-7-((4E/Z)-4-(ethoxyimino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-((6E/Z)-6-(methoxyimino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(6,7-dihydro-l-benzothien-2-yl)-8-methoxy-4-oxo-l,4-dihydro-3- 135 quinohnecarboxylic acid;
. l-cyclopropyl-8-methoxy-7-((4E/Z)-4-(4-mo holinylimino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4,5-dihydroxy-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8-methoxy- 4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; 140 7-(5-(aminomethyl)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(6-amino-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid;
7-((4E/Z)-4-(tert-butoxyimino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- 145 cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-((4E/Z)-4-((benzyloxy)imino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-((4E/Z)-4-(l-pyrrolidinylimino)-4,5,6,7- tetrahydro- l-benzothien-2-yl)-l ,4-dihydro-3-quinolinecarboxylic acid; 150 7-(4-amino-4,5,6,7-tetrahydro-l-benzothien-3-yl)-l-cyclopropyl-8-methoxy-4-oxo- l,4-dihydro-3-quinolinecarboxylic acid;
7-(5-amino-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-[4-(methylamino)-4,5,6,7-tetrahydro-l-benzothien-2- 155 yl]-4-oxo- l ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-((5E/Z)-5-(ethoxyimino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid;
7-((5E/Z)-5-((benzyloxy)imino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; 160 7-((4E/Z)-4-((aminocarbonyl)hydrazono)-4,5,6,7-tetrahydro-l-benzothien-2-yl)l- cyclopropyl-8-methoxy-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid; ethyl l-cyclopropyl-8-methoxy-7-((4E/Z)-4-((4-methyl-l-piperazinyl)imino)- 4,5,6,7-tetrahydro-l-benzothien-2-yl)-4-oxo-l ,4-dihydro-3-quinolinecarboxylate; ethyl 1 -cyclopropyl-8-methoxy-7-((4E/Z)-4-(((2R)-2- 165 (methoxymethyl)pyrrolidinyl)imino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-4-oxo-l ,4- dihydro-3-quinolinecarboxylate; l-cyclopropyl-7-(4-(dimethylamino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-((4E/Z)-4-[(aminocarbothioyl)hydrazono)-4,5,6,7-tetrahydro-l-benzothien-2-yl)- 170 l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyI-8-methoxy-7-((4E/Z)-4-(((methylamino)carbothioyl)hydrazono)- 4,5,6,7-tetrahydro-l-benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-(5-methylene-4-oxo-4,5,6,7-tetrahydro-l-benzothien- 2-yl)-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid; 175 ethyl l-cyclopropyl-8-methoxy-7-(5-methylene-4-oxo-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylate; l-cyclopropyl-8-methoxy-7-(4-((methylsulfonyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-(lH-pyrrol-l-yl)-4,5,6,7-tetrahydro-l- 180 benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-((4E/Z)-4-(((ethylamino)carbothioyl)hydrazono)-4,5,6,7- tetrahydro-l-benzothien-2-yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-((4E/Z)-4-((amino(oxo)acetyl)hydrazono)-4,5,6,7-tetrahydro-l-benzothien-2-yl)- l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; 185 l-cyclopropyl-8-methoxy-7-((4E/Z)-4-((4-methyl-l-piperazinyl)imino)-4, 5,6,7- tetrahydro-l-benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-((tert-butyl(dimethyl)silyl)oxy)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-((3-pyridinylmethyl)amino)-4,5,6,7- 190 tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid; ethyl 7-(4-((tert-butyl(dimethyl)silyl)oxy)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate;
7-((4E/Z)-4-(acetylhydrazono)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; 195 7-(4-(benzylamino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4-(ethylamino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8-methoxy- 4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-(difluoromethoxy)-7-(4-hydroxy-4,5,6,7-tetrahydro-l-benzothien- 200 2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-((4E/Z)-4-(4,5-dihydro-lH-imidazol-2-ylhydrazono)-4,5,6,7- tetrahydro-l-benzothien-2-yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-amino-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- (difluoromethoxy)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; 205 l-cyclopropyl-7-(4-hydroxy-2-methyl-l,l-dioxido-3,4-dihydro-2H-thieno[3,2- e][l,2]thiazin-6-yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; ethyl l-cyclopropyl-8-methoxy-7-(5-methyl-4-oxo-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylate; l-cyclopropyl-7-(4-((3-fluorobenzyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)- 210 8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-((4E/Z)-4-[(aminocarbothioyl)(methyl)hydrazono)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-(5-methyl-4-oxo-4,5,6,7-tetrahydro-l-benzothien-2- yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; 215 l-cyclopropyl-8-(difluoromethoxy)-7-(4-(methylamino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-6-fluoro-7-(4-(methylamino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)- 4-oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylic acid;
7-(4-amino-2-methyl-l,l-dioxido-3,4-dihydro-2H-thieno[3,2-e][l,2]thiazin-6-yl)- 220 l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4-(hydroxymethyl)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-(l-pyrrolidinylmethyl)-4,5,6,7-tetrahydro-l- benzothien-2-yl)- 1 ,4-dihydro-3-quinolinecarboxylic acid; 225 l-cyclopropyl-8-methoxy-4-oxo-7-(4-((2-pyrrolidinylmethyl)amino)-4,5,6,7- tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-(acetylamino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-(propionylamino)-4,5,6,7-tetrahydro-l- 230 benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-(4-((methoxyacetyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-((tetrahydrofuranyl-2-carbonyl)amino)- 4,5,6,7-tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid; 235 l-cyclopropyl-8-methoxy-4-oxo-7-(4-((tetrahydrofuranyl-3-carbonyl)amino)-
4,5,6,7-tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-(4-((4-moφholinylacetyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-(4-((3-(4-morpholinyl)propanoyl)amino)-4, 5,6,7- 240 tetrahydro-l-benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-((lH-pyrrol-2-ylcarbonyl)amino)-4, 5,6,7- tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-((3-pyridinylacetyl)amino)-4,5,6,7- tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid; 245 l-cyclopropyl-8-methoxy-4-oxo-7-(4-((3-pyridazinylcarbonyl)amino)-4,5,6,7- tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4-((lH-imidazol-2-ylcarbonyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-((l,3-thiazol-2-ylcarbonyl)amino)-4, 5,6,7- 250 tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyI-8-methoxy-7-(5-(methylamino)-4,5,6,7-tetrahydro-l-benzothien-2- yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-(4-(4-moφholinylmethyl)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid; 255 l-cyclopropyl-7-(4-((dimethylamino)methyl)-4,5,6,7-tetrahydro-l-benzothien-2- yl)-8-methoxy-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4-(((dimethylamino)acetyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-((2-pyridinylacetyl)amino)-4,5,6,7- 260 tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-(aminomethyl)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l ,4-dihydro-3 -quinohnecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-((4E/Z)-4-((4-pyridinylmethoxy)imino)-4, 5,6,7- tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid; 265 7-(4-((2-aminoethyI)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-
8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-(4-((l-methyl-4-piperidinyl)amino)-4,5,6,7-tetrahydro- l-benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-((4E/Z)-4-(hydroxyimino)-5-methyl-4,5,6,7-tetrahydro-l- 270 benzothien-2-yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4-hydroxy-7,7-dioxido-5,6-dihydro-4H-thieno[2,3-&]thiopyran-2- yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-(((5-chloro-l,3-dimethyl-lH-pyrazol-4-yl)suIfonyl)amino)-4,5,6,7-tetrahydro- l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-(((4-cyanophenyl)sulfonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-((phenylsulfonyl)amino)-4,5,6,7-tetrahydro- 1 -benzothien-2-yl)- 1 ,4-dihydro-3-quinolinecarboxylic acid; 7-(4-(((2-cyanophenyl)sulfonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-(4-(((4-methoxyphenyl)sulfonyl)amino)-4,5,6,7- tetrahydro-l-benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-(4-(((3-nitrophenyl)sulfonyl)amino)-4,5,6,7- tetrahydro-l-benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(5-((2-pyrrolidinylmethyl)amino)-4,5,6,7- tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-amino-7,7-dioxido-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4-(((3,5-dimethyl-4-isoxazolyl)sulfonyl)amino)-4,5,6,7- tetrahydro-l-benzothien-2-yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-((2,l,3-benzoxadiazol-4-ylsulfonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2- yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4-(((dimethylamino)sulfonyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-8-methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-((2-thienylsulfonyl)amino)-4, 5,6,7- tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-(((3-cyanophenyl)sulfonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; 7-(4-(((4-(acetylamino)phenyl)sulfonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2- yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-((2,l,3-benzothiadiazol-4-ylsulfonyl)amino)-4,5,6,7-tetrahydro-l-benzothien- 2-yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4-(((5-(3-isoxazolyl)-2-thienyl)sulfonyl)amino)-4,5,6,7- tetrahydro-l-benzothien-2-yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4-(((4-fluorophenyl)sulfonyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-(((6-chloroimidazo[2,l-b][l,3]thiazol-5-yl)sulfonyl)amino)-4,5,6,7- tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3- 310 quinohnecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-((4-pyridinylacetyl)amino)-4,5,6,7- tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4-((2-hydroxyethyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)- 8-methoxy-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid; 315 7-(4-amino-4,5 ,6,7-tetrahydro- 1 -benzothien-2-yl)- 1 -cyclopropyl-6-fluoro-4-oxo- l,4-dihydro[l ,8]naphthyridine-3-carboxylic acid;
7-(4-((glycyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-((D-alanyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- 320 methoxy-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-((D-prolyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-(((2R)-2-amino-3-(lH-imidazol-5-yl)propanoyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; 325 7-(4-((leucyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid;
7-(4-((D-tyrosyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-((O-methyl-D-tyrosyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- 330 cyclopropyl-8-methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid;
7-(4-((D-methionyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-(((2Λ)-2-amino-3-(3-pyridinyl)propanoyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-l-cyclopropyl-8-methoxy-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid; 335 l-cyclopropyl-8-methoxy-4-oxo-7-(4-(((2R)-piperidinylcarbonyl)amino)-4, 5,6,7- tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-((4-pyrimidinylcarbonyl)amino)-4,5,6,7- tetrahydro-l-benzothien-2-yl)-l ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-((l,3-thiazol-2-ylcarbonyl)amino)-4,5,6,7- 340 tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-((phenylacetyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-l ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4-(3-furoylamino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; 345 l-cyclopropyl-8-methoxy-4-oxo-7-(4-((2-pyridinylcarbonyl)amino)-4,5,6,7- tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(4-((lH-pyrazol-4-ylcarbonyl)amino)-4, 5,6,7- tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-((D-aspartyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- 350 methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-((4R)-4-((N-methyl-D-leucyl)amino)-4,5,6,7- tetrahydro-l-benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-((4Λ)-4-((D-norleucyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; 355 methyl l-cyclopropyl-8-methoxy-4-oxo-7-(4-((4-pyrimidinylcarbonyl)amino)-
4,5,6,7-tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylate; methyl l-cyclopropyl-8-methoxy-4-oxo-7-(4-((l ,3-thiazol-2-ylcarbonyl)amino)- 4,5,6,7-tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylate; methyl l-cyclopropyl-8-methoxy-4-oxo-7-(4-((2-pyridinylcarbonyl)amino)-4, 5,6,7- 360 tetrahydro-l-benzothien-2-yl)- l,4-dihydro-3-quinolinecarboxylate;
7-(4-((β-O-methyl-D-aspartyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-((4E)-4-((3-pyridinylmethoxy)imino)-4,5,6,7--' tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid; 365 l-cyclopropyl-8-methoxy-4-oxo-7-((4E)-4-((2-pyridinylmethoxy)imino)-4,5,6,7- tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid; ethyl 7-(4-((tert-butyl(dimethyl)silyl)oxy)-5-methyl-4,5,6,7-tetrahydro-l- benzothien-2-yl)-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate; l-cyclopropyl-7-(4-hydroxy-5-methyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- 370 methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxyIic acid; l-cyclopropyl-8-methoxy-7-(4-(((methylanilino)carbonyl)amino)-4, 5,6,7- tetrahydro-l-benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinoIinecarboxylic acid; l-cyclopropyl-7-(4-(((diethylamino)carbonyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-8-methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid; 375 l-cyclopropyl-7-(4-(((diisopropylamino)carbonyl)amino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-(4-((4-moφholinylcarbonyl)amino)-4,5,6,7-tetrahydro- l-benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-(4-((methoxycarbonyl)amino)-4,5,6,7-tetrahydro-l- 380 benzothien-2-yl)-4-oxo:l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-(((benzyloxy)carbonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4-((isobutoxycarbonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2- yl)-8-methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid; 385 l-cyclopropyl-7-(4-((ethoxycarbonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2- yl)-8-methoxy-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid;
7-(4-((butoxycarbonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-(((4-chlorobutoxy)carbonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- 390 cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-((5E/Z)-5-(hydroxymethylene)-4-oxo-4,5,6,7-tetrahydro-l- benzothien-2-yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-((4E/Z)-4-((3-pyridinylmethoxy)imino)-4,5,6,7- tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid; 395 l-cyclopropyl-7-(4-(3-hydroxy-l-azetidinyl)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-
8-methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid;
7-(4-amino-5-methyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid;
7-(4-amino-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-4-oxo-l,4- 400 dihydro[l,8]naphthyridine-3-carboxylic acid;
7-(7-amino-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(7-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-8- methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid; 405 l-cyclopropyl-8-methoxy-4-oxo-7-(7-oxo-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2- yl)-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; ethyl 7-(4-azido-5-methyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- 410 methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate;
7-(4-amino-5,5-difluoro-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(5-(hydroxymethyl)-5-methyl-4-oxo-4,5,6,7-tetrahydro-l- benzothien-2-yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; 415 7-(7-amino-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-l-cyclopropyl-8-methoxy-
4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-6-fluoro-8-methoxy-7-(4-(methylamino)-4,5,6,7-tetrahydro-l- 420 benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride; l-cyclopropyl-8-methoxy-4-oxo-7-(4-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2- yl)-l,4-dihydro-3-quinolinecarboxylic acid;
7-[4-(3-amino-l-azetidinyl)-4,5,6,7-tetrahydro-l-benzothien-2-yl]-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; 425 l-cyclopropyl-7-(4-hydroxy-5,5-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-((tert-butoxycarbonyl)amino)-5-methyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)- l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; methyl 7-[4-(acetyloxy)-4,5,6,7-tetrahydro-l-benzothien-2-yl]-l-cyclopropyl-8- 430 methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylate; l-cyclopropyl-8-methoxy-7-(7-(methylamino)-4,5,6,7-tetrahydro-l-benzothien-2- yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; methyl l-cyclopropyl-6-fluoro-7-(4-hydroxy-4,5,6,7-tetrahydro-l-benzothien-2-yl)- 8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate; 435 l-cyclopropyl-7-(7-hydroxy-4,4-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; methyl 7-(4-azido-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-6-fluoro-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylate; methyl 7-(4-((tert-butoxycarbonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- 440 cyclopropyl-6-fluoro-8-methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylate;
7-(4-((tert-butoxycarbonyl)amino)-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l- cyclopropyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(7-amino-4,4-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; 445 l-cyclopropyl-8-methoxy-4-oxo-7-(4-oxo-5-spiro-3'-(N-benzylpyrrolidine)-4,5,6,7- tetrahydro-l-benzothien-2-yl)-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-amino-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-6-fluoro-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; 7-(4-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-l-cyclopropyl-8-methoxy- 450 4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(7-azido-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-l-cyclopropyl-8-methoxy- 4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4,4-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid; 455 7-(7-amino-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-6-fluoro-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(5-acetyl-7-amino-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-l-cyclopropyl-8- methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid;
7-(7-amino-5-(methylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-l- 460 cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-amino-5,5-difluoro-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid;
7-(4-amino-3-methyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; 465 l-cyclopropyl-7-((4E/Z)-4-(hydroxyimino)-5,5-dimethyl-4,5,6,7-tetrahydro-l- benzothien-2-yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4-hydroxy-6,6-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid;
7-(7-amino-6-methyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- 470 methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride; l-cyclopropyl-7-(6,6-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8-methoxy-4- oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid;
7-(7-amino-6-fluoro-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid; 475 7-(4-amino-6,6-dimethyl-4,5,6,7-tetrahydro- 1 -benzothien-2-yl)- 1 -cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(7-oxo-4,5,6,7-tetrahydro-l,3-benzothiazol-2- yl)- 1 ,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(6-fluoro-7-hydroxy-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- 480 methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(7-hydroxy-6,6-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-((65,75)-7-hydroxy-6-methyl-4,5,6,7-tetrahydro-l-benzothien-2- yl)-8-methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid; 485 l-cyclopropyl-8-methoxy-4-oxo-7-(4,5,6,7-tetrahydro-l-benzothien-2-yl)-l,4- dihydro-3-quinolinecarboxylic acid;
7-(7-amino-6,6-difluoro-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(7-amino-6,6-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- 490 methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-6-fluoro-8-methoxy-7-(7-(methylamino)-4,5,6,7-tetrahydro-l- benzothien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-4-oxo-7-(5-oxo-5,6-dihydro-4H-cyclopenta[b]thien-2- yl)-l,4-dihydro-3-quinolinecarboxylic acid; 495 l-cyclopropyl-8-methoxy-7-((5E/Z)-5-(methoxyimino)-5,6-dihydro-4H- cyclopenta[έ»]thien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(5-amino-5,6-dihydro-4H-cyclopenta[b]thien-2-yl)-l-cyclopropyl-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(5-((ethoxycarbonyl)amino)-5,6-dihydro-4H-cyclopenta[b]thien-2- 500 yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-(5-((methoxycarbonyl)amino)-5,6-dihydro-4H- cyclopenta[b]thien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(5-(acetylamino)-5,6-dihydro-4H-cyclopenta[i>]thien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; 505 l-cyclopropyl-8-methoxy-7-(5-(((4-methylphenyl)sulfonyl)amino)-5,6-dihydro-4H- cyclopenta[&]thien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-8-methoxy-7-(5-((methylsulfonyl)amino)-5,6-dihydro-4H- cyclopenta[fe]thien-2-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-((5E/Z)-5-((benzyloxy)imino)-5,6-dihydro-4H-cyclopenta[b]thien-2-yl)-l- 510 cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-((5E/Z)-5-(hydroxyimino)-5,6-dihydro-4H-cyclopenta[/7]thien-2- yl)-8-methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-amino-4-methyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; 515 l-cyclopropyl-7-(5-(dimethylamino)-5,6-dihydro-4H-cyclopenta[b]thien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(4-azido-5,5-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid;
7-(7-amino-4,5,6,7-tetrahydro-l-benzothien-3-yl)-l-cyclopropyl-8-methoxy-4-oxo- 520 l,4-dihydro-3-quinolinecarboxylic acid; 7-(7-amino-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- (difluoromethoxy)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(7-hydroxy-5,5-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; 525 7-(7-amino-5,5-dimethyl-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid; l-cyclopropyl-7-(4-hydroxy-4,5,6,7-tetrahydro-l-benzofuran-2-yl)-8-methoxy-4- oxo-l,4-dihydro-3-quinolinecarboxylic acid; and 530 7-(4-amino-4,5,6,7-tetrahydro-l-benzofuran-2-yl)-l-cyclopropyl-8-methoxy-4-oxo- l,4-dihydro-3-quinolinecarboxylic acid.
21. A compound according to Claim 20 which is
7-(7-amino-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-cyclopropyl-8-methoxy-4-oxo- l,4-dihydro-3-quinolinecarboxylic acid hydrochloride.
PCT/US2000/030551 1999-11-05 2000-11-06 Quinoline and naphthyridine carboxylic acid antibacterials WO2001032655A2 (en)

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JP2001535357A JP2003524633A (en) 1999-11-05 2000-11-06 Quinoline and naphthyridine carboxylic acid antibacterial agents
BR0010728-0A BR0010728A (en) 1999-11-05 2000-11-06 Antibacterial agents of quinoline and naphthyridine carboxylic acid
MXPA02004474A MXPA02004474A (en) 1999-11-05 2000-11-06 Quinoline and naphthyridine carboxylic acid antibacterials.
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BG106679A BG106679A (en) 1999-11-05 2002-05-09 Quinoline and naphthyridine carboxylic acid antibacterials
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AU1468901A (en) 2001-05-14
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