EP1631570A1 - Dérivés de naphthyridine comme agents antibactériens - Google Patents

Dérivés de naphthyridine comme agents antibactériens

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Publication number
EP1631570A1
EP1631570A1 EP03723732A EP03723732A EP1631570A1 EP 1631570 A1 EP1631570 A1 EP 1631570A1 EP 03723732 A EP03723732 A EP 03723732A EP 03723732 A EP03723732 A EP 03723732A EP 1631570 A1 EP1631570 A1 EP 1631570A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
nhc
substituted
oxo
dihydro
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP03723732A
Other languages
German (de)
English (en)
Inventor
David Anderson
Bruce Beutel
Todd D. Bosse
Richard Clark
Curt Cooper
Peter Dandliker
Caroline David
Yu-Gui Gu
Todd Matthew Hansen
Mira Hinman
Douglas Kalvin
Daniel P. Larson
Linda Lynch
Zhenkun Ma
Christopher Motter
Fabio Palazzo
Teresa Rosenberg
Tamara Rehm
William Sanders
Michael Tufano
Rolf Wagner
Moshe Weitzberg
Hong Yong
Tianyuan Zhang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Laboratories
Original Assignee
Abbott Laboratories
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Filing date
Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority claimed from US10/387,318 external-priority patent/US8163769B2/en
Publication of EP1631570A1 publication Critical patent/EP1631570A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • 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

Definitions

  • TECHNICAL FIELD This invention is directed to compounds having antibacterial activity, processes for making the compounds and intermediates used in the processes, compositions containing the compounds, and methods for prophylaxis or treatment of bacterial infections using the compounds .
  • a first embodiment of the invention is directed to compounds, and salts, prodrugs, and salts of prodrugs thereof, which are useful as antibacterials, the compounds having formula (I)
  • R is absent or is hydrogen , alkyl , -CH 2 CF 3 ,
  • op R is phenyl, naphthyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 3-thiadiazolyl, 1, 3, -thiadiazolyl, 1, 2, 3-triazolyl, pyridyl, quinolinyl, pyrazinyl, pyrimidinyl, cyclohexyl,
  • R 4 is hydrogen, aryl, -NH 2 , -OH, -NH(R 8 ), -N (R 9 ) (R 10 ) , -OR 11 , -N(R 12 ) 2 , or -NHR 37 ;
  • R is hydrogen, alkyl, aryl, heteroaryl, halo, -OH, -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 , -NH 2 , -NHR 11 , -NR 1X R 12 , -NHC(0)R 11 , -NR U C(0)R 12 , -NHS(0) 2 R 1:L , -NR 1:L S (0) 2 R 12 , or -OR 11 ;
  • R A is phenyl, naphthyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 3-thiadiazolyl, 1, 3, 4-thiadiazolyl, 1, 2, 3-triazolyl, pyridyl, quinolinyl, pyrazinyl, pyrimidinyl, cyclohexyl, pyrrolidinyl, pyrrolidonyl, uracilyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or methyl optionally substituted with one, two or three substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, halo, -CN, -OH,
  • R is halo, aryl, heteroaryl, heterocyclyl, bicyclic heterocycloalkyl, -NH(R 12 ), or -N (R 13 ) (R 14 ) ;
  • R is alkyl, cycloalkyl, aryl, heteroaryl, cycloalkyl fused with phenyl, or alkyl substituted with one or two substituents independently selected from the group consisting of aryl, heteroaryl, and -N (alkyl) 2 ;
  • R 9 and R 10 are independently methyl, ethyl, propyl, or iso-propyl, each of which is unsubstituted or substituted with one substituent selected from the group consisting of -OH and -O(alkyl); or R 9 and R10 together are alkylene or heteroalkylene;
  • R 11 is alkyl, - (C ⁇ -C-alkylene) -alkenyl, - (C 1 -C 4 - alkylene) -alkynyl, or alkyl substituted with one aryl substituent;
  • R 13 and R14 are independently alkyl or alkyl substituted with -N(CH 3 ) 2 ; or
  • R 13 and R14 together are alkylene
  • R and R are independently alkyl or alkyl substituted with one substituent selected from the group consisting of -NH 2 , -NH (alkyl), and -N (alkyl) 2 ; R is alkyl or alkyl substituted with one substituent selected from the group consisting of halo and -O(alkyl);
  • R is phenyl, naphthyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1, 2 , 3-oxadiazolyl, 1, 2, 3-thiadiazolyl,
  • a fourth embodiment of this invention is directed to a composition for the prophylaxis or treatment of bacterial infections in a fish or a mammal, the composition comprising a therapeutically effective amount of a compound of the first embodiment.
  • a fifth embodiment of this invention is directed to a method of prophylaxis or treatment of bacterial infection in a fish or a mammal, the method comprising administering to the fish or the mammal a therapeutically effective amount of a compound of the first embodiment.
  • An sixth embodiment of this invention is directed to a composition for inhibiting bacterial protein synthesis, the composition comprising a therapeutically effective amount of a compound having formula (I)
  • R and R is absent or hydrogen and the other ⁇ s hydrogen, -OH, -N(CH 3 ) 2 , -NHR 12 , or -NR 35 R 12 ; or
  • R is absent or is hydrogen, alkyl, -CH 2 CF 3 ,
  • R 4 is hydrogen, aryl, -NH 2 , -OH, -NH(R 8 ), -N(R 9 ) (R 10 ), -OR 11 , -N(R 12 ) 2 , or -NHR 37 ;
  • R is hydrogen, alkyl, aryl, heteroaryl, halo, -OH, -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 , -NH 2 , -NHR 11 , -NR U R 12 , -NHC(0)R 1X , -NR n C(0)R 12 , -NHS(0) 2 R 11 , -NR 1X S (0) 2 R 12 , or -OR 11 ;
  • R 6A is phenyl, naphthyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 3-thiadiazolyl, 1, 3, 4-thiadiazolyl, 1, 2, 3-triazolyl, pyridyl, quinolinyl, pyrazinyl, pyrimidinyl, cyclohexyl, pyrrolidinyl, pyrrolidonyl, uracilyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or methyl optionally substituted with one, two or three substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, halo, -CN, -OH,
  • R is halo, aryl, heteroaryl, heterocyclyl, bicyclic heterocycloalkyl, -NH(R 12 ), or -N (R 13 ) (R 14 ) ; g
  • R is alkyl, cycloalkyl, aryl, heteroaryl, cycloalkyl fused with phenyl, or alkyl substituted with one or two substituents independently selected from the group consisting of aryl, heteroaryl, and - (alkyl) ;
  • R 9 and R10 are independently methyl, ethyl, propyl, or iso-propyl, each of which is unsubstituted or substituted with one substituent selected from the group consisting of -OH and -0 (alkyl) ; or R 9 and R10 together are alkylene or heteroalkylene; R is alkyl, - (C ⁇ -C 4 -alkylene) -alkenyl, - (C 1 -C 4 - alkylene) -alkynyl, or alkyl substituted with one aryl substituent;
  • R and R are independently alkyl or alkyl substituted with -N(CH 3 ) 2 ; or R and R together are alkylene;
  • R and R are independently alkyl or alkyl substituted with one substituent selected from the group consisting of -NH 2 , -NH (alkyl), and -N (alkyl) 2 ;
  • R 30 is alkyl or alkyl substituted with one substituent selected from the group consisting of halo and -O(alkyl);
  • R 40 is phenyl, naphthyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2 , 3-thiadiazolyl,
  • the bacterial protein synthesis is antibacterial-resistant bacterial protein synthesis .
  • the bacterial protein synthesis is bacterial protein synthesis in vitro.
  • the bacterial protein synthesis is cell-free bacterial protein synthesis in vitro.
  • the bacterial protein synthesis is bacterial protein synthesis in a fish or a mammal.
  • a seventh embodiment of this invention is directed to a composition for inhibiting bacterial growth, the composition comprising a therapeutically effective amount of a compound having formula (I)
  • R is absent or is hydrogen, alkyl, -CH 2 CF 3 ,
  • R 4 is hydrogen, aryl, -NH 2 , -OH, -NH(R 8 ), -N(R 9 )(R 10 ), -OR 11 , -N(R 12 ) 2 , or -NHR 37 ;
  • R 5 is hydrogen, alkyl, aryl, heteroaryl, halo, -OH, -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 , -NH 2 , -NHR 11 , -NR U R 12 , -NHC(0)R 11 , -NR U C(0)R 12 , -NHS(0) 2 R 11 , -NR 1X S (0) 2 R 12 , or -OR 11 ;
  • R 6A is phenyl, naphthyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 3-thiadiazolyl, 1, 3, 4-thiadiazolyl, 1, 2, 3-triazolyl, pyridyl, quinolinyl, pyrazinyl, pyrimidinyl, cyclohexyl, pyrrolidinyl, pyrrolidonyl, uracilyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or methyl optionally substituted with one, two or three substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, halo, -CN, -OH,
  • R is halo, aryl, heteroaryl, heterocyclyl, bicyclic heterocycloalkyl, -NH(R 12 ), or -N (R 13 ) (R 14 ) ; g
  • R is alkyl, cycloalkyl, aryl, heteroaryl, cycloalkyl fused with phenyl, or alkyl substituted with one or two substituents independently selected from the group consisting of aryl, heteroaryl, and -N (alkyl) 2 ;
  • R 9 and R10 are independently methyl, ethyl, propyl, or iso-propyl, each of which is unsubstituted or substituted with one substituent selected from the group consisting of -OH and -0 (alkyl); or
  • R and R together are alkylene or heteroalkylene;
  • R 11 is alkyl, - (Ci ⁇ C 4 -alkylene) -alkenyl, - (C 1 -C 4 - alkylene) -alkynyl, or alkyl substituted with one aryl substituent;
  • R and R are independently alkyl or alkyl substituted with -N(CH 3 ) 2 ; or
  • R 13 and R14 together are alkylene
  • R and R are independently alkyl or alkyl substituted with one substituent selected from the group consisting of -NH 2 , -NH (alkyl), and -N (alkyl) 2 ;
  • R is alkyl or alkyl substituted with one substituent selected from the group consisting of halo and -0 (alkyl);
  • R 4 is phenyl, naphthyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1, 2, 3-oxadiazol
  • the bacterial growth is antibacterial-resistant bacterial growth. In another preferred seventh embodiment, the bacterial growth is quinolone-resistant bacterial growth.
  • the bacterial growth is bacterial growth in vitro.
  • the bacterial growth is bacterial growth in a fish or a mammal .
  • a eighth embodiment of this invention is directed to a composition for prophylaxis or treatment of antibacterial- resistant bacterial infection in a fish or a mammal, the composition comprising a therapeutically effective amount of compound having formula (I)
  • R 3B is phenyl, naphthyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 3-thiadiazolyl, 1, 3, 4-thiadiazolyl, 1, 2, 3-triazolyl, pyridyl, quinolinyl, pyrazinyl, pyrimidinyl, cyclohexyl, pyrrolidin
  • R 4 is hydrogen, aryl, -NH 2 , -OH, -NH(R 8 ), -N(R ) (R 10 ), -OR 11 , -N(R 12 ) 2 , or -NHR 37 ;
  • R is hydrogen, alkyl, aryl, heteroaryl, halo, -OH, -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 , -NH 2 , -NHR 11 , -NR 11 R 12 , -NHCfOR 11 , -NR 11 C(0)R 12 , -NHS(0) 2 R 11 , -NR S (0) 2 R 12 , or -OR 11 ;
  • R is phenyl, naphthyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 3-thiadiazolyl,
  • R is halo, aryl, heteroaryl, heterocyclyl, bicyclic heterocycloalkyl, -NH(R 12 ), or -N (R 13 ) (R 14 ) ;
  • g R is alkyl, cycloalkyl, aryl, heteroaryl, cycloalkyl fused with phenyl, or alkyl substituted with one or two substituents independently selected from the group consisting of aryl, heteroaryl, and -N (alkyl) 2 ;
  • R 9 and R10 are independently methyl, ethyl, propyl, or iso-propyl, each of which is unsubstituted or substituted with one substituent selected from the group consisting of -OH and -O(alkyl); or
  • R 9 and R 10 together are alkylene or heteroalkylene
  • R 11 is alkyl, - (Cx-Cj-alkylene) -alkenyl, - (C ⁇ C- alkylene) -alkynyl, or alkyl substituted with one aryl substituent;
  • R and R are independently alkyl or alkyl substituted with -N(CH 3 ) 2 ; or
  • R 13 and R14 together are alkylene;
  • R and R are independently alkyl or alkyl substituted with one substituent selected from the group consisting of -NH 2 , -NH (alkyl), and -N (alkyl) 2 ;
  • R is alkyl or alkyl substituted with one substituent selected from the group consisting of halo and -0 (alkyl);
  • R 80 is phenyl, naphthyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 3-thiadiazolyl,
  • the antibacterial- resistant bacterial infection is quinolone-resistant bacterial infection.
  • An ninth embodiment of this invention is directed to a method for inhibiting bacterial protein synthesis in vitro or in a fish or a mammal, the method comprising administering to an administrant a therapeutically effective amount of a compound having formula (I)
  • ( I ) in which is a single bond or a double bond; one of R 1 and R2 is absent or hydrogen and the other is hydrogen, -OH, -N(CH 3 ) 2 , -NHR 12 , or -NR 35 R 12 ; or
  • R 4 is hydrogen, aryl, -NH 2 , -OH, -NH(R 8 ), -N(R 9 )(R 10 ), -OR 11 , -N(R 12 ) 2 , or -NHR 37 ;
  • R is hydrogen, alkyl, aryl, heteroaryl, halo, -OH, -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 , -NH 2 , -NHR 11 , -NR U R 12 , -NHC(0)R U , -NR X1 C(0)R 12 , -NHS(0) 2 R n , -NR 11 S (0) 2 R 12 , or -OR 11 ;
  • R 6A is phenyl, naphthyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1, 2 , 3-oxadiazolyl, 1, 2, 3-thiadiazolyl, 1, 3, -thiadiazolyl, 1, 2, 3-triazolyl, pyridyl, quinolinyl, pyrazinyl, pyrimidinyl, cyclohexyl, pyrrolidinyl, pyrrolidonyl, uracilyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or methyl optionally substituted with one, two or three substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, halo, -CN,
  • R is halo, aryl, heteroaryl, heterocyclyl, bicyclic heterocycloalkyl, -NH(R 12 ), or -N (R 13 ) (R 14 ) ; g
  • R is alkyl, cycloalkyl, aryl, heteroaryl, cycloalkyl fused with phenyl, or alkyl substituted with one or two substituents independently selected from the group consisting of aryl, heteroaryl, and -N (alkyl) 2 ;
  • R and R are independently methyl, ethyl, propyl, or iso-propyl, each of which is unsubstituted or substituted with one substituent selected from the group consisting of -OH and -O(alkyl); or
  • R and R together are alkylene or heteroalkylene;
  • R 11 is alkyl, - (C ⁇ -C 4 -alkylene) -alkenyl, - (C ⁇ C 4 - alkylene) -alkynyl, or alkyl substituted with one aryl substituent;
  • R and R are independently alkyl or alkyl substituted with -N(CH 3 ) 2 ; or
  • R and R together are alkylene
  • R and R are independently alkyl or alkyl substituted with one substituent selected from the group consisting of -NH 2 , -NH (alkyl), and -N (alkyl) 2 ;
  • R30 is alkyl or alkyl substi•tuted with one substituent selected from the group consisting of halo and -O(alkyl);
  • R is phenyl, naphthyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1, 2, 3-oxadiazolyl,
  • -OC(0)R 35 -OC(0)OR 35 , -OC(0)NH 2 , -OC (O) NH (R 35 ) , -OC(0)N(R 35 ) (R 36 ) , -NHC(0)H, -NHC(0)R 35 , -NHC (O) OR 35 , -NHC(0)NH 2 , -NHC(NH)NH 2 , -NHC (0) NH (R 35 ) , -NHC (O) N (R 35 ) (R 36 ) , -S0 2 NH 2 , -S0 2 NH(R 35 ), -S0 2 N (R 35 ) (R 36 ) , or R 81 ;
  • the bacterial protein synthesis is antibacterial-resistant bacterial protein synthesis .
  • a tenth embodiment of this invention is directed to a method for inhibiting bacterial growth in vitro or in a fish or a mammal, the method comprising administering to an administrant a therapeutically effective amount of a compound having formula (I) in which is a single bond or a double bond;
  • R and R is absent or hydrogen and the other is hydrogen, -OH, -N(CH 3 ) 2 , -NHR 12 , or -NR 35 R 12 ; or
  • R 4 is hydrogen, aryl, -NH 2 , -OH, -NH(R 8 ), -N (R 9 ) (R 10 ) , -OR 11 , -N(R 12 ) 2 , or -NHR 37 ;
  • R is hydrogen, alkyl, aryl, heteroaryl, halo, -OH, -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 , -NH 2 , -NHR 11 , -NR 1X R 12 , -NHCfOJR 11 , -NR 11 C(0)R 12 , -NHS(0) 2 R 11 , -NR X1 S (0) 2 R 12 , or -OR 11 ;
  • R A is phenyl, naphthyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 3-thiadiazolyl,
  • R is halo, aryl, heteroaryl, heterocyclyl, bicyclic heterocycloalkyl, -NH(R 12 ), or -N (R 13 ) (R 14 ) ;
  • p R is alkyl, cycloalkyl, aryl, heteroaryl, cycloalkyl fused with phenyl, or alkyl substituted with one or two substituents independently selected from the group consisting of aryl, heteroaryl, and -N (alkyl) 2 ;
  • R 9 and R10 are independently methyl, ethyl, propyl, or iso-propyl, each of which is unsubstituted or substituted with one substituent selected from the group consisting of -OH and -O(alkyl); or
  • R 9 and R10 together are alkylene or heteroalkylene
  • R 11 is alkyl, - (C ⁇ -C 4 -alkylene) -alkenyl, -(C ⁇ -C 4 - alkylene) -alkynyl, or alkyl substituted with one aryl substituent;
  • R and R are independently alkyl or alkyl substituted with -N(CH 3 ) 2 ; or
  • R and R together are alkylene;
  • R and R are independently alkyl or alkyl substituted with one substituent selected from the group consisting of -NH 2 , -NH(alkyl), and - (alkyl) 2 ;
  • R is alkyl or alkyl substituted with one substituent selected from the group consisting of halo and -O(alkyl);
  • R is phenyl, naphthyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 3-thiadiazolyl,
  • the bacterial growth is antibacterial-resistant bacterial growth.
  • the bacterial growth is quinolone-resistant bacterial growth.
  • the bacterial growth is bacterial growth in vitro.
  • the recipient is a fish or a mammal.
  • An eleventh embodiment of this invention is directed to a composition for the prophylaxis or treatment of antibacterial-resistant bacterial infection in a fish or a mammal, the composition comprising a therapeutically effective amount of compound having formula (I)
  • R 1 and R2 in which is a single bond or a double bond; one of R 1 and R2 is absent or hydrogen and the other is hydrogen, -OH, -N(CH 3 ) 2 , -NHR 12 , or -NR 35 R 12 ; or
  • R is phenyl, naphthyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, is
  • R 4 is hydrogen, aryl, -NH 2 , -OH, -NH(R 8 ), -N (R 9 ) (R 10 ) , -OR 11 , -N(R 12 ) 2 , or -NHR 37 ;
  • R 5 is hydrogen, alkyl, aryl, heteroaryl, halo, -OH, -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 , -NH 2 , -NHR 11 , -NR 1X R 12 , -NHC(0)R U , -NR n C(0)R 12 , -NHS(0) 2 R n , -NR 12 S (0) 2 R 12 , or -OR 11 ;
  • R is halo, aryl, heteroaryl, heterocyclyl, bicyclic heterocycloalkyl, -NH(R 12 ), or -N (R 13 ) (R 14 ) ;
  • R is alkyl, cycloalkyl, aryl, heteroaryl, cycloalkyl fused with phenyl, or alkyl substituted with one or two substituents independently selected from the group consisting of aryl, heteroaryl, and -N (alkyl) 2 ;
  • R 9 and R10 are independently methyl, ethyl, propyl, or iso-propyl, each of which is unsubstituted or substituted with one substituent selected from the group consisting of -OH and -O(alkyl); or
  • R 9 and R10 together are alkylene or heteroalkylene;
  • R 11 is alkyl, - (C_-C 4 -alkylene) -alkenyl, - (C x -C 4 - alkylene) -alkynyl, or alkyl substituted with one aryl substituent;
  • R 12 is alkyl, -NH 2 , -NHR 6a , or alkyl substituted with one substituent selected from the group consisting of cycloalkenyl, aryl, heteroaryl, heterocyclyl, -NH 2 ,
  • R and R are independently alkyl or alkyl substituted with -N(CH 3 ) 2 ; or R 13 and R14 together are alkylene; R and R are independently alkyl or alkyl substituted with one substituent selected from the group consisting of -NH 2 , -NH (alkyl), and -N (alkyl) 2 ;
  • R 30 is alkyl or alkyl substituted with one substituent selected from the group consisting of halo and -0 (alkyl);
  • R is phenyl, naphthyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 3-thiadiazolyl,
  • the antibacterial- resistant bacterial infection is quinolone-resistant bacterial infection.
  • the compounds of the invention comprise a parent moiety and variable moieties, the latter of which are identified by a capital letter and accompanying numerical and/or alphabetical superscript, for which the following terms have the meanings indicated.
  • alkenyl means a onovalent, straight or branched hydrocarbon having two to eight carbon atoms and at least one carbon-carbon double bond.
  • alkyl means a monovalent, saturated, straight or branched hydrocarbon, having one to eight carbon
  • alkylene means a divalent, saturated, straight or branched hydrocarbon, having one to eight carbon atoms .
  • alkynyl means a monovalent, straight or branched hydrocarbon having two to eight carbon atoms and at least one carbon-carbon triple bond.
  • aryl means phenyl which is unfused or fused with cycloalkyl, cycloalkenyl, heteroaryl, another phenyl, naphthyl, or the saturated part of indan.
  • benzyl means -CH 2 - (phenyl) .
  • bicyclic cycloalkyl means a monovalent five-, six-, seven-, or eight-membered carbocyclic ring having two non-adjacent carbon carbons connected by a covalent bond, -CH 2 -, or -CH 2 CH 2 -;
  • bicyclic heterocyclyl means a monovalent six-membered ring having one or two nitrogen atoms and the remaining atoms are carbon, zero double bonds, and two non-adjacent carbons connected by a covalent bond or -CH 2 -, attached through a carbon atom or nitrogen atom; a monovalent or divalent, seven- or eight-membered ring with one, two, or three nitrogen atoms and the remaining atoms are carbon, zero or one double bonds, and two non- adjacent carbons connected by a covalent bond, attached through a carbon atom or nitrogen atom; a monovalent seven- or eight-membered ring with one nitrogen atom and with or without an additional nitrogen, oxygen, or sulfur atom and the remaining atoms are carbon, zero double bonds, and two non-adjacent carbons connected by a covalent bond, attached through a carbon atom or a nitrogen atom; and a monovalent, nine-membered ring with one nitrogen atom or one nitrogen atom and
  • cycloalkyl means a monovalent, saturated cyclic hydrocarbon, having three to eight carbon atoms.
  • halo or halogen means fluoro (-F) , chloro (-C1), bromo (-Br) , or iodo (-1).
  • heteroaryl means a monovalent, aromatic, five-membered ring having two double bonds and one oxygen or one sulfur atom, one, two, three, or four nitrogen atoms, or one or two nitrogen atoms and one oxygen or one sulfur atom and the remaining atoms are carbon atoms, attached through a carbon atom or a nitrogen atom, and unfused or fused with a moiety selected from the group consisting of phenyl, cycloalkyl, cycloalkenyl, heterocycle, and another heteroaryl, and a monovalent aromatic, six-membered ring having three double bonds and one, two, or three nitrogen atoms and the remaining atoms are carbon atoms, attached through a carbon atom and unfused or fused with phenyl, cycloalkyl, cycloalkenyl, heterocycle, or another heteroaryl .
  • heterocyclyl means a monovalent, non-aromatic three- or four-membered ring having one nitrogen, oxygen, or sulfur atom and the remaining atoms are carbon atoms, zero double bonds, attached through a carbon atom or a nitrogen atom, and unfused or fused with phenyl or heteroaryl; a monovalent, non-aromatic five-membered ring having one or two nitrogen, oxygen, or sulfur atoms and the remaining atoms are carbon atoms, and zero or one double bonds, attached through a carbon or nitrogen atom, and unfused or fused with phenyl or heteroaryl; and a monovalent, non-aromatic six or seven-membered ring having one, two, or three nitrogen, oxygen, or sulfur atoms and the remaining atoms are carbon, and zero, one, or two double bonds, attached through a carbon or a nitrogen atom, and unfused or fused with phenyl or heteroaryl.
  • R 1 is absent and R2 is 3- (aminomethyl) - benzylamino, 2- (guanidinyl) ethylamino, or N-methyl- (2-
  • R is hydrogen
  • -L 1-R4 is ( (1, 2-diphenylethyl) amino) methyl, ( (2, 4-difluorobenzyl) amino)methyl, ( (3- (diethylamino) propyl) amino) methyl, ( (3, 4-difluorobenzyl) amino) methyl, (( 3-phenylpropyl) amino) ethyl, (1,2,3,4- tetrahydronaphthalen-l-ylamino)methyl, (2, 5-dimethyl- pyrrolidin-1-yl) carbonyl, (morpholin-4-yl) carbonyl, (pyrrolidin-1-yl) carbonyl, (thiomorpholin-4-yl) carbonyl, carbamoyl, carboxy, ethoxycarbonyl, hydrogen, N-(2- (methylthio) ethyl) carbamoyl, N- (2-isopropoxyethyl) carbamoyl, N
  • R is hydrogen, methyl, ethyl, trifluoromethyl, or iodo
  • R moiety is hydrogen, fluoro, bromo, chloro, -CN, methyl, phenylethynyl, prop-1-ynyl, -0(CH 2 - (phenyl) ) , aminomethyl, or -(0)CH 3 ; or R 5 and R 6 together are C 2 -C 4 -alkylene or C 2 -C 4 -heteroalkylene.
  • R is (lR,5R)-3- ( (benzyloxy) carbonyl) -3, ⁇ -diazabicyclo (3.2.0) hept-6-yl,
  • a compound of the first, sixth, seventh, eighth, ninth, or tenth embodiment in which is a single bond or a double bond; one of R 1 and R2 is absent or hydrogen and the other is -N(CH 3 ) 2 , -NHR 12 , or -N (alkyl) (R 12 ) , in which R 12 is alkyl substituted with one substituent selected from the group consisting of -NH 2 , -NH (alkyl), -N (alkyl) 2 , -NH (C NH) NH , and phenyl which is unsubstituted or substituted with alkyl which is unsubstituted substituted with a substituent selected from the group consisting of -NH 2 , -NH (alkyl), and -N (alkyl) 2 ; or
  • alkyl substituted with one or two substituents independently selected from the group consisting of halo, -CN, -OH, -NH , -NH (alkyl), -N (alkyl) 2 , -C(0)NH 2 , -S0 2 NH 2 , ' -S0 2 NH (alkyl) , and -S0 2 N (alkyl) 2 , and
  • R is phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 3-thiadiazolyl, 1, 3, 4-thiadiazolyl, 1, 2, 3-triazolyl, pyridyl, pyrazinyl, or pyrimidinyl, each of which is unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of alkyl, halo, -CN, -OH, -N0 2 , -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 , -0 (alkyl), -S (alkyl), -OCF 3 , -OCH 2 CF 3 , -OCF 2 CF 3 , -NH 2 , -NH (alkyl),
  • R 4 is hydrogen, -OH, -0 (alkyl), phenyl, -NH 2 , -NH(R 8 ), or -N(R 9 ) (R 10 ) , in which R 8 is alkyl, phenyl, pyridyl, -NHC(0)CF 3 , cycloalkyl fused with phenyl, alkyl substituted with one or two substituents independently selected from the group consisting of -S (alkyl), -0 (alkyl), -N (alkyl) 2 , and phenyl which is unsubstituted or substituted with one or two independently selected halo substituents, and in which R 9 and R10 are independently alkyl or alkyl substituted with -O(alkyl); or
  • R 9 and R10 are taken together and are morpholinyl, thiomorpholinyl, pyrrolidinyl, or pyrrolidinyl substituted with two alkyl substituents;
  • R is hydrogen, alkyl, aryl, heteroaryl, halo, -OH, -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 , -NH 2 , -NHR 11 , -NR X1 R 12 , -NHC(0)R , -NR U C(0)R 12 , -NHS(0) 2 R 1:L , -NR U S (0) 2 12 , or -0 (alkyl);
  • R 5 and R6 taken together are C 3 -C 4 -alkylene or
  • R 13 and R14 are independently alkyl or alkyl substituted with -N (alkyl) 2 ;
  • R and R are independently alkyl or alkyl substituted with -NH 2 .
  • a compound of the first, sixth, seventh, eighth, ninth, or tenth embodiment in which is a single bond or a double bond; one of R 1 and R2 is absent or hydrogen and the other is -N(CH 3 ) 2 , -NHR 12 , or -N (alkyl) (R 12 ) , in which R 12 is alkyl substituted with one substituent selected from the group consisting of -N (alkyl) 2 , -NH (C NH) NH 2 , and phenyl substituted with alkyl substituted with -NH 2 ; or
  • R a is pyridinyl, piperidinyl, 2 , 3-dihydrobenzofuranyl,
  • bicyclic cycloalkyl is a six-membered, saturated carbocyclic ring having two non-adjacent carbon atoms connected by a -CH 2 - bridge and is substituted with two independently selected alkyl substituents
  • the aryl is phenyl which is unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of halo, -OH, -NH 2 , -N (alkyl) 2 , -B(OH) 2 , -C0 2 H, -0 (alkyl), -S (alkyl), and alkyl substituted with one substituent selected from the group consisting of -NH 2 and
  • R 4 is hydrogen, -OH, -0 (alkyl), phenyl, -NH 2 , -NH(R 8 ), -N(R 9 ) (R ) , in which R is alkyl, phenyl, pyridyl, -NHC(0)CF 3 , cycloalkyl fused with phenyl, alkyl substituted with one or two substituents independently selected from the group consisting of -S (alkyl), -0 (alkyl), -N (alkyl) 2 , and phenyl which is unsubstituted or substituted with one or two
  • R 9 independently selected halo substituents, and in which R and R are independently alkyl or alkyl substituted with -0 (alkyl) ; or R 9 and R10 are taken together and are morpholinyl, thiomorpholinyl, pyrrolidinyl, or pyrrolidinyl substituted with two alkyl substituents;
  • R is hydrogen, alkyl, aryl, halogen, or -CF 3 ;
  • R is hydrogen, halogen, alkyl, -N 3 , -CN, -CH 2 NH 2 , -C(0) (alkyl) , -C __C- (alkyl) , -C ⁇ C- (phenyl) , or -O-alkylene- phenyl; or
  • R taken together are C 3 -C 4 -alkylene or C 3 -C 4 - heteroalkylene ;
  • the R 35 and R 36 of the -N(R ) (R ) are independently alkyl, alkyl substituted with phenyl, or alkyl substituted with a substituent selected from the group consisting of -N (alkyl) 2 and -OH;
  • the bicyclic heterocyclyl is six-membered with one or two nitrogen atoms and two non-adjacent carbons attached by a covalent bond or CH 2 , seven-membered with two nitrogen atoms, eight-membered with 1 nitrogen atom and zero double bonds, eight-membered with two nitrogen atoms, or nine-membered with two nitrogen atoms and zero double bonds, each of which is unsubstituted or substituted with a substituent selected
  • R 12 is alkyl substituted with a substituent selected from the group consisting of heterocyclyl, -NH 2 , -N(R 15 ) (R 16 ) , and -OC(0)CF 3 , in which the heterocyclyl is piperazinyl or pyrrolidinyl, each of which is unsubstituted or substituted with alkyl substituted with -NH 2 ;
  • R 13 and R 14 are independently alkyl or alkyl substituted with -N (alkyl) 2;
  • R are independently alkyl or alkyl substituted with -NH 2 .
  • R a is pyridinyl, piperidinyl, 2 , 3-dihydrobenzofuranyl, benzodioxolyl, -N (alkyl) (alkyl) , -NH 2 , -C ⁇ CR 3B ,
  • bicyclic cycloalkyl is a six-membered, saturated carbocyclic ring having two non-adjacent carbon atoms connected by a -CH 2 - bridge and is substituted with two independently selected Ci-alkyl substituents
  • the aryl is phenyl which is unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of halo, -OH, -NH 2 , - (alkyl) 2 , -B(OH) 2 , -C0 2 H, -0 (alkyl), -S (alkyl), and alkyl substituted with one substituent selected from the group consisting of -NH 2 and
  • R 4 is hydrogen, -OH, -O(alkyl), phenyl, -NH 2 , -NH(R 8 ), -N(R 9 )(R 10 ), p in which R is alkyl, phenyl, pyridyl, -NHC(0)CF 3 , cycloalkyl fused with phenyl, alkyl substituted with one or two substituents independently selected from the group consisting of -S (alkyl), -0 (alkyl), - (alkyl) 2 , and phenyl which is unsubstituted or substituted with one or two independently selected halo substituents, and in which R 9 and R10 are independently alkyl or alkyl substituted with -0 (alkyl); or
  • R 9 and R10 are taken together and are morpholinyl, thiomorpholinyl, pyrrolidinyl, or pyrrolidinyl substituted with two alkyl substituents;
  • R is hydrogen, alkyl, aryl, halogen, or -CF 3 ;
  • R is hydrogen, halogen, alkyl, -N 3 , -CN, -CH 2 NH 2 , -C(O) (alkyl), -C ⁇ C- (alkyl) , -C ⁇ C- (phenyl) , or -OR 11 , in which R 11 is alkyl substituted with phenyl; or
  • R 5 and R6 taken together are C -Cs-alkylene or C 2 -C 5 - heteroalkylene;
  • Ci-alkyl substituted with phenyl in which the phenyl is substituted with one or two substituents independently selected from the group consisting of -CH 2 NH 2 , -OH, -0 (Ci-alkyl) , -NH 2 , halo, -0 (Ci-alkyl) , -0(alkylene)-N(Ci-alkyl) 2 , pyridyl, and -NHC (0) (Ci-alkyl) , in which the R 35 and R 36 of the -N(R 35 ) (R 36 ) are independently Ci-alkyl, Ci-alkyl substituted with phenyl, or C 2 -alkyl substituted with a substituent selected from the group consisting of -N (Ci-alkyl) 2 and -OH; the bicyclic heterocyclyl is six-membered with one or two nitrogen' atoms and two non-adjacent carbons attached by a covalent bond
  • -C (0) OR 35 is alkyl or Ci-al kyl substituted with phenyl ;
  • R 12 is C 3 -alkyl substituted with a substituent selected from the group consisting of heterocyclyl, -NH 2 , -N(R 15 ) (R 16 ) , and -OC(0)CF 3 , in which the heterocyclyl is piperazinyl or pyrrolidinyl, each of which is unsubstituted or substituted with alkyl substituted with -NH 2 ;
  • R and R are independently Ci-alkyl or C 2 -alkyl substituted with -N (Ci-alkyl) 2 ;
  • R are independently C ⁇ C 2 -alkyl or C 2 -C 4 -alkyl substituted with -NH 2 .
  • Preferred compounds of this invention include 7- ( (3R) -3-aminopyrrolidin-l-yl) -6-fluoro-5-methyl-4- oxo-1, 4-dihydro-l, 8-naphthyridine-3-carboxylic acid,
  • 6-fluoro-4-oxo-7- (3- ( (thien-3- ylmethyl) amino) pyrrolidin-1-yl) -1, 4-dihydro-l, 8- naphthyridine-3-carboxylic acid, 6-fluoro-7- (3- ( (lH-imidazol-4- ylmethyl) amino) pyrrolidin-1-yl) -4-oxo-l, 4-dihydro-l, 8- naphthyridine-3-carboxylic acid, l-oxo-6-piperazin-l-yl-4 ,7,8, 9-tetrahydro-lH- cyclopenta (c) -1, 8-naphthyridine-2-carboxylic acid, 6-fluoro-4-oxo-7- (3- ( (1-phenylethyl) amino) pyrrolidin-1- yl) -1, 4-dihydro-l, 8-naphthyridine-3-car
  • 6-fluoro-7- (3- ( (1-methyl-l- phenylethyl) amino) pyrrolidin-1-yl) -4-oxo-l, -dihydro-l, 8- naphthyridine-3-carboxylic acid
  • 6-fluoro-7- (3- ( (4-hydroxybenzyl) amino) pyrrolidin-1-yl ) - 4-oxo-l, -dihydro-l, 8-naphthyridine-3-carboxylic acid
  • 6-fluoro-4-oxo-7- (3- ( (lH-pyrazol-5- yl ethyl) amino) pyrrolidin-1-yl) -1, -dihydro-l, 8- naphthyridine-3-carboxylic acid, ethyl 7- (3-aminopyrrolidin-l-yl) -6-fluoro-4-oxo-l- (3- pyridin-4-ylprop-2-ynyl) -1, 4-dihydro-l, 8-naphthyridine-3- carboxylate,
  • 6-fluoro-4-oxo-7- (3- ( (l-thien-2- ylethyl) amino) pyrrolidin-1-yl) -1, 4-dihydro-l, 8- naphthyridine-3-carboxylic acid, 7- (3- ( (2- (dimethylamino) ethyl) amino) pyrrolidin-1-yl) -6- fluoro-4-oxo-l, 4-dihydro-l, 8-naphthyridine-3-carboxylic acid,
  • 6-fluoro-7- (3- ( (3-fluoro-4- methoxybenzyl) amino) pyrrolidin-1-yl) -4-oxo-l, 4-dihydro-l, 8- naphthyridine-3-carboxylic acid, 7- ( (IS, 4S) -2, 5-diazabicyclo (2.2.1) hept-2-yl) -6-fluoro- 1- (4-methoxybenzyl) -4-oxo-l, -dihydro-l, 8-naphthyridine-3- carboxylic acid, 6-fluoro-4-oxo-7- (3- ( (quinolin-2- ylmethyl) amino) pyrrolidin-1-yl) -1, 4-dihydro-l, 8- naphthyridine-3-carboxylic acid,
  • 6-fluoro-4-oxo-7- (3- ( (piperidin-4- ylmethyl) amino) pyrrolidin-1-yl) -1, 4-dihydro-l, 8- naphthyridine-3-carboxylic acid, ethyl 7- (3-aminopyrrolidin-l-yl) -6-fluoro-4-oxo-l- (3- phenylprop-2-ynyl) -1, 4-dihydro-l, 8-naphthyridine-3- carboxylate,
  • 6-fluoro-7- (3- ( ( (1R) -2-hydroxy-l- phenylethyl) amino) pyrrolidin-1-yl) -4-oxo-l, 4-dihydro-l, 8- naphthyridine-3-carboxylic acid, 7- (3- ( (4- (aminosulfonyl) benzyl) amino) pyrrolidin-1-yl) - 6-fluoro-4-oxo-l, 4-dihydro-l, 8-naphthyridine-3-carboxylic acid,
  • 6-fluoro-4-oxo-7- (3- ( (3-pyridin-4- ylbenzyl) amino) pyrrolidin-1-yl) -1, 4-dihydro-l, 8- na ⁇ hthyridine-3-carboxylic acid, 1- (4-a inobutyl) -7- ( (IS, 4S) -2,5- diazabicyclo (2.2.1) hept-2-yl) -6-fluoro-4-oxo-l, 4-dihydro- 1, 8-naphthyridine-3-carboxylic acid,
  • 6-fluoro-7- (3-fluoropyrrolidin-1-yl) -4-oxo-l, 4-dihydro- 1, 8-naphthyridine-3-carboxylic acid, l-benzyl-7- ( (IS, 4S) -2, 5-diazabicyclo (2.2.1) hept-2-yl) - 6-fluoro-4-oxo-l, 4-dihydro-l, 8-naphthyridine-3-carboxylic acid,
  • all stereoisomers of the compounds of the invention are meant to be included in the invention, including racemic mixtures, mixtures of diastereomers, as well as individual optical isomers, including, enantiomers and single diastereomers of the compounds of the invention substantially free from their enantiomers or other diastereomers.
  • substantially free is meant greater than about 80% free of other enantiomers or diastereomers of the compound, more preferabl greater than about 90% free of other enantiomers or diastereomers of the compound, even more preferably greater than about 95% free of other enantiomers or diastereomers of the compound, even more highly preferably greater than about 98% free of other enantiomers or diastereomers of the compound and most preferably greater than about 99% free of other enantiomers or diastereomers of the compound.
  • Individual stereoisomers of the compounds of this invention can be prepared by any one of a number of methods which are within the knowledge of one of ordinary skill in the art.
  • Stereospecific synthesis involves the use of appropriate chiral starting materials and synthetic reactions which do not cause racemization or inversion of stereochemistry at the chiral centers .
  • Diastereomeric mixtures of compounds resulting from a synthetic reaction can often be separated by chromatographic techniques which are well-known to those of ordinary skill in the art.
  • Chromatographic resolution of enantiomers can be accomplished on chiral chromatography resins. Chromatography columns containin chiral resins are commercially available. In practice, the racemate is placed in solution and loaded onto the column containing the chiral stationary phase. The enantiomers are then separated by HPLC.
  • Resolution of enantiomers can also be accomplished by converting the enantiomers in the mixture to diastereomers by reaction with chiral auxiliaries.
  • the resulting diastereomers can then be separated by column chromatography. This technique is especially useful when the compounds to be separated contain a carboxyl, amino or hydroxyl group that will form a salt or covalent bond with the chiral auxiliary. Chirally pure amino acids, organic carboxylic acids or organosulfonic acids are especially useful as chiral auxiliaries.
  • Enzymes such as esterases, phosphatases and lipases, can be useful for resolution of derivatives of the enantiomers in an enantiomeric mixture.
  • an ester derivative of a carboxyl group in the compounds to be separated can be prepared.
  • Certain enzymes will selectively hydrolyze only one of the enantiomers in the mixture. Then the resulting enantiomerically pure acid can be separated from the unhydrolyzed ester.
  • Geometric isomers assigned E or Z, may result from the arrangement of substituents around the carbon-carbon or carbon-nitrogen double bond in the compounds.
  • Double bonds with an excess of one arrangement over the other are assigned the arrangement in the higher amount, preferably an excess of about 85%-90%, more preferably an excess of about 95%-99%, and still more preferably an excess of greater than about 99%.
  • the compounds may also exist as an equilibrium mixture comprising two geometric isomers.
  • solvates and hydrates of the compounds are meant to be included in this invention.
  • any variable for example R 1 , R 2 , and R 3 , etc.
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • combinations c substituents are permissible only if such combinations result in stable compounds.
  • Stable compounds are compounds which can be isolated in a useful degree of purity from a reaction mixture.
  • This invention is intended to encompass compounds when prepared by synthetic processes or by metabolic processes. Preparation of the compounds of the invention by metabolic processes include those occurring in the human or animal body ( in vivo) or processes occurring in vi tro .
  • prodrug-forming moieties may have attached thereto prodrug-forming moieties.
  • the prodrug-forming moieties are removed by metabolic processes and release the compounds having the freed hydroxyl, amino, or carboxylic acid in vivo.
  • Prodrugs are useful for adjusting such pharmacokinetic properties of the compounds as solubility and/or hydrophobicity, absorption in the gastrointestinal tract, bioavailability, tissue penetration, and rate of clearance.
  • the compounds may exist as acid addition salts, basic addition salts, or zwitterions. Salts of the compounds are prepared during their isolation or following their purification. Acid addition salts of the compounds are those derived from the reaction of the compounds with an acid. For example, the acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, aleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, picrate, propionate, succinate, tartrate, thi
  • basic addition salts may be prepared therefrom by reaction with a base such as the hydroxide, carbonate, or bicarbonate of cations such as lithium, sodium, potassium, calcium, and magnesium.
  • a base such as the hydroxide, carbonate, or bicarbonate of cations such as lithium, sodium, potassium, calcium, and magnesium.
  • the compounds may be administrated with or without another antibacterials and with or without an excipient.
  • Excipients include encapsulating materials or formulation additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents, and mixtures thereof.
  • absorption accelerators such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents, and mixtures thereof.
  • Excipients for orally administered compounds in solid dosage forms include agar, alginic acid, cocoa butter, gelatin, isotonic saline, malt, powdered tragacanth, Ringer's solution, talc, water, aluminum hydroxide, magnesium hydroxide, sodium and potassium phosphate salts, cellulose, cellulose acetate, ethyl cellulose, sodium carboxymethyl cellulose, ethyl laureate, ethyl oleate, magnesium stearate, sodium lauryl sulfate, castor oil, corn oil, cottonseed oil, germ oil, groundnut oil, olive oil, peanut oil, safflower oil, sesame oil, soybean oil, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, ethanol, ethyl acetate, ethyl carbonate, glycerol, isopropanol, propylene glycol, tetrahydrofurfuryl
  • Excipients for ophthalmically and orally administered compounds in liquid dosage forms include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, cottonseed oil, groundnut oil, corn oil, germ oil, olive oil, castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan, and mixtures thereof.
  • Excipients for osmotically administered compounds include water, ethanol, isopropanol, chlorofluorohydrocarbons, and mixtures thereof.
  • Excipients for parenterally administered compounds include water, 1, 3-butanediol, Ringer's solution, U.S. P. or isotonic sodium chloride solution, oleic acid, castor oil, corn oil, cottonseed oil, germ oil, groundnut oil, olive oil, peanut oil, safflower oil, sesame oil, soybean oil, liposomes, and mixtures thereof.
  • Excipients for rectally and vaginally administered compounds include cocoa butter, polyethylene glycol, wax, and mixtures thereof.
  • the compounds may be administered parenterally (subcutaneously, intravenously, intramuscularly, and intrasternally) , orally, osmotically, ophthalmically, rectally, topically, and vaginally.
  • Orally administered compounds in solid dosage forms may be administered as capsules, dragees, granules, pills, powders, and tablets.
  • Ophthalmically and orally administered compounds in liquid dosage forms may be administered as elixirs, emulsions, microemulsions, solutions, suspensions, and syrups.
  • Osmotically and topically administered compounds may be administered as creams, gels, inhalants, lotions, ointments, pastes, powders, solutions, and sprays.
  • Parenterally administered compounds may be administered as aqueous or oleaginous solutions or aqueous or oleaginous suspensions, the latter of which contains crystalline, amorphous, or otherwise insoluble forms of the compounds.
  • Rectally and vaginally administered compounds may be administered as creams, gels, lotions, ointments, and pastes.
  • Dosage forms for the compounds depend on the species being treated, the disorder being treated and the severity thereof, the composition comprising the compounds, the time of administration, the route of administration, the duration of treatment, the potency of the compounds, and the rate of excretion of the compounds.
  • the daily therapeutically effective amount of the compounds administered to a patient in single or divided doses range from about 0.1 to about 200 mg/kg body weight, preferably from about 0.25 to about 100 mg/kg body weight.
  • Single dose compositions contain these amounts of the compounds or combinations of submultiples thereof.
  • the antibacterial activity of the compounds was superior to the control containing no compound and in the range of about 2-8 ⁇ M against AA and about 0.25-l ⁇ M against BB. These data demonstrate that the compounds are antibacterials and are therefore useful for the prophylaxis and treatment of bacterial infections.
  • Bacterial protein synthesis inhibitory activity of the compounds and the aformentioned commercially-available antibacterials was determined by translation assays performed using the firefly luciferase reporter system described by Murray et al., (2001), "Staphylococcus aureus Cell Extract Transcription-Translation Assay: Firefly Luciferase Reporter System for Evaluating Protein Translation Inhibitors, " Antimicrob. Agents Chemother.
  • the IC 5 o's of the compounds defined as concentrations of the same which caused 50% inhibition of bacterial protein synthesis, was in the range of about 0.01-40 ⁇ M.
  • the IC 5 o's of the commercially-available quinolones tested were greater than about lOO ⁇ M compared to the IC 50 of Linezolid which is about 3 ⁇ M.
  • the compounds function by a mechanism more similar to Linezolid (which inhibits bacterial protein synthesis) than quinolones (which inhibit DNA gyrase) .
  • the compounds inhibit the growth of quinolone resistant bacteria at least as well as the growth of quinolone susceptible bacteria, and because they function by a mechanism which differs from quinolones, they are useful not only for prophylaxis and treatment of bacterial infections but also for prophylaxis and treatment of bacterial infections for which quinolones would be ineffective or only partially effective.
  • the following schemes illustrate representative processes by which the compounds may be made. It is meant to be understood that the order of the steps in the processes may be varied, other reagents may be substituted for those specifically mentioned, and vulnerable substituents may be protected and deprotected during the process .
  • DME 1, 2-dimethoxyethane
  • DMF N,N-dimethylformamide
  • DMSO dimethylsulfoxide
  • THF tetrahydrofuran
  • Compounds having formula (1) in which X is -Br or -Cl, may be converted to compounds having formula (2) by reacting the former and a halogenating agent to provide an acid chloride (la) and subsequently reacting (la) and a compound having formula (i)
  • Halogenating agents include oxalyl chloride/DMF and thionyl chloride.
  • Step (a) is typically conducted at about 25°C to 50 °C, over about 1 to 6 hours, in solvents such as dichloromethane and chloroform.
  • Step (b) is typically conducted at about 0°C to 25°C, over about 1 to 24 hours, in solvents such as dichloromethane, chloroform, THF, and mixtures thereof.
  • Compounds having formula (2) may be converted to compounds having formula (3) -a by reacting the former, triethyl orthoformate, and acetic anhydride.
  • the reaction is typically conducted from about 1 to 6 hours, at about 80°C to 140°C, in acetic anhydride.
  • Compounds of formula (la) may be converted to compounds of formula (3)-b by reacting the former, 3, 3-dimethylaminoacrylate, and triethylamine .
  • the reaction is typically conducted from about 1 to 3 hours, at about 80°C to 110°C, in solvents such as benzene, toluene, or THF.
  • R P -NH 2 ( ⁇ ), p in which R is a nitrogen protecting group and (b) reacting the product of step (a) with a second base.
  • Nitrogen protecting groups include allyloxy, 2, 4-dimethoxybenzyl, 2-cyanoethyl, 4-methoxybenzyl, trimethylsilyl, tert-butyl, and triphenylmethyl .
  • Second bases include potassium carbonate, sodium carbonate, sodium hydride, and potassium hydride. The reaction is typically conducted from about 1/2 hour to 7 days, at about 0°C to 100°C, in solvents such as dichloromethane, acetonitrile, THF, and mixtures thereof.
  • Third bases include potassium bicarbonate, sodium bicarbonate, potassium phosphate, potassium carbonate, triethylamine, diisopropylethylamine, and 1, 8-diazabicyclo- (5.4.0) undec-7-ene.
  • the reaction is typically conducted from about 5 hours to 7 days, at about 25°C to 160°C, in solvents such as acetonitrile, dichloromethane, DMSO, DMF, dimethylacetamide, N-methylpyrrolidine, water, and mixtures thereof.
  • Compounds having formula (I)-c may be converted to compounds having formula (I)-d by reacting the former and a fourth base.
  • Fourth bases include lithium hydroxide, sodium hydroxide, and potassium hydroxide.
  • the reaction is typically conducted from about 3 to 24 hours, at about 25°C to 110°C, and at atmospheric or elevated pressures, in solvents such as THF, 1,4-dioxane, methanol, ethanol, iso-propanol, dichloromethane, water, and mixtures thereof.
  • Coupling agents include 1,3- dicyclohexylcarbodiimide and 1- (3-dimethylaminopropyl) -3- ethylcarbodiimide, l-hydroxy-7-azobenzotriazole, 0-(7- azabenzotriazol-1-yl) -N,N,N' ,N' -tetramethyluronium hexafluorophosphate, iso-butyl chloroformate, and iso-propenyl chloroformate.
  • First additives include trimethylaluminum, 1-hydroxybenzotriazole, and 4, 4-dimethylaminopyridine.
  • the reaction is typically conducted from about 12 to 24 hours, at about -25°C to 25°C, in solvents such as N, N-dimethylacetamide, dichloromethane, chloroform, DMF, and THF.
  • R is aryl or heteroaryl
  • Q 1 is B(V 1 ) 2 or Sn(alkyl) 3 .
  • V 1 is alkyl, -0 (alkyl), or -OH, a coupling catalyst, a fifth base, and, optionally, a second additive.
  • Coupling catalysts include tetrakis (triphenylphosphine) palladium (0) , tris (dibenzylideneacetone) dipalladium(O) , (1,1' -bis (diphenylphosphino) ferrocene) dichloropalladium (II), and dichlorobis (triphenylphosphine) palladium (II) .
  • Fifth bases include potassium bicarbonate, sodium bicarbonate, potassium phosphate, potassium carbonate, cesium carbonate, cesium fluoride, triethylamine, diisopropylethylamine, and 1, 8-diazabicyclo- (5.4.0) undec-7- ene .
  • Second additives include phosohines such as tributylphosphine, tricyclohexylphosphine, triphenylphosphine, trinaphthylphosphine, tri(fury-2- yl) phosphine, tri (pyrid-3-yl) phosphine, triphenylarsine, 1, 4-bis (diphenylphosphino) butane (dppb) , 1, 2-bis (diphenyl- phosphino) ethane (dppe) , 1, 1-bis (diphenylphosphino) methane (dppm) , 1, 2-bis (dimethylphosphino) ethane (dmpe) , and 1, 1 ' -bis (diphenylphosphino) ferrocene (dppf), and salts such as copper (I) iodide and copper (I) chloride.
  • the reaction is typically conducted from about 3 to 24 hours,
  • Hydrogenation catalysts include platinum on carbon with hydrogen gas and triethylsilane with trifluoroacetic acid. The reaction is typically conducted from about 3 to 24 hours, at about 0°C to 35°C, in solvents such as dichloromethane, chloroform, and carbon tetrachloride .
  • Compounds having formula (I) can be converted to compounds having formula (I)-g by reacting the former and a reducing agent.
  • Reducing agents include sodium borohydride and sodium cyanoborohydride .
  • the reaction is typically conducted from about 1 to 18 hours, at about 0°C to 35°C, in solvents such as methanol, ethanol, THF, water, and mixtures thereof.
  • EXAMPLE IB ethyl 3- (2, 6-dichloro-5-fluoro-4-methyl-pyrid-3-yl) -3- oxopropanoate and ethyl 3- (2, 6-dichloro-5-fluoro-4-ethyl-pyrid-3-yl) -3- oxopropanoate
  • EXAMPLE IA 9.48 mmol
  • dichloromethane (20 mL) was treated with oxalyl chloride (8 mL) and DMF (2 drops) , stirred for 1 hour, and concentrated; and the concentrate was dissolved in THF (25 mL) to provide an acid chloride solution.
  • a slurry of the mono-potassium salt of ethyl malonate (4.0 g) in acetonitrile (40 mL) at 0 °C was treated with triethylamine (3.3 mL) and magnesium chloride (3.2 g) , warmed to ambient temperature, stirred for 4 hours, treated with the acid chloride solution, stirred for 1 hour, treated with IM HCl, and extracted with ethyl acetate. The extract was washed with brine, dried (Na 2 S0 4 ), filtered, and concentrated; and the concentrate was flash chromatographed on silica gel with 90:10 hexanes/ethyl acetate.
  • EXAMPLE ID ethyl 7-chloro-l- (2, 4-dimethoxybenzyl) -6-fluoro-5-methyl-4- oxo-1, 4-dihydro-l, 8-naphthyridine-3-carboxylate and ethyl 7-chloro-l- (2, 4-dimethoxybenzyl) -6-fluoro-5-ethyl-4- oxo-1, 4-dihydro-l, 8-naphthyridine-3-carboxylate
  • a solution of Example IC (6 mmol) in dichloromethane (20 mL) at 0 °C was treated with dimethoxybenzylamine (0.96 mL) , stirred at ambient temperature for 90 minutes, and concentrated.
  • the concentrate was dissolved in acetonitrile (10 mL) , treated with potassium carbonate (2.3 g) , refluxed for 7 days then cooled, stirred at ambient temperature for 2 days, diluted with dichloromethane, washed with water, 10% citric acid, and brine, and dried (Na 2 S0 4 ) , filtered, and concentrated; and the concentrate was flash chromatographed on silica gel with a hexanes/ethyl acetate gradient to provide the desired products.
  • a solution of Example IF (334 mg) in trifluoroacetic acid (25 mL) was refluxed for 3 hours then cooled and concentrated.
  • the concentrate was azeotroped with toluene and dissolved in water (250 mL) ; and this solution was washed with diethyl ether, filtered through a 0.45 ⁇ m syringe membrane filter, and lyophilized.
  • EXAMPLE 2A ethyl 7- (3- ( (tert-butoxycarbonyl) amino) pyrrolidin-1-yl) -1- (2, 4-dimethoxybenzyl) -6-fluoro-5-methyl-4-oxo-l, 4-dihydro- 1, 8-naphthyridine-3-carboxylate
  • This example was prepared by substituting 3- (tert- butoxycarbonylamino) pyrrolidine for (3R) - (3-tert- butoxycarbonylamino) pyrrolidine in EXAMPLE IE.
  • EXAMPLE 2C 7- (3-aminopyrrolidin-l-yl) -6-fluoro-5-methyl-4-oxo-l, 4- dihydro-1, 8-naphthyridine-3-carboxylic acid
  • EXAMPLE 2B was prepared by substituting EXAMPLE 2B for EXAMPLE IF in EXAMPLE IG and purified by reverse phase HPLC (Cia column with a continuous water/0.5% trifluoroacetic acid to acetonitrile/0.5% trifluoroacetic acid gradient followed by lypholization of appropriate fractions) .
  • EXAMPLE 3A ethyl 7- (3- ( (tert-butoxycarbonyl) amino) pyrrolidin-1-yl) -1- (2, 4-dimethoxybenzyl) -5-ethyl-6-fluoro-4-oxo-l, 4-dihydro- 1, 8-naphthyridine-3-carboxylate
  • This example was prepared by substituting ethyl 7- chloro-1- (2, 4-dimethoxybenzyl) -6-fluoro-5-ethyl-4-oxo-l, 4- dihydro-1, 8-naphthyridine-3-carboxylate for ethyl 7-chloro- 1- (2, 4-dimethoxybenzyl) -6-fluoro-5-methyl-4-oxo-l, 4-dihydro- 1, 8-naphthyridine-3-carboxylate and 3-(tert- butoxycarbonylamino) pyrrolidine for (3R)
  • EXAMPLE 3C 7- (3-aminopyrrolidin-l-yl) -5-ethyl-6-fluoro-4-oxo-l, 4- dihydro-1, 8-naphthyridine-3-carboxylic acid
  • EXAMPLE 3B was prepared by substituting EXAMPLE 3B for EXAMPLE IF in EXAMPLE IG.
  • NMR 300 MHz, DMSO-d 6 ) ⁇ 9.47 (s, IH), 4.02-3.77 (m, 5H) , 3.29 (m, 2H) , 2.30 (m, IH) , 2.10 (m, IH) , 1.20 (m, 3H) .
  • This example was prepared by substituting (3S) -3- (tert- butoxycarbonylamino) pyrrolidine for (3R) -3- (tert- butoxycarbonylamino) pyrrolidine in EXAMPLE IE.
  • EXAMPLE 4C 7- ( (3S) -3-aminopyrrolidin-l-yl) -6-fluoro-5-methyl-4-oxo-l, 4- dihydro-1, 8-naphthyridine-3-carboxylic acid
  • This example was prepared by substituting EXAMPLE 4B for EXAMPLE IF in EXAMPLE IG.
  • NMR 300 MHz, DMSO-d 6 ) ⁇ 8.46 (s, IH) , 4.05-3.70 (m, 5H) , 2.71 (m, 3H) , 2.30 (m, IH) , 2.10 (m, IH) .
  • EXAMPLE 5A ethyl 7-azetidin-l-yl-l- (2, 4-dimethoxybenzyl) -6-fluoro-5- methyl-4-oxo-l, -dihydro-l, 8-naphthyridine-3-carboxylate
  • a mixture of ethyl 7-chloro-l- (2, 4-dimethoxybenzyl) -6- fluoro-5-methyl-4-oxo-l, 4-dihydro-l, 8-naphthyridine-3- carboxylate (254 mg) , azetidine (0.085 mL) , and potassium carbonate (160 mg) in dichloromethane (5 mL) was stirred for 3 days, diluted with dichloromethane, washed with water and 10% citric acid, filtered through a cotton plug, and concentrated.
  • EXAMPLE 5B ethyl 7-azetidin-l-yl-6-fluoro-5-methyl-4-oxo-l, 4-dihydro- 1, 8-naphthyridine-3-carboxylate
  • a solution of Example 5A (267 mg) in trifluoroacetic acid (11 mL) was stirred at 40 °C for 3 hours and concentrated; and the concentrate was azeotroped with toluene .
  • EXAMPLE 5C 7-azetidin-l-yl-6-fluoro-5-methyl-4-oxo-l, 4-dihydro-l, 8- naphthyridine-3-carboxylic acid
  • a solution of Example 5B (0.58 mmol) in THF (10 mL) was treated with IM LiOH (30 mL) , stirred for 12 hours, heated at 70 °C for 8 hours then cooled, stirred at ambient temperature for 2 days, heated at 70 °C for 8 hours then cooled, treated with 10% citric acid, and filtred.
  • Example 5C A suspension of Example 5C (81 mg) in water (100 mL) was treated with 0.2014M NaOH (1.3 mL) , sonicated for 1 hour, and filtered first through filter paper and then a 0.45 ⁇ m membrane; and the filtrate was lyophilized.
  • NMR 300 MHz, DMSO-d 6 ) ⁇ 8.6 (s, IH) , 4.2 (m, 4H) , 2.7 (m, 3H) , 2.3 (m, 2H) .
  • EXAMPLE 6B ethyl 3- (2, 6-dichloro-5-fluoro-4-iodopyridin-3-yl) -3- oxopropanoate This example was prepared by substituting EXAMPLE 6A for EXAMPLE IA in EXAMPLE IB and flash chromatographed on silica gel with 15:85 ethyl acetate/hexane .
  • EXAMPLE 6C ethyl (2Z) -2- ( (2, 6-dichloro-5-fluoro-4-iodopyridin-3- yl) carbonyl) -3-ethoxyacrylate This example was prepared by substituting EXAMPLE 6B for EXAMPLE IB in EXAMPLE IC.
  • EXAMPLE 6D ethyl 7-chloro-l- (2, 4-dimethoxybenzyl) -6-fluoro-5-iodo-4- oxo-1, 4-dihydro-l, 8-naphthyridine-3-carboxylate
  • EXAMPLE 6C ethyl 7-chloro-l- (2, 4-dimethoxybenzyl) -6-fluoro-5-iodo-4- oxo-1, 4-dihydro-l, 8-naphthyridine-3-carboxylate
  • EXAMPLE 6E ethyl 7- (3- ( (tert-butoxycarbonyl) amino) pyrrolidin-1-yl) -1- (2, 4-dimethoxybenzyl) -6-fluoro-5-iodo-4-oxo-l, 4-dihydro-l, 8- naphthyridine-3-carboxylate
  • EXAMPLE 6D was prepared by substituting EXAMPLE 6D for EXAMPLE ID in EXAMPLE IE, 3- (tert- butoxycarbonylamino) pyrrolidine for (3R) -3- (tert- butoxycarbonylamino) pyrrolidine, and 1:1 DMSO/methanol for dichloromethane, and flash chromatographed on silica gel with a methanol/dichloromethane gradient.
  • EXAMPLE 7 7-azetidin-l-yl-6-fluoro-4-oxo-l, 4-dihydro-l, 8- naphthyridine-3-carboxylic acid
  • EXAMPLE 7A ethyl (2E/Z) -2- ( (2, 6-dichloro-5-fluoropyridin-3- yl) carbonyl) -3- (ethoxy) prop-2-enoate
  • a solution of ethyl 3- (2, 6-dichloro-5-fluoropyridin-3- yl) -3-oxopropanoate (40 g) and triethyl orthoformate (26.1 mL) in acetic anhydride (100 mL) was heated at 85 °C for 6.5 hours then cooled and concentrated; and the concentrate was azeotroped with toluene and crystallized from hexanes, with a small amount of diethyl ether and dichloromethane.
  • EXAMPLE 7B ethyl (2E/Z) -2- ( (2, 6-dichloro-5-fluoropyridin-3- yl) carbonyl) -3- (dimethylamino) prop-2-enoate
  • a solution of 2, 6-dichloro-5-fluoronicotinoyl chloride (62.5 g), ethyl 3, 3-dimethylaminoacrylate (58.8 g) , and triethylamine (69 g) in toluene (600 mL) was heated at 90 °C for 1 hour then cooled and concentrated.
  • the concentrate was dissolved in dichloromethane (60 mL) , diluted with diethyl ether, and filtered. The filtrate was concentrated, and the concentrate was crystallized from hexanes : diethyl ether.
  • Example 7A A solution of Example 7A (20 g) in acetonitrile (400 mL) at 0 °C was treated with 3-aminopropionitrile (4.6 mL) , stirred at 0 °C for 15 minutes and ambient temperature for 30 minutes, treated with potassium carbonate (15 g) , heated at 75 °C for 18 hours then cooled, diluted with ethyl acetate , washed with water, 10% citric acid, water, and brine, and dried (MgS0 ) . filtered, and concentrated; and the concentrate was plug filtered through silica gel with 9:1 ethyl acetate/dichloromethane .
  • EXAMPLE 7C (alternative) The desired product may be prepared by substituting EXAMPLE 7B for EXAMPLE 7A in EXAMPLE 7C.
  • EXAMPLE 7D ethyl 7-azetidin-l-yl-l- (2-cyanoethyl) -6-fluoro-4-oxo-l, 4- dihydro-1, 8-naphthyridine-3-carboxylate
  • a solution of Example 7C (13.26 g) , azetidine hydrochloride (9.58 g) and triethylamine (17.2 mL) in dichloromethane (650 mL) was stirred for 2 hours, treated with triethylamine (900 mg) , stirred for 1 hour, diluted with dichloromethane, washed with water and brine, dried (MgS0 4 ), filtered, and concentrated; and the concentrate was triturated with refluxing dichloromethane, treated with diethyl ether and hexanes, and filtered.
  • EXAMPLE F ethyl 7-chloro-l- (2, 4-dimethoxybenzyl) -6-fluoro-4-oxo-l, 4- dihydro-1, 8-naphthyridine-3-carboxylate
  • the desired compound was prepared by substituting 2,4- dimethoxybenzylamme for 3-aminopropionitrile in EXAMPLE 7C.
  • EXAMPLE 7G ethyl 7-azetidin-l-yl-l- (2, 4-dimethoxybenzyl) -6-fluoro-4- oxo-1, -dihydro-l, 8-naphthyridine-3-carboxylate This example was prepared by substituting EXAMPLE 7F for EXAMPLE 7C in EXAMPLE 7D.
  • EXAMPLE 7H 7-azetidin-l-yl-l- (2, 4-dimethoxybenzyl) -6-fluoro-4-oxo-l, 4- dihydro-1, 8-naphthyridine-3-carboxylic acid
  • the desired compound was prepared by substituting EXAMPLE 7G for EXAMPLE 7D in EXAMPLE 7E.
  • This example was prepared by substituting 2, 6-dichloro- 4- (trifluoromethyl) nicotinamide for 2, 6-dichloro-4-methyl- nicotinamide in EXAMPLE 65A.
  • EXAMPLE 8B ethyl 3- (2, 6-dichloro-4- (trifluoromethyl) pyridin-3-yl) -3- oxopropanoate This example was prepared by substituting EXAMPLE 8A for EXAMPLE 65A in EXAMPLE 65B.
  • EXAMPLE 8C ethyl (2E/Z) -2- ( (2, 6-dichloro-4- (trifluoromethyl) pyridin-3- yl) carbonyl) -3- (ethoxy) prop-2-enoate This example was prepared by substituting EXAMPLE 8B for EXAMPLE 65B in EXAMPLE 65C.
  • EXAMPLE 8D ethyl 7-chloro-l- (2, 4-dimethoxybenzyl) -4-oxo-5- (trifluoromethyl) -1, 4-dihydro-l, 8-naphthyridine-3- carboxylate
  • EXAMPLE 8C ethyl 7-chloro-l- (2, 4-dimethoxybenzyl) -4-oxo-5- (trifluoromethyl) -1, 4-dihydro-l, 8-naphthyridine-3- carboxylate
  • EXAMPLE 10B ethyl 7- ( (1R, 5S) -cis-6- ( (tert-butoxycarbonyl) amino) -3- azabicyclo (3.1.0) hex-3-yl) -1- (2, 4-dimethoxybenzyl) -6-fluoro- 5-methyl-4-oxo-l, 4-dihydro-l, 8-naphthyridine-3-carboxylate
  • EXAMPLE 10A was prepared by substituting EXAMPLE 10A for (3R) -3- (tert-butoxycarbonylamino) pyrrolidine in EXAMPLE IE.
  • EXAMPLE 10D 7- ( (1R, 5S) -cis-6-amino-3-azabicyclo (3.1.0) hex-3-yl) -6- fluoro-5-methyl-4-oxo-l, -dihydro-l, 8-naphthyridine-3- carboxylic acid
  • This example was prepared by substituting EXAMPLE 10C for EXAMPLE IF in EXAMPLE IG and conducting the reaction at reflux for 18 hours.
  • NMR 300 MHz, DMSO-d 6 ) ⁇ 8.43 (s, IH) , 4.03 (m, 2H) , 3.83 (m, 2H) , 2.68 (m, 3H) , 2.14 (m, 2H) .
  • the filtrate was concentrated, and the concentrate was dissolved in dichloromethane, applied to a silica gel-containing solid-phase extraction cartridge, and eluted with 25% ethyl acetate/hexanes then 10% methanol/dichloromethane.
  • the product was dissolved in trifluoroacetic acid, stirred at 80 °C for 18 hours in a sealed vial, and concentrated.
  • This concentrate was dissolved in methanol, treated with anion exchange resin, and filtered.
  • the filtrate was concentrated, and the concentrate was purified by reverse phase HPLC.
  • This example was prepared by substituting tert- butylamine for 3-aminopropionitrile in EXAMPLE 7C.
  • EXAMPLE 15B ethyl 7- (( 3R) -3- ( (tert-butoxycarbonyl) amino) pyrrolidin-1- yl) -l-tert-butyl-6-fluoro-4-oxo-l, -dihydro-l, 8- naphthyridine-3-carboxylate
  • a solution of Example 15A (300 mg) in acetonitrile (40 mL) at 0 °C was treated with potassium carbonate (1 g) , heated at 60°C for 18 hours then cooled, diluted with ethyl acetate, washed with water, 10% citric acid, water and brine, dried (MgS0 4 ) , filtered, and concentrated; and the concentrate was flash chromatographed on silica gel with ethyl acetate.
  • EXAMPLE 15C 7- ( (3R) -3-aminopyrrolidin-l-yl) -6-fluoro-4-oxo-l, 4-dihydro- 1, 8-naphthyridine-3-carboxylic acid hydrochloride
  • a suspension of EXAMPLE 15B (260 mg) in ethanol (60 mL) was treated with HCl gas to saturation, heated at 120 °C for 18 hours then cooled, treated with diethyl ether and filtered to provide the desired product.
  • EXAMPLE 17 6-fluoro-5-methyl-7- (4- (methylamino) hexahydrocyclopenta (c) pyrrol-2 (IH) -yl) -4-oxo- 1, 4-dihydro-l, 8-naphthyridine-3-carboxylic acid
  • EXAMPLE ID for EXAMPLE 7C in EXAMPLE 9, tert-butyl methyl (octahydrocyclopenta (c) pyrrol-4-yl) carbamate for (3S)- 3- (tert-butoxycarbonylamino) pyrrolidine, and dimethylacetamide for acetonitrile and conducting the reaction at 100 °C for 18 hours; the deprotection step substituted trifluoroacetic acid for hydrochloric acid and was conducted at 70 °C for 18 hours; and the concentrate was triturated with diethyl ether to provide the desired product.
  • EXAMPLE 18A ethyl 7- (azetidin-1-yl) -1- (2, -dimethoxybenzyl) -5-methyl-4- oxo-1, -dihydro-l, 8-naphthyridine-3-carboxylate
  • a solution of Example 65D (400 mg) , azetidine hydrochloride (108 mg) , and N, N-diisopropylethylamine (0.503 mL) in acetonitrile (10 mL) was heated at 60 °C for 18 hours then cooled, diluted with dichloromethane, washed with 0. IM HCl, saturated sodium bicarbonate, and brine, and dried (MgS0 4 ), filtered, and concentrated; and the concentrate was recrystallized from diethyl ether to provide the desired product .
  • EXAMPLE 19 6-fluoro-5-methyl-7-octahydro-6H-pyrrolo (3, 4-b) pyridin-6-yl- 4-oxo-l, -dihydro-l, 8-naphthyridine-3-carboxylic acid
  • This example was prepared by substituting 1-tert- butoxycarbonyloctahydro-lH-pyrrolo (3, 4-b) pyridine for tert - butyl methyl (octahydrocyclopenta (c) pyrrol-4-yl) carbamate in EXAMPLE 17.
  • EXAMPLE 20A ethyl 7- (3- ( (tert-butoxycarbonyl) amino) azetidin-1-yl) -1- (2- cyanoethyl) -6-fluoro-4-oxo-l, 4-dihydro-l, 8-naphthyridine-3- carboxylate
  • EXAMPLE 20C 7- (3-aminoazetidin-l-yl) -6-fluoro-4-oxo-l, 4-dihydro-l, 8- naphthyridine-3-carboxylic acid
  • a solution of EXAMPLE 20B (0.12 g) in trifluoroacetic acid (6 L) was stirred for 10 minutes and concentrated; and the concentrate was azeotroped with toluene to provide the desired product.
  • NMR 300 MHz, DMSO-d 6 ) ⁇ 8.51 (s, IH) , 8.03 (m, IH) , 4.58 (m, 2H) , 4.26 (m, 2H) , 4.16 (br s, IH) .
  • EXAMPLE 21A ethyl 7- (3- ( (tert-butoxycarbonyl) amino) pyrrolidin-1-yl) -1- tert-butyl-6-fluoro-4-oxo-l, 4-dihydro-l, 8-naphthyridine-3- carboxylate
  • This example was prepared by substituting 3- (tert- butoxycarbonylamino) pyrrolidine for (3R) -3- (tert- butoxycarbonylamino) pyrrolidine in EXAMPLE 15B.
  • EXAMPLE 24 7- ( (3aR, 6aS) -hexahydropyrrolo (3, 4-c)pyrrol-2 (IH) -yl) -6- fluoro-5-methyl-4-oxo-l, 4-dihydro-l, 8-naphthyridine-3- carboxylic acid
  • This example was prepared by substituting (3aR,6aS)- octahydropyrrolo (3, 4-c) pyrrole for tert-butyl methyl (octahydrocyclopenta (c) pyrrol-4-yl) carbamate in EXAMPLE 17.
  • EXAMPLE 25A 7- (3- ( (tert-butoxycarbonyl) amino) pyrrolidin-1-yl) -1- (2, 4- dimethoxybenzyl) -6-fluoro-5-methyl-4-oxo-l, 4-dihydro-l, 8- naphthyridine-3-carboxamide
  • EXAMPLE 25B 7- (3-aminopyrrolidin-l-yl) -1- (2, 4-dimethoxybenzyl) -6-fluoro- 5-methyl-4-oxo-l, 4-dihydro-l, 8-naphthyridine-3-carboxamide This example was prepared by substituting EXAMPLE 2B for EXAMPLE IF in EXAMPLE IG, conducting the reaction at reflux for 18 hours, and purifying the product by reverse phase HPLC.
  • EXAMPLE 28A ethyl 7- (3- ( (tert-butoxycarbonyl) amino) pyrrolidin-1-yl) -1- (2, 4-dimethoxybenzyl) -4-oxo-5- (trifluoromethyl) -1, 4-dihydro- 1, 8-naphthyridine-3-carboxylate
  • This example was prepared by substituting EXAMPLE 8D and 3- (tert-butoxycarbonylamino) pyrrolidine for EXAMPLE 65D and azetidine hydrochloride, respectively, in EXAMPLE 18A.
  • EXAMPLE 28B 7- (3-aminopyrrolidin-l-yl) -4-oxo-5- (trifluoromethyl) -1, 4- dihydro-1, 8-naphthyridine-3-carboxylic acid, trifluoroacetic acid salt This example was prepared by substituting EXAMPLE 28A for EXAMPLE 65D in EXAMPLE 65E.
  • EXAMPLE 29 7- (3-aminopyrrolidin-l-yl) -4-oxo-5- (trifluoromethyl) -1, 4- dihydro-1, 8-naphthyridine-3-carboxylic acid, trifluoroacetic acid salt
  • EXAMPLE 29A ethyl 1- (2-cyanoethyl) -6-fluoro-7- (3-hydroxyazetidin-l-yl ) - 4-oxo-l, 4-dihydro-l, 8-naphthyridine-3-carboxylate This example was prepared by substituting 3-azetidinol hydrochloride for azetidine hydrochloride in EXAMPLE 7D.
  • EXAMPLE 29B 6-fluoro-7- (3-hydroxyazetidin-l-yl) -4-oxo-l, 4-dihydro-l, 8- naphthyridine-3-carboxylic acid This example was prepared by substituting EXAMPLE 29A for EXAMPLE 7D in EXAMPLE 7E.
  • EXAMPLE 30A ethyl 1- (2, -dimethoxybenzyl) -6-fluoro-7- (2-furyl) -4-oxo- 1, 4-dihydro-l, 8-naphthyridine-3-carboxylate
  • EXAMPLE 3OB 1- (2, 4-dimethoxybenzyl) -6-fluoro-7- (2-furyl) -4-oxo-l, 4- dihydro-1, 8-naphthyridine-3-carboxylic acid
  • a solution of EXAMPLE 30A (166 mg) in THF (8 mL) was treated with lithium hydroxide monohydrate (155 mg) in water (7.4 mL) , stirred at ambient temperature for 3 hours, diluted with 10% ammonium chloride (20 mL) , adjusted to pH 3 with IM HCl, and extracted with dichloromethane. The extract was dried (Na 2 S0 4 ), filtered, and concentrated.
  • EXAMPLE 30C 6-fluoro-7- (2-furyl) -4-oxo-l, 4-dihydro-l, 8-naphthyridine-3- carboxylic acid
  • a solution of EXAMPLE 30B (130 mg) in trifluoroacetic acid (8 mL) was heated at 50 °C for 2 hours then cooled and concentrated. The concentrate was diluted with diethyl ether, stirred at ambient temperature for 4 hours, and filtered to provide the desired product.
  • EXAMPLE 32C 4-oxo-7-pyrrolidin-l-yl-5- (trifluoromethyl) -1, 4-dihydro-l, 8- naphthyridine-3-carboxylic acid This example was prepared by substituting EXAMPLE 32B for EXAMPLE 18B in EXAMPLE 18C.
  • NMR 300 MHz, DMSO-d 6 ) ⁇ 15.57 (s, IH), 13.10 (m, IH) , 8.46 (m, IH) , 7.07 (s, IH) , 3.67-3.58 (m, 4H) , 2.06-1.94 (m, 4H) .
  • EXAMPLE 34B 5-methyl-4-oxo-7- (3-pyridin-3-ylpyrrolidin-l-yl) -1, 4- dihydro-1, 8-naphthyridine-3-carboxylic acid, trifluoroacetic acid salt
  • EXAMPLE 34A was prepared by substituting EXAMPLE 34A for EXAMPLE 65D in EXAMPLE 65E.
  • NMR 300 MHz, DMSO-d 6 ) ⁇ 12.79 (s, IH) , 8.76 (s, IH) , 8.66 (m, IH) , 8.39 (m, IH) ,
  • EXAMPLE 36A ethyl 7- (3- ( (tert-butoxycarbonyl) amino) pyrrolidin-1-yl) -1- (2, 4-dimethoxybenzyl) -6-fluoro-4-oxo-l, 4-dihydro-l, 8- naphthyridine-3-carboxylate
  • EXAMPLE 7F was prepared by substituting EXAMPLE 15F for EXAMPLE 15A and 3- (tert-butoxycarbonylamino) pyrrolidine for (3R) -3- (tert- butoxycarbonylamino) pyrrolidine in EXAMPLE 15B.
  • EXAMPLE 36B ethyl 7- (3-aminopyrrolidin-l-yl) -6-fluoro-4-oxo-l, 4-dihydro- 1, 8-naphthyridine-3-carboxylate, trifluoroacetic acid salt
  • a solution of EXAMPLE 36A (115 mg) in trifluoroacetic acid (10 mL) was refluxed for 18 hours and concentrated; and the concentrate was purified by reverse phase HPLC.
  • EXAMPLE 37 7- ( (3- (4- (3-aminopropyl) piperazin-1-yl) propyl) amino) -6- fluoro-5-methyl-4-oxo-l, 4-dihydro-l, 8-naphthyridine-3- carboxylic acid
  • the filtrate was concentrated, dissolved in 50% DMSO/methanol (1.5 mL) , and purified by reverse phase HPLC.
  • the product was suspended in iso-propanol (1 mL) , treated with IM LiOH (1.2 mL) , heated at 80 °C for 18 hours in a sealed vial then cooled, and concentrated.
  • the concentrate was acidified to pH 4-6 with 1-2 mL of 10% citric acid and filtered.
  • the filtrant was treated with trifluoroacetic acid (1.5 mL) , heated at 70 °C for 18 hours then cooled and concentrated.
  • the concentrate was triturated with diethyl ether and filtered.
  • EXAMPLE 38 7- ( (3-aminopropyl) amino) -6-fluoro-5-methyl-4-oxo-l, 4- dihydro-1, 8-naphthyridine-3-carboxylic acid This example was prepared by substituting propane-1,3- diamine for 3-4- (3-aminopropyl) piperazin-1-yl) propylamine in EXAMPLE 37.
  • EXAMPLE 39A ethyl 1- (2, -dimethoxybenzyl) -6-fluoro-7- (3-fluorophenyl) -4- oxo-1, 4-dihydro-l, 8-naphthyridine-3-carboxylate
  • a solution of EXAMPLE 7F (210 mg) , potassium acetate (176 mg) , 3-fluorobenzeneboronic acid (84 mg) , and (1,1'- bis (diphenylphosphino) ferrocene) dichloropalladium (II) (12 mg) in DMF (6 mL) was heated at 90 °C for 3 hours then cooled, diluted with dichloromethane, washed with water, and dried (Na 2 S0 4 ) f filtered, and concentrated; and the concentrate was flash chromatographed on silica gel with 0-2% methanol/dichloromethane.
  • This example was prepared by substituting EXAMPLE 39A for EXAMPLE 30A in EXAMPLE 30B and conducting the reaction for 4 hours .
  • EXAMPLE 40A 7- (3- ( (tert-butoxycarbonyl) amino) pyrrolidin-1-yl) -1- (2,4- dimethoxybenzyl) -6-fluoro-4-oxo-l, -dihydro-l, 8- naphthyridine-3-carboxamide
  • a suspension of ammonium chloride (19 mg) in toluene (5 mL) was treated with 2M trimethylaluminum in toluene (350 ⁇ L) , stirred for 30 minutes, treated with EXAMPLE 36A (200 mg) heated at 65 °C for 18 hours, diluted with dichloromethane (40 mL) , washed with 10% citric acid, water, and brine, and dried (MgS0 4 ), filtered, and concentrated; and the concentrate was crystallized from dichloromethane/diethyl ether.
  • EXAMPLE 0B 7- (3-aminopyrrolidin-l-yl) -6-fluoro-4-oxo-l, 4-dihydro-l, 8- naphthyridine-3-carboxamide, trifluoroacetic acid salt This example was prepared by substituting EXAMPLE 40A for EXAMPLE 36A in EXAMPLE 36B.
  • EXAMPLE 43 7- ( (2- (dimethylamino) ethyl) (ethyl) amino) -6-fluoro-5-methyl- 4-oxo-l, 4-dihydro-l, 8-naphthyridine-3-carboxylic acid
  • This example was prepared by substituting N-ethyl- N ' ,N ' -dimethylethane-1, 2-diamine for tert-butyl methyl (octahydrocyclopenta (c) pyrrol-4-yl) carbamate in EXAMPLE 17.
  • EXAMPLE 45 6-fluoro-4-oxo-7- (3-pyridin-2-ylpyrrolidin-l-yl) -1, 4- dihydro-1, 8-naphthyridine-3-carboxylic acid
  • This example was prepared by substituting 2-pyrrolidin- 3-ylpyridine for (3S) -3- (tert- butoxycarbonylamino) pyrrolidine in EXAMPLE 9 and omitting HCl/dioxane.
  • EXAMPLE 6A ethyl 1- (2, 4-dimethoxybenzyl) -6-fluoro-5-methyl-4-oxo-7- pyrrolidin-l-yl-1, 4-dihydro-l, 8-naphthyridine-3-carboxylate This example was prepared by substituting pyrrolidine for (3R) -3- (tert-butoxycarbonylamino) pyrrolidine in EXAMPLE
  • Example 46A 6-fluoro-5-methyl-4-oxo-7-pyrrolidin-l-yl-l, 4-dihydro-l, 8- naphthyridine-3-carboxylic acid, sodium salt
  • a solution of Example 46A (260 mg) in trifluoroacetic acid (30 mL) was refluxed for 3 hours and concentrated.
  • the concentrate was azeotroped with toluene, suspended in water (200 mL) and IM NaOH (0.48 mL) , sonicated for 3 hours (in an unsuccessful attempt to make the sodium salt) , and filtered through filter paper and a 0.2 ⁇ syringe filter.
  • EXAMPLE 47B 7- ( (2- (dimethylamino) ethyl) (methyl) amino) -5-methyl-4-oxo- 1, 4-dihydro-l, 8-naphthyridine-3-carboxylic acid, trifluoroacetic acid salt This example was prepared by substituting EXAMPLE 47A for EXAMPLE 65D in EXAMPLE 65E.
  • EXAMPLE 51A ethyl 7-chloro-l- (2, 4-dimethoxybenzyl) -6-fluoro-4-oxo-l, 4- dihydro-1, 8-naphthyridine-3-carboxylate This example was prepared by substituting 2,4- dimethoxybenzylamine for 3-aminopropionitrile in EXAMPLE 7C.
  • EXAMPLE 51B ethyl 1- (2, 4-dimethoxybenzyl) -6-fluoro-4-oxo-7-pyrrolidin-l- yl-1, 4-dihydro-l, 8-naphthyridine-3-carboxylate
  • the concentrate was dissolved in dichloromethane, washed with water, 10% citric acid, water, and brine, and dried (MgS0 4 ) , filtered, and concentrated; and the concentrate was recrystallized from dichloromethane/diethyl ether/hexane .
  • EXAMPLE 51C (2, 4-dimethoxybenzyl) -6-fluoro-4-oxo-7-pyrrolidin-l-yl- 1, 4-dihydro-l, 8-naphthyridine-3-carboxylic acid
  • a solution of Example 51B (17.9 g) in THF (750 mL) and methanol (70 mL) was treated with IM LiOH (196 mL) , stirred for 1.5 hours, and filtered.
  • the filtrant was dissolved in 2:1 methanol/water (1.5 L) , and this solution was treated with IM HCl and water (500 mL total) and filtered.
  • EXAMPLE 55 7- ( (4-aminobutyl) amino) -6-fluoro-5-methyl-4-oxo-l, 4-dihydro- 1, 8-naphthyridine-3-carboxylic acid This example was prepared by substituting butane-1,4- diamine for 3- (4- (3-aminopropyl) piperazin-1-yl) propylamine in EXAMPLE 37.
  • EXAMPLE 56A ethyl 1- (2, -dimethoxybenzyl) -6-fluoro-4-oxo-7-thien-2-yl- 1, 4-dihydro-l, 8-naphthyridine-3-carboxylate
  • This example was prepared by substituting 2- (tributylstannyl) thiophene for 2- (tributylstannyl) furan in EXAMPLE 30A and conducting the reaction for 23 hours.
  • EXAMPLE 56C 6-fluoro-4-oxo-7-thien-2-yl-l, 4-dihydro-l, 8-naphthyridine-3- carboxylic acid This example was prepared by substituting EXAMPLE 56B for EXAMPLE 30B in EXAMPLE 30C and conducting the reaction for 18 hours.
  • NMR 300 MHz, DMS0-d 6 ) ⁇ 14.05 (br s, IH) , 10.00 (s, IH), 8.52 (m, IH) , 8.08 (m, IH) , 8.03(m, IH) , 7.32 (m, IH) , 6.52 (s, IH) .
  • EXAMPLE 58A ethyl l-tert-butyl-6-fluoro-7- ( (3R) -3-hydroxypyrrolidin-l- yl) -4-oxo-l, -dihydro-l, 8-naphthyridine-3-carboxylate
  • This example was prepared by substituting (3R)-3- pyrrolidinol hydrochloride for (3R) -3- (tert- butoxycarbonylamino) pyrrolidine in EXAMPLE 15B.
  • Example 5A 7-azetidin-l-yl-l- (2, 4-dimethoxybenzyl) -6-fluoro-5-methyl-4- oxo-1, 4-dihydro-l, 8-naphthyridine-3-carboxylic acid
  • THF 30 mL
  • dichloromethane 10 mL
  • IM LiOH 15 mL
  • EXAMPLE 63 6-fluoro-7- (4- (methylamino) hexahydrocyclopenta (c) pyrrol— 2 (IH) -yl) -4-oxo-l, 4-dihydro-l, 8-naphthyridine-3-carboxyllc acid
  • This example was prepared by substituting tert-butyl methyl (octahydrocyclopenta (c) pyrrol-4-yl) carbamate for (3S)- 3- (tert-butoxycarbonylamino) pyrrolidine in EXAMPLE 9.
  • the concentrate was treated with IM HCl (100 mL) and extracted with ethyl acetate.
  • the extract was washed with IM HCl, saturated sodium bicarbonate and brine, dried (MgS0 4 ) , filtered, and concentrated; and the concantrate was flash chromatographed on silica gel with 25% ethyl acetate/hexanes .
  • EXAMPLE 65C ethyl (2E/Z) -2- ( (2, 6-dichloro-4-methylpyridin-3- yl) carbonyl) -3- (ethyloxy) prop-2-enoate
  • a solution of Example 65B (4.1 g) and triethylorthoformate (2.72 mL) in acetic anhydride (30 mL) were heated at 130 °C for 1.5 hours then cooled and concentrated; and the concentrate was azeotroped with toluene.
  • EXAMPLE 65D ethyl 1- ( (2, 4-bis (methyloxy) phenyl) methyl) -7-chloro-5- methyl-4-oxo-l, 4-dihydro-l, 8-naphthyridine-3-carboxylate
  • a solution of Example 65C (4.93 g) and 2,4- dimethoxybenzylamine (2.34 mL) in dichloromethane (60 mL) was stirred at ambient temperature for 30 minutes and concentrated.
  • the concentrate was dissolved in THF (60 mL) , cooled to 0 °C, treated with 60% oily sodium hydride (0.623 g) over 5 minutes, stirred at ambient temperature for 1 hour, treated with water, poured into 0. IM HCl (500 mL) , and filtered; and the filtrant was recrystallized from diethyl ether to provide the desired product.
  • Example 65D (0.200 g) in 1.4-dioxane (5 mL) was treated with lithium hydroxide monohydrate (0.100 g) , stirred for 16 hours, and concentrated. The concentrate was dissolved in trifluoroacetic acid (8 mL) , heated at 60 °C for 12 hours, and concentrated; and this concentrate was purified by reverse phase HPLC to afford the desired product.
  • NMR 300 MHz, DMS0-d 6 ) ⁇ 14.95 (s, IH) , 13.79 (s, IH), 8.72 (s, IH), 7.57 (s, IH) , 2.89 (s, 3H) .
  • EXAMPLE 66A ethyl 7- (4- ( (tert-butoxycarbonyl) amino) piperidin-1-yl) -1- (2- cyanoethyl) -6-fluoro-4-oxo-l, 4-dihydro-l, 8-naphthyridine-3- carboxylate
  • a solution of EXAMPLE 7C (0.5 g) and 1, 1-dimethylethyl piperidin-4-ylcarbamate in dichloromethane (100 mL) was stirred for 2 hours, diluted with dichloromethane (100 mL) , washed with water, 10% citric acid, and brine, and dried (MgS0 4 ), filtered, and concentrated.
  • EXAMPLE 66C 7- (4-aminopiperidin-l-yl) -6-fluoro-4-oxo-l, -dihydro-l, 8- naphthyridine-3-carboxylic acid
  • a solution of Example 66B was treated with trifluoroacetic acid (20 mL) , stirred for 10 minutes and concentrated; and the concentrate was azeotroped with toluene and dried under vacuum.
  • EXAMPLE 67A ethyl 1- (2, 4-dimethoxybenzyl) -6-fluoro-4-oxo-7-phenyl-l, 4- dihydro-1, 8-naphthyridine-3-carboxylate This example was prepared by substituting phenylboronic acid for 3-fluorophenylboronic acid in EXAMPLE 39A and conducting the reaction for 18 hours.
  • EXAMPLE 67B 1- (2, 4-dimethoxybenzyl) -6-fluoro-4-oxo-7-phenyl-l, 4-dihydro- 1, 8-naphthyridine-3-carboxylic acid This example was prepared by substituting EXAMPLE 67A for EXAMPLE 30A in EXAMPLE 30B and conducting the reaction for 2 hours .
  • EXAMPLE 67C 6-fluoro-4-oxo-7-phenyl-l, 4-dihydro-l, 8-naphthyridine-3- carboxylic acid This example was prepared by substituting EXAMPLE 67B for EXAMPLE 30B in EXAMPLE 30C.
  • NMR 300 MHz, DMS0-d 6 ) ⁇ 14.50 (brs, IH) , 8.85 (s, IH) , 8.57 (m, IH) , 8.04 (m, 2H) , 7.63 (m, 3H) , 6.03 (s, IH) .
  • EXAMPLE 69A ethyl l-tert-butyl-7- (dimethylamino) -6-fluoro-4-oxo-l, 4- dihydro-1, 8-naphthyridine-3-carboxylate
  • This example was prepared using EXAMPLE 15A and substituting 2M dimethylamine in methanol for (3R) -3- (tert- butoxycarbonylamino) pyrrolidine in EXAMPLE 15B.
  • EXAMPLE 69B 7- (dimethylamino) -6-fluoro-4-oxo-l, 4-dihydro-l, 8- naphthyridine-3-carboxylic acid
  • a solution of EXAMPLE 69A (155 mg) in 6M HCl (10 mL) was heated at 110°C for 18 hours then cooled and filtered.
  • EXAMPLE 70 7- ( (1R, 5R) -3- ( (benzyloxy) carbonyl) -3, 6- diazabicyclo (3.2.0) hept-6-yl) -6-fluoro-4-oxo-l, -dihydro- 1, 8-naphthyridine-3-carboxylic acid
  • EXAMPLE 73A ethyl 3- (2, 6-dichloropyridin-3-yl) -3-oxopropanoate This example was prepared by substituting 2,6- dichloronicotinic acid for 2, 6-dichloro-4-methyl-nicotinic acid in EXAMPLE 65B.
  • Example 73C (0.19 g) , 3- (tert- butoxycarbonylamino) pyrrolidine (0.344 g) , and potassium carbonate (0.255 g) in dichloromethane (6.2 mL) was refluxed for 4 hours then cooled, stirred for 18 hours, diluted with dichloromethane (50 mL) , washed with 0. IM HCl, saturated sodium bicarbonate, and brine, and dried (MgS0 4 ), filtered, and concentrated; and the concentrate was recrystallized from diethyl ether.
  • Example 73C 210 mg
  • potassium carbonate 150 mg
  • pyrrolidine 113 ⁇ l
  • dichloromethane was stirred for 3 days, treated with potassium carbonate (150 mg) and pyrrolidine (113 ⁇ L) , stirred for 3 more days, and concentrated; and the concentrate was purified by flash column chromatography on silica gel with a methanol/dichloromethane gradient .
  • EXAMPLE 74B 4-oxo-7-pyrrolidin-l-yl-l, 4-dihydro-l, 8-naphthyridine-3- carboxylic acid
  • a solution of Example 74A (63.2 mg) in ethanol (2.5 mL) and 6M HCl (2.5 mL) was heated in a sealed tube at 130 °C for 18 hours then cooled, diluted with diethyl ether, and filtered.
  • NMR 300 MHz, DMS0-d 6 ) ⁇ 8.43 (s, IH) , 8.22 (m, IH) , 6.80 (m, IH) , 3.55 (m, 4H) , 2.00 (m, 4H) .
  • EXAMPLE 75A ethyl 7- ( (3S) -3- ( (tert-butoxycarbonyl) amino) pyrrolidin-1- yl) -1- (2, 4-dimethoxybenzyl) -6-fluoro-4-oxo-l, 4-dihydro-l, 8- naphthyridine-3-carboxylate
  • a solution of Example 7F (0.5 g) , (3S)- (tert- butoxycarbonylamino) pyrrolidine (0.44 g) , and potassium carbonate (0.25 g) in dichloromethane was stirred for 3 days at ambient temperature, loaded onto a flash silica gel column, and eluted with a 0-6% methanol/dichloromethane gradient .
  • EXAMPLE 75B 7- ( (3S) -3- ( (tert-butoxycarbonyl) amino) pyrrolidin-1-yl) -1- (2, 4-dimethoxybenzyl) -6-fluoro-4-oxo-l, -dihydro-l, 8- naphthyridine-3-carboxylic acid
  • a solution of Example 75A (678 mg) and IM LiOH (4.75 mL) in THF (20 mL) was stirred for 18 hours, diluted with 10% citric acid, and extracted with dichloromethane. The extract was dried (Na 2 S0 4 ), filtered, and concentrated.
  • EXAMPLE 75C 7- ( (3S) -3- ( (tert-butoxycarbonyl) amino) pyrrolidin-1-yl) -1- (2, 4-dimethoxybenzyl) -6-fluoro-4-oxo-l, -dihydro-l, 8- naphthyridine-3-carboxamide
  • a suspension of EXAMPLE 75B (350 mg) and triethylamine (0.098 L) in dichloromethane (4 mL) and THF (3 mL) at 0 °C was treated with isopropenyl chloroformate (0.077 mL) , stirred for 30 minutes, treated with concentrated ammonium hydroxide (0.100 mL) , stirred for 18 hours at ambient temperature, loaded onto a flash silica gel column, and eluted with a methanol/dichloromethane gradient.
  • EXAMPLE 75D 7- ( (3S) -3-aminopyrrolidin-l-yl) -6-fluoro-4-oxo-l, 4-dihydro- 1, 8-naphthyridine-3-carboxamide This example was prepared by substituting EXAMPLE 75C for EXAMPLE IF in EXAMPLE IG, conducting the reaction at reflux for 18 hours, and crystallizing the concentrate from methanol/diethyl ether.
  • EXAMPLE 77B 7- (3-aminopyrrolidin-l-yl) -5-ethyl-6-fluoro-4-oxo-l, 4- dihydro-1 , 8-naphthyridine-3-carboxamide
  • the title compound was prepared by substituting EXAMPLE 77A for EXAMPLE IF in EXAMPLE IG, conducting the reaction at reflux for 18 hours, and purifying the product by reverse phase HPLC.
  • EXAMPLE 78A 7- (3- ( (tert-butoxycarbonyl) (methyl) amino) pyrrolidin-1-yl) -1- (2, 4-dimethoxybenzyl) -6-fluoro-4-oxo-l, 4-dihydro-l, 8- naphthyridine-3-carboxamide
  • a suspension of EXAMPLE 22B (410 mg) and triethylamine (0.113 mL) in dichloromethane (4 mL) and THF (3.5 mL) at 0 °C was treated with isopropenyl chloroformate (0.088 mL) , stirred for 30 minutes, treated with concentrated ammonium hydroxide (0.114 mL) , stirred for 18 hours at ambient temperature, loaded onto a flash silica gel column, and eluted with a methanol/dichloromethane gradient.
  • EXAMPLE 78B 6-fluoro-7- (3- (methylamino) pyrrolidin-1-yl) -4-oxo-l, 4- dihydro-1, 8-naphthyridine-3-carboxamide This example was prepared by substituting EXAMPLE 78A for EXAMPLE IF in EXAMPLE IG, conducting the reaction at reflux for 18 hours, and purifying the concentrate by reverse phase HPLC.
  • EXAMPLE 79A ethyl 6-bromo-l-tert-butyl-4-oxo-7-pyrrolidin-l-yl-l, 4- dihydro-1 , 8-naphthyridine-3-carboxylate
  • a solution of Example 74A (343.42 mg) and 1,3-dibromo- 5, 5-dimethylhydantoin (171.5 mg) in dichloromethane (15 mL ) was stirred for 15 minutes, treated with 10% sodium bisulfite, and extracted with dichloromethane (50 mL) . The extract was washed with water and brine, dried (MgS0 4 ), filtered, and concentrated; and the concentrate was crystallized from dichloromethane/diethyl ether.
  • EXAMPLE 80A ethyl l-tert-butyl-6-chloro-4-oxo-7-pyrrolidin-l-yl-l, 4- dihydro-1, 8-na ⁇ hthyridine-3-carboxylate
  • a solution of Example 74A (448 mg) and 1, 3-dichloro- 5, 5-dimethylhydantoin (282 mg) in dichloromethane (15 mL) was stirred for 8 hours, diluted with 10% sodium bisulfite (30 mL) , and extracted with dichloromethane. The extract was washed with water and brine (30 mL) , and dried (MgS0 4 ), filtered, and concentrated.
  • EXAMPLE 80B 6-chloro-4-oxo-7-pyrrolidin-l-yl-l, 4-dihydro-l, 8- naphthyridine-3-carboxylic acid
  • a solution of EXAMPLE 80A (160 mg) in 1:1 9M HCl/1,4- dioxane (15 mL) was heated in a sealed tube at 115 °C for 15 minutes and at 95 °C for 24 hours then cooled, diluted with water (20 mL) , and filtered.
  • EXAMPLE 8 IB ethyl 7-chloro-l- (2-cyanoethyl) -4-oxo-l, 4-dihydro-l, 8- naphthyridine-3-carboxylate A solution of EXAMPLE 81A (20 g) and 3- aminopropionitrile (4.9 mL) in 1:1 ethanol/diethyl ether (400 mL) was stirred for 15 minutes, diluted with hexanes (1 L) , and filtered.
  • the filtrant was dissolved in acetonitrile (400 mL) , and the resulting solution was treated with potassium carbonate (17.4 g) , heated at 75 °C for 18 hours then cooled, diluted with water (1.5 L) , stirred for 1 hour,' and filtered.
  • EXAMPLE 81C ethyl 7-azetidin-l-yl-l- (2-cyanoethyl) -4-oxo-l, 4-dihydro- 1, 8-naphthyridine-3-carboxylate
  • a solution of EXAMPLE 81B (16 g) , azetidine hydrochloride (12.2 g) and triethylamine (21.9 mL) in acetonitrile (500 mL) was stirred for 2 hours, treated with triethylamine (900 mg) , stirred for one hour, diluted with water (1.5 L) , stirred for 1 hour, and filtered.
  • EXAMPLE 81C (0.50 g) and 1, 3-dichloro- 5, 5-dimethylhydantoin (0.30 g) in chloroform (100 mL) was refluxed for 2 hours then cooled, diluted with chloroform, washed with 10% sodium bisulfate and brine, and dried
  • EXAMPLE 8IE 7-azetidin-l-yl-6-chloro-4-oxo-l, 4-dihydro-l, 8- naphthyridine-3-carboxylic acid A suspension of EXAMPLE 81D (0.50 g) in methanol (100 mL) at reflux was treated with a IM LiOH (50 mL) , stirred for 3 hours then cooled, treated with 10% citric acid, and filtered.
  • NMR 300 MHz, DMSO-d 6 ) ⁇ 8.67 (s, IH) , 8.13 (s, IH), 4.28 (m, 4H) , 2.28 ( , 2H) .
  • EXAMPLE 83A ethyl 7-azetidin-l-yl-6-cyano-l- (2-cyanoethyl) -4-oxo-l, 4- dihydro-1, 8-naphthyridine-3-carboxylate
  • a solution of EXAMPLE 82A (0.50 g) , dicyanozinc (0.29 g) , 2- (di-tert-butylphosphino) biphenyl (0.15 g) , and tris (dibenzylideneacetone) dipalladium(O) (0.11 g) in acetonitrile (20 mL) was refluxed for 1 hour then cooled and filtered; and the filtrate was diluted with water and filtered.
  • EXAMPLE 84A ethyl 7- ( (IS, 4S) -5- (tert-butoxycarbonyl) -2, 5- diazabicyclo(2.2.1)he ⁇ t-2-yl) -1- (2, -dimethoxybenzyl) -6- fluoro-4-oxo-l, -dihydro-l, 8-naphthyridine-3-carboxylate
  • EXAMPLE 7F 500 mg
  • diisopropylethylamine (0.622 mL) in acetonitrile (11.9 mL) was heated at 50 °C for 18 hours then cooled, diluted with dichloromethane, washed with saturated ammonium chloride and brine, and dried (MgS0 4 ), filtered,
  • a solution of EXAMPLE 84B in trifluoroacetic acid (10 mL) was heated at 50 °C for 18 hours then cooled and concentrated; and the concentrate was purified by reverse phase HPLC.
  • EXAMPLE 85A A suspension of methyl 2-oxocyclopentanecarboxylate (83.8 g) in methanol (220 mL) at 25°C was treated with 2-cyanoacetamide (49.57 g) and potassium hydroxide (35 g) in methanol (75 mL) , stirred for 2 hours, heated at reflux for 18 hours and cooled, treated with water (1.5L), acidified with concentrated HCl to a pH of less than 1, and filtered.
  • EXAMPLE 85B A suspension of EXAMPLE 85A (30 g) in phosphorous oxychloride (130.5 g) at 170°C was stirred in sealed tube for 5 hours, poured over ice, and filtered; and the filtrant was flash chromatographed on silica gel with dichloromethane .
  • EXAMPLE 85C A suspension of EXAMPLE 85B (27.7 g) in concentrated sulfuric acid (80 mL) was heated at 110°C for 4 hours and cooled, poured over ice, and filtered.
  • EXAMPLE 85D A suspension of EXAMPLE 85C (29.2 g) in acetic anhydride (200 mL) at 0°C was treated with acetic acid (100 mL) and sodium nitrite (69 g) , stirred for 18 hours at 25°C, treated with water (1.3 L) , acidified with concentrated HCl, and filtered.
  • EXAMPLE 85E A suspension of EXAMPLE 85D (15.7 g) in dichloromethane (120 mL) at 25°C was treated with oxalyl chloride (9 mL) and N,N-dimethylformamide (2 drops), stirred for 3.5 hours, and concentrated.
  • EXAMPLE 85F A suspension of potassium onoethyl malonate (27.4 g) in acetonitrile (200 mL) at 0°C was treated with MgCl 2 (21.5 g) and triethylamine (22.5 mL) , stirred for 3 hours at 25°C. The reaction mixture was treated with EXAMPLE 85E (16.9 g) in tetrahydrofuran (60 L) , stirred for 18 hours (250 L) , acidified with concentrated HCl, concentrated to half volume, and extracted with ethyl acetate (400 mL) . The extract was washed with IM HCl, water, aqueous sodium bicarbonate, water, and brine and dried (MgS0 4 ), filtered through silica gel with ethyl acetate, and concentrated.
  • EXAMPLE 85G A solution of EXAMPLE 85F (11 g) in acetic anhydride (25 mL) at 25°C was treated with triethylorthoformate (7 mL) , heated for 2 hours at 70°C and 2 hours at 100°C, and concentrated with a toluene azeotrope.
  • EXAMPLE 85H A solution of EXAMPLE 85G (13.0 g) in dichloromethane (75 mL) at 25°C was treated with tert-butylamine (4.01 mL) , stirred for 15 minutes, and concentrated.
  • EXAMPLE 851 A solution of EXAMPLE 85H (14 g) in acetonitrile was treated with potassium carbonate (11 g) , heated for 48 hours at reflux and cooled, treated with ethyl acetate, washed with 10% citric acid and brine, and dried (MgS0 ), filtered, and concentrated; the concentrate was flash chromatographed on silica gel with dichloromethane and ethyl acetate.
  • EXAMPLE 85J A suspension of EXAMPLE 851 (370 mg) in acetonitrile (30 mL) was treated with potassium carbonate (1.2 g) and tert-butyl pyrrolidin-3-ylcarbamate (987 mg) , heated for 18 hours at reflux and cooled, treated with water, and filtered.
  • EXAMPLE 85K A solution of the EXAMPLE 85J (498.6 mg) in methanol (50 mL) at 25°C was treated with IM LiOH (7 mL) , stirred for 18 hours, concentrated to one quarter volume, treated with 10% citric acid, and filtered.
  • EXAMPLE 85 A solution of EXAMPLE 85K (374 mg) in trifluoroacetic acid (5 mL) at 25°C was treated with concentrated sulfuric acid (0.5 mL) , stirred for 3 hours, treated with ether, and filtered. NMR (300 MHz, DMSO-d 6 ) ⁇ ppm 8.41 (s, IH) , 3.94 (m, 5H), 3.38 (t, 2H) , 3.16 (t, 2H) , 2.07 (m, 3H) , 2.28 ( , IH) .
  • EXAMPLE 86A A solution of EXAMPLE 65C (9.5 g) in dichloromethane
  • EXAMPLE 86B A suspension of EXAMPLE 86A (456 mg) in acetonitrile (12 mL) at 25°C was treated with tert-butyl methyl (pyrrolidin-3-yl) carbamate (1.14 g) , stirred for 18 hours, treated with 10% citric acid, and extracted with dichloromethane; and the extract was washed with 10% citric acid and brine and dried (MgS0 ), filtered, and concentrated.
  • EXAMPLE 86C A solution of EXAMPLE 86B (250 mg) in chloroform (10 L) at 25°C was treated with 1, 3-dichloro-5, 5- dimethylimidazolidine-2, 4-dione (107 mg) , stirred for 30 minutes, treated with chloroform, washed with 10% sodium bisulfite, water, and brine, and dried (MgS0 4 ), filtered, and concentrated.
  • EXAMPLE 86 A solution of EXAMPLE 86D (140 mg) in trifluoroacetic acid (5 mL) at 25°C was stirred for 18 minutes, treated with diethyl ether, and filtered. NMR (300 MHz, DMSO-d 6 ) ⁇ ppm 15.63 (s, IH) , 13.11 (d, IH) , 8.80 (bs, 2H) , 8.52 (d, IH) ,
  • EXAMPLE 87A A suspension of EXAMPLE 86A (1.2 g) in acetonitrile (20 mL) at 25°C was treated with tert-butyl pyrrolidin-3- ylcarbamate (2.1 g) , stirred for 18 hours at 45°C and cooled, treated with 10% citric acid, and extracted with dichloromethane. The extract was washed with 10% citric acid, water and brine, dried (MgS0 4 ) , filtered, and concentrated.
  • EXAMPLE 87B A solution of EXAMPLE 87A (358 mg) in acetonitrile (10 mL) at 25°C was treated with 1, 3-dichloro-5, 5- dimethylimidazolidine-2, -dione (158 mg) , stirred for 90 minutes, treated with diethyl ether, and filtered; and the filtrant was rinsed with diethyl ether, 10% sodium bisulfite, and water.
  • EXAMPLE 87C A solution of EXAMPLE 87B (265 mg) in ethanol (15 mL) at 25°C was treated with IM LiOH (3 mL) , heated for 6 hours at 80°C and cooled, treated with water (35 mL) and 10% citric acid (50 mL) , and filtered.
  • EXAMPLE 87 A solution of EXAMPLE 87C (139 mg) in trifluoroacetic acid (5 mL) at 25°C was stirred for 10 minutes and concentrated with a toluene azeotrope; and the concentrate was triturated with diethyl ether and filtered.
  • NMR 300 MHz, DMSO-d 6 ) ⁇ ppm 15.64 (s, IH) , 13.09 (d, IH) , 8.50 (d, IH), 8.14 (s, 3H), 3.97 (m, 5H) , 2.94 (s, 3H) , 2.29 (m, IH), 2.06 (d, IH) .
  • EXAMPLE 88A A suspension of EXAMPLE 851 (360 mg) in acetonitrile (30 mL) was treated with potassium carbonate (1.2 g) and azetidine hydrochloride (482 mg) , heated for 18 hours at reflux and cooled, treated with water, and extracted with dichloromethane; and the extract was washed with water and brine and dried (MgS0 4 ) , filtered, and concentrated.
  • EXAMPLE 88B A solution of EXAMPLE 88A (293 mg) in methanol (50 mL) at 25°C was treated with IM LiOH (8 mL) , stirred for 18 hours, concentrated to one quarter volume, treated with 10% citric acid, and filtered.
  • EXAMPLE 88 A solution of EXAMPLE 88B (243 mg) in trifluoroacetic acid (5 mL) at 25°C was treated with concentrated sulfuric acid (0.2 mL) , stirred for 2.5 hours, treated with diethyl ether, and filtered. NMR (500 MHz, DMS0-d 6 ) ⁇ ppm 8.34 (s, IH), 4.32 (t, 4H) , 3.35 (t, 2H) , 2.92 (t, 2H) , 2.35 (m, 2H) , 2.09 (m, 2H) .
  • EXAMPLE 89A A solution of EXAMPLE 86A (590 mg) in acetonitrile (30 mL) at 25°C was treated with tert-butyl methyl (pyrrolidin-3- yl)carbamate (1.1 g) , stirred for 5 hours at 55°C and cooled, concentrated to half volume, treated with water, and extracted with dichloromethane; and the extract was washed with water and brine and dried (MgS0 4 ) , filtered, and concentrated.
  • EXAMPLE 89B A solution of EXAMPLE 89A (185 mg) in chloroform (10 L) at 25°C was treated with 1, 3-dibromo-5, 5- dimethylimidazolidine-2, -dione (65.6 mg) , stirred for 30 minutes, treated with chloroform, washed with 10% sodium bisulfite, water, and brine, and dried (MgS0 ) , filtered, and concentrated.
  • EXAMPLE 89 A solution of EXAMPLE 89C (110 mg) in trifluoroacetic acid (5 mL) at 25°C was stirred for 16 minutes, treated with diethyl ether, and filtered. NMR (300 MHz, DMSO-d 5 ) ⁇ ppm 15.60 (s, IH) , 13.11 (s, IH) , 8.77 (s, 2H) , 8.54 (d, IH) , 3.97 (m, 5H) 3.01 (s, 3H) , 2.66 (br. s. 3H) , 2.31 (m, IH) , 2.13 (m, IH) .
  • EXAMPLE 90A A suspension of methyl 2-methyl-3-oxobutanoate (83.8 g) in methanol (220 mL) at 25°C was treated with 2- cyanoacetamide (49.57 g) and potassium hydroxide (35 g) in methanol (75 mL) , stirred for 2 hours, heated at reflux for 18 hours and cooled, treated with water (1.5 L) , acidified with concentrated HCl to a pH of less than 1, and filtered.
  • EXAMPLE 90B A solution of EXAMPLE 90A (27.17 g) in phosphorous oxychloride (71 mL) at 170°C was stirred in sealed tube for 5 hours, poured over ice, and filtered; and the filtrant was flash chromatographed on silica gel with dichloromethane.
  • Example 90C A suspension of EXAMPLE 90B (60 mL) in sulfuric acid
  • EXAMPLE 90D A suspension of EXAMPLE 90C (23 g) in acetic anhydride (150 mL) at 0°C was treated with acetic acid (75 mL) and sodium nitrite (52 g) over 1.5 hours, stirred for 18 hours at 25°C, treated with water (1.3 L) , acidified with concentrated HCl, and filtered.
  • EXAMPLE 90E A suspension of EXAMPLE 90D (18.6 g) in dichloromethane (150 mL) at 25°C was treated with oxalyl chloride (11.2 mL) and N,N-dimethylformamide (3 drops), stirred for 4 hours, and concentrated.
  • Example 90F A suspension of potassium monoethyl malonate (36 g) in acetonitrile (200 L) at 0°C was treated with MgCl 2 (28.16 g) and triethylamine (29.5 mL) , stirred for 3 hours at 25°C, treated with EXAMPLE 90E (20.1 g) in tetrahydrofuran (60 mL) , stirred for 18 hours at 25°C, treated with water (250 mL) , acidified with concentrated HCl, concentrated to half volume, and extracted with ethyl acetate; and the extract was washed with IM HCl, water, sodium bicarbonate, water, and brine, and dried (MgS0 4 ) , filtered through silica gel with ethyl acetate, and concentrated.
  • EXAMPLE 9OH A solution of EXAMPLE 90G (4.05g) in dichloromethane (75 mL) at 25°C was treated with 2, -dimethoxybenzylamine (4.01 mL) , stirred for 15 minutes, and concentrated.
  • EXAMPLE 901 A solution of EXAMPLE 90H (5.46g) in tetrahydrofuran (200 mL) at 0°C was treated with 60% suspension of sodium hydride in mineral oil (468 mg) , stirred for for 1 hour, treated with more 60% suspension of sodium hydride in mineral oil (93.5 mg) , stirred for another hour at 25°C, treated with IM HCl, and filtered.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

L'invention concerne des antibactériens de formule (I), ainsi que des sels, des promédicaments, et des sels de leurs promédicaments, des procédés de fabrication des composés et intermédiaires utilisés dans lesdits procédés, des compositions contenant ces composés, et des procédés de prévention et de traitement d'infections bactériennes au moyen de ces composés.
EP03723732A 2003-03-12 2003-03-12 Dérivés de naphthyridine comme agents antibactériens Withdrawn EP1631570A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US10/387,318 US8163769B2 (en) 2002-03-12 2003-03-12 Antibacterial compounds
PCT/US2003/007689 WO2004083207A1 (fr) 2003-03-12 2003-03-12 Derives de naphthyridine comme agents antibacteriens

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EP1631570A1 true EP1631570A1 (fr) 2006-03-08

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EP (1) EP1631570A1 (fr)
JP (1) JP2006514964A (fr)
CA (1) CA2518443A1 (fr)
MX (1) MXPA05009688A (fr)
WO (1) WO2004083207A1 (fr)

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WO2005026165A1 (fr) * 2003-09-12 2005-03-24 Warner-Lambert Company Llc Agents antibacteriens a base de quinolone
ATE486875T1 (de) * 2005-11-10 2010-11-15 Chemocentryx Inc Substituierte chinolone und verwendungsverfahren
JP5373613B2 (ja) 2006-10-16 2013-12-18 バイオノミクス リミテッド 新規な抗不安薬化合物
US10954231B2 (en) 2006-10-16 2021-03-23 Bionomics Limited Anxiolytic compounds
EP1972338A1 (fr) * 2007-03-19 2008-09-24 Technische Universität Carolo-Wilhelmina zu Braunschweig Agents anti-infectieux
FR2928150A1 (fr) * 2008-02-29 2009-09-04 Vetoquinol Sa Sa Nouveaux derives 7-substitues de 3-carboxy-oxadiazino-quinolones, leur preparation et leur application comme anti-bacteriens
US8129417B2 (en) * 2008-11-26 2012-03-06 Abbott Laboratories Substituted octahydrocyclopenta[C]pyrrol-4-amines as calcium channel blockers
CN102140098A (zh) * 2010-01-29 2011-08-03 南京医科大学 7-（2-取代-3-氨基-1-四氢吡咯[3，4-c]吡唑基）喹啉羧酸衍生物及其制备方法和在抗菌抗结核上的应用
KR101491938B1 (ko) 2010-07-14 2015-02-10 노파르티스 아게 Ｉｐ 수용체 효능제 헤테로시클릭 화합물
US9023848B2 (en) 2011-03-02 2015-05-05 Bionomics Limited Small-molecules as therapeutics
WO2012151640A1 (fr) 2011-05-12 2012-11-15 Bionomics Limited Procédés pour la préparation de naphtyridines
US8937069B2 (en) 2012-01-13 2015-01-20 Novartis Ag Substituted pyrrolo[2,3-B]pyrazine compounds and their use
GB201206384D0 (en) * 2012-04-11 2012-05-23 Redx Pharma Ltd Antibacterial drug derivatives
EP2956455B1 (fr) 2013-02-13 2017-05-17 Novartis AG Composes heterocycliques a activite agoniste sur le recepteur ip
AU2018238079B2 (en) 2017-03-24 2022-03-03 Wakunaga Pharmaceutical Co., Ltd. Novel pyridone carboxylic acid derivative or salt thereof

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JP2006514964A (ja) 2006-05-18
MXPA05009688A (es) 2005-12-05
CA2518443A1 (fr) 2004-09-30

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