Synthesis and structure-activity relationships of 2-pyridones: A novel series of potent DNA gyrase inhibitors as antibacterial agents

Article abstract of DOI:10.1021/jm960207w

Two novel series of 2-pyridones were synthesized by transposition of the nitrogen of 4-quinolones to the bridgehead position. This subtle interchange of the nitrogen atom with a carbon atom yielded two novel heterocyclic nuclei, pyrido[1,2-a]pyrimidine and quinolizine, which had not previously been evaluated as antibacterial agents and were found to be potent inhibitors of DNA gyrase. Quinolizines with a methyl group at the 9-position such as (S)-45a (ABT-719) demonstrate exceptional broad spectrum antibacterial activity. Most notably, they are active against resistant bacteria such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant strains of enterococci, and ciprofloxacin-resistant organisms. In addition, 2-pyridones also possess favorable physiochemical and pharmacokinetic properties. These 2-pyridones were synthesized from the commercially available starting materials by 10-17 linear transformations. The structure of an adduct yielded by this sequence, (S)-45a (ABT-719), was determined by X-ray crystallographic analysis.

Full text of DOI:10.1021/jm960207w

3070
J . Med. Chem. 1996, 39, 3070 3088
Syn th esis a n d Str u ctu r e Activity Rela tion sh ip s of 2-P yr id on es: A Novel Ser ies
of P oten t DNA Gyr a se In h ibitor s a s An tiba cter ia l Agen ts
Qun Li,* Daniel T. W. Chu, Akiyo Claiborne, Curt S. Cooper, Cheuk M. Lee, Kathleen Raye, Kristine B. Berst,
Pamela Donner, Weibo Wang, Lisa Hasvold, Anthony Fung, Zhenkun Ma, Michael Tufano, Robert Flamm,
Linus L. Shen, J ohn Baranowski, Angela Nilius, J eff Alder, J onathan Meulbroek, Kennan Marsh,
DeAnne Crowell, Yuhua Hui, Louis Seif, Laura M. Melcher, Rodger Henry, Steven Spanton, Ramin Faghih,
Larry L. Klein, S. Ken Tanaka, and J acob J . Plattner
Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-3500
Received March 14, 1996X
Two novel series of 2-pyridones were synthesized by transposition of the nitrogen of 4-quinolones
to the bridgehead position. This subtle interchange of the nitrogen atom with a carbon atom
yielded two novel heterocyclic nuclei, pyrido[1,2-a]pyrimidine and quinolizine, which had not
previously been evaluated as antibacterial agents and were found to be potent inhibitors of
DNA gyrase. Quinolizines with a methyl group at the 9-position such as (S)-45a (ABT-719)
demonstrate exceptional broad spectrum antibacterial activity. Most notably, they are active
against resistant bacteria such as methicillin-resistant Staphylococcus aureus, vancomycin-
resistant strains of enterococci, and ciprofloxacin-resistant organisms. In addition, 2-pyridones
also possess favorable physiochemical and pharmacokinetic properties. These 2-pyridones were
synthesized from the commercially available starting materials by 10 17 linear transforma-
tions. The structure of an adduct yielded by this sequence, (S)-45a (ABT-719), was determined
by X-ray crystallographic analysis.
In tr od u ction
Since the introduction of antibacterial fluoroquinolo-
nes in the early 1980s,1 the utility of this class of
compounds has flourished for the chemotherapeutic
intervention of bacterial infections.2 Quinolones have
the advantages of being broad spectrum are orally active
and are unique by virtue of their inhibition of DNA
gyrase.3 Despite their ubiquitous presence in the clini-
F igu r e 1. Structures of two clinically utilized 4-quinolones.
cal arena, the limited spectra of activity against strep-
tococci and anaerobes represent obstacles for the use of
these drugs in the treatment of infections. The in-
creased frequency of bacterial resistance to quinolones
as well as to many other existing antibiotics has
6
emerged as a serious problem.4
Studies have shown
that 80% of methicillin-resistant Staphylococcus aureus
(MRSA) in the United States are now resistant to
ciprofloxacin,6 and some 40% of hospital-acquired sta-
phylococci are resistant to all forms of therapy except
vancomycin.5c The alarming frequency of Streptococcus
pneumoniae resistance to penicillin threatens the use
of â-lactam agents for the treatment of pneumonococcal
infections in the future.4e The National Nosocomial
Infection Surveillance System4g revealed that the oc-
currence of vancomycin-resistant enterococci (VRE)4d in
intensive care centers in the United States increased
from 0.4% in 1989 to 13.6% in 1992. The absence of
clinically useful drugs for the treatment of VRE strains
of bacteria poses a therapeutic challenge to the medical
community. The potential spread of this type of resis-
tance to other organisms such as Staph. aureus under-
scores an urgent need for potent broad spectrum anti-
biotics that are efficacious against resistant microbes.
F igu r e 2. Structures and names of the 4-quinolone and
2-pyridone nuclei.
methodology pioneered in the carbacephem structural
motif.7 This approach consists of transposition of the
nitrogen of 4-quinolones to the bridgehead position
(Figure 2). This subtle interchange of the nitrogen with
a carbon atom yielded two novel heterocyclic nuclei that
had not previously been evaluated as antibacterial
agents.8 This manuscript outlines the full details of the
synthesis, physiochemical properties, antibacterial ac-
tivities, and pharmacokinetics of these two new series
of 2-pyridones.9
As part of a program designed to identify new DNA
gyrase inhibitors, modification of the quinolone ring
structure was undertaken by implementation of the
X Abstract published in Advance ACS Abstracts, J uly 15, 1996.
S0022-2623(96)00207-5 CCC: $12.00 © 1996 American Chemical Society

2-Pyridones as Potent DNA Gyrase Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16 3071
Sch em e 1
Attempts to extend the above sequence to the syn-
thesis of the 9-cyclopropyl analogs resulted in opening
of the adjacent cyclopropyl ring upon formation of the
dianion of 4 (R1
cyclopropyl). Scheme 2 depicts an
alternate route that was developed for the synthesis of
the cyclopropyl analogs. Cyclopropylacetonitrile 15 was
reacted with sodium hydride and ethyl carbonate in
refluxing toluene to give the cyanoacetate 1613 in 77%
yield. Transformation of 16 to the amidine 17, followed
by cyclization with 3 utilizing the same methods de-
scribed above, provided a mixture of ethyl and methyl
esters. Reduction of the esters with diisobutylalumi-
num hydride at 78 °C in toluene followed by cyclization
with dibenzyl malonate afforded 21 in 47% yield. The
same reaction sequence outlined in Scheme 1 was used
to synthesize 24 from 21.
The key synthetic challenge (Schemes 3 and 4) to the
synthesis of quinolizinones 42 49 was the incorporation
of a fluorine atom at the 7-position of the pyridone ring.
The starting fluoropyridines 27 31, 33, and 35 were
prepared according to the procedures depicted in Scheme
3. Treatment of the commercially available regioiso-
merically impure fluoropyridines (25, 70% pure, the
remainder is 4-chlorotetrafluoropyridine)14 with 1 equiv
of sodium tert-butoxide15 produced 27 in 53% yield in
addition to minor quantities of the 6-tert-butoxypyridine,
while leaving the less reactive 4-chlorotetrafluoropyri-
dine intact. Repeating the same reaction starting with
pentafluoropyridine yielded tert-butoxytetrafluoropyri-
dine 28 (69%). Hydrogenolysis of 27 with 10% Pd(OH)2
under hydrogen in the presence of triethylamine gave
29 in 83% yield, which followed by lithiation with
lithium diisopropylamide (LDA) and subsequent alky-
lation with methyl iodide or ethyl iodide afforded 30 or
31, respectively, in high yield, which was used directly
in the next step without purification. Conversion of 29
to the hydroxypyridine 32 (84% yield) was achieved by
lithiation with LDA followed by reaction with trimethyl
borate and subsequent oxidation with hydrogen perox-
ide. Methylation of 32 by Mitsunobu conditions pro-
vided the methoxypyridine 33 in 91% yield. Although
direct methylation of 27 with methyllithium failed,
reaction with [(trimethylsilyl)methyl]lithium gave a
reasonably good yield of 34 (65%). Hydrogenolysis of
34 resulted in the removal of the chlorine atom, and
subsequent desilylation afforded 35 in 73% yield.
Ch em istr y
The synthesis of pyrido[1,2-a]pyrimidines 11 14 with
aromatic R1 groups is illustrated in Scheme 1. The
construction of the 5-fluoropyrimidines 4 was achieved
by the cyclization of the amidines 2, prepared from the
corresponding nitriles 1, with 310 in refluxing methanol
in the presence of triethylamine. Treatment of pyrim-
idines 4 with 2 equiv of n-butyllithium at 78 °C and
subsequent quenching of the resulting dianions with
ethyl (ethoxymethylene)malonate (EMME) yielded the
addition products 5. Cyclization of 5 was realized in
refluxing ethanol in the presence of a catalytic amount
of piperidine and acetic acid to give 6. Since alkaline
hydrolysis of esters 9 resulted in the destruction of the
carbon nitrogen bond at the 2-position,11 the ethyl
esters 6 were converted to the benzyl esters 7 through
titanate-mediated ester exchange reactions.12 Reaction
of 7 with N,N-dimethylformamide and phosphorus
oxychloride in methylene chloride at room temperature
provided the 2-chloro compounds 8. The orange-colored
intermediates 8 were found to be very reactive toward
nucleophiles and were titrated with amines R2R3NH (9)
to afford 10. Figure 3 depicts the R2R3N groups that
were used. When diamines were utilized, one of the
nitrogens rendered nonnucleophilic was protected with
a tert-butyloxycarbonyl group. Removal of the benzyl
groups in 10 by hydrogenolysis followed by treatment
with hydrochloric acid yielded the desired final products
11 14.
Synthesis of pyridones 42 49 is illustrated in Scheme
4. Selective defluorination of the 6-fluoropyridines 27
31 and 3316 was effected by replacement of the fluorine
atom with hydrazine and oxidation of the hydrazino
product with oxygen17 to give 36 in 47 91% yield.
Reaction of the 2-fluoropyridine 35 and 36 with cyclo-
propylacetonitrile anion yielded 37 in 80 96% yield. No
reaction occurred when cyclopropylacetonitrile was
substituted with ethyl cyclopropylacetate. All attempts
to convert the nitrile 37 directly to the corresponding
aldehyde failed. Thus, trifluoroacetic acid-mediated
deprotection of the tert-butyl ether 37 provided a hy-
droxypyridine which was chlorinated with phosphorus
oxychloride in N,N-dimethylformamide. Acidic ethanol
was used to hydrolyze the nitrile to the ethyl ester 38
in 17 66% yield. Modification of the oxidation state of
the oxygen-bearing carbon was achieved by lithium
aluminum hydride reduction of the ester followed by
Swern oxidation to produce the desired aldehyde. Con-
densation of the aldehyde with diethyl malonate af-

3072 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16
Li et al.
F igu r e 3. R2R3N groups used for this study.
Sch em e 2
mediated hydrolysis of the ester followed by acidic
removal of the amine-protecting group completed the
synthesis.
Synthesis of the 7-desfluoropyridones was achieved
by the lithiation and ethylation of 4-chloro-2-picoline
(50) as illustrated in Scheme 5, providing 51 in 60%
yield. Lithiation of 51, subsequent reaction with EMME,
and thermal cyclization provided 53 in 54% yield.
Nucleophilic displacement of the chlorine of 53 with
3-[N-(tert-butyloxycarbonyl)amino]pyrrolidine followed
by acid-mediated removal of the nitrogen-protecting
group and subsequent hydrolysis of the ethyl ester
afforded 54 in 29% yield.
Preparation of the 3-nitromethylcarbonyl analogs was
achieved by the hydrolysis of 41 (Y H, X CH3) to
acid 45. Activation of the carboxylic acid moiety of 45
with carbonyldiimidazole followed by reaction with the
anion of nitromethane yielded the red-colored 3-ni-
troacetyl analog 55 in 46% yield after removal of the
amine-protecting group under acidic conditions.
The requisite R2R3N groups of amines 9 used for this
study as discussed earlier are summarized in Figure 3.
The amines which were not commercially available were
prepared by literature methods as designated.
Resu lts a n d Discu ssion
The minimum inhibitory concentrations (MICs) of the
pyrido[1,2-a]pyrimidine analogs (Table 1) against sev-
eral representative Gram-positive and Gram-negative
bacteria are summarized along with data for their
isosteres tosufloxacin and ciprofloxacin for comparison
purposes. The most active analogs in the 6-oxopyri-
dopyrimidine series are 12a and 24a which possess a
2,4-difluorophenyl group and a cyclopropyl group at the
9-position, respectively. Although the isosteric tosu-
floxacin and 12a exhibited almost identical activity, the
9-cyclopropyl derivative 24a showed improved activity
against ciprofloxacin-resistant strain of Staph. aureus
1775. Substitution of 4-fluorophenyl (11cc), 4-methox-
yphenyl (13a ), or pentafluorophenyl (14a ) at the 9-posi-
forded 39. Thermal cyclization of 39 in Dowtherm A18
at 240 °C furnished 40 as a yellow solid in 26 73%
overall yield. Nucleophilic displacement of the chloride
40 with R2R3NH (9) in refluxing acetonitrile provided
the desired coupled adduct 41. Lithium hydroxide-

2-Pyridones as Potent DNA Gyrase Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16 3073
Sch em e 3
Sch em e 4
Sch em e 5
Sch em e 6
of the 9-(2,4-difluorophenyl) analog versus the 9-cyclo-
propyl derivative.
The 4-oxoquinolizine series33 demonstrates much
higher levels of in vitro antibacterial potency in com-
parison to the 6-oxopyridopyrimidine series as the MICs
are consistently lower than those of ciprofloxacin (Table
2). In general, the structure activity relationship
(SAR) is similar to that of the quinolones,2e with some
exceptions. Deletion of the fluorine group at the 7-posi-
tion resulted in significant loss of activity. In general,
the 2-(1-piperazinyl) derivatives are much less active
than the 2-(3-amino-1-pyrrolidinyl) ones, while the 2-(1-
piperazinyl) derivatives are more potent in the context

3074 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16
Li et al.
Ta ble 1. In Vitro Antibacterial Activity of Selected Pyrido[1,2-a]pyrimidones
MIC,a µg/mL
Gram-positive organisms
Gram-negative organisms
Staph. aureus
Pseud. aerug.
ATCC- NCTC-
Ent. faecium Strep. bovis Strep. pyog. E. coli Ent. aerog.
K. pneum. Prov. stuartii
DPHD-
compd
11cc
12a
(S,S)-12f
12g
12j
12cc
13a
14a
24a
24a a
24bb
24cc
tosufloxacin
ciprofloxacin
6538p 10649M 1775 ATCC-8043
A-5169
EES61
J UHL ATCC-13048 ATCC-8045
CMX-640
5007
2862
0.39
0.1
0.39
0.1
25
100
50
25
0.78
0.78
1.56
0.78
6.2
25
100
1.56
100
12.5
25
1.56
1.56
3.1
6.2
12.5
25
100
3.1
100
12.5
50
6.2
0.39
0.78
0.78
0.78
3.1
0.39
0.02
0.02
0.78
0.1
0.39
25
6.2
0.02
3.1
0.78
0.05
0.1
3.1
0.39
0.78
0.2
25
1.56
6.2
25
6.2
6.2
0.02
0.01
0.39
0.05
0.2
0.39
0.39
3.1
0.78
6.2
100
50
0.39
25
0.39
100
50
100
100
100
50
0.1
0.1
0.1
0.2
25
0.05
0.2
0.05
0.2
100
100
100
100
25
100
50
100
100
100
25
50
50
0.2
50
50
0.2
25
100
25
6.2
12.5
3.1
0.02
0.39
0.05
0.1
100
100
1.56
100
12.5
50
100
25
1.56
100
12.5
12.5
0.39
0.78
0.02
3.1
0.05
0.39
0.05
0.02
6.2
6.2
0.78
1.56
0.05
0.2
1.56
0.78
0.05
0.39
0.05
0.2
100
100
100
25
12.5
0.2
0.78
3.1
0.39
0.2
0.78
0.78
0.05
0.02
0.02
0.02
1.56
1.56
a
See Experimental Section.
tion (54 vs 48a and 44bb) resulted in substantial loss
of activity. The optimal substituent for the 1-position
is a cyclopropyl as opposed to an ethyl group (48 vs 45).
In contrast to the quinolones,2e,34 the 6-methyl analog
49a is basically devoid of activity. J udicious substitu-
tion at the 9-position of the ring resulted in substantial
increase in potency, especially against ciprofloxacin-
resistant bacteria. Unlike the quinolone analogs, the
9-halo derivatives2e,35 42a and 43a and the 9-methoxy
derivative2e,36 47a are surprisingly inactive. The 9-
methyl analogs2e,37 45 are exceptionally active, being at
least 5 10 times more potent than the 9-chloro (42a ),
9-fluoro (43a ), and 9-methoxy (47a ) derivatives. The
decrease in activity associated with placement of an
ethyl group at the 9-position (46a ) suggests the biologi-
cal target has difficulty in accommodating bulky sub-
stituents in that region of its binding domain.
terial activity against strains of vancomycin-resistant
Enterococcus faecium and Enterococcus faecalis (Table
3).
According to our proposed model of the mechanism
of action of DNA gyrase inhibition,3e the 4-carbonyl and
3-carboxylic groups of the quinolone nucleus are inti-
mately involved in the binding of the drug to DNA in
the ternary complex. It was surmised that replacement
of the carboxylic acid tethered to the 3-position with an
acidic nitroacetyl moiety (55) would produce an active
analog. Biological evaluation of (S)-55a demonstrates
a surprisingly good spectrum of activity against Gram-
negative bacteria, and its overall activity is similar to
that of ciprofloxacin.
The most potent drug candidate identified was (R,S)-
45x, which exhibited extremely potent in vitro activity
against ciprofloxacin-sensitive bacteria such as Staphy-
lococcus, Escherichia, Enterobacteriaceae, and Strepto-
coccus. It is also very active against organisms that are
less sensitive to ciprofloxacin such as Pseudomonas and
anaerobes.
Cyclic amino substituents at the 8-position of the
quinolizine nucleus are presumed to play a crucial role
in the binding to gyrase in the ternary complex.3e
Consequently, extensive modifications of this side chain
have been carried out on the most active 9-methyl core.
In general, the compounds containing a pyrrolidine
group are much more active than piperazine (45d d ),
homopiperazine (45ee), azetidine (45z), morpholine, and
noncyclic amine (45ff,gg) derivatives. The 3-(amino-
methyl)pyrrolidine derivatives are usually more active
than the 3-aminopyrrolidine ones, particularly against
Gram-positive organisms, but are somewhat less active
against Pseudomonas aeruginosa. The absolute config-
uration of the chiral carbon on the amine side chain also
affects the activity. The (S)-3-aminopyrrolidine (S)-45a ,
is about 1 2-fold more active than its enantiomer (R)-
45a . The difference between the potency of the two
antipodes is even larger in the cases of 3-hydroxypyr-
rolidine 45j and 3-(1-amino-1-ethyl)pyrrolidine 45x. The
most active analog synthesized and also perhaps the
most potent antibacterial agent in this class of com-
pounds that has been disclosed in the literature is (R,S)-
45x. When evaluated against resistant bacteria, (R,S)-
45x was found to be over 2000-fold more potent than
ciprofloxacin against MRSA. ABT-719 ((S)-45a ) and
(R,S)-45x are about 10 times more potent against
ciprofloxacin-sensitive and 16-fold more potent against
ciprofloxacin-resistant P. aeruginosa. Furthermore,
ABT-719 and other 2-pyridones exhibit potent antibac-
Several of these compounds were evaluated in a DNA
cleavage assay using the purified DNA gyrase isolated
from Escherichia coli H560 (Table 4). This assay
determines the drug concentration that is necessary to
achieve one-half of the gyrase-mediated maximal DNA
enzymatic cleavage. The poor correlation between MIC
data and the cleavage concentration (CC50) data may
be a reflection of variables such as cell permeability, cell-
killing kinetics, species variability of gyrase, and the
presence of a secondary target. Compound (R,S)-45x,
which was the most active compound in vitro, had a
CC50 value of 0.3 µg/mL, only about equipotent in vitro
to ciprofloxacin. Conversely, ABT-719 ((S)-45a ) exhib-
ited the most potent gyrase activity (CC50
0.03 µg/
mL), approximately 8 times more potent than cipro-
floxacin. The 3-nitroacetyl analog (S)-55a showed only
moderate gyrase activity at 3.0 vs 0.24 µg/mL for
ciprofloxacin, although they have similar MICs.
The in vivo efficacies of several of the compounds were
determined in acute murine lethal infections. The
results are shown in Table 5 against Staph. aureus,
Strep. pneumoniae, E. coli, and P. aeruginosa. An
interesting feature of these results is that the ED50 ratio
of oral (po) versus subcutaneous (sc) dosage of drug for
most of the selected compounds is substantially less

2-Pyridones as Potent DNA Gyrase Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16 3075
Ta ble 2. In Vitro Antibacterial Activity of Selected Quinolizinones
MIC,a µg/mL
Gram-positive organisms
Gram-negative organisms
P. aerug.
Staph. aureus
ATCC- NCTC-
Ent. faecium Strep. bovis Strep. pyog. E. coli Ent. aerog. K. pneum. Prov. stuartii
DPHD-
compd
6538p 10649M 1775 ATCC-8043
A-5169
EES61
J UHL ATCC-13048 ATCC-8045 CMX-640 5007 2862
42a
43a
44bb
45a
0.2
0.1
0.2
0.01
0.2
0.1
6.2
6.2
50
0.39
0.78
0.78
0.02
0.02
0.05
0.1
0.78
0.78
3.1
0.02
0.02
0.1
0.39
0.78
1.56
0.02
0.02
0.05
0.05
0.1
0.05
0.39
0.05
0.2
0.05
0.01
0.01
0.002
0.002
0.005
0.005
0.02
0.005
0.05
0.005
0.1
0.1
0.05
0.01
0.01
0.002
0.005
0.005
0.005
0.02
0.005
0.05
0.01
0.01
0.01
0.02
0.01
0.02
0.05
0.05
0.05
0.01
0.01
0.005
0.01
0.01
0.02
0.005
0.02
0.02
0.02
0.05
0.01
0.005
0.01
0.01
0.001
0.005
0.2
3.1
3.1
1.56
0.2
0.2
0.2
0.39
3.1
0.78
3.1
0.78
3.1
0.39
0.39
0.39
0.05
0.05
0.05
0.2
0.39
0.1
1.56
0.2
0.78
0.2
0.2
0.39
0.78
1.56
0.39
0.2
0.39
0.2
0.78
0.39
0.2
0.39
0. 1
0.39
0.39
0.39
0.78
0.2
0.39
0.39
0.2
6.2
6.2
25
0.78
0.78
1.56
1.56
12.5
1.56
25
3.1
3.1
6.2
6.2
3.1
0.02
0.05
0.005
0.005
0.01
0.02
0.1
0.02
0.2
0.05
0.1
0.05
0.02
0.1
0.2
0.39
0.2
0.39
0.01
0.01
0.02
0.02
0.05
0.02
0.05
0.01
0.02
0.05
0.005
1.56
0.78
1.56
1.56
0.78
0.78
3.1
1.56
0.78
1.56
0.2
0.39
1.56
0.39
0.78
6.2
0.78
0.39
0.78
0.39
3.1
6.2
0.39
6.2
0.39
0.1
0.2
1.56
0.39
0.39
0.2
0.39
0.05
6.2
(S)-45a (ABT-719) 0.01
(R)-45a
(S)-45b
(S)-45c
45d
0.01
0.0.2
0.05
0.02
0.05
0.01
0.01
0.02
0.01
0.1
0.1
0.39
0.02
0.39
0.05
0.1
0.1
0.05
0.1
0.05
0.39
0.1
0.05
0.1
0.05
0.05
0.2
0.1
0.05
0.2
0.1
0.1
0.1
0.05
0.1
0.2
0.01
0.1
0.02
0.02
0.05
0.1
0.05
0.05
0.01
0.01
e0.001
0.39
0.2
45e
(S,S)-45f
(S,R)-45h
45i
0.1
0.05
0.01
0.02
0.02
0.1
0.78
0.2
45j
(S)-45j
(R)-45j
(S)-45k
45l
(S,S)-45m
45n
0.005 0.005
0.39
0.78
1.56
0.39
0.78
0.78
0.39
1.56
0.78
0.39
0.39
0.39
1.56
0.78
0.39
1.56
0.78
0.39
0.78
0.39
0.78
0.2
0.02
0.02
0.01
0.1
0.01
0.01
0.05
0.02
0.05
0.05
0.002 0.002
0.05 0.05
0.005 0.005
0.005 0.005
0.01
0.02
0.002 0.02
0.005 0.01
0.02
0.01
0.01
0.2
0.02
0.01
0.05
0.02
0.05
0.1
0.2
0.2
0.2
25
25
0.1
0.05
0.2
0.01
0.05
0.05
0.05
0.1
0.01
0.02
0.05
0.005
0.05
0.02
0.02
0.05
0.005
0.001
0.02
0.01
0.05
0.01
0.01
0.01
0.01
0.001
12.5
6.2
3.1
3.1
12.5
6.2
3.1
6.2
0.39
0.05
0.05
0.05
0.05
0.1
0.39
0.002
0.1
0.01
0.002
0.05
0.1
0.1
0.05
0.02
0.05
0.05
0.05
0.05
0.01
0.05
0.1
(S,S)-45n
(R,R)-45n
45o
(S,S)-45ob
(R,R)-45ob
45p
0.002
0.1
0.02
0.005
0.05
0.1
1.56
45q
45r
45s
45t
45u
45v
45w
(S,R)-45x
(R,R)-45x
(R,S)-45x
45y
45z
45d d
45ee
45ff
45gg
46a
3.1
6.2
6.2
12.5
6.2
3.1
6.2
3.1
6.2
1.56
100
12.5
12.5
6.2
0.1
0.02
0.02
0.78
0.02
0.05
0.05
0.02
0.01
0.01
0.39
0.05
0.1
0.01
0.02
0.002 0.002
0.002 0.002
e0.001 e0.001
0.1
0.1
0.005
0.01
e0.001
e0.001
0.005
e0.001 e0.001
1.56
0.39
0.39
0.39
6.2
12.5
0.39
0.2
0.39
3.1
25
0.2
0.05
6.2
0.2
0.05
0.1
0.39
0.01
0.02
0.02
0.2
0.78
0.2
0.02
0.01
0.2
12.5
1.56
3.1
3.1
6.2
6.2
6.2
25
100
100
0.78
0.78
0.78
12.5
12.5
0.01
0.02
0.05
0.2
0.2
0.1
0.01
0.02
0.1
3.1
0.02
0.02
0.2
0.1
0.1
0.39
0.2
3.1
3.1
0.39
0.2
0.2
6.2
50
0.39
0.78
1.56
0.78
0.78
6.2
1.56
0.39
0.2
1.56 100
6.2
0.39
0.2
0.2
0.1
0.78
1.56
0.1
0.05
0.1
0.78
3.1
0.05
0.2
1.56
1.56
0.1
0.05
0.1
1.56
6.2
0.1
0.39
1.56
0.39
0.05
0.05
0.39
3.1
50
25
3.1
100
50
3.1
12.5
6.2
47a
48a
49a
54
(S)-55a
ciprofloxacin
3.1
12.5
50
0.39
0.78
6.2
25
0.2
1.56
0.78
12.5
25
1.56
1.56
3.1
0.02
0.02
6.2
100
0.2
0.78
0.1
0.02
6.2
25
0.39
0.78
a
b
See Experimental Section. The absolute configurations are assigned arbitrarily.
Ta ble 3. MICs of Selected 2-Pyridones against
against P. aeruginosa, is inferior compared to Gram-
positive bacteria, the 2-pyridones are comparable to
ciprofloxacin in most cases. Three of the most potent
drug candidates in vitro in this series (ABT-719 ((S)-
45a ), (S,S)-45n , and (R,S)-45x) demonstrated also the
best overall effectiveness in vivo. Although the hy-
droxypyrrolidine analog 45j showed excellent activity
in vitro, it was only moderately effective against Gram-
positive and almost inactive against Gram-negative
bacteria in vivo. This result suggests that a basic amine
group at the 8-position is required for optimal in vivo
efficacy. The biological properties of the molecule such
as bioavailability and serum binding change as a
function of this basic nitrogen and may be responsible
for this enhanced efficacy. Analogous to the in vitro
activity differences observed for compounds in opposite
enantiomeric series, (S)-45a /(R)-45a , (S,S)-45n /(R,R)-
45n and (S,S)-45o/(R,R)-45o, (S,R)-45x/(R,S)-45x ex-
hibited different in vivo activities. Although the 9-chlo-
ro analog 42a is substantially less potent in vitro in
Vancomycin-Resistant Enterococci (µg/mL)a
compd
E. faecium Van A
E. faecalis Van B
(S)-45a (ABT-719)
(S)-45b
45n
(S)-45k
(S)-45c
0.25
0.5
0.5
0.5
1
0.03
0.06
0.06
0.03
0.12
0.015
1
45p
ciprofloxacin
vancomycin
0.03
4
128
32
a
See Experimental Section.
than that of ciprofloxacin. The clinical utility of this
feature in pharmacodynamic profile remains to be
elucidated but is consistent with relatively high oral
bioavailability. In accordance with the in vitro results,
most compounds were significantly more effective against
Gram-positive bacteria than ciprofloxacin, especially
against Strep. pneumoniae. While the efficacy of the
compounds against Gram-negative bacteria, especially

3076 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16
Li et al.
Ta ble 4. Activity of Gyrase-Mediated DNA Cleavage of
Selected Pyridones
44bb, was about 3 times greater in aqueous solubility,
Cmax, and bioavailability. This example is indicative of
the differences between quinolones and 2-pyridones. In
general, the 2-pyridones have not only exhibited en-
hanced aqueous solubility but are also more soluble in
organic solvents. Apparently, transposition of the ni-
trogen of a quinolone to the bridgehead position results
in a change to the overall polar nature of the molecule
and perhaps a perturbation to the planarity of the core
structure that is associated with molecular packing.
These changes are associated with a favorable change
in the solubility and pharmacokinetics of the 2-pyri-
dones.
The regiochemistry of the substituents on the pyri-
done ring was verified through the X-ray structure of a
single crystal of ABT-719 ((S)-45a ) (Figure 5). The
steric congestion created by the interaction of the methyl
group with the cyclopropane forces the methyl and
cyclopropyl groups out of the plane of the pyridone ring
with a twist that was estimated to be approximately 30°.
This deviation from planarity appears to be responsible
for the enhanced solubility of the 2-pyridones. Another
salient structural feature that was observed was that
the nitrogen atom of the pyrrolidine that is attached to
the 8-position adopts an sp2 configuration despite the
steric congestion. Figure 5 shows two molecules of ABT-
719 self-assembled head to tail through π π stacking
with an average distance of about 3.4 Å. It is speculated
that the type of packing observed in ABT-719 is perhaps
the most favorable for gyrase binding and is in ac-
cordance with a proposed ternary model.3e
a
a
compd
CC50
,
µg/mL
compd
45n
45o
45p
45q
45r
45s
45t
CC50, µg/mL
12a
0.5
0.5
1.3
0.5
12.5
0.15
1.5
2.0
1.0
0.31
2.2
0.15
0.05
0.03
0.15
0.08
0.06
0.2
0.3
0.1
0.05
0.4
0.3
0.3
2.6
0.3
0.6
0.4
0.3
0.3
1.5
1.8
0.8
0.3
3.2
(S,S)-12f
12g
12j
14a
24a
24a a
24bb
24cc
42a
43a
45u
(S,R)-45x
(R,R)-45x
(R,S)-45x
45y
45z
45d d
45ff
47a
48a
49a
(S)-55a
ciprofloxacin
44bb
45a
(S)-45a (ABT-719)
(R)-45a
(S)-45b
45d
(S,S)-45f
(S)-45k
45l
10
3.0
0.24
0.04
0.07
a
CC50 is defined as the drug concentration which causes 50%
of the gyrase (E. coli H560)-mediated maximal DNA cleavage. See
Experimental Section.
comparison to ABT-719, it is almost equally effective
in vivo. The 3-nitroacetyl group does not appear to be
a good pharmacophore in this SAR as (S)-55a did not
exhibit significant efficacy in vivo despite its moderate
in vitro activity. In the pyridopyrimidine series, the
most active compound was 12a , which possesses a
9-difluorophenyl and a 2-(3-aminopyrrolidine) group. A
few simple amino acid prodrugs38 (12a -N-Ala, 12a -N-
Ala-Ala, 12a -N-Nov) were prepared in order to improve
the solubility and perhaps also the in vivo efficacy.
These experiments met with limited success since only
12a -N-Ala-Ala demonstrated improved efficacy against
Staph. aureus.
Solu bility a n d P h a r m a cok in etic P r op er ties. In
order to optimize the in vivo efficacy, a limited system-
atic study of the pharmacokinetic properties (maximum
plasma concentration (Cmax), plasma half-life (t1/2), and
percent bioavailability (F)), as well as solubility at
physiological pH (7.4 in phosphate buffer saline), was
undertaken (Table 6). Almost all of the compounds
tested exhibited enhanced aqueous solubility relative to
ciprofloxacin. The isostere of tosufloxacin (12a ) is 2.5
times more soluble than tosufloxacin. Synthesis of the
N-Ala-Ala prodrug of 12a (12a -N-Ala-Ala) significantly
increased the water solubility from 0.02 to 1.0 mg/mL.
Surprisingly, the least aqueous soluble analogs by virtue
of their nonzwitterionic nature, 45j,l, demonstrated the
highest Cmax (1.42 µg/mL). Although the 8-piperazinyl
analogs 44bb and 45d d showed diminished levels of in
vitro antibacterial activity, they exhibited half-lives and
bioavailabilities better than the simple aminopyrrolidine
analogs 45a c. As noted before, chirality has a re-
markable pharmacokinetic and physiochemical effect
((S)-45a /(R)-45a , (S,S)-45n /(R,R)-45n ). The S-isomers
in both cases have 3 10 times higher Cmax and 3 times
higher bioavalability than the R-isomers. All three of
the most potent members of this study, ABT-719 ((S)-
45a ), (S,S)-45n , and (R,S)-45x, showed excellent solu-
bility and pharmacokinetic properties.
Su m m a r y of th e Resu lts
In conclusion, the synthesis of novel substituted
2-pyridones by transposition of the nitrogen of 4-quino-
lines to the bridgehead position has been described. This
subtle interchange of the nitrogen atom with a carbon
atom yielded two novel heterocyclic nuclei that had not
previously been evaluated as antibacterial agents. The
2-pyridones have been shown to be excellent DNA
gyrase inhibitors. They exhibit broad spectrum anti-
bacterial activity and are potent against organisms that
are resistant to many of the clinically utilized fluoro-
quinolones. Most notably they were active against
resistant bacteria such as MRSA, vancomycin-resistant
strains of enterococci, and ciprofloxacin-resistant organ-
isms. In addition, 2-pyridones possess favorable phys-
iochemical and pharmacokinetic properties. The brevity
and conciseness of the synthesis as well as the excellent
antibacterial activity of these molecules will expedite
the biological evaluation of numerous analogs of the
2-pyridones.
Exp er im en ta l Section
Gen er a l. Melting points were taken on a Fisher-J ohns
melting point apparatus and are uncorrected. 1H NMR spectra
were recorded on a General Electric QE300 spectrometer. A
Varian Unity 500 spectrometer was used for 19F NMR spectra.
Chemical shifts are reported in parts per million relative to
Me4Si for 1H NMR and CFCl3 for 19F NMR as internal
standards. The desorption chemical ionization (DCI/NH3) and
fast atom bombardment (FAB) mass spectra were measured
on a Finningan SSQ 700 instrument and Finningan MAT 95
instrument, respectively. IR spectra were taken on either
Nicolet 5 SXC or 60 SX FT IR instruments. Column chroma-
tography refers to flash column chromatography conducted on
E. Merck silica gel 60 (230 400 mesh). THF was distilled from
sodium/benzophenone ketyl. All other solvents and reagents
The mean plasma concentrations of ABT-719 ((S)-
45a ), (R)-45a , and 44bb relative to ciprofloxacin after
single oral administration in rats of 5 mg/kg are
illustrated in Figure 4. The isostere of ciprofloxacin,

2-Pyridones as Potent DNA Gyrase Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16 3077
Ta ble 5. In Vivo Efficacy of Selected Pyridones in Micea
ED50, mg/kgb,c
Staph. aureus NCTC-10649M
Strep. pneum. ATCC-6303
E. coli J UHL
P. aeruginosa 5007
compd
scd
poe
sc
po
sc
po
sc
po
f
12a
4.4
12.0
14.4
3.0
24.0
12.8
25.3
12.0
5.7
14.6
4.1h
3.4
3.1
3.1
1.0
2.5
2.5
2.5
4.8
3.3g
1.0
1.0
5.6
10.3
34.4
14.8
11.4
50
42.1
68.8
68.8
29.8
12a -N-Ala
12a -N-Ala-Ala
12a -N-Nov
12f
12f-N-Ala-Ala
24a
42a
43a
45a
(S)-45a (ABT-719)
(R)-45a
(S)-45b
(S)-45c
45s
2.7
2.8
8.0
8.0
11.4
8.0
1.6
2.9
1.0h
0.6
0.9
0.9
4.7
0.3
11.3
1.5
6.1
0.9
0.5h
6.1h
0.7
1.5
0.6
1.8
4.1
1.2
1.5
0.3g
0.2
0.2g
4.4
12.0
4.1
79.8
49.7
164.2
140.5
16.6
14.3
25.0
20.0
26.7g
4.7
50
70
100
8.5h
11.1h
5.6
3.3
17.0
6.2h
1.6
12.5h
5.3
0.4
0.1
0.3
0.7
1.9
0.3
0.6
1.0
1.1
10.0
0.5h
1.9
2.4
2.8
4.6h
14.5
6.2
7.2
25.0
1.4
15.2
5.3
25.0h
44.1h
8.0
8.0
50
50
45j
7.4g
2.0g
2.0g
4.4h
2.2
41.5g
10.0g
10.0g
12.5h
3.6
1.0g
5.0g
(S)-45j
(R)-45j
45n
(S,S)-45n
(R,R)-45n
45o
(S,S)-45o
(R,R)-45o
45q
45u
45v
45w
(S,R)-45x
(R,R)-45x
(R,S)-45x
45d d
(S)-55a
ciprofloxacin
11.2
3.1
1.0h
3.3h
1.0
8.0
8.0
8.0
36.4
21.4
50
2.5h
29.3h
5.0
8.0
32.2
1.0
0.4
0.8
0.5
1.1h
1.4
4.5g
2.3g
7.6g
2.5
10.0
1.1
6.4h
18.0
5.0
39.9h
50
5.0
1.5
3.6
14.6
6.3
11.2g
17.9
42.8
50
6.4h
9.5h
6.7
3.6h
10.0
8.0
18.0
6.3
1.9
12.8
1.2g
1.1
8.0
5.4g
1.0
8.0
3.2
0.8
33.0
24.4g
13.0
12.7
50
0.5g
0.5
5.7g
3.3
7.2g
4.8
1.3
8.0
8.0
3.1
49.4
50
1.3
2.1
25.2
28.2
5g
10g
19.1
100
0.1
1.0
21.1
a
b
See Experimental Section. Effective dosage that protects 50% of mice from lethal infection. c Unless otherwise indicated, mice were
d
g
infected at 100 × LD50
.
sc: subcutaneously administered. e po: orally administered. f Not tested. Mice were infected at 10 × LD50
.
h
Mice were infected at 1000 × LD50
.
Ta ble 6. Aqueous Solubility and Pharmacokinetic Properties
of Selected 2-Pyridones
PK after a 5 mg/kg
single oral dose in ratsa
solubility,b
mg/mL
d
compd
Cmax,c µg/mL t1/2
,
h
F,e %
g
12a
0.02f
1.0
0.25
0.25
0.10
3.7
12a -N-Ala-Ala
44bb
(S)-45a (ABT-719)
(R)-45a
45b
45d
(S,S)-45f
45j
0.30
0.27
0.08
0.36
0.17
0.74
1.42
1.42
0.53
0.05
1.13
0.33
0.25
0.05
0.49
0.18
0.15
3.4
1.2
1.1
1.8
2.1
1.6
5.4
4.8
3.5
3.0
4.1
5.7
5.7
7.1
4.5
1.3
3.0
46
32
10
44
23
44
50
32
42
13
62
41
40
18
87
25
16
0.07
0.003
0.001
3.1
45l
(S,S)-45n
(R,R)-45n
45o
F igu r e 4. Mean (n
pyridones after single oral administration of 5 mg/kg to rats
in aqueous solution.
4) plasma concentrations of selected
45q
1.94
(R,R)-45x
(R,S)-45x
45d d
47a
ciprofloxacin
0.10
1.77
0.35
0.08
2-(3-Am in o-1-p yr r olid in yl)-9-(2,4-d iflu or op h en yl)-3-
flu or o-6H-6-oxopyr ido[1,2-a ]pyr im idin e-7-car boxylic Acid
Tr iflu r oa cetic Acid Sa lt (12a ). a . 2-(2,4-Diflu or op h en yl)-
a ceta m id in e Hyd r och lor id e (2, R1 2,4-d iflu or op h en yl).
To a solution of (2,4-difluorophenyl)acetonitrile (49.44 g, 0.323
mol) in absolute ethanol (20.8 mL, 0.354 mol) cooled in an ice
bath was passed gaseous HCl (14.61 g, 0.400 mol). After 20
min the reaction mixture solidified. It was then allowed to
warm to room temperature and held at this temperature for
72 h. To the mixture was then added ethanol (140 mL)
followed by a solution of ammonia in ethanol (150 mL, 4.2 M,
0.42 mol). This mixture was stirred for an additional 3 h at
room temperature. The reaction mixture was filtered, and the
filtrate was concentrated to afford 65.7 g (90%) of the title
compound as a white solid, mp 163 164 °C. 1H NMR (DMSO-
a
b
See Experimental Section. Solubility determined in pH 7.4
phosphate buffer solution (0.05 M) at 37 °C. c Maximal plasma
concentration. Plasma half-life. e Bioavailability. f Solubility for
d
g
tosufloxacin at pH 7.4 is 0.008 mg/mL. Not tested.
were obtained commercially and used without further purifica-
tion. Unless otherwise specified, all nonaqueous reactions
were carried out under a dry nitrogen atmosphere, using oven-
dried glassware, and all reaction solvents were removed by
rotary evaporator. All elemental analyses were within 0.4%
of the calculated values.

3078 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16
Li et al.
washed once with 1 N HCl and three times with water. The
solution was dried over anhydrous magnesium sulfate and
concentrated to leave a yellow solid. This material was
triturated with ether; the solid was filtered and dried under
vacuum at room temperature to afford 6.66 g (81%) of the title
compound as a yellow solid, mp 218 219 °C. MS (DCI/NH3):
427 (M H). 1H NMR (DMSO-d6): δ 5.26 (s, 2H), 7.15 7.45
(m, 8H), 8.00 (s, 1H), 9.00 (d, J
7 Hz, 1H). IR (KBr): 1710,
1
1675, 1620 cm
.
e. Ben zyl 2-[3-[N-(ter t-bu toxyca r bon yl)a m in o]-1-p yr -
r olidin yl]-9-(2,4-diflu or oph en yl)-3-flu or o-6H-6-oxopyr ido-
[1,2-a ]p yr im id in e-7-ca r boxyla t e (10, R 1
2,4-d iflu or o-
p h en yl, R2R3N 3-ter t-BOCa m in o-1-p yr r olid in yl). 7 (R1
2,4-difluorophenyl) (1.20 g, 2.82 mmol) was stirred with
DMF (2.50 mL) and POCl3 (2.95 mL) in methylene chloride
(45 mL) at room temperature for 2.5 h. The reaction was then
quenched with ice and water and the mixture extracted with
methylene chloride. The extract was washed with water until
the acidity of the rinse water was above pH 3 and then dried
over magnesium sulfate. To the dried solution was added an
excess of 3-[N-(tert-butoxycarbonyl)amino]pyrrolidine until the
color of the solution changed from orange to light yellow. The
solution was then concentrated, and the product was purified
by column chromatography eluting with 0.5:5:100 concentrated
ammonium hydroxide:methanol:methylene chloride to afford
1.58 g (94%) of the title compound as a light yellow crystalline
solid, mp 103 104 °C. MS (DCI/NH3): 595 (M H). 1H NMR
(CDCl3): δ 1.45 (s, 9H), 1.85 2.30 (m, 2H), 3.42 4.35 (m, 5H),
4.65 (br, 1H), 5.38 (s, 2H), 6.89 (m, 2H), 7.30 7.50 (m, 6H),
F igu r e 5. Stereoview of ORTEP drawing of the X-ray crystal
structure of a pair of (S)-45a (ABT-719).
d6): δ 3.72 (s, 2H), 7.16 (m, 1H), 7.33 (m, 1H), 7.50 (m, 1H),
8.95 (br, 4H). Anal. (C8H9ClF2N2 0.1H2O) C, H, N.
b . 2-(2,4-Diflu or ob en zyl)-5-flu or o-4-h yd r oxyp yr im i-
d in e (4, R1 2,4-d iflu or op h en yl). A mixture of 2 (R1 2,4-
difluorophenyl) (68.0 g, 0.33 mol), the sodium salt of ethyl
2-fluoro-3-hydroxy-2-propenoate (3)10 (0.34 mol) in anhydrous
methanol (300 mL), and triethylamine (50 mL) was heated at
reflux for 23 h. The solvent was removed, and water (200 mL)
was added. The mixture was acidified to pH 3 4 with 10%
HCl and then extracted with methylene chloride. The extract
was washed with water, dried over anhydrous MgSO4, and
concentrated to give a dark oil which solidified upon standing.
The solid was washed with ethyl acetate, ethyl acetate/hexane,
and hexane to afford 29.8 g of the title compound as a white
solid. A second crop of 10.2 g of product was obtained from
the filtrates after column chromatography, eluting with 2.5%
methanol in methylene chloride. Total weight was 40.0 g
(50%), mp 155 156 °C. MS (DCI/NH3): 258 (M NH4), 241
8.35 (s, 1H), 9.15 (d, J
(KBr): 1735, 1710, 1660 cm
N.
9 Hz, 1H), 9.16 (d, J
9 Hz, 1H). IR
1
.
Anal. (C31H29F3N4O5) C, H.
f. 2-[3-[N-(ter t-Bu toxycar bon yl)am in o]-1-pyr r olidin yl]-
9-(2,4-d iflu or op h en yl)-3-flu or o-6H-6-oxop yr id o[1,2-a ]p y-
r im idin e-7-car boxylic Acid (12, R2R3N 3-ter t-BOCam in o-
1-p yr r olid in yl). A solution of 10 (R1
2,4-difluorophenyl,
R2R3N 3-tert-BOCamino-1-pyrrolidinyl) (1.77 g, 2.97 mmol)
was stirred with formic acid (98%, 4.0 mL) and 10% Pd/C (0.2
g) in methanol (80 mL) at room temperature for 40 min. After
filtration and evaporation of the solvent, the product was
purified by column chromatography, eluting with 1:10:100
acetic acid:methanol:methylene chloride to afford, after re-
moval of the solvent, 1.13 g (75%) of the title compound as a
yellow solid, mp 209.5 210.5 °C. MS (DCI/NH3): 505 (M
H). 1H NMR (CDCl3/CD3OD): δ 1.45 (s, 9H), 1.90 2.30 (m,
2H), 3.50 4.35 (m, 5H), 6.91 (m, 2H), 7.32 (m, 1H), 8.44 (s,
(M H). 1H NMR (CDCl3): δ 4.02 (s, 2H), 6.88 (m, 2H), 7.33
1
(m, 1H), 7.89 (d, J
3 Hz, 1H). IR (KBr): 1690, 1605 cm
.
Anal. (C11H7F3N2O) C, H, N.
c. Eth yl 9-(2,4-Diflu or op h en yl)-3-flu or o-2-h yd r oxy-6H-
6-oxop yr id o[1,2-a ]p yr im id in e-7-ca r boxyla te (6, R1 2,4-
d iflu or op h en yl). 4 (R1
2,4-difluorophenyl) (4.80 g, 20.0
1H), 9.03 (d, J
8 Hz, 1H), 9.04 (d, J
8 Hz, 1H). IR (KBr):
1714, 1662, 1620 cm 1. Anal. (C24H23F3N4O5 1/4H2O) C, H, N.
mmol) was dissolved in THF (150 mL) and cooled to 78 °C.
To this was slowly added dropwise n-butyllithium (16.40 mL,
2.5 N in hexanes, 41.0 mmol), and the mixture was stirred for
30 min. Then diethyl (ethoxymethylene)malonate (4.85 mL,
24.0 mmol) was added, and the mixture was stirred for an
additional 30 min at 78 °C. The reaction was quenched with
10% HCl until the mixture was at pH 3. It was then extracted
with ethyl acetate. The extract was dried over anhydrous
magnesium sulfate, and the solvent was removed to afford the
title compound as a yellow oil. This oil was dissolved in
ethanol (80 mL). Piperidine (2 mL) and acetic acid (0.2 mL)
were added, and the mixture was heated at reflux for 16 h.
The solvent was removed, and the residue was washed with
methanol and methylene chloride to give 4.79 g of a pale yellow
solid. The washings were concentrated and then purified by
column chromatography, eluting with 2:10:100 acetic acid:
methanol:methylene chloride to afford an additional 2.22 g of
the title compound as a pale yellow solid, with a total weight
of 7.01 g (96%), mp 239 240 °C. MS (DCI/NH3): 382 (M
g. 2-(3-Am in o-1-p yr r olid in yl)-9-(2,4-d iflu or op h en yl)-
3-flu or o-6H -6-oxop yr id o[1,2-a ]p yr im id in e-7-ca r b oxylic
Acid Tr iflu or oa cetic Acid Sa lt (12a ). 12 (R2R3N 3-tert-
BOCamino-1-pyrrolidinyl) (0.100 g, 0.198 mmol) was dissolved
in 4 N HCl in dioxane (2.0 mL, 8.0 mmol) and stirred at room
temperature for 3 h. The solvent was removed to yield a yellow
solid which was dissolved in water and neutralized to pH 7
with 5% sodium bicarbonate solution. The resulting precipi-
tate was filtered off, washed with water, and dried to afford
75 mg (93%) of the free base of 12a as a yellow solid, mp 250
°C. MS (DCI/NH3): 405 (M
1.90 2.30 (m, 2H), 3.00 4.10 (m, 5H), 7.16 (m, 2H), 7.30 (m,
H). 1H NMR (DMSO-d6): δ
1H), 8.18 (s, 1H), 9.17 (d, J
1H). IR (KBr): 1715, 1660 cm
8 Hz, 1H), 9.18 (d, J
.
8 Hz,
1
A 0.879 g (2.17 mmol) portion of the above free base was
dissolved in 10 mL of trifluoroacetic acid. The excess acid was
then removed. The yellow residue was dissolved in 600 mL
of water containing 1 mL of trifluoroacetic acid. The resulting
solution was filtered through a sintered glass funnel and
freeze-dried to afford 0.876 g (78%) of the title compound as a
light yellow solid, mp 161 162 °C dec. MS (DCI/NH3): 405
(M H). 1H NMR (CD3OD): δ 2.10 2.55 (m, 2H), 3.75 4.20
(m, 5H), 7.05 (m, 2H), 7.50 (m, 1H), 8.30 (s, 1H), 9.19 (d, J
NH4), 365 (M H). 1H NMR (DMSO-d6): δ 1.23 (t, J
7 Hz,
3H), 4.14 (q, J
7 Hz, 2H), 7.08 (m, 1H), 7.21 (m, 1H), 7.40
(m, 1H), 7.83 (s, 1H), 8.74 (d, J
8 Hz, 1H). IR (KBr): 1710,
1
1675, 1620 cm
.
d . Ben zyl 9-(2,4-Diflu or op h en yl)-3-flu or o-2-h yd r oxy-
6H-6-oxop yr id o[1,2-a ]p yr im id in e-7-ca r boxyla te (7, R 1
2,4-d iflu or op h en yl). To a solution of the ethyl ester 6 (R1
2,4-difluorophenyl) (7.00 g, 19.2 mmol) dissolved in benzyl
alcohol (200 mL) was added titanium tetraethoxide (0.70 mL),
and the mixture was heated with stirring at 100 °C for 2.5 h.
The reaction mixture was diluted with methylene chloride and
8 Hz, 1H). IR (KBr): 1720, 1660, 1620 cm 1. Anal. (C19H15
F3N4O3 CF3CO2H H2O) C, H, N.
-
Following the same procedures as described for 12a , starting
from either different amines or different nitriles, the following
compounds were made.

2-Pyridones as Potent DNA Gyrase Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16 3079
3-Flu or o-9-(4-flu or oph en yl)-2-(4-m eth yl-1-piper azin yl)-
chloride, and the solvent was removed to afford the title
compound as a viscous off-white oil, which was taken directly
to the next step.
6H-6-oxopyr ido[1,2-a ]pyr im idin e-7-car boxylic acid (11cc):
mp 225 230 °C. MS (DCI/NH3): 401 (M
H). 1H NMR
(CDCl3): δ 1.68 (br, 1H), 2.33 (s, 3H), 2.53 (br, 4H), 3.98 (br,
4H), 7.10 (t, 2H), 7.48 (m, 2H), 8.57 (s, 1H), 9.08 (d, 2H). Anal.
(C20H18F2N4O3 0.75H2O) C, H, N.
c. Meth yl 2-Cyclop r op yl-2-(5-flu or o-4-h yd r oxy-2-p y-
r im id in yl)a ceta te (18) a n d Eth yl 2-Cyclop r op yl-2-(5-
flu or o-4-h yd r oxy-2-p yr im id in yl)a ceta te (19). A mixture
of the above crude product 17 (0.253 mol), 0.254 mol of the
sodium salt of ethyl 2-fluoro-3-hydroxy-2-propenoate (3),10 and
triethylamine (37.0 mL, 0.265 mol) in anhydrous methanol
(250 mL) was heated at reflux for 17 h. Following removal of
the solvent, 200 mL of water was added and the residue was
acidified to pH 5 with acetic acid. This mixture was then
extracted with methylene chloride. The extract was washed
with water, dried over anhydrous magnesium sulfate, and
concentrated to give a dark brown oil. This was purified by
column chromatography eluting with 1:1 ethyl acetate:hexane
to afford 22.8 g (40%) of the methyl ester 18 and 6.45 g (11%)
of the ethyl ester 19, both as pale yellow viscous oils. Methyl
2-((2S,4S)-4-Am in o-2-m eth yl-1-p yr r olid in yl)-9-(2,4-d i-
flu or op h en yl)-3-flu or o-6H-6-oxop yr id o[1,2-a ]p yr im idin e-
7-ca r boxylic a cid h yd r och lor id e ((S,S)-12f): mp 204 °C
dec. [ ]22
(M
35.4° (c 0.5, CH3OH). MS (DCI/NH3): 419
Cl). 1H NMR (CD3OD): δ 1.16 and 1.41 (2d, J
7 Hz,
3H), 2.15 2.31 (m, 2H), 3.75 4.40 (m, 4H), 7.04 (m, 2H), 7.46
D
(m, 1H), 8.25 and 8.30 (2s, 1H), 9.11 and 9.21 (2d, J
9 Hz,
1H). IR (KBr): 1710, 1660, 1630 cm 1. Anal. (C20H17F3N4O3
HCl H2O) C, H, N.
2-((2S,4S)-4-Aceta m id o-2-m eth yl-1-p yr r olid in yl)-9-(2,4-
d iflu or op h en yl)-3-flu or o-6H -6-oxop yr id o[1,2-a ]p yr im i-
d in e-7-ca r boxylic a cid (12g): mp 163 164 °C. [ ]23
D
H). 1H
ester 18: MS (DCI/NH3) 227 (M
0.43 (m, 1H), 0.52 (m, 1H), 0.65 (m, 1H), 0.77 (m, 1H), 1.42
H). 1H NMR (CDCl3): δ
50.2° (c
NMR (CDCl3/CD3OD): δ 1.09 and 1.39 (2d, J
0.5, CHCl3). MS (DCI/NH3): 461 (M
6 Hz, 3H),
(m, 1H), 2.97 (d, J
10 Hz, 1H), 3.80 (s, 3H), 7.88 (d, J
3
1.92 2.15 (m, 2H), 2.00 (s, 3H), 3.97 (m, 1H), 4.16 (m, 1H),
4.32 (m, 1H), 4.72 (m, 1H), 6.90 (m, 2H), 7.25 (m, 1H), 8.17
Hz, 1H), 11.8 (br, 1H). IR (neat): 1740, 1690, 1615 cm 1. Anal.
(C10H11FN2O3 1/4H2O) C, H, N. Ethyl ester 19: MS (DCI/NH3)
and 8.31 (2s, 1H), 8.93 and 8.97 (2d, J
8 Hz, 1H). IR (KBr):
258 (M
1H), 0.66 (m, 1H), 0.74 (m, 1H), 1.31 (t, J
NH4). 1H NMR (CDCl3): δ 0.47 (m, 1H), 0.54 (m,
1720, 1660, 1035 cm 1. Anal. (C22H19F3N4O4 H2O) C, H, N.
9-(2,4-Diflu or op h en yl)-3-flu or o-2-(3-h yd r oxy-1-p yr r o-
lid in yl)-6H -6-oxop yr id o[1,2-a ]p yr im id in e-7-ca r b oxylic
a cid (12j): mp 168 170 °C dec. MS (DCI/NH3): 406 (M
H). 1H NMR (DMSO-d6): δ 2.00 2.15 (m, 2H), 3.55 3.70 (m,
2H), 3.97 4.12 (m, 2H), 4.50 4.60 (m, 1H), 6.93 (m, 2H), 7.35
7 Hz, 3H), 1.34
10 Hz, 1H), 4.27 (m, 2H), 7.83 (d, J 3
(m, 1H), 2.96 (d, J
Hz, 1H), 11.0 (br, 1H). IR (neat): 1735, 1682, 1605 cm 1. Anal.
(C11H13FN2O3 0.3H2O) C, H, N.
d . 2-Cyclop r op yl-2-(5-flu or o-4-h yd r oxy-2-p yr im id in -
yl)a ceta ld eh yd e (20). To a solution of the methyl ester 18
(4.96 g, 21.9 mmol) in toluene (40 mL) stirring at 70 °C was
added a solution of diisobutylaluminum hydride in toluene (1.0
N, 46 mL, 46.0 mmol). The reaction mixture was stirred for
40 min, and then the reaction was quenched by acetic acid (5
mL). The mixture was allowed to warm to room temperature,
and the reaction mixture was extracted with ethyl acetate. The
extract was washed with water (3×), dried over anhydrous
magnesium sulfate, and concentrated to afford 2.23 g of the
title compound as a white solid. This compound was used
(m, 1H), 8.43 (s, 1H), 9.01 and 9.04 (2d, J
4 Hz, 1H). IR
(KBr): 1715, 1665, 1625 cm 1. Anal. (C19H14F3N3O4 1/2H2O)
C, H, N.
9-(2,4-Diflu or op h en yl)-3-flu or o-2-(4-m eth yl-1-p ip er a zi-
n yl)-6H-6-oxop yr id o[1,2-a ]p yr im id in e-7-ca r boxylic a cid
1
(12cc): mp 246 248 °C dec. MS (DCI/NH3): 419 (M H). H
NMR (CDCl3/CD3OD): δ 2.34 (s, 3H), 2.53 (m, 4H), 3.85 4.00
(m, 4H), 6.90 (m, 2H), 7.32 (m, 1H), 8.49 (s, 1H), 9.07 (d, J
9 Hz, 1H). IR (KBr): 1720, 1660 cm 1. Anal. (C20H17F3N4O3)
C, H, N.
1
directly in the next step. MS (DCI/NH3): 214 (M NH4). H
2-(3-Am in o-1-p yr r olid in yl)-3-flu or o-9-(4-m e t h oxy-
p h en yl)-6H -6-oxop yr id o[1,2-a ]p yr im id in e-7-ca r b oxylic
a cid (13a ): mp 230 235 °C dec. MS (DCI/NH3): 399 (M
Cl). 1H NMR (CD3OD): δ 2.16 2.58 (m, 2H), 3.86 (s, 3H),
NMR (CDCl3): δ 0.48 (m, 2H), 0.91 (m, 2H), 1.35 (m, 1H), 7.40
(d, J
(d, J
10 Hz, 1H), 7.75 (d, J
10 Hz, 1H). IR (KBr): 1695, 1660, 1635 cm
4 Hz, 1H), 9.61 (br, 1H), 13.64
1
.
3.90 4.21 (m, 5H), 6.98 (m, 2H), 7.51 (m, 2H), 8.31 (s, 1H),
e. Ben zyl 9-Cyclop r op yl-3-flu or o-2-h yd r oxy-6H-6-ox-
op yr id o[1,2-a ]p yr im id in e-7-ca r boxyla te (21). The above
crude aldehyde 18 was dissolved in anhydrous ethanol (100
mL). To this was added dibenzyl malonate (3.5 mL, 14.0
mmol), piperidine (2.5 mL), and acetic acid (0.25 mL). This
reaction mixture was heated to reflux for 3 h and stirred at
room temperature overnight. The solvent was removed. The
residue was then dissolved in methylene chloride, washed with
water, and dried over anhydrous magnesium sulfate. The
solvent was removed to give a yellow oil which was purified
by column chromatography, eluting with 1:5:100 acetic acid:
methanol:methylene chloride. Removal of the solvent afforded
1.80 g (47%) of the title compound as a pale yellow solid, mp
1
9.20 (d, J
9 Hz, 1H). Anal. (C20H19FN4O4 HCl /4H2O) C,
H, N.
2-(3-Am in o-1-pyr r olidin yl)-3-flu or o-9-(2,3,4,5,6-pen taflu -
or op h en yl)-6H-6-oxop yr id o[1,2-a ]p yr im id in e-7-ca r boxy-
lic a cid h yd r och lor id e sa lt (14a ): mp 202 204 °C. MS
(DCI/NH3): 459 (M Cl). 1H NMR (CD3OD): δ 2.12 2.54 (m,
2H), 3.70 4.36 (m, 5H), 8.42 (s, 1H), 9.21 (d, J
9 Hz, 1H).
1
IR (KBr): 1715, 1660, 1630 cm
HCl 0.5H2O) C, H, N.
.
Anal. (C19H12F6N4O3 -
Ben zyl 9-Cyclop r op yl-3-flu or o-2-h yd r oxy-6H-6-oxop y-
r id o[1,2-a ]p yr im id in e-7-ca r boxyla te (21). a . Eth yl 2-Cy-
a n o-2-cyclop r op yla ceta te (16). A modified procedure of
Carney and Wojtkunski13 was used. To a suspension of NaH
(60%, 49.6 g, 0.94 mol) and diethyl carbonate (97.2 mL, 0.800
mol) in refluxing toluene (240 mL) was added, over a period
of 40 min, a solution of cyclopropaneacetonitrile (32.44 g, 0.400
mol) in toluene (120 mL). The reaction mixture was refluxed
for another 2 h. Approximately 120 mL of acetic acid was
added with ice bath cooling. The mixture was extracted with
ethyl acetate (3×). The combined extracts were washed with
saturated brine (2×), dried over MgSO4, and concentrated. The
product was obtained as a colorless liquid after distillation at
reduced pressure (47.0 g, 77%, bp 69 72 °C at 4 mmHg).
b. 2-Cyclop r op yl-2-(eth oxyca r bon yl)a ceta m id in e Hy-
d r och lor id e (17). Into a stirred solution of 16 (38.72 g, 0.253
mol) in anhydrous ethanol (17.7 mL, 0.303 mol) was introduced
gaseous hydrogen chloride (10.0 g, 0.274 mol) with ice cooling.
The mixture was allowed to warm to room temperature and
stand for 72 h. The reaction mixture was diluted with
anhydrous ethanol (100 mL), and a solution of ammonia in
ethanol (4.17 M, 70 mL, 0.292 mol) was added slowly at room
temperature. The reaction mixture was stirred for 3 h. The
reaction mixture was filtered to remove the ammonium
225.5 226.5 °C. MS (DCI/NH3): 355 (M
(CDCl3): δ 0.64 (m, 2H), 1.08 (m, 2H), 1.62 (m, 1H), 5.37 (s,
H). 1H NMR
2H), 7.35 7.48 (m, 5H), 8.28 (s, 1H), 9.00 (d, J
6 Hz, 1H).
IR (KBr): 1720, 1700, 1690 cm 1. Anal. (C19H15FN2O4 1/4H2O)
C, H, N.
2-(3-Am in o-1-p yr r olid in yl)-9-cyclop r op yl-3-flu or o-6H-
6-oxop yr id o[1,2-a ]p yr im id in e-7-ca r boxylic Acid Hyd r o-
ch lor id e Sa lt (24a ). a . Ben zyl 2-Ch lor o-9-cyclop r op yl-
3-flu or o-6H -6-oxop yr id o[1,2-a ]p yr im id in e -7-ca r b ox-
yla te (22). A mixture of 21 (0.200 g, 0.564 mmol), DMF (0.50
mL, 6.46 mmol), and phosphorous oxychloride (0.60 mL, 6.44
mmol) in methylene chloride (10 mL) was stirred at room
temperature for 4 h. Ice was added to the reaction mixture.
The mixture was extracted with methylene chloride, which was
then washed with water, dried over anhydrous magnesium
sulfate, and concentrated to yield the title compound as an
orange residue. This compound was taken directly to the next
step.
b. Ben zyl 2-[3-[N-(ter t-bu toxyca r bon yl)a m in o]-1-p yr -
r olid in yl]-9-cyclop r op yl-3-flu or o-6H-6-oxop yr id o[1,2-a ]-
p yr im id in e-7-ca r boxyla te (23, R2R3N ter t-BOCa m in o-

3080 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16
Li et al.
1-p yr r olid in yl). The above crude 22 was dissolved in dry
methylene chloride (5 mL) and cooled to 0 °C. To this solution
was added 3-[N-(tert-butoxycarbonyl)amino]pyrrolidine (0.25
g, 1.34 mmol), and the reaction mixture was stirred at room
temperature overnight. The solvent was removed, and the
product was purified by column chromatography, eluting with
10% methanol in methylene chloride to afford 0.295 g (100%)
of the title compound as a yellow solid, mp 159 160 °C. MS
in THF (40 mL) was stirred at room temperature for 2 h. The
solvent was evaporated off. The residue was then dissolved
in methylene chloride which was washed with water (3×),
dried over anhydrous magnesium sulfate, and concentrated.
The product was purified by column chromatography, eluting
with 5% methanol in methylene chloride, to afford 1.32 g (95%)
of 10 (R1 2,4-difluorophenyl, R2R3N
pyrrolidinyl) as a yellow crystalline solid, mp 104 107 °C. MS
(DCI/NH3): 700 (M
H). 1H NMR (CDCl3): δ 1.43 (m, 3H),
3-(CBZAla)amino-1-
(DCI/NH3): 523 (M
H). 1H NMR (CDCl3): δ 0.60 (m, 2H),
0.87 (m, 2H), 1.46 (s, 9H), 1.90 2.40 (m, 2H), 3.70 4.45 (m,
5H), 4.94 (br, 1H), 5.37 (s, 2H), 7.29 (m, 1H), 7.37 (m, 2H),
1.95 2.30 (m, 2H), 3.40 4.40 (m, 5H), 4.75 5.35 (m, 5H), 6.77
(m, 2H), 7.10 7.40 (m, 1H), 8.18 8.40 (m, 2H). IR (KBr):
1720, 1660 cm 1. Anal. (C37H32F3N5O6 1/2H2O) C, H, N.
The compound (1.26 g, 1.80 mmol) from the previous step
was suspended in methanol (80 mL) and formic acid (98%, 4.0
mL), and 10% Pd/C (0.200 g) was added. The mixture was
stirred at room temperature for 1.7 h. THF (40 mL) was then
added, and the mixture was stirred for an additional 0.3 h.
The catalyst was filtered off, and the filtrate was concentrated
to leave a yellow solid residue. This was dissolved in 500 mL
of water to which 4 mL of concentrated HCl was added. The
solution was filtered through sintered glass and freeze-dried
to afford 0.877 g (96%) of the title compound as a yellow solid,
7.50 (m, 2H), 7.99 (br, 1H), 9.10 (d, J
10 Hz, 1H). IR (KBr):
1715, 1685, 1660 cm 1. Anal. (C28H31FN4O5 1/2H2O) C, H, N.
c. 2-(3-Am in o-1-p yr r olid in yl)-9-cyclop r op yl-3-flu or o-
6H-6-oxop yr id o[1,2-a ]p yr im id in e-7-ca r boxylic Acid Hy-
d r och lor id e Sa lt (24a ). To the benzyl ester 23 (R2R3N
tert-BOCamino-1-pyrrolidinyl) (135 mg, 0.259 mmol) in metha-
nol (20 mL) and THF (2 mL) were added formic acid (98%, 2.0
mL) and 10% Pd/C (50 mg). This mixture was stirred at room
temperature for 37 min. The catalyst was removed by filtra-
tion, and the solvent was concentrated. The crude product was
purified by column chromatography, eluting with 1:5:100 acetic
acid:methanol:methylene chloride to afford the title compound
as a yellow solid after removal of the solvent. This solid was
reacted with 4 N HCl in dioxane (10 mL, 40 mmol) at room
temperature for 3 h. The solvent was removed; the yellow solid
was dissolved in distilled water and filtered through a sintered
glass funnel. The filtrate was freeze-dried to afford 68.1 mg
(71%) of the title compound as a yellow solid, mp 234 °C dec.
mp 198 200 °C dec. MS (FAB): 476 (M
(DMSO-d6): δ 1.33 (apparent t, J 7 Hz, 3H), 1.90 2.30 (m,
2H), 3.35 4.40 (m, 6H), 7.17 (m, 1H), 7.32 (m, 1H), 7.58 (m,
Cl). 1H NMR
1H), 8.20 (d, J
8 Hz, 1H), 9.19 (m, 1H), 13.45 (br, 1H). IR
(KBr): 1715, 1665, 1620 cm 1. Anal. (C22H21ClF3N5O4 1.5H2O)
C, H, N.
9-(2,4-Diflu or oph en yl)-3-flu or o-2-[3-(N-(S)-n or valylam i-
n o)-1-p yr r olid in yl]-6H-6-oxop yr id o[1,2-a ]p yr im id in e-7-
ca r boxylic Acid Hyd r och lor id e Sa lt (12a -N-Nov). The
title compound was prepared from N-[(benzyloxycarbonyl)-(S)-
norvalyl]succinamide using the same procedures as described
MS (DCI/NH3): 333 (M
2H), 0.96 (m, 2H), 2.20 2.65 (m, 3H), 3.58 4.35 (m, 5H), 7.80
Cl). 1H NMR (CDCl3): δ 0.64 (m,
1
(d, J
10 Hz, 1H), 9.05 (br, 1H). IR (KBr): 1665, 1620 cm .
Anal. (C16H17FN4O3 HCl H2O) C, H, N.
1
Following the same procedures as described above for 24a
and replacing the 3-BOCaminopyrrolidine with different amines,
the following compounds were made.
for 12a -N-Ala, mp 192 194 °C. MS (FAB): 504 (M H). H
NMR (CD3OD): δ 0.96 (m, 3H), 1.90 2.35 (m, 6H), 3.50 4.60
(m, 5H), 7.02 (m, 2H), 7.48 (m, 1H), 8.22 (br, 1H), 8.35 (br,
2H), 9.09 (m, 1H). IR (KBr): 1710, 1665, 1610 cm 1. Anal.
(C24H25F3N5O4 2H2O) C, H, N.
2-[3-(N-(S)-Ala n yl-(S)-a la n yla m in o)-1-p yr r olid in yl]-9-
(2,4-d iflu or op h en yl)-3-flu or o-6H-6-oxop yr id o[1,2-a ]p yr i-
m id in e-7-ca r b oxylic Acid H yd r och lor id e (12a -N-Ala -
9-Cyclop r op yl-3-flu or o-2-(1-m or p h olin yl)-6H-6-oxop y-
r id o[1,2-a ]p yr im id in e-7-ca r boxylic a cid (24a a ): mp 260
°C. MS (DCI/NH3): 334 (M
(m, 2H), 0.95 (m, 2H), 2.19 (m, 1H), 3.90 (t, J
H). 1H NMR (CDCl3): δ 0.68
6 Hz, 4H),
4.10 (t, J
6 Hz, 4H), 8.15 (s, 1H), 9.06 (d, J
10 Hz, 1H). IR
(KBr): 1720, 1660, 1620 cm 1. Anal. (C16H16FN3O4 H2O) C,
H, N.
Ala ). A mixture of 10 (R1
2,4-difluorophenyl, R2R3N
3-amino-1-pyrrolidinyl) (0.905 g, 1.83 mmol), N-(benzyloxy-
carbonyl)-(S)-alanyl-(S)-alanine (0.81 g, 2.75 mmol), 1-ethyl-
3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDAC)
(0.530 g, 2.76 mmol), and 1-hydroxybenzotriazole hydrate
(HOBT) (0.370 g, 2.74 mmol) in DMF (10 mL) was stirred for
30 min at 0 °C and then at room temperature for 2 h. The
solvent was removed using a Kugelrohr apparatus. The
residue was dissolved in methylene chloride, washed with
water (2×), saturated sodium bicarbonate solution (2×), and
water (2×), and dried over magnesium sulfate. The solvent
was removed, and the product was purified by column chro-
matography, eluting with 10% methanol in methylene chloride
to afford 1.19 g (84%) of 10 (R1 2,4-difluorophenyl, R2R3N
3-(CBZ-Ala-Ala)amino-1-pyrrolidinyl) as yellow crystals, mp
123 126 °C. MS (DCI/NH3): 771 (M H). 1H NMR (CDCl3):
δ 1.37 (m, 6H), 1.92 2.18 (m, 2H), 3.58 4.48 (m, 5H), 4.76
5.00 (m, 2H), 5.30 (s, 2H), 5.32 (s, 2H), 6.80 (m, 2H), 7.10
9-Cyclop r op yl-3-flu or o-2-(1-p ip er a zin yl)-6H-6-oxop y-
r id o[1,2-a ]p yr im id in e-7-ca r boxylic a cid (24bb): mp 198
199 °C. MS (DCI/NH3): 333 (M
0.67 (m, 2H), 0.94 (m, 2H), 2.19 (m, 1H), 3.08 (t, J
H). 1H NMR (CDCl3): δ
6 Hz,
10 Hz, 1H). IR
4H), 4.08 (m, 4H), 8.11 (s, 1H), 9.01 (d, J
(KBr): 1710, 1660 cm 1. Anal. (C16H17FN4O3 0.1H2O) C, H,
N.
9-Cyclop r op yl-3-flu or o-2-(4-m eth yl-1-p ip er a zin yl)-6H-
6-oxop yr id o[1,2-a ]p yr im id in e-7-ca r boxylic a cid (24cc):
mp 219 220 °C. MS (DCI/NH3): 347 (M
(CDCl3): δ 0.67 (m, 2H), 0.95 (m, 2H), 2.18 (m, 1H), 2.39 (s,
3H), 2.65 (t, J 6 Hz, 4H), 4.13 (m, 4H), 8.11 (s, 1H), 9.02 (d,
H). 1H NMR
1
J
10 Hz, 1H). IR (KBr): 1720, 1660, 1620 cm . Anal.
(C17H19FN4O3 0.6CH3COOH) C, H, N.
2-[3-(N-(S)-Ala n yla m in o)-1-p yr r olid in yl]-9-(2,4-d iflu o-
r op h en yl)-3-flu or o-6H -6-oxop yr id o[1,2-a ]p yr im id in e-7-
ca r boxylic Acid Hyd r och lor id e (12a -N-Ala ). a . 2-(3-
Am in o-1-p yr r olid in yl)-9-(2,4-d iflu or op h en yl)-3-flu or o-
7.45 (m, 1H), 8.23 and 8.30 (2s, 1H), 8.87 and 8.93 (2d, J
Hz, 1H). IR (KBr): 1720, 1660 cm 1. Anal. (C40H37F3N6O7
2H2O) C, H, N.
8
/
1
6H -6-oxop yr id o[1,2-a ]p yr im id in e-7-ca r b oxylic
Ben zyl E st er (10, R 1 2,4-d iflu or op h en yl, R 2R 3N
3-a m in o-1-p yr r olid in yl). A TFA (10 mL) solution of 10 (R1
2,4-difluorophenyl, R2R3N 3-tert-BOCamino-1-pyrrolidi-
Acid
The compound from the previous step (1.13 g, 1.47 mmol)
was dissolved in methanol (80 mL). Formic acid (98%, 4.0 mL)
and 10% Pd/C (0.20 g) were added. The mixture was stirred
for 1 h at room temperature. The catalyst was filtered off,
and the filtrate was concentrated to leave a yellow residue.
This was dissolved in 500 mL of distilled water containing 3
mL of concentrated HCl. The resulting solution was filtered
through a sintered glass funnel and freeze-dried to afford 0.729
g (85%) of the title compound as a pale yellow solid, mp 217
nyl) (2.56 g, 4.66 mmol) was stirred at room temperature for
1 h. The solvent was removed, and the residue was suspended
in methylene chloride and washed with saturated sodium
bicarbonate (1×) and water (2×). The organic solution was
dried over MgSO4 and concentrated to give 1.98 g (86%) of the
title compound, mp 185 186 °C. 1H NMR (CDCl3): δ 1.75
2.19 (m, 2H), 3.33 4.07 (m, 5H), 5.38 (s, 2H), 6.87 (m, 2H),
7.32 (m, 4H), 7.48 (m, 2H), 8.33 (s, 1H), 9.13 (apparent d, J
9 Hz, 1H).
219 °C dec. MS (FAB): 547 (M
δ 1.24 (m, 3H), 1.32 (d, J 7 Hz, 3H), 1.80 2.20 (m, 2H),
Cl). 1H NMR (DMSO-d6):
3.40 4.50 (m, 7H), 7.17 (m, 1H), 7.31 (m, 1H), 7.57 (m, 1H),
b. 12a -N-Ala . A suspension of 10 (R1 2,4-difluorophenyl,
R2R3N 3-amino-1-pyrrolidinyl) (0.982 g, 1.99 mmol) and (S)-
N-[(benzyloxycarbonyl)alanyl]succinamide (0.700 g, 2.22 mmol)
8.20 (br, 4H), 8.47 (m, 1H), 8.66 (m, 1H), 9.19 (m, 1H), 13.45
1
(br, 1H). IR (KBr): 1710, 1660, 1630 cm
F3N6O5 HCl H2O) C, H, N.
. Anal. (C25H25-

2-Pyridones as Potent DNA Gyrase Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16 3081
2-[(2S,4S)-4-(N-(S)-Ala n yl-(S)-a la n yla m in o)-2-m et h yl-
1-p yr r olid in yl]-9-(2,4-d iflu or op h en yl)-3-flu or o-6H-6-ox-
op yr id o[1,2-a ]p yr im id in e-7-ca r boxylic Acid Hyd r och lo-
r id e ((S,S)-12f-N-Ala -Ala ). The compound was prepared
rated brine (1×), dried over MgSO4, and concentrated in vacuo
with a bath temperature at ∼35 °C to give 3 as a pale yellow
liquid (89.13 g) which was used directly in the next step. MS
(DCI/NH3): 220 (M
H). 1H NMR (CDCl3): δ 1.47 (m, 9H),
from 10 (R1
2,4-difluorophenyl, R2R3N
(2S,4S)-4-tert-
2.12 (m, 3H). 19F NMR (CDCl3, CFCl3 as reference): δ 75.91
BOCamino-4-methyl-1-pyrrolidinyl) using the procedures de-
scribed for 12a -N-Ala and 12a -N-Ala-Ala, mp 198 200 °C. MS
(FAB): 561 (M Cl). 1H NMR (CD3OD): δ 1.14 and 1.40 (2d,
(dd apparent, J 1
(apparent dd, J 1
1F).
15.0 Hz, J 2
15.0 Hz, J 2
22.1 Hz, 1F), 93.17
22.1 Hz, 1F), 156.54 (m,
J
7 Hz, 3H), 1.34 and 1.35 (2d, J
7 Hz, 3H), 1.50 and 1.51
4-ter t-Bu toxy-3-eth yl-2,5,6-tr iflu or op yr id in e (31): fol-
lowing the procedure for 30, replacing the methyl iodide with
ethyl iodide. 1H NMR (CDCl3): δ 1.15 (t, J 7.5 Hz, 3H), 1.48
(2d, J 7 Hz, 3H), 1.96 2.11 (m, 2H), 3.50 4.60 (m, 6H), 7.40
(m, 2H), 7.47 (m, 1H), 8.26 and 8.29 (2s, 1H), 9.12 and 9.16
(2d, J
9 Hz, 1H). Anal. (C26H27F3N6O5 2.0HCl 2.0H2O) C,
(m, 9H), 2.61 (q, J
7.5 Hz, 2H).
H, N.
4-ter t-Bu toxy-3-m eth oxy-2,5,6-tr iflu or op yr id in e (33).
a . 4-ter t-Bu toxy-3-h yd r oxy-2,5,6-tr iflu or op yr id in e (32).
A solution of 29 (11.16 g, 54.39 mmol) in THF (50 mL) was
cooled to 78 °C. To this solution was added a solution of LDA
which was generated from diisopropylamine (9.20 mL, 65.6
mmol) and n-butyllithium (2.5 M in hexanes, 25.0 mL, 62.5
mmol) in THF (50 mL) with stirring. The mixture was stirred
for 30 min at 78 °C, during which a solid precipitated. To
this mixture was added trimethoxyborane (7.5 mL, 66.0 mmol)
with stirring at 78 °C. The reaction mixture was stirred at
78 °C for 25 min before adding 10 mL of acetic acid. The
mixture was stirred and allowed to warm to 0 °C. Next 30%
hydrogen peroxide (100 mL) and 2 N sodium hydroxide (100
mL) were added while cooling in an ice bath. The mixture
was then stirred at room temperature for 16 h followed by
quenching with saturated NH4Cl solution. The mixture was
extracted with ether, and the extract was washed with brine
and dried over MgSO4. The solvent was removed, and the
residue was purified by flash chromatography, eluting with
1:8 ethyl acetate:hexane to give 9.77 g (81%) of the title product
as a colorless liquid. MS (EI): 221 (M). 1H NMR (CDCl3): δ
1.51 (m, 9H), 5.17 (br, 1H). 19F NMR (CDCl3, CFCl3 as
reference): δ 92.41 (m, 1F), 97.44 (m, 1F), 153.87 (m, 1F).
Anal. (C9H10FNO2) C, H, N.
4-ter t-Bu toxy-3-ch lor o-2,5,6-tr iflu or op yr id in e (27). To
a stirred solution of 2,4,5,6-tetrafluoro-3-chloropyridine (25;
106.0 g, 0.400 mol, 70% pure from Aldrich, remainder 4-chloro-
2,3,5,6-tetrafluoropyridine) in anhydrous THF (250 mL) was
added a solution of NaO-tert-Bu (38.30 g, 0.3985 mol) in
anhydrous THF (350 mL), dropwise at 78 °C. After the
addition, the reaction mixture was stirred for 2 h at 78 °C
followed by ambient temperature for 16 h. The mixture was
poured into 500 mL of hexane and filtered through Celite. The
filtrate was concentrated in vacuo with a bath temperature of
30 35 °C. The residue was purified by chromatography,
eluting first with hexane and then AcOEt:hexane
1:16 to
give the byproduct 6-tert-butoxy-3-chloro-2,4,5-trifluoropyri-
dine as a colorless liquid (24.6 g, 26%), the mixture (9.5 g, 10%),
and 27 (51.29 g, 53%) as a colorless liquid, bp 63 66 °C (1.5
mmHg). MS (DCI/NH3): 238, 240 (M H). 1H NMR (CDCl3):
δ 1.52 (d, J
reference): δ 73.75 (dd, J 1
89.71 (dd, J 1 14.2 Hz, J 2 21.9 Hz, 1F), 152.42 (apparent
2 Hz, 9H). 19F NMR (CDCl3, CFCl3 as
14.2 Hz, J 2
23.2 Hz, 1F),
t, J
22 Hz, 1F).
4-ter t-Bu toxytetr a flu or op yr id in e (28). Pentafluoropy-
ridine (26) (158.5 g, 0.938 mmol) was dissolved in THF (600
mL) and cooled to 78 °C. To this was added sodium tert-
butoxide (88.29 g, 0.919 mmol) in anhydrous THF (800 mL)
over a 30 min period, with stirring while maintaining the
temperature at 78 °C. The mixture was stirred for another
30 min at this temperature. The temperature of the bath was
raised to 20 °C, and the reaction mixture was stirred at this
temperature for 64 h. The reaction mixture was removed from
the cold bath, diluted with 1.5 L of ether, and filtered through
a diatomaceous earth filter aid. The solvent was removed to
leave a yellow oil. The oil was purified by vacuum distillation
to afford 141.34 g (69%) of the title product, bp 43 44 °C (1
mmHg). MS (DCI/NH3): 238, 240 (M H). 1H NMR (CDCl3):
δ 1.48 (s, 9H). 19F NMR (CDCl3, CFCl3 as reference): δ 91.16
(m, 2F), 152.82 (m, 2F).
4-ter t-Bu toxy-2,5,6-tr iflu or op yr id in e (29). A mixture of
27 (90 g, 0.38 mol), triethylamine (83 g, 0.82 mol), and 10%
Pd(OH)2/C (dry form, 16.2 g) in ethyl acetate (1.9 L) was stirred
at ambient temperature for 18 h under 4 atm of hydrogen.
The mixture was filtered, and the filtrate was washed with
water (2×), dried over MgSO4, and concentrated. The dechlo-
rinated product was purified by chromatography (ethyl acetate:
hexane, 1:16) as a colorless liquid (65 g, 83%). MS (DCI/
NH3): 233 (M NH4). 1H NMR (CDCl3): δ 1.52 (s, 9H), 6.51
(m, 1H). 19F NMR (CDCl3, CFCl3 as reference): δ 72.60 (dd,
J 1 14.3 Hz, J 2 21.0 Hz, 1F), 89.74 (dd, J 1 14.3 Hz, J 2
b. 4-ter t-Bu toxy-3-m eth oxy-2,5,6-tr iflu or opyr idin e (33).
DEAD (5.04 mL, 32.0 mmol) was added dropwise to a stirred
solution of 32 (6.44 g, 29.1 mmol), triphenylphosphine (8.40
g, 32.03 mmol), and methanol (1.62 mL, 40.0 mmol) in
anhydrous THF (50 mL) at room temperature. The reaction
was complete in 10 min. The solvents were removed, and the
residue was purified by column chromatography, eluting with
1:16 ethyl acetate:hexane to give 6.22 g (91%) of the title
product as a colorless liquid. MS (DCI/NH3): 236 (M
H).
1H NMR (CDCl3): δ 1.47 (m, 9H), 3.90 (m, 3H). 19F NMR
(CDCl3, CFCl3 as reference): δ 86.45 (m, 1F), 93.31 (m, 1F),
154.31 (m, 1F).
4-ter t-Bu t oxy-2,5-d iflu or o-6-m et h ylp yr id in e (35). a .
4-t er t -Bu t oxy-3-ch lor o-2,5-d iflu or o-6-(t r im e t h ylsilyl-
m eth yl)p yr id in e (34). To a stirred solution of 4-tert-butoxy-
3-chlorotrifluoropyridine (27) (7.55 g, 31.51 mmol) in THF (200
mL) at 78 °C was added [(trimethylsilyl)methyl]lithium (1.0
M in pentane, 66 mL) dropwise. The resulting solution was
stirred for 1 h at 78 °C before quenching with saturated NaCl
solution. The mixture was extracted with ether, and the
extract was washed with brine, dried over MgSO4, and
concentrated. The residue was purified by column chroma-
tography, eluting with 1:32 ethyl acetate:hexane to give 6.26
g (65%) of title compound. 1H NMR (CDCl3): δ 0.05 (m, 9H),
4 Hz, 2H). 19F NMR (CDCl3, CFCl3
21.0 Hz, 1F), 164.68 (dt, J 1
4.2 Hz, J 2
21.0 Hz, 1F).
1.47 (m, 9H), 2.27 (d, J
as reference): δ 72.92 (d, J
30.6 Hz, 1F), 136.74 (d, J
4-ter t-Bu toxy-3-m eth yl-2,5,6-tr iflu or op yr id in e (30). n-
BuLi (2.5 M in hexanes, 185 mL, 0.463 mol) was added
dropwise via a syringe to a stirred solution of diisopropylamine
(65 mL, 0.464 mol) in anhydrous THF (250 mL) at 78 °C.
The reaction mixture was stirred for 5 min at 78 °C and at
0 °C for 15 min and then cooled back to 78 °C. The LDA
solution generated above was cannulated into a stirred solution
of 29 (79.55 g, 0.3877 mol) in anhydrous THF (500 mL) which
was precooled to 78 °C. The reaction mixture changed from
orange to brown with formation of a yellow precipitate.
Stirring was continued for 25 min at 78 °C. MeI (34.5 mL,
0.554 mol) was added dropwise to the above solution. The
mixture was allowed to stir at 78 °C for 30 min and at
ambient temperature for 30 min. The reaction was quenched
with saturated aqueous NH4Cl solution and the mixture
extracted with hexane. The extract was washed with satu-
30.6 Hz, 1F).
b. 4-ter t-Bu toxy-2,5-d iflu or o-6-m eth ylp yr id in e (35).
34 (6.26 g, 20.35 mmol) was shaken with 10% Pd/C (1.3 g)
and triethylamine (15 mL) in ethyl acetate (100 mL) under 4
atm of H2 for 24 h. The catalyst was filtered off, and the
filtrate was concentrated. The residue was purified by column
chromatography, eluting with 1:32 ethyl acetate:hexane to give
4.38 g (79%) of 4-tert-butoxy-2,5-difluoro-6-[(trimethylsilyl)-
methyl]pyridine as a colorless liquid. 4-tert-Butoxy-2,5-dif-
luoro-6-[(trimethylsilyl)methyl]pyridine (1.00 g, 3.66 mmol)
was stirred with Bu4NF (1.0 M in THF, 3.7 mL) in 10 mL of
THF at room temperature for 2.5 h. The solvent was removed,
and the residue was dissolved in ether, which was then washed
with water and brine, dried over MgSO4, and concentrated.
The product was purified by column chromatography, eluting

3082 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16
Li et al.
with 1:32 ethyl acetate:hexane, to give 0.68 g (93%) of the title
compound as a colorless liquid. This was used directly. 1H
NaHCO3 until the pH was ∼8 9. The mixture was extracted
with methylene chloride (2×). The extracts were washed with
water (2×), dried over MgSO4, and concentrated. The residue
was purified by column chromatography eluting with AcOEt:
hexane 3:7 to give 17.26 g (88%) of the title compound as a
white solid, mp 64 65 °C. MS (DCI/NH3): 272, 274 (M H).
1H NMR (CDCl3): δ 0.12 (m, 1H), 0.38 (m, 1H), 0.53 (m, 1H),
NMR (CDCl3): δ 1.50 (m, 9H), 2.41 (d, J
1H).
4 Hz, 3H), 6.45 (m,
(S)-8-(3-Am in o-1-p yr r olid in yl)-1-cyclop r op yl-7-flu or o-
9-m eth yl-4-oxo-4H-qu in olizin e-3-ca r boxylic Acid Hyd r o-
ch lor id e (ABT-719, (S)-45a ). a . 4-ter t-Bu toxy-3-m eth yl-
0.76 (m, 1H), 1.20 (t, J
3.23 (d, J
Anal. (C13H15ClFNO3) C, H, N.
7 Hz, 3H), 1.67 (m, 1H), 2.40 (s, 3H),
7 Hz, 2H), 8.36 (s, 1H).
2,5-d iflu or op yr id in e (36, Y
H, X
Me). The crude 30
9 Hz, 1H), 4.16 (q, J
(∼0.388 mol) and hydrazine monohydrate (100 mL, 2.06 mol)
were dissolved in 500 mL of n-propanol. The mixture was
heated to reflux for 3 h. The solvent was removed in vacuo,
and the residue was dissolved in methylene chloride which
was washed with water (2×) and concentrated to give the
intermediate hydrazino product as a yellow oil.
The above oil was dissolved in 700 mL of MeOH. To this
was added 150 mL of a 20% NaOH solution. Air was passed
through the above solution with vigorous stirring for 3 days
during which time another 50 mL of a 20% NaOH solution
was added. The mixture became deep blue. MeOH was
d . Eth yl 8-Ch lor o-1-cyclop r op yl-7-flu or o-9-m eth yl-4-
oxo-4H-qu in olizin e-3-ca r boxyla te (40, X Me, Y H, R1
cyclop r op yl). To a stirred solution of 38 (X Me, Y H,
R1 cyclopropyl) (5.577 g, 20.53 mmol) in anhydrous THF (10
mL) in a water bath cooling was added LiAlH4 (10.5 mL, 10.5
mmol, 1.0 N in THF) dropwise. The resulting mixture was
stirred at ambient temperature for 1 h, and then the reaction
was carefully quenched with water. A 20% NaOH solution
was added to dissolve the solid (Al2O3), and the mixture was
extracted with ether (1×). The extract was washed with
saturated brine (3×), dried over MgSO4, and concentrated to
give the alcohol as a pale yellow oil which was taken directly
on to the next step.
A solution of oxalyl chloride (2.0 N in CH2Cl2, 12.3 mL, 24.6
mmol) was added dropwise to a stirred solution of anhydrous
DMSO (3.6 mL, 50.73 mmol) in anhydrous methylene chloride
(40 mL) at 78 °C. After the mixture was stirred for an
additional 15 min, a solution of the above alcohol in 35 mL of
methylene chloride was added dropwise at 78 °C. The
solution was stirred for 15 min before triethylamine (14.2 mL,
102 mmol) was added. The stirring was continued at 78 °C
for 5 min and at 10 °C for 10 min. The reaction was
quenched with water and the mixture extracted with meth-
ylene chloride (2×). The combined extracts were washed with
water (1×), dried over MgSO4, and concentrated to give 4.70
g (theory: 4.67 g) of the aldehyde as a colorless oil which was
taken directly on to the next step.
The above aldehyde was dissolved in 150 mL of absolute
ethanol, and to this solution were added piperidine (5 mL),
acetic acid (5 mL), and diethyl malonate (16 mL, 105 mmol).
The solution was heated at reflux for 5 h. The solvents were
removed, and the residue was dissolved in ether. The ether
solution was washed with water (1×) and saturated brine (2×),
dried over MgSO4, and concentrated. The diethyl malonate
was removed by Kugelrohr distillation at 50 60 °C at 0.1
mmHg. The remaining yellow oil (7.77 g, theory: 7.59 g) was
dissolved in 30 mL of Dowtherm A (prepared from 23% of
biphenyl and 77% of phenyl ether, v/v). The solution was
added quickly to 100 mL of Dowtherm A preheated to 250 °C.
The mixture was stirred at 235 240 °C for 30 min before
cooling to room temperature. The reaction mixture was
transferred to a silica gel column directly, eluting first with
hexane to remove Dowtherm A and then with AcOEt:hexane
1:2 and finally with AcOEt to give 4.86 g of 40 (X Me, Y
removed in vacuo (bath temperature
30 °C). The residue
(dark brown-colored oil) was dissolved in ether which was
washed with water (1×), 2% HCl (1×), and saturated brine
(3×) and dried over MgSO4. The solvent was removed in vacuo
and the crude product purified by column chromatography
eluting first with hexane followed by AcOEt:hexane
1:32
and 1:16 to give 71.12 g of the title compound as a colorless
liquid (91% in three steps), bp 50 60 °C (1.0 mmHg). MS
(DCI/NH3): 202 (M H). 1H NMR (CDCl3): δ 1.43 (d, J
1.5
Hz, 9H), 2.18 (d, J
1.5 Hz, 3H), 7.85 (br, 1H). 19F NMR
(CDCl3, CFCl3 as reference): δ 73.37 (d, J
24.5 Hz, 1F),
142.17 (d, J
24.5 Hz, 1F).
b. 2-(4-ter t-Bu toxy-5-flu or o-3-m eth yl-2-p yr id in yl)cy-
clop r op yla ceton itr ile (37, X Me, Y H, R1 cyclop r o-
p yl). A freshly prepared solution of LDA (0.103 mol) (14.4
mL of diisopropylamine and 40.5 mL of n-BuLi (2.5 M in
hexanes) in 50 mL of THF) was added dropwise to a stirred
solution of cyclopropylacetonitrile (8.30 g, 0.102 mol) in 50 mL
of anhydrous THF at 78 °C. The mixture was stirred at 78
°C for 15 min and then cannulated into a stirred solution of
4-tert-butoxy-3-methyl-2,5-difluoropyridine (36, X Me, Y
H) (8.21 g, 40.80 mmol) in 40 mL of anhydrous THF at 78
°C. Stirring was continued for 1 h at 78 °C followed by 1 h
at 0 °C. The reaction was then quenched with saturated
aqueous NH4Cl solution and the mixture extracted with ether
(2×). The extracts were washed with saturated brine (2×),
dried over MgSO4, and concentrated. The product was purified
by column chromatography eluting with AcOEt:hexane 1:4
to yield 37 (X Me, Y H, R1
liquid, which solidified on standing (10.33 g, 97%), mp 52 54
°C. MS (DCI/NH3): 263 (M
H). 1H NMR (CDCl3): δ 0.50
(m, 2H), 0.63 (m, 1H), 0.73 (m, 1H), 1.60 (m, 1H), 1.43 (d, J
cyclopropyl) as a colorless
2 Hz, 9H), 2.29 (s, 3H), 3.76 (d, J
8 Hz, 1H), 8.30 (d, J
3
-
Hz, 1H). IR (neat): 2240, 1580, 1470 cm 1. Anal. (C15H19
FN2O) C, H, N.
H, R1
mp 143 144 °C. MS (DCI/NH3): 324, 326 (M H). 1H NMR
(CDCl3): δ 0.75 (m, 2H), 1.07 (m, 2H), 1.42 (t, J 7 Hz, 3H),
2.31 (m, 1H), 3.08 (s, 3H), 4.42 (q, J 7 Hz, 2H), 8.40 (s, 1H),
9.44 (d, J 6 Hz, 1H). Anal. (C16H15ClFNO3) C, H, N, Cl.
cyclopropyl) as a yellow solid (73% in four steps),
c. Eth yl 2-(4-Ch lor o-5-flu or o-3-m eth yl-2-p yr id in yl)-
cyclop r op yla ceta te (38, X Me, Y H, R1 cyclop r op yl).
A trifluoroacetic acid solution (150 mL) of 37 (X Me, Y H,
R1
cyclopropyl) (70.8 g, 0.27 mol) was stirred at room
temperature for 1 h. The TFA was then removed in vacuo,
and the residue was further dried under vacuum to give an
oily material.
(S)-8-(3-Am in o-1-p yr r olid in yl)-1-cyclop r op yl-7-flu or o-
9-m eth yl-4-oxo-4H-qu in olizin e-3-ca r boxylic Acid Hyd r o-
ch lor id e (ABT-719, (S)-45a ). A mixture of 40 (X Me, Y
H) (7.0 g, 21.6 mmol), (3S)-3-(tert-BOCamino)pyrrolidine (8.3
g, 44.6 mmol), and sodium bicarbonate (8.5 g, 0.101 mol) in
100 mL of anhydrous acetonitrile was refluxed for 4 h. After
cooling to room temperature, the reaction mixture was diluted
with methylene chloride, washed with water (1×), 5% HCl
(1×), and water (2×) again, dried over MgSO4, and concen-
trated. The residue which weighed 11.25 g (theory: 10.23 g)
was used directly in the next step.
To the above product in 750 mL of anhydrous methylene
chloride and 100 mL of DMF was added slowly POCl3 (127
mL) with water bath cooling. The solution was stirred
overnight. It was then poured over ice and extracted with
methylene chloride (2×). The combined extracts were washed
with water (1×), saturated NaHCO3 solution (1×), and water
(2×), dried over MgSO4, and concentrated. The chloronitrile
was purified by column chromatography, eluting with AcOEt:
hexane
1:4, as a pale yellow solid (45.16 g, 75%).
The above chloronitrile (16.25 g, 0.072 mol) was dissolved
in 72 mL of absolute ethanol and cooled with an ice bath.
Anhydrous gaseous HCl was bubbled through this solution
until 38 g had been dissolved (saturated). Then water (1.6
mL, 0.089 mol) was added, and the mixture was heated to 80
85 °C for 3 h. After cooling to room temperature, 100 mL of
water was added followed by cautious addition of solid
A mixture of the above product (∼21.6 mmol) and LiOH H2O
(10.3 g, 0.245 mol) in 360 mL of THF and 185 mL of water
was stirred for 10 h at 60 °C. After cooling to room temper-
ature, 266 mL of 1.0 N HCl was added followed by 500 mL of
water. The solid was filtered and washed with water until
the pH of the washes became ∼7. The solid was then dissolved
in methylene chloride. The resulting solution was washed

2-Pyridones as Potent DNA Gyrase Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16 3083
with water once, dried over MgSO4, and concentrated to give
the product as a yellow solid (8.54 g, 89%). This material 45
9.12 (d, J
11 Hz, 1H), 11.14 (br, 1H), 13.83 (br, 1H). Anal.
(C20H24FN3O3 1/4H2O) C, H, N.
(X CH3, Y H, R2R3N
(S)-3-t-BOCamino-1-pyrrolidinyl)
8-(cis-3-Am in o-4-m eth yl-1-p yr r olid in yl)-1-cyclop r op yl-
7-flu or o-9-m eth yl-4-oxo-4H-qu in olizin e-3-ca r boxylic a cid
h yd r och lor id e (45d ): mp 207 208 °C. MS (FAB): 360 (M
Cl). 1H NMR (DMSO-d6): δ 0.60 (m, 2H), 0.99 (m, 2H), 1.18
was taken directly to the next step, mp 129 130 °C. 1H NMR
(CDCl3): δ 0.68 (m, 2H), 1.00 (m, 2H), 1.49 (s, 9H), 2.12 (m,
2H), 2.29 (m, 1H), 2.62 (s, 3H), 3.60 (m, 1H), 3.79 (m, 1H),
3.98 (m, 2H), 4.37 (m, 1H), 5.10 (br, 1H), 8.13 (s, 1H), 8.99 (d,
(d, J
7 Hz, 3H), 2.30 (m, 1H), 2.62 (s, 3H), 3.48 4.00 (m,
J
11 Hz, 1H). Anal. (C23H28FN3O5 1/4H2O) C, H, N.
6H), 7.94 (s, 1H), 8.40 (m, 3H), 9.10 (d, J 10.5 Hz, 1H). Anal.
(C19H22FN3O3 HCl 1.25H2O) C, H, N.
A solution of HCl in acetic acid (1.0 N, 85 mL) was added
8-(tr a n s-3-Am in o-4-m et h oxy-1-p yr r olid in yl)-1-cyclo-
p r op yl-7-flu or o-9-m eth yl-4-oxo-4H-qu in olizin e-3-ca r box-
at room temperature to a stirred solution of the above crude
product in 85 mL of anhydrous methylene chloride. After
stirring for 10 min, a precipitate began to appear. After
stirring for another 30 min, more methylene chloride was
added and the precipitate was collected by filtration and
washed with methylene chloride. The solid was dissolved in
distilled water, filtered through a sintered glass funnel, and
freeze-dried to give (S)-45a (ABT-719) as a yellow solid (7.16
g, 83% in three steps), mp 252 255 °C dec. MS (FAB): 346
(M Cl). 1H NMR (DMSO-d6): δ 0.59 (m, 2H), 0.99 (m, 2H),
2.14 (m, 1H), 2.31 (m, 2H), 2.63 (s, 3H), 3.76 (m, 2H), 3.98
ylic a cid h yd r och lor id e (45e): mp
250 °C dec. MS
(FAB): 376 (M Cl). 1H NMR (CD3OD): δ 0.71 (m, 2H), 1.88
(m, 2H), 2.30 (m, 1H), 2.74 (s, 3H), 3.51 (s, 3H), 3.84 (m, 2H),
3.98 (m, 1H), 4.24 (m, 3H), 8.02 (s, 1H), 9.02 (d, J
3.5 Hz,
1H). Anal. (C19H22FN3O4 HCl 4H2O) C, H; N: calcd, 8.68;
found, 9.36.
8-((2S,4S)-4-Am in o-2-m et h yl-1-p yr r olid in yl)-1-cyclo-
p r op yl-7-flu or o-9-m eth yl-4-oxo-4H-qu in olizin e-3-ca r box-
ylic a cid h yd r och lor id e ((S,S)-45f): mp 185 187 °C dec.
4.07 (m, 3H), 7.94 (s, 1H), 8.36 (br, 3H), 9.11 (d, J
11 Hz,
MS (DCI/NH3): 360 (M
Cl). 1H NMR (DMSO-d6): δ 0.51
1H). Anal. C18H20FN3O3 1.15HCl H2O) C, H, N, Cl
(m, 1H), 0.63 (m, 1H), 0.90 (m, 1H), 1.09 (m, 1H), 1.17 (d, J
6 Hz, 3H), 2.01 (m, 1H), 2.40 (m, 2H), 2.64 (s, 3H), 3.40 (m,
1H), 3.98 (m, 1H), 4.31 (m, 1H), 4.61 (m, 1H), 8.00 (s, 1H),
Following the procedures described for (S)-45a , starting
from either different amines (Figure 2, a gg) or different
pyridines (Scheme 4, 27 29, 31, 33, 35), the following com-
pounds were made.
9.17 (d, J
11 Hz, 1H). Anal. (C19H22FN3O3 HCl H2O) C, H,
N.
8-((2S,4R)-4-Am in o-2-m et h yl-1-p yr r olid in yl)-1-cyclo-
p r op yl-7-flu or o-9-m eth yl-4-oxo-4H-qu in olizin e-3-ca r box-
ylic a cid h yd r och lor id e ((S,R)-45h ): mp 184 185 °C dec.
MS (DCI/NH3): 360 (M
(m, 1H), 0.59 (m, 1H), 0.85 (m, 1H), 1.06 (m, 1H), 1.12 (d, J
1-Cyclop r op yl-9-ch lor o-7-flu or o-8-(3-a m in o-1-p yr r o-
lid in yl)-4-oxo-4H-qu in olizin e-3-ca r boxylic a cid tr iflu o-
r oa cetic a cid sa lt (42a ): mp 125 127 °C. MS (FAB): 366
(M CF3CO2). 1H NMR (DMSO-d6): δ 0.58 (m, 2H), 0.97 (m,
2H), 2.11 (m, 1H), 2.31 (m, 1H), 2.44 (m, 1H), 3.83 (m, 1H),
3.97 (m, 2H), 4.10 (m, 1H), 4.20 (m, 1H), 8.09 (s, 1H), 8.09 (br,
Cl). 1H NMR (DMSO-d6): δ 0.50
6 Hz, 3H), 1.22 (m, 1H), 1.75 (m, 1H), 2.33 (m, 1H), 2.57 (s,
1H), 7.98 (s, 1H), 8.48 (br, 3H), 9.02 (d, J
10 Hz, 1H). Anal.
3H), 9.18 (d, J
11 Hz, 1H). Anal. (C17H17ClFN3O3 CF3-
(C19H22FN3O3 HCl H2O) C, H, N.
COOH 0.5H2O) C, H, N.
8-(3-Am in o-3-m et h yl-1-p yr r olid in yl)-1-cyclop r op yl-7-
flu or o-9-m eth yl-4-oxo-4H-qu in olizin e-3-ca r boxylic a cid
h yd r och lor id e (45i): mp 243 247 °C dec. MS (FAB): 360
8-(3-Am in o-1-p yr r olid in yl)-1-cyclop r op yl-7,9-d iflu or o-
4-oxo-4H -q u in olizin e-3-ca r b oxylic a cid h yd r och lor id e
(43a ): mp 167 170 °C dec. MS (FAB): 350 (M Cl). 1H NMR
(DMSO-d6): δ 0.65 (m, 2H), 0.90 (m, 2H), 2.15 2.30 (m, 3H),
3.95 4.00 (m, 3H), 4.18 (m, 2H), 7.81 (s, 1H), 8.46 (br, 3H),
(M
1.63 (s, 3H), 2.31 (m, 3H), 2.74 (s, 3H), 3.95 (m, 4H), 8.12 (s,
Cl). 1H NMR (CD3OD): δ 0.69 (m, 2H), 1.07 (m, 2H),
1H), 9.14 (d, J
9 Hz, 1H). Anal. (C19H23ClFN3O3 H2O) C,
9.17 (d, J
9 Hz, 1H). Anal. (C17H17F2N3O3 HCl H2O) C, H,
H, N.
N.
1-Cyclop r op yl-7-flu or o-8-(3-h yd r oxy-1-p yr r olid in yl)-9-
m eth yl-4-oxo-4H-qu in olizin e-3-ca r boxylic a cid h yd r o-
ch lor id e (45j): mp 232 234 °C. MS (DCI/NH3): 346 (M
H). 1H NMR (DMSO-d6): δ 0.59 (m, 2H), 0.93 (m, 1H), 1.03
(m, 1H), 1.96 2.01 (m, 3H), 2.29 (m, 1H), 2.49 (s, 3H), 3.43
(m, 1H), 3.69 (m, 1H), 4.01 (m, 2H), 4.42 (m, 1H), 5.15 (d, J
1-Cyclopr opyl-7-flu or o-8-(1-piper azin yl)-4-oxo-4H-qu in -
olizin e-3-ca r boxylic a cid h yd r och lor id e (44cc): mp 219
220 °C. MS (FAB): 332 (M Cl). 1H NMR (DMSO-d6): δ 0.61
(m, 2H), 1.03 (m, 2H), 2.09 (m, 1H), 3.33 (m, 4H), 3.85 (m,
4H), 7.50 (d, J
9 Hz, 1H), 7.87 (s, 1H), 9.26 (d, J
11 Hz,
1H), 13.88 (br, 1H). Anal. (C17H18FN3O3 2HCl) C, H, N.
(R)-8-(3-Am in o-1-p yr r olid in yl)-1-cyclop r op yl-7-flu or o-
9-m eth yl-4-oxo-4H-qu in olizin e-3-ca r boxylic a cid h yd r o-
3 Hz, 1H), 7.89 (s, 1H), 9.05 (d, J
11 Hz, 1H), 13.86 (br,
1H). IR (KBr): 3425, 1690, 1650, 1600 cm 1. Anal. (C18H19
FN2O4) C, H, N.
-
ch lor id e ((R)-45a ): mp 243 246 °C dec. MS (FAB): 346 (M
1-Cyclopr opyl-7-flu or o-8-(3(S)-h ydr oxy-1-pyr r olidin yl)-
9-m et h yl-4-oxo-4H -q u in olizin e-3-ca r b oxylic a cid ((S)-
45j): mp 244 245 °C. MS (DCI/NH3): 347 (M H). 1H NMR
(DMSO-d6): δ 0.58 (m, 2H), 0.93 (m, 1H), 1.03 (m, 1H), 1.96
2.02 (m, 2H), 2.29 (m, 1H), 2.59 (s, 3H), 3.41 (m, 1H), 3.69 (m,
1
Cl). IR (KBr): 3440, 1700, 1650, 1610 cm
.
1H NMR
(DMSO-d6): δ 0.59 (m, 2H), 1.00 (m, 2H), 2.15 (m, 1H), 2.31
(m, 2H), 2.63 (s, 3H), 3.76 (m, 2H), 4.00 4.07 (m, 3H), 8.40
(br, 3H), 9.10 (d, J
11 Hz, 1H). Anal. (C18H20FN3O3
HCl H2O) C, H, N.
1H), 4.01 (m, 2H), 4.42 (m, 1H), 5.16 (d, J
3 Hz, 1H), 7.89
8-(3-Am in o-1-p yr r olid in yl)-1-cyclop r op yl-7-flu or o-9-
m eth yl-4-oxo-4H-qu in olizin e-3-ca r boxylic a cid h yd r o-
ch lor id e (45a ): mp 230 232 °C dec. MS (FAB): 346 (M
Cl). 1H NMR (DMSO-d6): δ 0.58 (m, 2H), 0.99 (m, 2H), 2.15
(m, 1H), 2.31 (m, 2H), 2.63 (s, 3H), 3.77 (m, 2H), 3.99 4.06
(s, 1H), 9.04 (d, J
FN2O4) C, H, N.
11 Hz, 1H), 13.86 (s, 1H). Anal. (C18H19
-
1-Cyclopr opyl-7-flu or o-8-(3(R)-h ydr oxy-1-pyr r olidin yl)-
9-m et h yl-4-oxo-4H-q u in olizin e-3-ca r boxylic a cid ((R)-
45j): mp 244 245 °C. MS (DCI/NH3): 347 (M H). 1H NMR
(DMSO-d6): δ 0.58 (m, 2H), 0.92 (m, 1H), 1.02 (m, 1H), 1.94
2.00 (m, 2H), 2.29 (m, 1H), 2.59 (s, 3H), 3.41 (m, 1H), 3.69 (m,
(m, 3H), 7.94 (s, 1H), 8.39 (br, 3H), 9.10 (d, J
11 Hz, 1H),
Anal. (C18H20-
1
13.85 (br, 1H). IR: 3440, 1695, 1610 cm
.
3
FN3O3 HCl /4H2O) C, H, N.
1H), 4.01 (m, 2H), 4.43 (m, 1H), 5.15 (d, J
3 Hz, 1H), 7.88
(S)-1-Cyclopr opyl-7-flu or o-9-m eth yl-8-[3-(m eth ylam in o)-
1-p yr r olid in yl]-4-oxo-4H-qu in olizin e-3-ca r boxylic a cid
h yd r och lor id e ((S)-45b): mp 223 225 °C dec. MS (FAB):
360 (M
2H), 2.26 (m, 1H), 2.33 (m, 3H), 2.65 (s, 6H), 3.75 (m, 1H),
3.90 (m, 2H), 4.05 (m, 2H), 7.94 (s, 1H), 9.12 (d, J 10 Hz,
(s, 1H), 9.03 (d, J
FN2O4) C, H, N.
11 Hz, 1H), 13.86 (s, 1H). Anal. (C18H19
-
1-Cyclop r op yl-7-flu or o-9-m eth yl-4-oxo-8-[3-((S)-1-p yr -
r olyl)-1-p yr r olid in yl]-4H-qu in olizin e-3-ca r boxylic Acid
((S)-45k ). A mixture of (S)-45a (25 mg, 0.070 mmol) and
sodium acetate (40 mg, 0.49 mmol) in 0.7 mL of acetic acid
was heated to 100 °C. To this solution was added dimethoxy-
tetrahydrofuran (9 µL, 0.070 mmol) dropwise. The reaction
mixture was stirred at 110 °C for 5 min, and then the reaction
was quenched by the addition of water. The mixture was
extracted twice with methylene chloride, and the extracts were
washed with water, dried over MgSO4, and concentrated. The
residue was purified by preparative TLC, eluting with 100:10
Cl). 1H NMR (DMSO-d6): δ 0.62 (m, 2H), 1.00 (m,
1H), 9.18 (br s, 2H), 13.86 (br, 1H). IR (KBr): 3450, 1710,
1650, 1610 cm 1. Anal. (C19H22FN3O3 HCl H2O) C, H, N.
(S)-1-Cyclopr opyl-8-[3-(dim eth ylam in o)-1-pyr r olidin yl]-
7-flu or o-9-m eth yl-4-oxo-4H-qu in olizin e-3-ca r boxylic a cid
1
((S)-45c): mp 146 148 °C. MS (DCI/NH3): 374 (M H). H
NMR (DMSO-d6): δ 0.64 (m, 2H), 1.02 (m, 2H), 2.23 2.43 (m,
3H), 2.66 (s, 3H), 2.83 (s, 6H), 3.78 4.17 (m, 5H), 7.95 (s, 1H),

3084 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16
Li et al.
chloroform:methanol, to give 13.6 mg (55%) of the title product
as a yellow solid, mp 208 209 °C. MS (DCI/NH3): 396 (M
H). 1H NMR (CDCl3): δ 0.67 (m, 2H), 1.00 (m, 2H), 2.20 (m,
1H), 2.46 (m, 1H), 2.56 (m, 1H), 2.66 (s, 3H), 3.89 (m, 1H),
[3.3.0]octane for the (S)-3-tert-BOCaminopyrrolidine, mp 199
202 °C. MS (FAB): 372 (M Cl). 1H NMR (DMSO-d6): δ 0.62
(m, 2H), 1.00 (m, 2H), 1.98 (m, 1H), 2.18 (m, 1H), 2.35 (m,
1H), 2.69 (s, 3H), 3.12 (m, 1H), 3.27 (m, 1H), 3.71 (m, 2H),
3.93 (m, 1H), 4.05 (m, 1H), 4.31 (m, 1H), 8.00 (s, 1H), 9.17 (d,
3.99 (m, 2H), 4.15 (m, 1H), 4.86 (m, 1H), 6.23 (t, J
2H), 6.79 (t, J 2 Hz, 2H), 8.32 (s, 1H), 9.15 (d, J
2 Hz,
10 Hz,
J
12 Hz, 1H). Anal. (C20H22FN3O3 HCl H2O) C, H, N.
1H), 13.83 (br, 1H). Anal. (C22H22FN3O3 1/4H2O) C, H, N.
1-Cyclop r op yl-7-flu or o-9-m et h yl-8-[3-(1,2,3-t r ia zol-1-
yl)-1-pyr r olidin yl]-4-oxo-4H-qu in olizin e-3-car boxylic acid
(45l): mp 183 184 °C. MS (DCI/NH3): 398 (M H). 1H NMR
(DMSO-d6): δ 0.61 (m, 2H), 0.99 (m, 2H), 2.31 (m, 1H), 2.56
(m, 2H), 2.62 (s, 3H), 3.84 (m, 1H), 3.99 (m, 1H), 4.10 (m, 1H),
4.36 (m, 1H), 5.46 (m, 1H), 7.80 (s, 1H), 7.92 (s, 1H), 8.32 (s,
1-Cyclopr opyl-8-((1S,5S)-2,7-diaza-7-bicyclo[3.3.0]octyl)-
7-flu or o-9-m eth yl-4-oxo-4H-qu in olizin e-3-car boxylic Acid
Hyd r och lor id e ((S,S)-45o). a . Sep a r a tion of th e Tw o
En a n tiom er s of 2-CBZ-7-ter t-BOC-2,7-d ia za bicyclo[3.3.0]-
octa n e. The racemic 2-CBZ-7-tert-BOC-2,7-diazabicyclo[3.3.0]-
octane prepared above in 45o was separated by preparative
HPLC using a Chiralpak column eluting with hexane:ethanol
90:10. The compound with a lower retention time (tR 8.3
min on an analytical column (AD 4.6 × 250 mm) with flow
rate of 1.0 mL/min) was assigned arbitrarily as (R,R)-2-CBZ-
7-BOC-2,7-diazabicyclo[3.3.0]octane. The compound with higher
1H), 9.11 (d, J
11 Hz, 1H). Anal. (C20H20FN5O3) C, H, N.
1-Cyclopr opyl-8-((1S,4S)-2,5-d ia za bicyclo[2.2.1]h epta n -
2-yl)-7-flu or o-9-m eth yl-4-oxo-4H-qu in olizin e-3-ca r boxy-
lic a cid h yd r och lor id e (45m ): mp 235 238 °C dec. MS
Cl). 1H NMR (DMSO-d6): δ 0.59 (m, 1H),
retention time (tR
17.2 min on an analytical column (AD
(FAB): 358 (M
4.6 × 250 mm) with flow rate of 1.0 mL/min) was arbitrarily
assigned as (S,S)-2-CBZ-7-BOC-2,7-diazabicyclo[3.3.0]octane.
b. 1-Cyclop r op yl-8-((1S,5S)-2,7-d ia za -7-bicyclo[3.3.0]-
octyl)-7-flu or o-9-m eth yl-4-oxo-4H-qu in olizin e-3-ca r boxy-
lic Acid Hyd r och lor id e ((S,S)-45o). Following the same
procedures as described for 45o, using the above arbitrarily
assigned optically pure (S,S)-2-CBZ-7-tert-BOC-2,7-diazabicyclo-
[3.3.0]octane, the title compound was obtained, mp 193 195
0.93 (m, 1H), 1.06 (m, 1H), 2.05 (m, 1H), 2.31 (m, 2H), 2.59 (s,
3H), 3.45 (m, 2H), 3.61 (m, 1H), 4.09 (m, 1H), 4.51 (m, 1H),
4.96 (m, 1H), 7.97 (s, 1H), 9.07 (br, 1H), 9.20 (d, J
10.5 Hz,
1H), 9.54 (br, 1H). Anal. (C19H20FN3O3 1.5HCl H2O) C, H,
N.
1-Cyclop r op yl-8-(2,8-d ia za -8-bicyclo[4.3.0]n on yl)-7-flu -
or o-9-m eth yl-4-oxo-4H-qu in olizin e-3-ca r boxylic a cid h y-
d r och lor id e (45n ): mp 250 253 °C dec. MS (FAB): 386 (M
Cl). 1H NMR (DMSO-d6): δ 0.56 (m, 1H), 0.62 (m, 1H), 0.93
(m, 1H), 1.07 (m, 1H), 1.60 1.80 (m, 4H), 2.28 2.32 (m, 2H),
2.67 (s, 3H), 2.72 (m, 1H), 2.94 (m, 1H), 3.70 (m, 2H), 3.91 (m,
1H), 4.03 (m, 1H), 4.35 (m, 1H), 7.93 (s, 1H), 8.90 (br, 1H),
°C. MS (FAB): 372 (M
Cl). 1H NMR (DMSO-d6): δ 0.62
(m, 2H), 1.00 (m, 2H), 1.98 (m, 1H), 2.18 (m, 1H), 2.36 (m,
1H), 2.69 (s, 3H), 3.13 (m, 1H), 3.28 (m, 1H), 3.71 (m, 2H),
3.91 (m, 1H), 4.04 (m, 1H), 4.31 (m, 1H), 8.00 (s, 1H), 9.17 (d,
J
11 Hz, 1H). Anal. (C20H22FN3O3 HCl 1.5H2O) C, H, N.
1-Cyclopr opyl-8-((1R,5R)-2,7-diaza-7-bicyclo[3.3.0]octyl)-
9.10 (d, J
11 Hz, 1H), 9.48 (br, 1H), 13.85 (br, 1H). IR
(KBr): 3400, 1690, 1650, 1600 cm 1. Anal. (C21H26Cl2FN3O3)
C, H, N.
7-flu or o-9-m eth yl-4-oxo-4H-qu in olizin e-3-ca r boxylic a cid
h yd r och lor id e ((R,R)-45o): same as described for (S,S)-45o,
using the arbitrarily assigned optically pure (R,R)-2-CBZ-7-
tert-BOC-2,7-diazabicyclo[3.3.0]octane (see (S,S)-45o), mp 190
192 °C. MS (FAB): 372 (M Cl). 1H NMR (DMSO-d6): δ 0.62
(m, 2H), 1.00 (m, 2H), 1.98 (m, 1H), 2.18 (m, 1H), 2.35 (m,
1H), 2.69 (s, 3H), 3.12 (m, 1H), 3.27 (m, 1H), 3.71 (m, 2H),
3.93 (m, 1H), 4.05 (m, 1H), 4.31 (m, 1H), 8.00 (s, 1H), 9.17 (d,
1-Cyclopr opyl-8-((1S,6S)-2,8-diaza-8-bicyclo[4.3.0]n on yl)-
7-flu or o-9-m eth yl-4-oxo-4H-qu in olizin e-3-ca r boxylic a cid
h ydr och lor ide ((S,S)-45n ): mp 232 234 °C. [ ]23
281.3°
D
(c
0.52, methanol). MS (FAB): 386 (M
Cl). 1H NMR
(DMSO-d6): δ 0.56 (m, 1H), 0.62 (m, 1H), 0.92 (m, 1H), 1.07
(m, 1H), 1.61 1.81 (m, 4H), 2.30 (m, 1H), 2.56 (m, 1H), 2.67
(s, 3H), 2.92 (m, 1H), 3.25 (m, 1H), 3.69 (m, 2H), 3.90 (m, 1H),
4.06 (m, 1H), 4.35 (m, 1H), 7.92 (s, 1H), 9.02 (br, 1H), 9.09 (d,
J
11 Hz, 1H). Anal. (C20H22FN3O3 HCl 1.75H2O) C, H, N.
J
11 Hz, 1H), 9.59 (br, 1H). Anal. (C21H24FN3O3
8-[3-(1-Am in om eth yl)-1-p yr r olid in yl]-1-cyclop r op yl-7-
HCl 1.25H2O) C, H, N.
flu or o-9-m eth yl-4-oxo-4H-qu in olizin e-3-ca r boxylic a cid
h yd r och lor id e (45p ): mp 233 235 °C. MS (DCI/NH3): 360
(M Cl). 1H NMR (DMSO-d6): δ 0.60 (m, 2H), 0.99 (m, 2H),
1.81 (m, 1H), 2.18 (m, 1H), 2.30 (m, 1H), 2.60 (s, 3H), 2.98 (m,
2H), 3.66 3.81 (m, 5H), 7.90 (s, 1H), 8.09 (br, 3H), 9.06 (d, J
11 Hz, 1H), 13.85 (br, 1H). Anal. (C19H22FN3O3 HCl H2O)
C, H, N.
1-Cyclop r op yl-8-((1R ,6R )-2,8-d ia za -8-b icyclo[4.3.0]-
n on a n yl)-1-cyclop r op yl-7-flu or o-9-m eth yl-4-oxo-4H-qu in -
olizin e-3-ca r boxylic a cid h yd r och lor id e ((R,R)-45n ): mp
184 185 °C. [ ]23
(FAB): 386 (M
275.1° (c
0.53, methanol). MS
D
Cl). 1H NMR (DMSO-d6): δ 0.56 (m, 1H),
0.62 (m, 1H), 0.92 (m, 1H), 1.08 (m, 1H), 1.63 1.81 (m, 4H),
2.31 (m, 1H), 2.56 (m, 1H), 2.68 (s, 3H), 2.91 (m, 1H), 3.25 (m,
1H), 3.69 (m, 2H), 3.90 (m, 1H), 4.06 (m, 1H), 4.35 (m, 1H),
7.92 (s, 1H), 9.02 (br, 1H), 9.09 (d, J
1H). Anal. (C21H24FN3O3 HCl 1.5H2O) C, H, N.
1-Cyclop r op yl-8-(2,7-d ia za -2-bicyclo[3.3.0]octyl)-1-cy-
clop r op yl-7-flu or o-9-m eth yl-4-oxo-4H-qu in olizin e-3-ca r -
boxylic a cid h yd r och lor id e (45q): mp 175 177 °C. MS
11 Hz, 1H), 9.60 (br,
(FAB): 372 (M
Cl). 1H NMR (DMSO-d6): δ 0.60 (m, 2H),
0.91 (m, 1H), 2.03 2.10 (m, 3H), 2.36 (m, 1H), 2.68 (s, 3H),
3.19 (m, 1H), 3.49 (m, 2H), 4.15 (m, 1H), 5.50 (m, 1H), 7.98 (s,
1-Cyclop r op yl-8-(2,7-d ia za -7-bicyclo[3.3.0]octyl)-7-flu -
or o-9-m eth yl-4-oxo-4H-qu in olizin e-3-ca r boxylic Acid Hy-
dr och lor ide (45o). a. 2-CBZ-7-ter t-BOC-2,7-diazabicyclo-
[3.3.0]octa n e. 7-tert-BOC-2,7-diazabicyclo[3.3.0]octane (1.06
g, 5.00 mmol)25 was dissolved in 12 mL of 1 N NaOH, and the
solution was cooled to 0 °C. To this solution was added benzyl
chloroformate (1.43 mL, 10.0 mmol) in 10 mL of ether over a
10 min period. The mixture was stirred for 4 h. The mixture
was then extracted with methylene chloride, and the extract
was washed with water, dried over MgSO4, and concentrated
to give the title compound (1.55 g, 90%).
1H), 9.14 (d, J
10 Hz, 1H), 9.40 (br, 1H). IR (KBr): 3400,
1700, 1650, 1605 cm 1. Anal. (C20H24Cl2FN3O3) C, H, N.
8-((1R*,2S*,6R*)-2-Am in o-8-a za -8-bicyclo[4.3.0]n on yl)-
1-cyclop r op yl-7-flu or o-4H-9-m eth yl-4-oxoqu in olizin e-3-
ca r boxylic a cid h yd r och lor id e (45r ): mp 209 214 °C dec.
MS (FAB): 400 (M
Cl). 1H NMR (DMSO-d6): δ 0.63 (m,
2H), 0.94 (m, 1H), 1.05 (m, 1H), 1.42 1.62 (m, 4H), 1.97 (m,
1H), 2.31 (m, 2H), 2.62 (s, 3H), 2.67 (m, 1H), 3.19 (m, 1H),
3.54 (m, 1H), 3.82 (m, 1H), 4.00 (m, 2H), 7.89 (s, 1H), 8.18 (br,
3H), 9.06 (d,
1.25HCl 1.5H2O) C, H, N.
8-((1R*,2R*,6R*)-2-Am in o-8-a za -8-bicyclo[4.3.0]n on yl)-
1-cyclop r op yl-7-flu or o-4H-9-m eth yl-4-oxoqu in olizin e-3-
ca r boxylic a cid h yd r och lor id e (45s): mp 215 220 °C dec.
J
11 Hz, 1H). Anal. (C22H26N3O3F
b. 2-CBZ-2,7-d ia za b icyclo[3.3.0]oct a n e. 2-CBZ-7-tert-
BOC-2,7-diazabicyclo[3.3.0]octane (1.10 g, 3.18 mmol) was
dissolved in ethyl acetate (20 mL) and treated with 4 N HCl
in dioxane (5.0 mL, 20.0 mmol) at room temperature overnight.
The solvent was removed, and the residue was dissolved in
5% NaHCO3. The mixture was extracted with 1:3 isopropyl
alcohol:methylene chloride. The extract was washed with
brine, dried over MgSO4, and concentrated to give 0.60 g (77%)
of the title compound.
c. 1-Cyclop r op yl-8-(2,7-d ia za -7-bicyclo[3.3.0]octyl)-7-
flu or o-9-m eth yl-4-oxo-4H-qu in olizin e-3-ca r boxylic a cid
h yd r och lor id e (45o): following the procedures as described
for (S)-45a and 12a-N-Ala, substituting 2-CBZ-2,7-diazabicyclo-
MS (FAB): 400 (M
Cl). 1H NMR (DMSO-d6): δ 0.53 0.61
(m, 2H), 0.95 1.06 (m, 2H), 1.30 (m, 2H), 1.60 (m, 2H), 1.81
(m, 2H), 2.29 (m, 1H), 2.49 (m, 1H), 2.64 (s, 3H), 2.77 (m, 1H),
3.32 3.49 (m, 3H), 4.16 (m, 2H), 7.91 (s, 1H), 8.33 (br, 3H),
9.06 (d, J 10 Hz, 1H). Anal. (C22H26N3O3F 1.0HCl 1.25H2O)
C, H, N.
1-Cyclop r op yl-7-flu or o-9-m et h yl-8-[3-(2-p yr id in yl)-1-
p yr r olid in yl]-4-oxo-4H-qu in olizin e-3-ca r boxylic a cid h y-

2-Pyridones as Potent DNA Gyrase Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16 3085
d r och lor id e (45t): mp 173 175 °C. MS (FAB): 408 (M
Cl). 1H NMR (DMSO-d6): δ 0.60 (m, 2H), 0.99 (m, 2H), 2.30
2.40 (m, 2H), 2.60 (m, 1H), 2.64 (s, 3H), 3.86 4.16 (m, 4H),
8-(3-Am in oa zetid in yl)-1-cyclop r op yl-7-flu or o-9-m eth -
yl-4-oxo-4H-qu in olizin e-3-ca r boxylic a cid h yd r och lor id e
(45z): mp 198 200 °C dec. MS (FAB): 332 (M Cl). 1H NMR
(DMSO-d6): δ 0.61 (m, 2H), 1.00 (m, 2H), 2.30 (m, 1H), 2.61
(s, 3H), 4.15 (m, 1H), 4.56 (m, 2H), 4.86 (m, 2H), 7.89 (s, 1H),
7.80 (m, 1H), 7.90 (s, 1H), 9.07 (d, J
11 Hz, 1H). Anal.
(C23H23FN3O3 HCl H2O) C, H, N.
8.51 (br s, 3H), 9.13 (d, J
FN3O3 1.25HCl H2O) C, H, N.
1-Cyclop r op yl-8-(cis-3,5-d im eth yl-1-p ip er a zin yl)-7-flu -
or o-9-m eth yl-4-oxo-4H-qu in olizin e-3-ca r boxylic a cid h y-
d r och lor id e (45d d ): mp 285 °C dec. MS (FAB): 374 (M
Cl). 1H NMR (DMSO-d6): δ 0.70 (m, 2H), 1.04 (m, 2H), 1.30
10 Hz, 1H). Anal. (C17H18-
8-((1 ,5 ,6 )-6-Am in o-3-a za bicyclo[3.1.0]h exa n -3-yl)-1-
cyclop r op yl-9-m et h yl-7-flu or o-4-oxo-4H -q u in olizin e-3-
ca r boxylic a cid h yd r och lor id e (45u ): mp 190 195 °C dec.
MS (FAB): 358 (M
2H), 1.01 (m, 2H), 2.12 (br, 2H), 2.33 (m, 1H), 2.62 (s, 3H),
3.81 (m, 5H), 7.97 (s, 1H), 8.46 (br, 3H), 9.11 (d, J 10.5 Hz,
Cl). 1H NMR (DMSO-d6): δ 0.61 (m,
1H), 13.83 (br, 1H). Anal. (C19H20FN3O3 1.5HCl 0.5H2O) C,
H, N.
(d, J
7 Hz, 6H), 2.41 (m, 1H), 2.80 (s, 3H), 3.40 3.65 (m,
9 Hz, 1H), 9.60 (br, 1H). IR
6H), 8.03 (s, 1H), 9.26 (d, J
1
(KBr): 3450, 1720, 1650, 1610 cm
HCl 0.75H2O) C, H, N.
1-Cyclop r op yl-7-flu or o-8-(1-h om op ip er a zin yl)-9-m eth -
. Anal. (C20H24FN3O3
8-((1S*,3R*)-1-Am in o-5-a za sp ir o[2.4]h ep ta n -5-yl)-1-cy-
clop r op yl-7-flu or o-9-m eth yl-4-oxo-4H-qu in olizin e-3-ca r -
boxylic Acid Hyd r och lor id e (45v). a . (1S*,3R*)-1-ter t-
BOCa m in o-5-a za sp ir o[2.4]h ep ta n e was prepared according
to literature procedures.30 The relative stereochemistry was
assigned by comparing NOE spectra of the precursors (1S*,3R*)-
yl-4-oxo-4H-qu in olizin e-3-ca r boxylic a cid , a cetic a cid
sa lt (45ee): mp 195 198 °C dec. MS (FAB): 360 (M
H).
1H NMR (DMSO-d6): δ 0.55 (m, 2H), 0.98 (m, 2H), 1.83 (s, 6H),
2.26 2.38 (m, 2H), 2.69 (br, 3H), 2.89 (m, 4H), 8.08 (br, 1H),
9.04 (br, 1H). Anal. (C19H22FN3O3 CH3CO2H 1.25H2O) C, H,
N.
5-benzyl-1-(ethoxycarbonyl)-5-azaspiro[2.4]heptane
and
(1R*,3S *)-5-ben zyl-1-(et h oxyca r bon yl)-5-a za spir o[2.4]-
heptane.
b. 8-((1S*,3R*)-1-Am in o-5-a za sp ir o[2.4]h ep ta n -5-yl)-1-
cyclop r op yl-7-flu or o-9-m et h yl-4-oxo-4H -q u in olizin e-3-
ca r boxylic Acid Hyd r och lor id e (45v). The title compound
was prepared using the procedures as described for (S)-45a ,
replacing 3-t-BOCaminopyrrolidine with (1S*,3R*)-1-tert-
BOCamino-5-azaspiro[2.4]heptane to produce a solid, mp 179
182 °C dec. MS (DCI/NH3): 372 (M Cl). 1H NMR (DMSO-
d6): δ 0.60 (m, 2H), 0.99 (m, 2H), 1.10 (m, 1H), 1.16 (m, 1H),
2.16 (m, 2H), 2.29 (m, 1H), 2.61 (s, 3H), 2.79 (m, 1H), 3.62 (m,
1H), 3.77 (m, 1H), 3.82 (m, 1H), 4.13 (m, 1H), 7.90 (s, 1H),
8-[(2-Am in oeth yl)am in o]-1-cyclopr opyl-7-flu or o-9-m eth -
yl-4-oxo-4H-qu in olizin e-3-ca r boxylic a cid h yd r och lor id e
(45ff): mp 197 199 °C. MS (FAB): 320 (M
Cl). 1H NMR
(D2O): δ 0.60 (m, 2H), 1.02 (m, 2H), 2.02 (m, 1H), 2.64 (s, 3H),
3.40 (m, 2H), 3.99 (m, 2H), 7.40 (s, 1H), 8.80 (d, J
10.5 Hz,
1H). Anal. (C16H18N3O3F HCl 0.85H2O) C, H, N.
8-[N-(2-Am in oeth yl)-N-m eth yla m in o]-1-cyclop r op yl-7-
flu or o-9-m eth yl-4-oxo-4H-qu in olizin e-3-ca r boxylic Acid
Hyd r och lor id e (45gg). (a ) N-[2-(Ben zyloxyca r bon yl)-
eth yl]m eth yla m in e. (Methylamino)acetonitrile hydrochlo-
ride (2.08 g, 19.5 mmol) and sodium carbonate (2.33 g, 22.0
mmol) were suspended in methanol (24 mL) and water (8 mL).
To the above mixture was added di-tert-butyl dicarbonate (6.7
mL, 29.3 mmol). The reaction mixture was stirred at room
temperature for 2.5 h. The methanol was removed, and the
residue was dissolved in methylene chloride. The methylene
chloride solution was washed with water, dried over MgSO4,
and concentrated. The product, [N-(tert-butoxylcarbonyl)-N-
methylamino]acetonitrile (3.33 g, 100%), was purified by
column chromatography eluting with AcOEt and hexanes (1:
8).
The above nitrile (19.5 mmol) was dissolved in methanol
(135 mL) and hydrogenated under H2 (4 atm) and RaNi 2800
(3.0 g) at room temperature for 3 days. The reaction mixture
was filtered and concentrated to give 2-[N-(tert-butoxycarbo-
nyl)-N-methylamino]ethylamine (3.02 g, 88%).
To a suspension of the above crude amine (17.3 mmol) and
sodium carbonate (2.15 g, 25.9 mmol) in dioxane (15 mL) and
water (15 mL) was added benzyl chloroformate (2.94 mL, 20.6
mmol) dropwise at 0 °C. The reaction mixture was then stirred
for 45 min at 0 5 °C and for 3 h at room temperature before
being diluted with ether. The organic phase was separated,
washed with saturated NaHCO3 and water, dried over MgOS4,
and concentrated. The residue was purified by column chro-
matography eluting with AcOEt and hexanes (1:4) to give
[2-[N-(benzyloxycarbonyl)-N-methylamino]ethyl]-N-(tert-bu-
toxycarbonyl)amine (2.86 g, 54%).
8.56 (br, 2H), 9.08 (d, J
11 Hz, 1H), 13.85 (br, 1H). Anal.
(C20H22FN3O3 HCl 2H2O) C, H, N.
8-((1R*,3R*)-1-Am in o-5-a za sp ir o[2.4]h ep ta n -5-yl)-1-cy-
clop r op yl-7-flu or o-9-m eth yl-4-oxo-4H-qu in olizin e-3-ca r -
boxylic Acid Hyd r och lor id e (45w ). The title compound
was prepared using the procedures as described for (S)-45a ,
replacing 3-BOCaminopyrrolidine with (1R*,3R*)-1-tert-BOCam-
ino-5-azaspiro[2.4]heptane (see 45v for preparation) to produce
a solid, mp 178 181 °C dec. MS (DCI/NH3): 372 (M
Cl).
1H NMR (DMSO-d6): δ 0.59 (m, 2H), 0.99 (m, 2H), 1.15 (m,
2H), 1.88 (m, 1H), 2.04 (m, 1H), 2.29 (m, 1H), 2.64 (s, 3H),
2.72 (m, 1H), 3.73 (m, 1H), 3.80 (m, 1H), 3.97 (m, 1H), 4.03
(m, 1H), 7.90 (s, 1H), 8.52 (br, 3H), 9.09 (d, J
11 Hz, 1H).
Anal. (C20H22FN3O3 HCl 2H2O) C, H, N.
8-[3-((3S,6R)-1-Am in oeth yl)-1-p yr r olid in yl]-1-cyclop r o-
p yl-7-flu or o-9-m et h yl-4-oxo-4H -q u in olizin e-3-ca r b oxy-
lic a cid h yd r och lor id e ((S,R)-45x): mp 235 240 °C dec. MS
(DCI/NH3): 374 (M H). 1H NMR (DMSO-d6): δ 0.59 (m, 2H),
1.00 (m, 2H), 1.29 (d, J
6 Hz, 3H), 1.76 (m, 1H), 2.13 (m,
1H), 2.28 (m, 1H), 2.41 (m, 1H), 2.63 (s, 3H), 3.30 (m, 1H),
3.74 (m, 3H), 3.94 (m, 1H), 7.90 (s, 1H), 8.16 (br, 3H), 9.07 (d,
J
11 Hz, 1H). Anal. (C20H24FN3O3 HCl 1.25H2O) C, H, N.
8-[3-((3R,6R)-1-Am in oeth yl)pyr r olidin yl]-1-cyclopr opyl-
7-flu or o-9-m eth yl-4-oxo-4H-qu in olizin e-3-ca r boxylic a cid
h yd r och lor id e ((R,R)-45x): mp 220 222 °C. MS (DCI/
NH3): 374 (M H). 1H NMR (DMSO-d6): δ 0.61 (m, 2H), 0.94
(m, 1H), 1.07 (m, 1H), 1.28 (d, J
2.27 (m, 2H), 2.46 (m, 1H), 2.62 (s, 3H), 3.57 (s, 1H), 3.92 (m,
1H), 7.90 (s, 1H), 8.17 (br, 3H), 9.07 (d, J 11 Hz, 1H), 13.84
6 Hz, 3H), 1.82 (m, 1H),
A 1.43 g (4.64 mmol) portion of the above BOC-protected
amine was stirred with 11.5 mL of HCl in dioxane (4.0 N, 46.0
mmol) in methylene chloride (20 mL) at room temperature.
The solvents were removed under vacuum, and the residue
was dissolved in water and basicified with 15% NaOH. The
mixture was extracted with methylene chloride and 2-propanol
(3:1) (2×). The extracts were dried over MgSO4 and concen-
trated to give the crude title product (0.98 g, 100%). It was
used directly in the next step. MS (DCI/NH3): 299 (M H).
(br, 1H). Anal. (C20H24FN3O3 HCl 1.5H2O) C, H, N.
8-[3-((3R,6S)-1-Am in oeth yl)pyr r olidin yl]-1-cyclopr opyl-
7-flu or o-9-m eth yl-4-oxo-4H-qu in olizin e-3-ca r boxylic a cid
h yd r och lor id e ((R,S)-45x): mp 250 255 °C dec. MS
(FAB): 374 (M
1.00 (m, 2H), 1.29 (d, J
H). 1H NMR (DMSO-d6): δ 0.59 (m, 2H),
7 Hz, 3H), 1.77 (m, 1H), 2.13 (m,
1H), 2.29 (m, 1H), 2.41 (m, 1H), 2.64 (s, 3H), 3.57 (s, 1H), 3.76
(m, 3H), 3.94 (m, 1H), 7.91 (s, 1H), 8.17 (br, 3H), 9.07 (d, J
1H NMR (CDCl3): δ 2.42 (s, 9H), 2.69 (s, 3H), 2.75 (t, J
6
1
11 Hz, 1H), 13.83 (br, 1H). Anal. (C20H24FN3O3 HCl /2H2O)
Hz, 2H), 3.31 (m, 2H), 5.10 (s, 2H), 5.41 (br, 1H), 7.34 (m, 5H).
b. 8-[N-(2-Am in oeth yl)-N-m eth ylam in o]-1-cyclopr opyl-
7-flu or o-9-m eth yl-4-oxo-4H-qu in olizin e-3-car boxylic Acid
Hyd r och lor id e (45gg). Following procedures described for
45o, starting from N-[2-(benzyloxycarbonyl)ethyl]methyla-
mine, the title compound was prepared, mp 205 207 °C dec.
C, H, N.
1-Cyclopr opyl-7-flu or o-8-(1-im idazolyl)-9-m eth yl-4-oxo-
4H-qu in olizin e-3-ca r b oxylic a cid (45y): mp 237 240 °C
dec. 1H NMR (CDCl3): δ 0.90 (m, 2H), 1.18 (m, 2H), 2.40 (m,
1H), 2.83 (s, 3H), 7.15 (s, 1H), 7.39 (s, 1H), 7.71 (s, 1H), 8.66
(s, 1H), 9.43 (d, J
6 Hz, 1H). HRMS (C17H14FN3O3
H):
MS (DCI/NH3): 334 (M
(m, 2H), 0.98 (m, 2H), 2.33 (m, 1H), 2.61 (s, 3H), 2.70 (s, 3H),
Cl). 1H NMR (DMSO-d6): δ 0.60
calcd, 328.1097; found, 328.1110.

3086 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16
3.15 (m, 2H), 3.79 (m, 2H), 7.80 (s, 1H), 9.19 (d, J 8 Hz,
1H), 13.93 (br, 1H). Anal. (C17H20FN3O3 HCl 2.75H2O) C, H,
N.
Li et al.
product. The filtrate was concentrated and the residue puri-
fied by column chromatography eluting with 2% methanol in
methylene chloride followed by 5% methanol in methylene
chloride to afford an additional 1.27 g of the desired product.
The total weight of the BOC-protected compound was 1.69 g
(92%).
8-(3-Am in o-1-p yr r olid in yl)-1-cyclop r op yl-9-eth yl-7-flu -
or o-4-oxo-4H-qu in olizin e-3-ca r boxylic a cid h yd r och lo-
r id e (46a ): MS (FAB) 360 (M Cl). 1H NMR (DMSO-d6): δ
0.52 (m, 2H), 0.87 (t, J
2H), 2.33 (m, 1H), 3.20 (m, 2H), 3.65 3.96 (m, 5H), 7.95 (s,
1H), 8.43 (br, 3H), 9.07 (d, J 10.5 Hz, 1H), 13.83 (br, 1H).
6 Hz, 3H), 0.98 (m, 2H), 2.20 (m,
A solution of the above solid (1.69 g, 3.94 mmol) in 25 mL
of trifluoroacetic acid (TFA) was stirred for 2 h at room
temperature. The TFA was evaporated, and the residue was
dissolved in 200 mL of methanol. To the resultant solution
was added 25 g of a strongly basic ion exchange resin, and
the mixture was stirred at room temperature for 2 h. The
mixture was filtered, and the filtrate was concentrated to
afford ethyl 8-(3-amino-1-pyrrolidinyl)-1-ethyl-4-oxo-4H-quino-
lizine-3-carboxylate which was then dissolved in 6 mL of THF
and 10.5 mL of a 1 M aqueous solution of sodium hydroxide.
The reaction mixture was heated at 60 °C for 2 h. After the
THF was removed, the reaction mixture was poured into
water, and the pH of the resultant solution was adjusted to
∼2 with concentrated hydrochloric acid. The solid was filtered
to afford 0.365 g (29%) of the title compound, mp 196 198 °C.
Anal. (C19H22N3O3F 1.25HCl 1.5H2O) C, H, N.
8-(3-Am in o-1-p yr r olid in yl)-1-cyclop r op yl-7-flu or o-9-
m eth oxy-4-oxo-4H-qu in olizin e-3-ca r boxylic a cid h yd r o-
ch lor id e (47a ): mp 187 190 °C dec. MS (FAB): 362 (M
Cl). 1H NMR (DMSO-d6): δ 0.62 (m, 2H), 0.91 (m, 2H), 2.12
(m, 1H), 2.29 (m, 1H), 2.39 (m, 1H), 3.62 (s, 3H), 3.81 (m, 1H),
3.94 (m, 2H), 4.06 (m, 2H), 7.79 (s, 1H), 8.30 (br, 3H), 9.13 (d,
J
10 Hz, 1H), 13.79 (br, 1H). IR (KBr): 3440, 1799, 1650,
1610 cm 1. Anal. (C18H20FN3O4 2HCl 0.5H2O) C, H, N.
8-(3-Am in o-1-p yr r olid in yl)-1-et h yl-7-flu or o-9-m et h yl-
4-oxo-4H -q u in olizin e-3-ca r b oxylic a cid h yd r och lor id e
(48a ): mp 215 217 °C. MS (FAB): 334 (M
Cl). 1H NMR
(DMSO-d6): δ 2.28 (m, 3H), 2.22 (m, 1H), 2.52 (m, 4H), 2.96
MS (DCI/NH3
): 302 (M Cl). 1H NMR (TFA-d): δ 1.41 (t, J
7.5 Hz, 3H), 2.39 (q, J
7.5 Hz, 2H), 2.70 (m, 3H), 4.0 (m,
(m, 2H), 3.88 4.18 (m, 5H), 8.01 (s, 1H), 9.05 (d, J
10 Hz,
3H), 4.53 (m, 1H), 6.93 (d, J
1.5 Hz, 1H), 7.33 (dd, J 1
9
1H). Anal. (C17H20FN3O3 HCl 1.5H2O) C, H, N.
Hz, J 2 1.5 Hz, 1H), 7.93 (s, 1H), 9.08 (d, J
(KBr): 3440, 2960, 1650. Anal. (C16H19N3O3 HCl) C, H, N.
8-((S)-3-Am in o-1-p yr r olid in yl)-1-cyclop r op yl-7-flu or o-
3-(n itr oa cetyl)-4-oxo-4H-qu in olizin e Hyd r och lor id e ((S)-
55a ). A mixture of 45 (X CH3, Y H, R2R3N
9 Hz, 1H). IR
8-(3-Am in o-1-p yr r olid in yl)-1-cyclop r op yl-7-flu or o-6-
m eth yl-4-oxo-4H-qu in olizin e-3-ca r boxylic a cid h yd r o-
ch lor id e (49a ): mp 262 °C dec. MS (FAB): 346 (M Cl).
1H NMR (DMSO-d6): δ 0.53 (m, 2H), 0.99 (m, 2H), 1.87 (m,
1H), 2.20 (m, 1H), 2.34 (m, 1H), 2.87 (d, J 5.5 Hz, 3H), 3.76
(S)-3-tert-
4.02 (m, 5H), 6.92 (d, J
9 Hz, 1H), 7.72 (s, 1H), 8.38 (br,
BOCamino-1-pyrrolidinyl) (1.23 g, 2.76 mmol) (see (S)-45a for
preparation) and carbonyldiimidazole (0.90 g, 5.55 mmol) in
30 mL of THF was refluxed for 8 h. The reaction mixture was
diluted with methylene chloride, and the solution was washed
with water (2×), dried over MgSO4, and concentrated. The
residue dissolved in 50 mL of DMF was added to a solution of
the anion of nitromethane in DMF (made from the addition of
nitromethane (1.0 mL, 11.1 mmol) to NaH (0.39 g, 60%
dispersion in mineral oil, 9.75 mmol) in 20 mL of DMF at room
temperature for 2 h). The mixture was heated to 40 °C for 8
h. The DMF was removed under vacuum. The residue was
dissolved in methylene chloride, washed with 1 N HCl (1×)
and water (1×), and dried over MgSO4. The residue, after
removal of the solvent, was purified by column chromatogra-
phy, eluting with 3% methanol in methylene chloride. This
BOC-protected compound was dissolved in methylene chloride
(40 mL). HCl in dioxane (10 mL, 4.0 N, 40 mmol) was added.
The reaction mixture was stirred at room temperature for 24
h before adding more methylene chloride. The precipitate was
collected by filtration and washed with methylene chloride.
The solid was dissolved in distilled water and filtered through
a sintered glass funnel. The filtrate was freeze-dried to give
(S)-55a as a dark red solid (0.722 g, 46%), mp 195 198 °C
3H). Anal. (C18H20FN3O3 HCl 1.5H2O) C, H, N.
8-(3-Am in o-1-p yr r olid in yl)-1-eth yl-4-oxo-4H-qu in oliz-
in e-3-ca r boxylic Acid Hyd r och lor id e (54). a . 4-Ch lor o-
2-p r op ylp yr id in e (51). To a stirred solution of LDA in
cyclohexane (100 mL, 1.5 M, 150 mmol) at 60 °C was added,
dropwise over a period of 30 min, a solution of 4-chloro-2-
picoline (17.47 g, 137 mmol) in 80 mL of THF. The reaction
mixture was stirred for 0.5 h at 60 °C, and then a solution
of ethyl iodide (10.95 mL, 137 mmol) in 30 mL of THF was
added over 20 min. Stirring was continued for 0.5 h at 60
°C and for 1.5 h at 30 °C before the mixture was poured into
cold brine. The aqueous mixture was extracted with methyl-
ene chloride. The organic extract was dried over anhydrous
sodium sulfate and concentrated. The residue was distilled
to afford 12.67 g (60%), bp 77 80 °C (10 mmHg), of the title
compound.
b. Dieth yl 3-(4-Ch lor o-2-p yr id yl)-3-eth ylp en t-1-en e-
1,1-d ica r boxyla te (52). To a stirred solution of LDA (89.9
mmol), prepared from diisopropylamine and n-butyllithium in
20 mL of THF at 60 °C, was added a solution of 4-chloro-2-
propylpyridine (12.66 g, 81.9 mmol) in 100 mL of THF over a
period of 30 min. The solution was stirred at 60 °C for 0.5
h, and then diethyl (ethoxymethylene)malonate (16.55 mL,
81.9 mmol) was added over 30 min. Stirring was continued
at 60 °C for 0.5 h and at 20 °C for 1.5 h. The reaction
mixture was then poured into cold brine, and the aqueous
mixture was extracted with methylene chloride. The combined
organic extracts were dried over MgSO4, filtered, and concen-
trated to afford 35.48 g of the title compound. The product
was carried on to the next step without purification.
dec. MS (DCI/NH3): 389 (M
0.56 (m, 2H), 0.96 (m, 2H), 2.13 (m, 1H), 2.29 (m, 2H), 2.61 (s,
3H), 3.77 (m, 2H), 3.96 4.07 (m, 3H), 6.00 (s, 1H), 7.25 (s, 1H),
Cl). 1H NMR (DMSO-d6): δ
8.33 (br, 3H), 9.09 (d, J
11 Hz, 1H), 12.25 (s, 1H). Anal.
(C19H21FN4O4 1.5HCl H2O) C, H, N.
Sin gle-Cr ysta l X-r a y An a lysis of ABT-719. The crystal
was grown in a mixture of ethanol and water. Crystal-
lographic data were collected on a Rigaku AFC5R single-
crystal diffractometer with Cu K radiation and a nickel filter.
Data were collected at ambient temperature, and cell constants
and orientation matrices for data collection were obtained from
a least-squares refinement using the setting angles of 18
c. Eth yl 8-Ch lor o-1-eth yl-4-oxo-4H-qu in olizin e-3-ca r -
boxyla te (53). A solution of 52 (35.48 g, 99.2 mmol) in 1 L of
xylene was heated at 150 °C for 24 h. The reaction mixture
was then concentrated. The residue was triturated with
hexane to afford 14.87 g (54%) of the title compound. MS
accurately centered reflections in the range 43°
2θ
82°,
(DCI/NH3): 280 (M H). 1H NMR (CDCl3): δ 1.31 (t, J
7.5
7.5 Hz, 2H),
using the ω 2θ scan technique with stationary background
and a scan speed of 16.0°/min. Space group was determined
from systematic absences or structure determination. Limits
of data collection were 6° e 2θ e 120°. No decay was observed
in the intensities of three representative reflections measured
after every 150 reflections. Data were reduced to a unique
set of intensities and associate σ values in the usual manner
using the TEXSCAN programs. The structure was solved by
a combination of direct methods using program SHELX86 and
Fourier techniques. All non-hydrogen atoms were anisotro-
pically refined. H atom contributions were idealized. The
absolute configuration was also determined by X-ray. Crystal
Hz, 3H), 1.43 (t, J
7.2 Hz, 3H), 2.78 (q, J
4.43 (q, J
1H), 7.70 (d, J
1H).
7.2 Hz, 2H), 7.10 (dd, J 1
2.4 Hz, J 2
8.1 Hz,
8.1 Hz,
2.4 Hz, 1H), 8.32 (s, 1H), 9.40 (d, J
d . 8-(3-Am in o-1-p yr r olid in yl)-1-eth yl-4-oxo-4H-qu in o-
lizin e-3-ca r boxylic Acid Hyd r och lor id e (54). A mixture
of 53 (1.20 g, 4.3 mmol), 3-[N-(tert-butoxycarbonyl)amino]-
pyrrolidine (1.04 g, 5.59 mmol), and triethylamine (1.8 mL,
12.9 mmol) in 15 mL of dry pyridine was heated at 60 °C for
12 h. The reaction mixture was then concentrated. The
residue was triturated with ethanol to give 0.42 g of the desired

2-Pyridones as Potent DNA Gyrase Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16 3087
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data for C18H21ClFN3O3 (ABT-719): yellow crystals, ortho-
rhombic, P212121; a 10.319(2) Å, b 29.785(8) Å, c 6.778-
(2) Å; V 2083.1(8) Å3; Z 4; Dcalc 1.217. Of 3710 reflections
collected (T
observed; R
296 K, 2θmax 120.1°), 1894 were unique and
6.9% and Rw 6.5%.
In Vitr o An tiba cter ia l Activity. MICs were determined
as described by the National Committee for Clinical Labora-
tory Standards39 except brain heart infusion agar was used.
The MIC was defined as the lowest concentration resulting in
inhibition of visible bacterial growth after incubation at 37 °C
for 18 24 h.33a
In Vivo An tiba cter ia l Effica cy. In vivo efficacy was
determined as previously described.33c,40 Mice were treated
at several concentrations with a single dose administered
either subcutaneously (sc) or orally (po). The ED50 is the
calculated dose that results in protecting 50% of the treated
animals.
Gyr a se In h ibition . Gyrase-mediated DNA cleavage of a
compound is expressed by a CC50 value that is defined as the
drug concentration which causes 50% of the maximal gyrase-
mediated DNA cleavage. The assay procedures were described
previously, using the gyrase from E. coli H560 and supercoiled
ColE1 DNA.41
Solu bility Stu d ies. Known excess weights of the com-
pounds in known volume of sodium phosphate buffer (0.05 M,
pH 7.4) containing 0.9% sodium chloride by weight were
capped, vortexed, and agitated overnight. The contents were
filtered through 0.45 µm filters. The filtrates were analyzed
by HPLC (column, 5 cm × 4.6 mm 3 µm Spherisorb OD-2;
mobile phase, acetonitrile:0.04 M H3PO4:0.01 M NaH2PO4:
0.005 M acetohydroxamic acid:0.2% SDS) at a flow rate of 1.0
mL/min with detection at 420 nm. The concentration of
compounds was calculated by least-squares linear regression
analysis of the peak area of spiked mobile phase standards
versus concentration.
P h a r m a cok in etic Stu d ies. Compounds were adminis-
tered orally and intravenously to male Sprague Dawley rats
(250 350 g) at a 5 mg/kg dose in water (the non-hydrochloride
compounds were dissolved in water with 1 2 mol equiv of
sodium hydroxide). Rats were fasted overnight prior to and
throughout the duration of study but allowed free access to
water. At the selected time points after dosing, sequential
blood samples were collected from a tail vein of each rat. The
plasma was separated from the red cells by centrifugation. The
compounds of interest were extracted into a mixed solvent of
methylene chloride and ethanol (9:1, by volume) at neutral
pH. The compounds were analyzed by HPLC (column, 5 cm
× 4.6 mm 5 µm Inertsil; mobile phase, acetonitrile:0.04 M H3-
PO4:0.01 M NaH2PO4:0.005 M acetohydroxamic acid:0.2%
SDS) at a flow rate of 1.0 mL/min with detection at 420 nm.
The plasma concentration of compound was calculated by
least-squares linear regression analysis of the peak area ratio
(parent/internal standard) of the spiked rat plasma versus
concentration.
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Ack n ow led gm en t. The authors wish to thank Dr.
Fariborz Mohamadi for helpful discussions. We thank
Mrs. Charlene Vojtko for MIC testing and Mr. Michael
Fitzgerald for HPLC separations. We also acknowledge
the support from the Structure Chemistry Department
for analysis of the compound.
Su p p or tin g In for m a tion Ava ila ble: X-ray crystallo-
graphic data of ABT-719 (tables of atomic coordinates, thermal
parameters, bond lengths, bond angles, torsion angles, inter-
molecular distances, and crystal packing diagram) and yields,
melting points, and spectroscopic data of intermediates for
Scheme 1 (12 pages). Ordering information is given on any
current masthead page.
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