CA2222322A1 - Quinolizinone type compounds - Google Patents

Abstract

Antibacterial compounds having formula (I) and the pharmaceutically acceptable salts, esters and amides thereof, selected preferred examples of which include those compounds wherein A is =CR6-; R1 is cycloalkyl of from three to eight carbon atoms or substituted phenyl; R2 is selected from the group consisting of (a), (b), (c) and (d); R3 is halogen; R4 is hydrogen, loweralkyl, a pharmaceutically acceptable cation, or a prodrug ester group; R5 is hydrogen, loweralkyl, halo(loweralkyl), or -NR13R14; and R6 is halogen, loeralkyl, halo(loweralkyl), hydroxy-substituted loweralkyl, loweralkoxy(loweralkyl), loweralkoxy, or amino(loweralkyl), as well as pharmaceutical compositions containing such compounds and the use of the same in the treatment of bacterial infections.

Description

~- - CA 02222322 1997-11-25 ' DEMA~DES OU BR~VETS VOLUMINEUX
.

LA P~RÉ~;E3YTE P~RTIE DE CErrE~ MANDE OU CE BREVET
COMPREND PLWS D'lJN TOME~

l::ECI E~ST LE TOME ~ D~

NOll~: Pour les tomes additionefs, Ye~illez c~ntacter le ~3ureau canadien des brevets JUIUIBO APPLICATIONS/PATENTS - .

THIS ~i'EC:lrlON OF THE APPLICAT10~/PATENT CONTAINS MORE
THAN ONE VOLUME
-THIS IS VOLUME J OF ~

PlO~E: Eor additionaf v~f~mes-p~ease c~nt~c~~the Canadian Patent Off~ce .

OUINOLIZINONE TYPE COMPOUNDS
This application is a continll~*-ln-in-part of co-pending United States patent application Serial No. 08/469,159, filed June 6, 1995, which is a continll~tion-in-part of copending United States patent application Serial No. 08/316,319, filed September 30, 1994, which is a continu~tinn-in-part of copending 13nited States patent application Serial s No. 08/137,236, filed October 14, 1993, which is a continuation-in-part of United States patent application Serial No. 07/940,870, filed October 27, 1992, abandoned, wnich is a continuation-in-part of United States patent application Serial No. 07/517,780, filed May 2, 1990, abandoned.
TEC~ICAL ~LD
The present invention relates to compounds having al-L,ll~i~;lubial activity, pharrn~-~e ~tic~l compositions conti1i..;"~ such compounds, methods of treatment lltili7ing such compounds, and processes for their chernical synthesis. More particularly, this invention relates to novel 4-oxo-4H-quinolizine-3-carboxylic acid compounds which are highly effective in the llG ~ of microbial and espe~i~lly b~ct~on~l infections, as well as 15 compositions co~ ing the same and the tne.~pellLic use of such compounds.
BACKGROUND OF THE INVEN'TION
There is a continuing need for new antib~çt~-ri~l agents. Although many compounds are known which are useful in the treatment of Gram-positive and Gram-nega~ive b~t~ri~l infections as well as other microbial infections, the widespread use of such compounds continues to give rise to resistant strains of microorg~nisms~ ., strains of microorg~nisms against which a particular antibiotic or group of antibiotics, which was previously effective, is no longer useful. Also, known antibiotics may be effective against only certain strains of microorganisms or have limited activity against either Gram-positive or Gram-negative, aerobic or anaerobic organisms.
The therapeutic use of certain quinolizinone derivatives has been described previously. For example, Y. Kitaura et al., in U.S. Patent No. 4,650,804, issued March 17, lg87, have disclosed quinolizinone compounds having a tetrazolylcarbamoyl substituent which are useful for the treatment of allergic and ulcer diseases. J.V. Heck and E.D. Thorsett, in Eul~lJeall Patent Application No. 0308019, published March 22, 1989, have disclosed the use of certain 4-oxo-4H-quinolizine-3-carboxylic acids and derivatives thereof for treating bacterial infections. However, there remains an ongoing need for novel compounds which have improved ~ntimiçrobial potency and/or different spectra of activity.

CA 02222322 1997-11-2~

SU~/IARY OF THE ~VENTION
In one aspect of the present invention are disclosed compounds represented by the following structural formula (I):

C o o R 4 R 1 (I) as well as the pharmaceutically acceptable salts, esters and amides thereof.

Rl in formula (I) is selected from (a) loweralkyl, (b) loweralkenyl, (c) halo(lower-alkyl), 10 (d) loweralkoxy, (e) cycloalkyl of from three to eight carbon atoms, (f) phenyl, (g) substituted phenyl, (h) halo, (i) cyano, (.1) nitro, (k) bicycloalkyl, (1) loweralkynyl, (m) loweralkoxycarbonyl, (n) nitrogen-co~t~ining aromatic heterocycle, (o) halo-substituted nitrogen-cnnt~ining aromatic heterocycle, (p) a ~, 5- or 6-membered cyclic ether, and 15 (q) -NR7R8. The radicals R7 and R8 are independently selected from hydrogen, loweralkyl and alkanoyl of from one to eight carbon atoms or, taken together with the nitrogen atom to which they are attached, R7 and R8 may form a ~-, 6- or 7-rr.el~.b~.t;d heterocycle, preferably in which the rern~incier of the ring atoms are carbon atoms.

20 R2 in formula (I) is selected from (a) halogen, (b) loweralkyl, (c) loweralkenyl, (d) cycloalkyl of from three to eight carbons, (e) cycloalkenyl of from four to eight carbons, (f) loweralkoxy, (g) aryloxy, (h) aryl(loweralkyl)oxy, (i) aryl(loweralkyl), (j) cycloalkyl(loweralkyl), (k) amino, (I) (loweralkyl)amino, (m) aryl(loweraLkyl)-amino, (n) hydroxy-s~lbstitllt~d (loweralkyl)amino, (o) phenyl, (p) substituted phenyl, (q) bicyclic 25 nitrogen-col-l;.;..;,.g heterocycle, (r) nitrogen-cont~ining aromatic heterocycle, (s) nitrogen-cont~ining heterocycle having the formula ~N \R10 9' (Ia), and WO 96/39407 PCTrUS96/08991 (t) non-nitrogen-containing heterocycle having the formula R31 (Y~ (Ib).

5 In subformula (Ia) above, x is zero, one, two or three, and R9 is either (i) -(CH2~m-where m is one, two or three, or (ii) -(CH2)nR13(CH2)p- where R13 is selected from -S-, -O- and -NH-, R10 is CH2, or when R9 is selected from option (i) may be O, S or N, n is one or two, and p is one or two. When present, the radical(s) 1~' is/areindependently selected at each occurrence from the following:
(i) loweralkyl, (ii) hydroxy, (iii) halogen, (iv) halo(loweraLkyl), (v) hydroxy-substituted loweraLtcyl, (vi) loweraLkenylamino, (viu) loweraL~ylamino, (viii) loweraLkoxy, (ix) (loweraL~oxy)loweraLkylamino, (x) loweraLkoxy(loweraL~cyl), (xi) loweraL~coxy(loweraLkoxy)(loweraLkyl), (xii) hydroxy-substituted loweraLkyl, (xiu) imino, (xiv) aL~coxycarbonyl, (xv) carbamoyl, (xvi) aryl(loweraLkyl), (xvii) aminoxy (xviii) amino(loweraLkyl), (xix) halo(loweraLIcyl)amino, (xx) halo(loweraL~cyl)amino(loweraL~cyl), (xxi) thioloweraL~coxy(loweraLkyl), (xxii) aminothioloweraLlcoxy, (xxiu) cycloaL~cyl of from three to six carbon atoms, (xxiv) cycloaL~cyl(loweraLIcyl), (xxv) cycloaLkylamino, CA 02222322 1997-11-2~

W O 96/39407 . PCTrUS96/08991 (xxvi) phenyl, (xxvii) substituted phenyl, (xxviii) sub~LiLu~ed phenyl(loweralkyl) (xxix) nitrogen-cont~ining aromatic heterocycle, (xxx) -NR1 1 R12 where Rll and R12 are independently selected from hydrogen and loweralkyl or, when one of Rl 1 and Rl2 is hydrogen, the other is alkanoyl of from one to eight carbon atoms, an alpha-amino acid, or a polypeptide residue of from two to five amino acids, and (xxxi) -C(R2l)(R22)NH2 where R21 and R22 are independently selected lo from among hydrogen, loweraL~yl, hydroxy-substituted loweralkyl, amino(loweraL~cyl), loweralkoxy-(loweralkyl), thioloweralkoxy(loweralkyl), cycloalkyl of from three to six carbon atoms, and loweralkyl sukstitlltfA with nitrogen-cont~ining aromatic heterocycle (or, taken together with the carbon atom to which they are attached, R2 1 and R22 form a ring structure selected from cycloalkyl of from three to six carbon atoms and nitrogen-c~ nt~ining heterocycle).

In subformula (Ib) above, x is zero, one, two or three, and R31 is -(CH2)qR32- where R32 is selected from -S- and -O-, q is one, two or three, and the radical(s) Y is/are as defined above.
R3 in formula (T) is selçcted from among hydrogen, halogen and loweralkoxy, while R4 is selected from hydrogen, loweralkyl, a ph~ ceutically acceptable cation, and a prodrug ester group.

R5 in formula (I) is selected from (a) hydrogen, (b) halogen, (c) hydroxy, (d) loweralkyl, (e) halo(loweralkyl), (f) loweraLkoxy, and (g) -NR13R14 where R13 and R14 are independently selected from among hydrogen, loweralkyl, hydroxy-substituted loweraL~cyl, loweralkoxy-(loweralkyl), and aLkanoyl of from one to eight carbon atoms.
A in formula (I) is =N- or =CR6-, where R6 is selected from (a) hydrogen, (b) halogen, (c) loweralkyl, (d) halo(loweraLkyl), (e) hydroxy-substituted loweralkyl, (f) loweraLkoxy-(loweralkyl), (h) loweraL~oxy, and (i) amino(loweralkyl).
Alternatively, taken together with the atoms to which they are attached, Rl and R6 may form a 6-membered saturated ring optionally cont~ining an oxygen or a sulfur atom and optionally substituted with loweralkyl, so as to produce a tricyclic compound.

, W O 96~9407 PCTrUS96/08991 The compounds of the present invention are subject to the proviso that, if R5 in formula (I) is hydrogen, A is =CR6-, and R6 is hydrogen, then R 1 may not be unsubstituted phenyl.
The above compounds of the invention are found to have a surprising degree of antirnicrobial activity against a wide spectrum of Gram-positive and Gram-negative bacteria S as well as enterobacteria Susceptible org~ni~mc whose growth can be inhihit~d generally include both aerobic and anaerobic pathogens of the genera Staphylococcus, Lactobacillus, Micrococcus, Enterococcus, Streptococcus, Sarcina, Escherichia, Enterobacter, Klebsiella, Pseudomonas, Acinobacter, Proteus, Providencia, Citrobacter, Nisseria, Bacillus,Bacteroides, Camphylobacter, Peptococcus, Clostridium, Salmonella, Shigella, Legionella, Serraha, Haemophilus, Brucella and the like. It is Lht;ltr()~ e~led that the compounds of the present invention will be useful in the Ll~dL~Ilenl and prevention of susceptible bacterial infections in both humans and lower ~nim~ls In addition, the compounds, by reason of their in vitro activity, may be used in scrub solutions for surface inhibition of bacterial growth.
Accordingly, in a further aspect of the present invention are disclosed pharm~c~euti~l compositions which are useful in the Ll~aLlll~;n~ and prophylaxis of b~ct~.ri~l and/or fungal infection in humans and ~nim~l~, comprising a compound of the invention in combination with a pharnl~ellti~lly acceptable carrier.
In yet another aspect of the present invention is disclosed a method of treating20 and/or preventing microbial infections in human or animal patients in need of such t comprising the a~imini ~ation to such patients of a therapeutically effective amounlt of a compound of the invention in amounts and for such a period of time as are sufficient to produce the desired result.
In still another aspect of the present invention are disclosed synthetic schemes and 2~ processes which are useful in the preparation of the compounds of the invention, as well as synthetic (chemical) ihlL~ t~ which can be utilized therein.
DFTAn Fn DESCRIPTION OF THE rNVENTIQN
Included among the compounds of the present invention are those in which A is =CR6- and R6 is selected from among halogen, loweralkyl, halo(loweraL~cyl), hydroxy-30 substituted loweralkyl, loweralkoxy(loweralkyl), loweralkoxy, or amino(loweralkyl). A
sub-class of such compounds, particularly plc;r~lled and found to be surprisingly effective antibacterial agents, comprises those in which R6 is methyl. In each case, more L~lc;r.,.l~,d compounds are those in which R3 is halogen (especially fluoro); R5 is hydrogen, loweralkyl, halo-(loweraL~cyl), or -NR13R14 (where R13 and R14 are as previously .

WO 96/39407 PCTrUS96/08991 defined); Rl is cycloaL~cyl of from three to eight carbon atoms or substituted phenyl; and/or R6 is halogen, lowerallcyl, or loweralkoxy.
The radical R2 in the above compounds is preferably bicyclic nitrogen-containingheterocycle or a nitrogen-cont~ining heterocycle of the formula \,NH
9~
R (Y)x (Ic), or, even more preferably, R2 is selected from among radicals of the formulae 10~ (Y)x \~ ~

N~ , Y)x ~ N~

r~ ~
--N ) --N N
\_ (Y)x, and \_ (Y)x In these radicals R2, x is preferably one or two, and Y is preferably either NR I l R 1 2 or -C(R2l)(R22)NH2, where Rl 1, R12, R21 and R22 are as defined above.
Especially ~IG~llGd among the compounds of the present invention are those having the general formula F N~COOH

CH3~
(Id) as well as the pharrn~el-tic~lly acceptable salts, esters and amides thereof, in which W O 96/39407 PCT~US96/08991 R2 is either bicyclic nitrogen-cont~ining heterocycle or a nitrogen-cont~ining heterocycle having the formula ~N H

R9 (Y) (Ic) .

Of these, particularly preferred compounds are those in which R2 is selected from among radicals having the formulae Q (Y)x \~

~'N~3~ ~N~Y~x ~N~

/--\ /--\
---N ~ --N N
\ (Y)x, and \_/ (Y)x and especially those in which x is one or two and Y is -NRl lR12 or -C(R21)(R22)NH2.
Also included among the compounds of the present invention are those which have the general formula R3 '~NJ~ COOR4 R2~
R16 (Ie), as well as the pharmaceutically acceptable salts, esters and amides thereof, in which CA 02222322 1997-11-2~

W O 96/39407 PCTAUS~'D~931 Z is -CH2-, -O- or -S-; R16 is loweraL~cyl; and R2, R3, R4 and R5 are as defined above.
Preferred among such compounds are those in which Z is -O- and R2 is a nitrogen-cont~inin~ heterocycle of the formula \;NH

R9 ~y) "
Particular compounds which are representative of the compounds of the present invention include the following:

3-fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin- 1 -yl)-6(H)-6-oxo-pyrido[ 1,2-a]pyri Tudine-7-carboxylic acid;
9-(2,4-difluorophenyl)-3-fluoro-2-(4-methylpiperazin- 1 -yl)-6(H)-6-oxo-pyrido[ 1,2-a~pyrimidine-7-carboxylic acid;
3-fluoro-9-cyclopropyl-2-(4-methylpiperazin- 1 -yl)-6(H)-6-oxo-pyrido[ 1 ,2-a]pyrimi-linlo.-7-carboxylic acid;
8-(3-aminopyrrolidin- 1 -yl)- 1 -ethyl-4H-quinolizin-4-one-3-carboxylic acid;
2-(3-arninopyrrolidin- 1-yl)-9-cyclopropyl-3-fluoro-6H-6-oxo-pyrido[l ,2-a]pyrimidine-7-carboxylic acid;
2-(3-aminopyrrolidin- 1 -yl)-9-cyclopropyl-3-fluoro-6H-6-oxo-pyrido[ 1 ,2-a]pyrimidine-7-carboxylic acid;
9-(2,4-difluorophenyl)-3-fluoro-2-(4-methylyiy~,ldzill- 1 -yl)-6H-6-oxopyrido[ 1,2-a]pyrilTudine-7-carboxylic acid;
2-(3-aminopyrrolidin- 1 -yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[ 1,2-a]pyrimidine-7-carboxylic acid;
2-(3-(N-t-butoxycarbonyl)aminopyrrolidin- 1 -yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylic acid;
2-(3-aminopyrrolidin- 1 -yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[ 1,2-a]pyrimidine-7-carboxylic acid;
9-cyclopropyl-3-fluoro-2-(4-methylpiperazin- 1 -yl)-6H-6-oxo-pyrido[ l ,2-a]pyrimidine-7-carboxylic acid;
9-cyclopropyl-3-fluoro-2-(piperazin- l -yl)-6H-6-oxo-pyrido[ 1 ,2-a]pyrimidine-7-carboxylic acid;
9-cyclopropyl-3-fluoro-2-(morpholin- 1 -yl)-6H-6-oxo-pyrido[ l ,2-a]pyrirnidine-7-carboxylic acid;
9-(2,4-difluorophenyl)-3-fluoro-2-(3-(N-(S)-norvalyl)aminopyrrolidin- 1 -yl)-6H-6-oxopyrido[ 1 ,2-a]pyrirnidine-7-carboxylic acid;

CA 02222322 1997-11-2~

WO 96/39407 PCTrUS96/08991 2-(3-(N-(S)-alanyl)aminopyrrolidin- 1-yl)-9-(2,4-difluorophenyl~-3-fluoro-6H-6-oxopyrido[l,2-a]py~.-imi~lin~-7-carboxylic acid;
2-(3-(N-(S)-alanyl-(S)-alanyl)aminopyrrolidin- l-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidiné-7-carboxylic acid;
2-((2S,4S)-4-acetamido-2-methylpyrrolidin- 1 -yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylic acid;
9-(2,4 -difluorophenyl)-3-fluoro-2-(3-hydroxypyrrolin- 1 -yl)-6H-6-oxopyrido[ 1,2-a]pyrimi~line-7-carboxylic acid;
2-((2S ,4S)-4-a~nino-2-methylpyrrolidin- 1 -yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[l,2-a]pyrimidine-7-carboxylic acid;
~-(3-amino- 1-pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinoliine-3-carboxylic acid;
8-(3-(~minf methyl)pyrrolidinyl)-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine 3-carboxylic acid;
8-(2S,4S-4-amino-2-methylpyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-~mino~7c.tidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3(S)-aminopyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-methyl- 1 -pi~ zi,.yl)-4H-quinolizine-3-carboxy~ic acid;
l-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-piperazinyl-4H-q--inc 1i7int--3-carboxy~ic acid;
1 -cyclopropyl-7-fluoro-9-methyl-8-(2-((N-methyl)aminomethyl)-4-morpholinyl)-4-oxo-4H-quino~izine-3-carboxylic acid;
I -cyclopropyl-7-fluoro-9-methyl-4-oxo-8-( 1 ,2,3,4-tetrahydro-2-isoquinolinyl)-4H-q~linoli*n~-3-carboxy~ic acid;
1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-amino- 1 -piperdinyl)-4H-quinolizine-3-carboxylic acid;
1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-amino- 1 -piperdinyl)-4H-quinolizine-3-carboxylic acid;
1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-(aminomethyl)- 1 -piperdinyl)-4H-quinolizine-3-carboxylic acid;
1 -cyclopropyl-7-fluoro-9-me~yl-4-oxo-8-(5-amino- 1 ,2,3,~tetrahydro-2-isoquinolinyl)-3s 4H-quinollzine-3-carboxylic acid;
1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-( 1 -pyrrolyl)- 1 -piperidinyl)-4H-quinolizine-3-carboxylic acid;

g CA 02222322 1997-11-2~

W O 96/39407 PCTnJS96/08991 1 -cyclopropyl-8-(cis-3.5-dimethyl- 1 -piperazinyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
1 -cyclopropyl-8-(2,7-diaza-7-bicyclo[3.3.0]oct-2-yl)-7-fluoro-9-methyl-4-oxo-4H-qninoli7ine-3-carboxylic acid;
s 1-cyclopropyl-8-(2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-9-methyl-4-oxo-4H-qninoli7ine-3-carboxylic acid;
1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3 (S )-(1 -pyrrolyl)- 1 -pyrrolidinyl)-4H-quinolizine-3-carboxylic acid;
1 -cyclopropyl-7-fluoro-8-(3-hydroxy- 1 -pyrrolidinyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
1 -cyclopropyl-7-fluoro-8-(4-methyl- 1 -pi~Cl d~inyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
l-cyclopropyl-9-chloro-7-fluoro-8-(3-amino- 1-pyrrolidinyl)-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-amino- 1 -pyrrolidinyl)- 1 -cyclopropyl-7,9-difluoro-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-amino- 1 -pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methoxy-4-oxo-4H-quinolizine-3-carboxylic acid.
1 -cyclopropyl-8-(2,7-diaza-7-bicyclo[3 .3 .0] oct-2-yl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
1 -cyclopropyl-8-(2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3 (S)-( 1 -pyrrolyl)- 1 -pyrrolidinyl)-4H-quinoli7ine-3-carboxylic acid;
1 -cyclopropyl-7-fluoro-8-(3-hydroxy- 1 -pyrrolidinyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
1 -cyclopropyl-7-fluoro-8-(4-methyl- 1 -piperazinyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
l-cyclopropyl-9-chloro-7-fluoro-8-(3-amino- 1-pyrrolidinyl)-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-amino- 1 -pyrrolidinyl)- 1 -cyclopropyl-7,9-difluoro-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-amino- 1 -pyrrolidinyl)- I -cyclopropyl-7-fluoro-9-methoxy-4-oxo-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-8-(3(S)-methylamino- l-pyrrolidinyl)-4-oxo-4H-qninoli7ine-3-carboxylic acid; v CA 02222322 1997~ 2~

WO 96/39407 PCT~US96/08991 1 -cyclopropyl-7-fluoro-9-methyl-8-(3(g)-methylamino- 1-pyrrolidinyl)-4-oxo-4H-quinolizine-3-carboxylic acid;
l-cyclopropyl-7-fluoro-9-methyl-8-(3(R)-amino- 1 -pyrrolidinyl)-4-oxo-4H-quinolizine-3-carboxylic acid;
(3S)-9-fluoro-3-methyl- 10-(4-methyl-1-piperazinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4-., ij]quinolizine-5-carboxylic acid;
3(R)-9-fluoro-3-methyl- 1 0-(4-methyl- 1 -piperazinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-S-carboxylic acid;
9-fluoro- 10-(1-morpholinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylic 10 acid;
(3S)- 10-(3-amino- 1 -pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylic acid;
3(S)- 1 0-(3-aminomethyl- 1 -pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylic aci~;
15 3(S)-10-((2S,4S)-4-amino-2-methyl-1-pyrrolidinyl)-9-fluoro-3-methyl-2H~3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylic acid;
3(S)-9-fluoro- 1 0-(3-hydroxy- 1 -pyrrolidinyl)-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylic acid;
9-fluoro- 1 0-(4-methyl- 1 -piperazinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-20 carboxylic acid;
8-(2,4-dirnethyl- l -piperazinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-(methylamino)- 1 -piperazinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-(methylamino)- 1 -morpholinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-(S)-(methylamino)- l-pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-(S)-( 1 -(methylamino)methyl)- 1 -pyrrolidinyl)- I -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-(S)-( 1 -(ethylamino)methyl)- 1 -pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(octahydropyrrolor3,4-c]pyrrol- l -yl)- I -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
~ 35 8-(octahydropyrrolo[374-c]pyridin-S-yl)- I -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-qninoli7ine-3-carboxylic acid;

CA 02222322 1997-11-2~

W O 96/39407 PCTrUS96/08991 8-(cis-4-amino-3-methylpyrrolidinyl)- 1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinoli7ine-3-carboxylic acid;
8-(trans-4-amino-3-methylpyrrolidinyl)- 1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-methyl-4-spirocyclopropylpyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-qninoli7ine-3-carboxylic acid;
8-(2S,4S-4-amino-2-methylpyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-(fluoro)methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-dimethylaminopyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-0 3-carboxylic acid;
(3R)-8-(3-dimethylaminopyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-qninnli7ine-3-carboxylic acid;
(3R, lS)-8-(3-(1 -aminoethyl)pyrrolidinyl)- I -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinoli7ine-3-carboxylic acid;
(3S,lR)-8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-qllinoli7ine-3-carboxylic acid;
(3R, l R)-8-(3-( 1 -aminoethyl)pyrrolidinyl)- I -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-qninoli7ine-3-carboxylic acid;
I -cyclopropyl-8-((R,S)-3-fluoropyrrolidine)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3 -carboxylic acid;
8-(4-( I-piperidyl)- I -piperidyl)- I -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(4-(1 -piperidyl)- 1 -piperidyl)- I -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(4-(2-pyridyl)- 1 -piperazinyl)- 1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-((2-amino)thioethoxy)- 1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
(3R, I S)-8-(3-( 1 -amino)propyl)pyrrolidinyl)- I -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
(3R, 1 S)-8-(3-( 1 -(N-methyl)amino)propyl)pyrrolidinyl)- I -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
(3R, I S)-8-(3-( 1 -amino-3-methylpropyl)pyrrolidinyl)- l -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-(1-aminocyclopropyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-qninoli7ine-3-carboxylic acid;

CA 02222322 1997-11-2~

W O 96/39407 PCT~US961Ga~l (3R, 1 S)-8-(3-( 1 -amino-2-hydroxyethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
(8-(3-(1 -arruno- 1 -methylethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-y qllin~li7ine-3-carboxylic acid;

5 8-(3-(1 -aminobutyl)pyrrolidinyl)- 1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(~rans-4-trifluolu~ ,Lllyl-3-aminopyrrolidinyl)-4H-quinolizine-3-carboxylic acid;
1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(trans-4-tn:fluolc",~LI,S~1-3-0 aminomethylpyrrolidinyl)-4H-quinolizine-3-carboxylic acid;
3(S)- I-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-(N-(S)-norvalylamino)pyrrolidinyl)-4H-quinolizine-3-carboxylic acid;
3(S)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-(N-(S)-alanylamino)pyrrolidinyl)-4H-quinolizine-3-carboxylic acid;
15 3(S)-I-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-(N-(S)-alanyl-(S)-alanylamino)pyrrolidinyl)-4H-q-linoli7ine-3-carboxylic acid;
1 -cyclopropyl-7-fluoro-6-methyl-4-oxo-8-(3-aminopyrrolidinyl)-4H-quinolizine-3-carboxylic acid;
l-cyclopropyl-7-fluoro-4H-8-(l-imi-1~701yl)-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-amino- 1 -pyrrolidinyl)- I -ethyl-7-fluoro-4H-4-oxo-9-methyl-quinolizine-3-carboxylic acid;
8-(3-amirlo- 1 -pyrrolidinyl)- I -cyclopropyl-9-ethyl-7-fluoro-4H-4-oxo-quinoli ine-3-carboxylic acid;
1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-8-(3-(1 ,2,3-triazol- 1 -yl)- I -pyrrolidinyl)-quinolizine-3-carboxylic acid;
1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-8-(cis-3-amino-4-methyl- 1 -pyrrolidinyl)-quinolizine-3-carboxylic acid;
8-(2-aminoethyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(ethyl~minnmethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(1 -aminoethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
l-cyclopropyl-7-fluoro-4H-9-methyl-8-(2-methyl-2,8-diaza-8-bicyclo[4.3.0]nonyl)-~oxo-qllinoli7;n~-3-carboxylic acid;
1 -cyclopropyl-7-fluoro-4H-8-(( lS,4S)-2,5-diaza-bicyclo[2.2. l]heptan-2-yl)-9-methyl-4-- oxo-quinolizine-3-carboxylic acid;

CA 02222322 1997-11-2~

WO 96/39407 . PCTAUS96/08991 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-8-(3-(2-pyridinyl)- 1 -pyrrolidinyl)-quinolizine-3-carboxylic acid;
8-((lR*,2S*,6R*)-2-amino-8-azabicyclo[4.3.0]nonan-8-yl))- 1-cyclopropyl-7-fluoro-4H-9-methyl~oxo-quinolizine-3-carboxylic acid;
8-((lR*,2R*,6R*)-2-amino-8-azabicyclo[4.3.0]nonan-8-yl))-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-((1 a,5a,6a)-6-amino-3-azabicyclo[3. 1 .O]hexan-3-yl))- 1 -cyclopropyl-9-methyl-7-fluoro-4H-4-oxo-quinolizine-3-carboxylic acid;
8-(tran s-3-amino-4-fluoro- 1 -pyrrolidinyl))- 1 -cyclopropyl-9-methyl-7-fluoro-4H-4-oxo-10 qninoli7ine-3-carboxylic acid;
I -cyclopropyl-7-fluoro-4H-8-( 1 -homopiperazinyl))-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
7,9-difluoro-4H-8-(4-methylpiperazinyl)-4-oxo-1-phenyl-quinolizine-3-carboxylic acid;
8-(spiro- 1,3-dioxacyclopentane[2.3]- 1 -piperidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-amino-4-methoxypyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(4-amino-4-methylpyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(4-(2-hydroxyethyl)piperidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(4-(methoxymethyl)piperidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-amino-3-methylpiperidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-pyrrolylpiperidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-aminopiperidinyl)- 1-cyclopropyl-7-fluoro-4H- 9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-amino-3-methylpyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-amino-4-( 1 ',3'-dioxolanyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-amino-4-hydroxy-pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-qninoli7into-3-carboxylic acid;
8-(4-(1-(N-ethylamino)methyl)piperidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;

CA 02222322 1997-11-2~

W O 96/39407 PCTrUS96/08991 1 -cyclopropyl-7-fluoro-8-(3-hydroxy-4-methylaminopyrrolidinyl)-4H-9-methyl-4-oxo-quinolizine-3-ca,l,o~ylic acid;
8-(3-aminomethylpiperidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-~oxo-quinolizine-3-carboxylic acid;
8-(2-aminomethyl-4-morpholinyl)- 1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(1 -(methylamino)methypiperidinyl)- I -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(methyl(methylenedioxy)methyl)piperidinyl)- 1-cyclopropyl-7-fluoro-4H-9-methyl-4-o oxo-quillolizine-3-carboxylic acid;
8-(3-(S)-aminopiperidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(S)-(N-ethyl-N-methylamino)piperidinyl)- l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
1 -cycl,opropyl-8-(4-(2'-(N-methylarnino)methyl- 1 ',3'-dioxolanyl)piperidinyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
I-cyclopropyl-8-(3-aza-6-amino-6-methylbicyclo[3.3.0]octan- 1-yl)-7-fluoro-9-methyl-4-oxo-4E~-quinolizine-3-carboxylic acid;
1-cyclopropyl-8-(3-flu~,Lo,~ llylpiperidinyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine;
1-cyclopropyl-8-(4-(N,N-dimethyl)aminopiperidinyl)-7-fluoro-9-methyl-~oxo-4H-qninnli7ine-3-carboxylic acid;
1 -cyclopropyl-8 -(6-amino-3-azabicyclo[3 .3 .O]octyl)-7-fluoro-9-methyl-4-oxo-4H-qninoli7ine-3-carboxylic acid;
1 -cyclopropyl-8-((2-aza-4-(dimethylaminomethyl)bicyclo[4.3.0]non-2-yl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine carboxylic acid;
l -cyclopropyl-8-(3-aza-6-(L-alanylamino)-6-methylbicyclo[3.3.0]octane)-7-fluoro-9-methyl-4-oxo-4H-quinolizine carboxylic acid;
(3R, 1 R)-8-(3-( 1 -(N-methyl)amino)propyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
(3R, 1 S)-8-(3-( 1 -amino-2-methoxyethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-(S)-(acetylamino)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-carbamoylpiperidinyl)- l -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-hydroxypiperidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-- carboxylic acid;

CA 02222322 1997-11-2~

W O 96/39407 PCTfUS96/08991 8-(3-hydroxymethylpiperidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(R)-hydroxypiperidinyl)- l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
(3R)-9-fluoro-3-methyl- 1 0-(piperazin- 1 -yl)-2H, 3H, 6H -6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylic acid;
1 -cyclopropyl-8-(S,S -2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
1 -cyclopropyl-8-(R,R-2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
1 -cyclopropyl-8-( 1 -amino-3-aza-bicyclo[3. 1 .O]hexan-3-yl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-amino-3-fluoromethyl- 1 -pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-aminomethyl-3-fluoro- 1 -pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(S)-hydroxy- l-pyrrolidinyl)- l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(R)-hydroxy- 1 -pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(7-(S )-amino-5-aza-spiro[2.4]heptan-S-yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride;
8-(7-(R)-amino-5-aza-spiro[2.4]heptan-S-yl)- l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinoli7ine-3-carboxylic acid hydrochloride;
8-(3-(1 -amino-2,2,2-trifluoroethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(S*)-( 1 -(S*)-amino-2,2,2-trifluoroethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-aminoxypyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(R)-aminoxypyrrolidinyl)- I -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(S)-aminoxypyrrolidinyl)- I -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(octahydropyrrolo[3,2-b]pyridin- 1 -yl)- I -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-qllinoli7ine-3-carboxylic acid;

CA 02222322 1997-11-2~

8-(trans-3-arnino-4-fluoromethylpyrrodin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(cis-3-amino-4-fluoromethylpyrrodin- 1 -yl)- 1 -cyclopropyl-7-fluoro~H-9-methyl-4-oxo-qllinoli7ine-3-carboxylic acid;
s 8-(8-arnino-6-azaspiror3.4]oct-6-yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-qninoli7ine-3-carboxylic acid;
8-(2-an~inomethyl-4-hydroxypyrrolidin- 1 -yl)- I -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinoli7ine-3-carboxylic acid;
8-(3-(R)-(aminomethyl)morpholin- l-yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(R)-(L-alanylamino)piperidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(5-arninooctahydroindol- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-qninQli7ine-3-carboxylic acid;
8-(3-(2-piperidyl)piperidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(5-amino-decahydroisoquinolin-2-yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(2,7-diazabicyclo[3.3 .0] oct-7-yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3,7 diazabicyclot3.3.0]oct-3-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-carboxypyrrolidin- 1 -yl)- I -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(~,2,2-trifluoroethyl)arninopyrrolidin- 1 -yl)- I -cyclopropyl-7-fluoro-4H-9-methyl-~
oxo-quinolizine-3-carboxylic acid;
8-(3-(2-fluoroethyl)aminopyrrolidin- 1 -yl)- I -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quin-)li7ine-3-carboxylic acid;
8-(3-((2-fluoroethyl)aminomethyl)pyrrolidin- 1 -yl)- 1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(S)-(2-fluoroethyl)aminopyrrolidin- 1 -yl)- I -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-qninoli7ine-3-carboxylic acid;
8-(3-(R)-(2-fluoroethyl)a~minopyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinoli~ine-3-carboxylic acid;
8-(3a-amino-octahydroisoindol-2-yl)- 1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;

CA 02222322 1997-11-2~

WO 96/39407 PCT~US96/08991 8-(6-amino-2-a_a-spiro[3.3]non-2-yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid (Isomer (I));
8-(3-amino-3-trifluolu",~,ll,ylpyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-q~lin~lli7in~-3-carboxylic acid;
8-(3-(S)-hydroxymethylazetidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-aminomethyl-3-trifluoromethyl-pyrrolidin- 1 -yl)- I -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(octahydropyrrolo[3.4-c]pyrid-2-yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(cyclopropylamino)pyrrolidin- l-yl)- 1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinoli7in~-3-carboxylic acid;
8-(6-amino-2-aza-spiro[3.3]non-2-yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl4-oxo-quinolizine-3-carboxylic acid (Isomer (II));
8-(2,7-diazabicyclo[3.3.0]oct-7-yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid Isomer A;
8-(2,7-diazabicyclo[3.3.0]oct-7-yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid Isomer B;
8-(3-(R)-(hydroxymethyl)pyrrolidin- I -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(S)-(hydroxymethyl)pyrrolidin- I -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(2-(R)-(hydroxymethyl)pyrrolidin- I -yl)- l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(2-(S )-(hydroxymethyl)pyrrolidin- I -yl)- I -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(2-(R)-aminomethyl-pyrrolidin- 1 -yl)- 1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(2-(S)-aminomethyl-pyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinoli7in~--3-carboxylic acid;
8-(3-(R)-( l-aminocyclopropyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-(S)-( 1 -aminocyclopropyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl4-oxo-4H-quinolizine-3-carboxylic acid 3s 8-(3-(1 -amino- 1-cyclopropyl-methyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid CA 02222322 1997-11-2~

W O 96139407 PCTrUS96/08991 8-(3-(R~-(pyrrolidin-2-(S)-yl)pyrrolidin- l-yl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-(aminomethyl)~ 7eti~1in - 1 -yl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
(8-(3-amino-4-methyl-piperidin- l-yl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizirle-3-carboxylic acid; and 8-(3-(7-amino-5-azaspiro[2.4]heptan-5-yl)- l -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(7-(S)-amino-5-aza-spiro[2.4]heptan-5-yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-lO quinolizine-3-carboxylic acid;
8-(7-(R)-amino-5-aza-spiro[2.4]heptan-5-yl)- 1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(tratts-3 -(S )-amino-4-(R)-cyclopropylpyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
15 8-(trans-3-(R)-amino-~(S)-cyclopropylpyrrolidin- l-yl)- l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-(S)-amino-4-(R)-methylpyrrolidin- l -yl)- l -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-(R)-amino-4-(S)-methylpyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(cis-3-(S)-amino-4-(S)-cyclopropylpyrrolidin- 1 -yl)- 1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(cis-3-(R)-amino-4-(R)-cyclopropylpyrrolidin- l -yl)- l -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-amino-4-ethylpyrrolidin- l -yl)- I -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomer A;
8-(trans-3-amino-4-ethylpyrrolidin- 1 -yl)- I -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomer B;
8-(cis-3-amino-4-ethylpyrrodin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-q--inoli7ine-3-carboxylic acid diastereomer A;
8-(cis-3-amino-4-ethylpyrrodin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomer B;
8-(cis-3-(S)-amino-4-(S)-methylpyrrodin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-ql~inolizine-3-carboxylic acid; and 3s 8-(cis-3-(R)-amino-4-(R)-methylpyrrodin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-ql~inolizine-3-carboxylic acid;
as well as the ph~ eutif~lly acceptable salts, esters and amides thereof.

CA 02222322 1997-11-2~

W O 96/39407 PCT~US96/08991 Preferred among the above representative compounds of the invention are the fO~Ilowing:
8-(3-(aminomethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3(S)-amino-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-amino- 1 -pyrrolidinyl)- I -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
(3R, 1 S)-8-(3-( 1 -amino)propyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-qninoli7ine-3-carboxylic acid;
8-(3-(1-aminobutyl)pyrrolidinyl)- 1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
(3R, 1 S)-8-(3-( 1 -amino-2-methoxyethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-amino- 1 -piperdinyl)-4H-quinolizine-3-carboxylic acid;
1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-(aminomethyl)- 1 -piperdinyl)-4H-quinolizine-3-carboxylic acid;
1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-amino- 1 -piperdinyl)-4H-quinolizine-3-carboxylic acid;
8-(3-(S)-aminopiperidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
l-cyclopropyl-8-(3-aza-6-amino-6-methylbicyclo[3.3.0]octan- 1-yl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
2s 1-cyclopropyl-8-(6-amino-3-azabicyclo[3.3.0]octyl)-7-fluoro-9-methyl-4-oxo-4H-qllinoli7ine-3-carboxylic acid;
8-((lR*,2S*,6R*)-2-amino-8-azabicyclo[4.3.0]nonan-8-yl))-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-((1 R*,2R*,6R*)-2-amino-8-azabicyclo[4.3.0]nonan-8-yl))- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-( l -aminoethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
(8-(3-(1 -amino- I -methylethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinoli_ine-3-carboxylic acid;
(3R, 1 S)-8-(3-( 1 -(N-methyl)amino)propyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;

CA 02222322 1997-ll-2~

W O 96/39407 PCT~US~J'~991 8-(3-arninopiperidinyl)- 1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-( l-arninocyclopropyl)pyrrolidinyl)- I -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
(3S,lR)-8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
(3R, lS)-8-(3-(1-aminoethyl)pyrrolidinyl)-1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
(3R, lR)-8-(3-(1 -arninoethyl)pyrrolidinyl)- I -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-qllinnli7ine-3-carboxylic acid;
1 -cyclopropyl-8-(S,S -2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-4H-9-methyl-4-oxo-quinoli_ine-3-carboxylic acid;
I -cyclopropyl-8-(R,R-2,8-diaza-8-bicyclo[4.3 .0] nonyl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
15 1-cyclopropyl-8-(1-arnino-3-aza-bicyclo[3.1.0]hexan-3-yl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-arnino-3-fluulu,l,cll,yl- 1 -pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinoli7ine-3-carboxylic acid;
8-(trans-3-amino-4-fluoru,,,clhylpyrrodin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(cis-3-amino-4-fluc.rol.,~tl.ylpyrrodin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(S)-(2-fluoroethyl)aminopyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(~)-(2-fluoroethyl)aminopyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(1~)-(hydroxymethyl)pyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-qninoli7ine-3-carboxylic acid;
8-(2-(~)-aminomethyl-pyrrolidin- 1 -yl)- 1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
(8-(3-amino-4-methyl-piperidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinl-li7ine-3-carboxylic acid;
8-(3-(7-amino-S-~za~yilu[2.4]heptan-s-yl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinoli_ine-3-carboxylic acid;
8-(7-(S)-amino-5-aza-spiro[2.4]heptan-5-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;

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W O 96139407 PCT~US9G/~99I
8-(7-(R)-amino-5-aza-spiro[2.4]heptan-5-yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-qnin~li7in~-3-carboxylic acid;
8-(trans-3-(S)-amino-4-(R)-cyclopropylpyrrolidin-l-yl)- 1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-(R)-amino-4-(S)-cyclopropylpyrrolidin- 1-yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid; "
8-(trans-3-(S)-amino-4-(R)-methylpyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-(R)-amino-4-(S)-methylpyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(cis-3-(S)-amino-4-(S)-cyclopropylpyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(cis-3-(R)-amino-4-(R)-cyclopropylpyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-amino-4-ethylpyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-qninoli7.in~-3-carboxylic acid dia~ LeleolnGl A;
~-(trans-3-amino-4-ethylpyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomer B;
8-(cis-3-amino-4-ethylpyrrodin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid dia~ L~ ,OIIIG1 A;
8-(cis-3-amino-4-ethylpyrrodin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomer B;
8-(cis-3-(S)-amino-4-(S)-methylpyrrodin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid; and 2~ 8-(cis-3-(R)-amino-4-(R)-methylpyrrodin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
as well as the ph~m~eutically acceptable salts, esters and amides thereof.
Especially ~lGr~,lled among the representative compounds of the present invention are the following:
8-(3(S)-amino- 1 -pyrrolidinyl)- I -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-amino- 1-pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
(3R, 1 S)-8-(3-( 1 -amino-2-methoxyethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
(8-(3-(1 -amino- 1 -methylethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;

-CA 02222322 1997-11-2~

W O 96/39407 PCTrUS~6,~93~1 8-(3-(1 -aminocyclopropyl)py~olidinyl~- 1 -cyclopropyl-7-fluoro-9-methyl-~oxo4H-quinolizine-3-carboxylic acid;
(3R, 1 S)-8-(3-( 1 -aminoethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-- quinolizine-3-carboxylic acid;
1-cyclopropyl-8-(S,S-2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
1 -cyclopropyl-8-(R,R-2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-4H-9-methyl-4-oxo-qllinoli7ine-3-carbOxylic acid;
1 -cyclopropyl-8-( 1 -amino-3-aza-bicyclo[3 .1 .O]hexan-3-yl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-arr~no-3-fluoromethyl- 1 -pyrrolidinyl)- 1 -cyclopropyl-7-lluoro-4H-9-methyl-4-oxo-quinoli;~ine-3-carboxylic acid;
8-(trans-3-amino-4-fluo~ hylpyrrodin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(cis-3-amino-4-fluo,u~ ylpyrrodin- 1 -yl)- 1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(S)-(2-fluoroethyl)aminopyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-qllinoli7ine-3-carboxylic acid;
8-(3-(R)-(2-fluoroethyl)aminopyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(R)-(hydroxymethyl)pyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(2-(R)-aminomethyl-pyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
2s (8-(3-amino-4-methyl-piperidin- I-yl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-(7-amino-5-a~a~ u[2.4]heptan-5-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(7-(S)-amino-5-aza-spiro[2.4]heptan-5-yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(7-(R)-amino-5-aza-spiro[2.4]heptan-5-yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-(S)-amino-4-(R)-cyclopropylpyrrolidin- 1 -yl)- 1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
3s 8-(trans-3-(R)-arr~ino-4-(S)-cyclopropylpyrrolidin- 1 -yl)- 1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;

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W O 96/39407 PCT~US96/08991 8-(trans-3-(S)-amino-4-~R)-methylpyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-~
oxo-quinolizine-3-carboxylic acid;
8-(trans-3-(R)-amino-4-(S)-methylpyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(cis-3-(S)-amino-4-(S)-cyclopropylpyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(cis-3-(R)-amino-4-(R)-cyclopropylpyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-amino-4-ethylpyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-10 q~lin~li7ine-3-carboxylic acid diastereomer A;
8-(trans-3-amino-4-ethylpyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-qllinoli7ine-3-carboxylic acid dia~ co-l.cl B;
8-(cis-3-amino-4-ethylpyrrodin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-qninC li7ine-3-carboxylic acid diastereomer A;
15 8-(cis-3-amino-4-ethylpyrrodin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid di~cieo.,.cr B;
8-(cis-3-(S)-amino-4-(S)-methylpyrrodin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl4-oxo-quinolizine-3-carboxylic acid; and 8-(cis-3-(R)-amino-4-(R)-methylpyrrodin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
as well as the pharmaceutically acceptable salts, esters and amides thereof.
It will be observed above and elsc~l.elc in the disclosure that numerous asymmetric centers may exist in the compounds of the present invention which will be found in the R or S configurations. Except where otherwise noted, the present invention conle,.,~ t~ the various stereoisomers and mixtures thereof.
A number of defined terms are used herein to cie~ignz~te particular elements of the present invention. When so used, the following meanings are inten~le-i-The term "alkanoyl of from one to eight carbons" refers to a radical of the formula -C(O)R 15 where R 15 is hydrogen or an aL~cyl radical of from one to eight carbon atoms in~lncling, but not limited to, acetyl and pivaloyl.
The term "aL~cyl" refers to s~ ~d, straight- or branched-chain hydrocarbon radicals cont~ining between one and ten carbon atoms including, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl and neopentyl.
The terms "alpha-amino acid" and "polypeptide residue" refer, respectively, to asingle amino acid and two to five amino acids each joined by amide (peptide) bonds. The amino acids may be any of the naturally-occurring amino acids such as valine, phenylalanine and glycine or synthetic alpha-amino acids such as cyclohexylalanine. and _ W O 96/39407 PCTrUS9C/~
further may be in either the L or D configuration or a mixture of the two isomers.
Preferably, amino acid substituents are optically active and have the L configuration.
The term "amino(loweralkyl)" refers to a loweralkyl radical having appended thereto at least one amino substituent which in turn is optionally sub..LiLuL~d with one or two s loweraLkyl radicals or an alpha-amino acid or polypeptide residue. Examples of. amino(loweraL~cyl) groups include aminoethyl, aminomethyl and N,N-dimethylaminoethyl.
The term L'aminooxy" refers to an amino group, optionally substituted once or twice with loweraLkyl or halo(loweraL~cyl), which is appended to the rest of the molecule via an oxygen atom; (e.g. {) NR'R" wherein R' and R" are hydrogen, loweraLkyl or 10 halo(lowerallyl).
The term "aminothioloweraLcoxy" refers to a thioloweraL~oxy radical having appended thereto an arnino group, as for example aminothiomethoxy and 2-aminothioethoxy.
The term "aromatic group" refers to a C6-to-C10 cyclic radical which is aromatic15 according to Huckel's rule. Examples of aromatic groups include carbocyclic aromatic radicals such as phenyl and naphthyl as well as nitrogen-~;onlA;..;.~g aromatic heterocyclic radicals, defined below.
The term "aryl(loweraLlcyl)" refers to a lowerallcyl radical having appended thereto an aronnatic hydrocarbon group, as for exarnple benzyl and phenylethyl.
The term "aryl(loweraLIcyl)amino" refers to an amino radical having appended thereto an aryl(lowerallcyl) group. Examples of aryl(lowerallcyl)amino groups include benzylamino and phenylethylamino.
The term "aryl(loweraL~cyl)oxy" refers to an aryl(loweralkyl) radical which is joined to the rest of the molecule via an ether linkage (i.e., through an oxygen atom).
Examples of aryl(lowerallcyl)oxy radicals include benzyloxy and phenyletnyloxy.
The term "aryloxy" refers to an aromatic hydrocarbon radical which is joined to the rest of the molecule via an ether linkage (i.e., through an oxygen atom), as for example phenoxy.
The term "bicycloallcyl" refers to a radical comprising a bridged, saturated or ~ t,--,-led hydrocarbon ring system having b~L~ ,n five and nine carbon atoms in which two non-adjacent carbon atoms of a first ring are linked by an allylene bridge of between one and three ,.~l~liti~nzll carbon atoms, the bicycloalkyl radical being optionally substituted with between one and three additional radicals selected from among aryl(loweralkyl), allcoxycarbonyl, lowerallcyl, halo(lowerallcyl), amino(lowerallcyl), hydroxy-substituted lowerallcyl, hydroxy, loweraLkoxy, halogen, and amino, (loweralkyl)amino or allcanoylamino of from one to eight carbon atoms in which the amino group may be further e SUh'.l;Llltt'CI with alkanoyl of from one to eight carbons, an alpha-amino acid or a CA 02222322 1997-11-2~

W O 96139407 PCTAJS96/a8931 polypeptide. Examples of bicycloa~yl radicals include, but are not limited to, norbornyl, bicylo[2.2.1]hept-2-enyl and bicyclo[l.l.l]pentanyl.
The term "bicyclic nitrogen-col ,li. i "i, Ig heterocyclic group" refers to a radical comprising a bicyclic ring system in which the the rings are of the (a) fused, (b) bridged or 5 (c) spiro form. Fused-ring bicyclic nitrogen-cont~ining heterocyclic groups are those in which a first nitrogen-cont~inin~ heterocycle or aromatic heterocycle has fused to it a second sdt~d~d or unsaturated cOEbocyclic or heterocyclic ring of between three and six atoms of which zero, one or two are h~;te.d~ollls selected from S, O, and N. Both the first and the second ring may be optionally substituted with between one and three additional 10 radicals A2 independently selected from among loweraLkyl, halo(loweraLkyl), hydroxy-substituted loweraL~cyl, hydroxy, halogen, amino(loweraLkyl), aL~canoylamino of from one to eight carbons, phenyl and -NR17R18 where R17 and R18 are independently hydrogen or loweralkyl or, when one is hydrogen, the other is an alpha-amino acid or a polypeptide residue. Examples of fused-ring bicyclic nitrogen-containing heterocyclic radicals are those having 5:3, 5:4, 5:5, 5:6 and 6:5 ring systems and include, but are not limited to, radicals of the formulae ~NH2 ~ --N~NH2 NH2 --N~ N(CH3)2 --N~
and Bridged-ring bicyclic nitrogen-clmt~inin& heterocyclic groups are those selectedthe formulae ~ (CH2)k (CH2)k7\ (C~H2)k7 HN ~,A1 HN ~ and A

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W O 96/39407 PCT~US96/08991 and llnc~fllr~tecl derivatives thereof, where j and k are independently one, two or three, and A1 is a carbon atom or a heteroatom selected from S, O and N, optionally substit~t~-l at any position with between one and three additional radicals A2 is as previously defined.
? Spiro-ring bicyclic nitrogen-contzlininE heterocyclic groups are those in which a S f~st nitrogen-cont~ining heterocycle or aromatic heterocycle to which is joined, by a single shared carbon atom, a second carbocyclic or heterocyclic ring of between three and six atoms of which zero, one or two are heter~toms selected from S, O, and N. Either the first or the second ring may be suh~ rA with between one and three additional radicals A2, where A2 is as previously defin~(l Examples of spiro-ring bicyclic nitrogen-cont~inin~
o heterocyclic radicals include, but are not limited to, those having the formulae N N
--N~C> ~N~
and The term "cyclic ether" refers to a 4- to 6-membered monocyclic hydrocarbon radical c~-nt~ining an oxygen ring atom and joined to the rest of the molecule via any of the carbon atoms including, but not limited to, oxetane.
The term "cycloalkenyl of from four to eight carbons" refers to a mono-C~ 1 monocyclic hydrocarbon radical having from four to eight carbon atoms in the ring, including, but not limited to, cyclobutenyl, cyclop~,n~t;nyl, cyclohexenyl and cycloheptenyl, and optionally ~.ub~ u~ed with be~v/een one and three ~ 1ition~lc radicals selected *om among aryl(loweralkyl), aLlcoxycarbonyl, loweraL~cyl, halo(loweraLkyl), amino(loweraL~cyl), hydroxy-substituted loweraL~cyl, hydroxy, loweraL~coxy, halogen, amino, loweralkylamino, and amino, (loweralkyl)amino or alkanoylamino of from one to eight carbon atoms in which the amino group may be further ~ub~ u~d with aLkanoyl of from one to eight carbons, an alpha-amino acid or a polypeptide.
The term "cycloalkyl of from three to eight carbons" refers to a saturated monocyclic hydrocarbon radical having from three to eight carbon atoms in ehe ring and optionally s--bstitllted with between one and three additional radicals selected from among aryl(loweraLkyl), aL~coxycarbonyl, loweralkyl, halo(loweraLkyl), amino(loweralkyl), hydroxy-substituted loweraL~cyl, hydroxy, loweraLkoxy, halogen, and amino, (loweraL~cyl)amino or alkanoylamino of from one to eight carbon atoms in which the amino group may be further substituted with aL~canoyl of from one to eight carbons, an alpha-amino acid or a polypeptide. Examples of cycloaL~cyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, l-fluoro-cyclopropyl, 2-fluorocyclopropyl and 2-aminocyclopropyl.

WO 96/39407 PCTrUS~6,Ce991 The term "cycloalkyl(amino)" refers to an amino group ~ 1 with at least one cycloalkyl group, typically having from three to eight carbons.
The terrn "cycloaLkyl(loweralkyl)" refers to a loweralkyl radical having appended thereto a cycloalkyl radical of from three to eight carbon atoms, which cycloaLkyl radical 5 may be optionally subsLiluL~d as described above.
The term "fused" as used herein refers to two cyclic groups having two adjacent ring atoms in common.
The terms "halo" and "halogen" refer to a monovalent radical selected from among chloro (Cl), bromo (Br), fluoro (F) and iodo (I).
The term "halo(loweraL~cyl)" refers to a loweraL~cyl radical having appended thereto between one and three halogen atoms. Examples of halo(loweralkyl) radicals include flu~rol.lGLhyl, trifluoromethyl, l-fluoroethyl, 2-fluoroethyl and 1,2-difluoroethyl.
The term "halo(loweraLIcyl)amino refers to an amino group ~ub~LiLuLed with at least one halo(loweraL~yl) group.
The term "halo(loweralkyl)amino(loweralkyl)" refers to an amino(loweraLlcyl) radical having appended thereto a halo(loweraLlcyl) group, as for example 2-fluoroethylaminomethyl.
The term "halo-substituted nitrogen-cont~ining aromatic heterocycle" refers to anitrogen-co"li.;"i~-g aromatic heterocycle radical having appended thereto between one and 20 three halogen atoms including, but not limited to, S-fluoro-2-pyrimidyl.
The term "hydroxy-substituted loweralkyl" refers to a loweraL~cyl radical havingappended thereto between one and three hydroxyl groups, as for example hydroxymethyl and 2-hydroxyethyl.
The term "hydroxy-substituted (loweraL~yl)amino" refers to a (loweraLlcyl)amino 2s radical having appended thereto bcL~ ,.I one and three hydroxyl groups, as for example hydroxymethylamino and 2-hydroxyethylamino.
The term "imino" refers to a divalent radical of the formula =N-OH.
The term "loweralkenyl" refers to a straight- or branched-chain hydrocarbon radical containing between two and six carbon atoms and possessing at least one carbon-30 carbon double bond. Examples of loweralkenyl radicals include vinyl, allyl, 2- or 3-butenyl, 2-,3- or 4-pentenyl, 2-,3-,4- or S-hexenyl and isomeric forms thereof.
The terrn "loweraL~coxy" refers to a loweralkyl radical which is appended to therest of the molecule via an ether linkage (i.e., through an oxygen atom), as for example methoxy, ethoxy, propoxy, tert-butoxy, pentyloxy, hexyloxy, isomeric forms thereof and 3s the like.

CA 02222322 1997-11-2~

The term "loweraLko~yc~l,ollyl" refers to a radical of the formula -C(o)R25 wl~ eill R25 is a loweraL~coxy group, as for example ethoxycarbonyl and methoxycarbonyl.
- The term ""loweraL~oxy(loweraL~oxy)(loweraL~yl)" refers to a s loweraL~oxy(loweraL~yl) radical having appended thereto a loweraL~coxy group, as for example methoxymethoxymethyl and ethoxymethoxymethyl The term "loweraLkoxy(lowera~yl)" refers to a loweraLIcyl radical having appended thereto a loweraL~oxy group and optionally substituted with an ~(I(li*on~l amino radical, as for example methoxyethyl, ethoxymethyl and l-amino-2-methoxyethyl.
The term "loweraL~cyl" refers to an aL~yl radical co,~l~h~ g one to six carbon atoms including, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl and neopen~yl.
The term "(loweraL~cyl)arnino" refers to an amino radical sllbstitl~tec~ with between one and three loweraL~yl radicals including, but not limited to, methylamino, ethylamino, 15 dimethylamino, propylamino and ethylmethylamino.
The tem "loweraL'cynyl" refers to a straight- or branched-chain hydrocarbon radical containing between two and six carbon atoms and possçs~ing at least one carbon-carbon triple bond. Examples of loweraL~cynyl radicals include ethynyl, 2-hexyn- 1 -yl, 3,3-dimethyl- I -butyn- I-yl and 3-methylbutyn-3-yl.
The term "nitrogen-c-,"l;,i.,i"g aromatic heterocycle" refers to a monocyclic aromatic radical having from five to seven ring atoms of which one ring atom is nitrogen;
zero, one or two ring atoms are additional he~ oa~o" s independently selected from S, 0 and N; and the rtom~ining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms. Examples of nitrogen-cont~ining aromatic heterocycles 25 include pyridine, pyrazine, pyrimi-line, pyrrole, pyrazole, imi(l~701e, thiazole, oxazole, isooxazole, thi~ 7ole, oxadiazole and s~lbssit--t~d derivatives thereof.
The term "nitrogen-cont~ining heterocycle" refers to a s~tnr~tecl or unsaturatedmonocyclic ring system radical having from four to seven ring atoms of which one is nitrogen; zero, one or two are additional heteroatoms independently selected from S, 0 and 30 N; and the rem~in-i~r are carbon, the radical being joined to the rest of the molecule via any of the ring atoms and being optionally substituted, either on a nitrogen or a carbon atom, by an additional radical selected from among aryl(loweraLkyl), aLIcoxycarbonyl, loweralkyl, halo(loweraLlcyl), amino(loweraL~yl), hydroxy-substituted loweraL~cyl, hydroxy, loweraLkoxy, halogen, amino, loweraLkylamino, and amino, (loweraL~yl)amino or 3s aL~canoylamino of from one to eight carbon atoms in which the amino group may be further su~inl~i with aLkanoyl of from one to eight carbons, an alpha-amino acid or a polypeptide. Examples of nitrogen-cont~ining heterocycles include pyrrolidine, dihydropyrrole, isooxazolidine, oxazolidine, ~etrhydropyridine, piperidine, piperazine, - morpholine, thiomorpholine, ~7iri~1in~ and azetidine.

CA 02222322 1997-11-2~

The term "ph~rm~elltic ~lly acceptable cation" refers to a positively-charged inorganic or organic ion that is generally considered suitable for human consumption.
Examples of ph~rm~(~elltis~lly acceptable cations are hydrogen, allcali metal (~ithium, sodium and potassium), m~gn~sium, calcium, ferrous, ferric, ammonium, S alkylammonillm, dialkyl~mmonillm, trialkylammonium, tetraalkylammonium, diethanolammmonium, triethanolammonium, and gll~niclinium ions, and protonated forms of lysine, procaine and choline. Cations may be interchanged by methods known in the art, such as ion exchange. Where compounds of the present invention are plGpared in the carboxylic acid form (that is, where R4 is hydrogen) addition of a base form of the cation, 0 (such as a hydroxide or a free amine) will yield the a~lul,liate cationic form.
By "pharmaceutically acceptable salts, esters and amides", as of the compounds of formula I, is meant those carboxylate salts, amino acid ~ lition salts, esters and amides which are, within the scope of sound merli~l judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic 15 response and the like, commen~-lrate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms thereof.
Pharmaceutically acceptable salts are well known in the art. For example, S. M
Berge, et al. describe ph~rm~eutica'lly acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977). Examples of pharrn~enti~?lly acceptable, nontoxic acid20 addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include nitrate, bisulfate, borate, formate, butyrate, 25 valerate, 3-phenylpropionate, camphorate, adipate, bçn70~te, oleate, palmitate, stearate, laurate, lactate, full-~dle, ascorbate, aspartate, nicotinate, p-tolu~nesl-lfonate, camphorsulfonate, methanesulfonate, 2-hydroxyeth~nçslllfonate, gluconate, glucohc~Lulld~G, lactobionate, glycerophosphate, pectinate, lauryl sulfate and the like or metal salts such as sodium, potassium, m~g.,f .~iu~ll or calcium salts or amino salts such as 30 ammonium, triethylamine salts and the like, all of which may be prepared according to conventional methods.
Examples of pharrn~eutic~lly acceptable, non-toxic esters of the present invention include C1-to-C6 aLkyl esters and C5-to-C7 cycloalkyl esters, although C1-to-C4 alkyl esters are plGrGIled. Esters of the compounds of formula I may be prepared35 according to conventional methods.
Examples of pharmzlreutic~lly acceptable, non-toxic amides of the present invention include amides derived from ammonia, primary C1-to-C6 alkyl amines and , CA 02222322 1997-11-2~

W O 96/39407 PCTrUS~ 31 secondlary Cl-to-C6 dialkyl amines. In the case of secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycle con~i~ g one nitrogen atom. Amides derived from ~mm~ , C1-to-C3 aLkyl primary amides and Cl-to-C2 dialkyl secondaryamides are ~-Grw-Gd. Amides of the compounds of formula I may be prepared according to 5 conventional methods. It is intended that amides of the present invention include amino acid and peptide derivatives of the compounds of formula I as well.
As used herein, the term "pharmz~r,elltir~lly acceptable caIrier" means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or fo~mll~tinn auxillary of any type. Some examples of the materials that can serve as pharm~relltir~lly 10 acceptable carriers are sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl c~llnlose, ethyl cellulose and cellulose acetate; powdered tr~r~nth; malt; gelatin; talc;
excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene 15 glycol; polyols such as glycerin, sorbitol, m:~nnitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as m~gn~ lm hydroxide and ~l.l.,.i.~....l hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution;
ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible s~lbst~nces used in pharm~euti~al f~ tion~ Wetting agents, emlll~ifiçrs and lubricants 20 such as sodium lauryl sulfate and m~gnesillm stearate, as well as coloring agents, r~lezlcing agents, coating agents, ~.wee~~ -g, flavoring and pc;lrull~ g agents, and preservatives can also be present in the composition, according to the judgement of the forrnulator.
The term "prodrug", as of the compounds of formula I, refers to derivative compounds that are rapidly ~ransformed in vivo to yield the parent compound of the '5 formula I, as for example by hydrolysis in blood. T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in "Pro-drugs as Novel Delivery Systems", Vol 14 of the A.C.S. Symposium Series, ~mericzln (~hemic~l Society (1975). Examples of esters useful as prodrugs for compounds containing carboxyl groups can be found on pages 14-21 of "Bioreversible Carriers in Drug Design: Theory and Application", edited 30 by E.B. Roche, Pergamon Press:New York (1987). lt is intencled that these references, and any others cited throughout this specification, are incorporated herein by reference.
The terrn "prodrug ester group" refers tO any of several ester-forming groups that are hydrolyzed under physiological conditions. Examples of prodrug ester groups include pivoyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as other 35 such groups known in the art, including a (5-B-2-oxo-1,3-dioxolen-4-yl)methyl group.
Other examples of prodrug ester groups can be found in the book "Pro-drugs as Novel - Delivery Systems", by Higuchi and Stella, cited above.

CA 02222322 1997-11-2~

WO 96/39407 PCT~US96/08991 The term "protecting group" is well-known in the art and refers to suhstit~-~nts on functional groups of compounds undergoing chemical transformation which prevent undesired reactions and degradations during a synthesis; see, for example, T.H. Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York (1981).
The term "~ub~ u~d phenyl" refers to a benzene ring having between one and five non-hydrogen substituents, each independently selected from among halogen, hydroxy, loweralkoxy, loweralkyl, hydroxy-substituted loweralkyl, amino, (loweralkyl)amino, amino(loweralkyl) and nitrogen-cont~ining heterocycle. Examples of substituted phenyl radicals include 2-fluorophenyl, 4-fluo.o~llcllyl and 2,4-difluorophenyl.
The term "thioloweraL~oxy" refers to a radical of the formula -SR35 where R35 isa loweralkyl group including, but not limited to, thiomethoxy and thioethoxy.
The term "thioloweralkoxy(loweralkyl)" refers to a loweralkyl radical having appended thereto a thioloweralkoxy group including, but not limited to, thiomethoxymethyl and thiomethoxyethyl.
According to the methods of Ll~a~lllen~ of the present invention, the compounds of the invention may be aclministered alone or in combination or in concurrent therapy with other agents. When utili7ing the compounds of the present invention for antimicrobial therapy, the specific thc~apeulically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the 20 disorder; activity of the particular compound used; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of allmini~tration, route of a~imini~tration, and rate of excretion of the specific compound employed; the duration of the l,e~ ; drugs used in colllbil.a~ion or coincidently with the specific compound employed; and like factors well hlown in the medical arts.
The total daily dose of the compounds of this invention a-lmini~tered to a host in single or in divided doses can be in amounts, as for example from 0.1 to 200 mg/kg body weight or more usually from 0.25 to 100 mg/lcg body weight. Single dose compositions may contain such amounts or submultiples thereof as make up the daily dose.
According to the pharm~-eutir~l compositions of the present invention, the 30 compounds of the invention may be a-lmini~tered orally, parenterally, by inhalation spray, rectally, or topically in unit dosage formulations containing conventional nontoxic ph;.. ~ u~;c~lly acceptable c~ rs, adjuvants, diluents and/or vehicles as desired. The term "pa~ l" as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
3s Injectable ~ al~lions, as for example sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a CA 02222322 1997-11-2~

W O 96/39407 PCT~US96/08991 sterile injectable solution or suspension in a nontoxic pd~ L~ lly acceptable diluent or solvent, as for example as a solution in 1,3-bnt:ln~inl. Among the acceptable vehicles and solvents that may be employed are water. Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including " synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
In order to prolong the effect of a drug, it is often desirable to slow the absorption of a drug from subcutaneous or intramuscular injection. The most cornrnon way to0 accomplish this is to inject a suspension of crystalline or amorphous material with poor water solubility The rate of absorption of the drug becomes dependent on the rate of dissolution of the drug which is, in turn, dependent on the physical state of the drug, for example, the crystal size and the crystalline form. Another approach to delaying absorption of a drug is to ~ minict~r the drug as a solution or suspension in oil. Injectable depot forms can also be made by forming microcapsule mzltric es of drugs and biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the composition of the polymer, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly-orthoesters and polyanhydrides. Depot injectables can also be made by c.lLId~yillg the drug in liposomes or microemnlcinns which are compatible with body tissues.
Suppositories for rectal or vaginal administration of the drug can be ~,~p~u~ bymixing the drug with a suitable nonirritating excipient such as cocoa butter andpolyethylene glycol which are solid at ordinary L~ JwdLult; but will melt in the rectum or in the vagina and release the drug.
2s Solid dosage forms for oral ~-lminictration may include capsules, tablets, pills, powders, prills and granules. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert ~liluentc, e.g., tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings and other release-controlling coatings.
Liquid dosage forms for oral ~dminic~r~tion may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs3s containing inert ~liluen~c commonly used in the art such as water. Such compositions may also comprise adjuvants, such as wetting agents; emulsifying and suspending agents; and ,e~e~ &, flavoring and ~elru~ g agents.

-CA 02222322 1997-11-2~

W O 96/39407 PCTrUS~6i'~931 If desired, the compounds of the present invention can be incorporated into slowrelease or targeted delivery systems such as polymer matrices, liposomes and microspheres. They may be sterili7~d, for example, by f1ltration through a bacteria-ret~ining filter, or by incul~uld~illg sterili7ing agents in the form of sterile solid 5 compositions which can dissolve in sterile water, or some other sterile injectable ~--ediul--immediately before use.
The active cûmpounds can also be in micro-encapsulated form with one or more excipients as noted above.
Dosage forms for topical or transdermal ~flminictration of a compound of this lo invention further include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inh~ nts or patches. The active component is admixed under sterile conditions with a ph~rm~en*~lly acceptable catTier and any needed preservatives or buffers as may be required. Ophth~lmic formulations, ear drops, eye ointm~nt~, powders and solutions are also contemplated as being within the scope of this invention.
The oi.~l.. ,c.-lc, pastes, creams and gels may contain, in a-i-lition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, trag~ nth, cellulose derivatives, polyethylene glycols, silicones, bçntonites, silicic acid, talc and zinc oxide, or llli~ul~,S thereof.
Powders and sprays can contain, in addition to the compounds of this invention, 20 ex~ipientc such as lactose, talc, silicic acid, al~min~lm hydroxide, calcium silicates and polyamide powder, or ll-i~lul~,s of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons or ~ub~LiLuleS therefor.
Transdermal patches have the added advantage of providing controlled delivery ofa compound to the body. Such dosage forms can be made by dissolving or dispersing the 25 compound in the proper ...ediu.n. Absorption e~h~n~ers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
A further possibility for delivery and/or utilization of the compounds of the present invention is by chemical conjugation of the compounds with other antibacterials 30 such as beta-lactams. Similar dual-action conjugates (between beta-lactams and quinolones) are proposed in the published European patent application No. 597 303 of Dax, et al. (p~bli~hed on May 18, 1994) and the published int~rn~tional patent application No. PCT/US92/08246 of White, et al. (Publication No. WO 93/07154, published on April 15, 1993). In the manner suggested by these references, a carbon-nitrogen bond or other 35 covalent link may be formed between, for example, either an amino substituent at the C-8 position or a carboxylic acid group at the C-3 position of a compound of the present invention, and an aL~yl or other group of a beta-lactam.

WO 96139407 PCTrUS96/08991 In general, the compounds of the present invention are synth~i7~d according to reaction Schemes I through XVIII presented below, in which Rl through R16, A, X, Y
and Z correspond to the groups defined in connection with formula (I), R is a loweralkyl group, X is a halogen atom, P is a protecting group and L is a suitable leaving group, as for example a halogen atom.
f Certain abbreviations are used repeatedly in the specification which follows.
These include: BOC for t-butoxycarbonyl; (BOC)2 for di-t-butyl dicarbonate; CBZ for benzyloxy-carbonyl; DMF for dimethyl f " ,n~llli~le; DMSO for dimethyl sulfoxide; HRMS
for high resolution mass spectroscopy; LAH for lithium ~ rnin1lm hydride; LDA for lithium diethyl amide; RaNi for Raney Nickel; and THF for tetrahydrofuran.
For the preparation of the compounds of formula (I) which are alpha-amino acid or peptide derivatives of amine groups at R2, the cnncien~z~tion of the amino group with amino acids and peptides may be effected in accordance with conventional con-l~n~ti~-n methods such as the azide method, the mixed acid anhydride method, the DCC
(dicyclohexylcarbodiimide) method, the active ester method ( p-nitrophenyl ester method, N-hydroxysuccinic acid imide ester method, cyanomethyl ester method and the like), the Woodlward reagent K method, the DCC-HOBT (l-hydroxy-b~n7oh-~7ole) method and thel~e. C~ .csi~l methods for amino acid con~le. .~ 1 ;on reactions are des~ibed in "Peptide Synthesis", Second Edition, M. Bodansky, Y.S. Klausner and M.A. Ondetti (1976). It is contemplated that the amino acid coupling reaction could be carried out before or after the amino-containing group is incorporated into the compound by displ~cem~nt of the 7-fluorine atom of the ~ ul -;ate i~ le~liate.
As in conventional peptide synthesis, branched chain amino and carboxyl groups at alpha and omega positions in amino acids may be protected and d~lut~;l~d if necec~ry.
The protecting groups for amino groups which can be used involve, for example, benzyloxycarbonyl (Z), o-chloro-benzyloxycarbonyl((2-Cl)Z), p-nitrobenzyloxycarbonyl (Z(NO2)), p-methoxybenzyloxycarbonyl (Z(OMe)), t-butoxycarbonyl (Boc), t-amyloxycarbonyl (Aoc), isobornealoxycarbonyl, adamantyloxycarbonyl (Adoc), 2-(~biphenyl)-2-propyloxy carbonyl (Bpoc), 9-fluorenyl-methoxycarbonyl (Fmoc), methylsulfonylethoxy carbonyl (Msc), trifluoroacetyl, phthalyl, formyl, 2-nitrophenylsulfenyl (Nps), diphenylphosphinothioyl (Ppt) and dimethylphosphino-thioyl (Mpt).
The examples of protecting groups for carboxyl groups involve, for example, benzyl ester (OBzl), cyclohexyl ester, ~nitrobenzyl ester (OBzlNO2), t-butyl ester (OtBu), 4-pyridylmethyl ester (OPic) and the like.
In the course of the synthesis of cer~ain of the compounds of the present - invention, specific amino acids having functional groups other than amino and carboxyl - 3s -W O 96/39407 PCTrUS9~'C~
groups in the branched chain such as arginine, cysteine, serine and the like may be protected, if necessary, with suitable protecting groups. It is preferable that, for example, the guanidino group (NG) in arginine be protected with nitro, p-toluenesulfonyl (Tos), benzyloxycarbonyl (Z), adamantyloxycarbonyl (Adoc), p-methoxybçn7ton~sulfonyl, 4-5 methoxy-2,6-dimethyl-benzenesulfonyl (Mts) or the like; that the thiol group in cysteine be protected with benzyl, p-methoxybenzyl, triphenylmethyl, ~cet~ lomethyl, ethylcarbamyl, 4-methylbenzyl (4-MeBzl), 2,4,6,-trimethylbenzyl (Tmb) or the like; and that the hydroxy group in serine may be protected with benzyl (Bzl), t-butyl, acetyl, tetrahydropyranyl (THP) or the like.

W O 96/39407 PCTrU596/S~9~1 Scheme I

F~C O O R NH2+CI-FCH2COOR+ HCOOH I-- ~J~ + H2N~
2 H O~ Na+ R

H O~C2Hs ~C2Hs F ~OR F N OR- F~.N OR-H O~ ~H OX N~J~ L N J~

R2~N~O H F~lO R~

W O 96/39407 PCTrUS96/08991 Scheme II

O Cl- +NH2 0 C ~ CN~OEt HzNJ~OEt O

H O~N~O R ~ ~ ~OEt R1 H ONa 8B ~ 7B
O O
Fr J~ F ~ O R

9B lOB ~¦~

O O O o ~N~OR ~ F~ OR

12B llB

O O
~NJ~O H
R2 ~N ~

CA 02222322 1997~ 25 W O 96J39407 PCTrUS96/08991 Scheme ~II

~CH3 LJ~CH3 ~lCH3 [~R1 8 OEt ~ ~ g OEt o ,~3,CO2R ~_ L CO2R

24 OEt R1 OEt 2 steps 2 8 O
~C~3,CO2R ~C~,CO2R ,~$3,CO2R

~,CO2H

PCTrUS96/'~&~1 Scheme IVA

~cl ~ 02N~CHa F~

1~ CH3 F~ ~CH3 N~2 L L

--~CH3 ~CH3 ~CH3 F~X F ~3~ F ~X

Scheme IVB

~-~ R~2C~--C~2R ''~,CO2R

IV A3 8 OEt OEt O
R2 X~CO2R F~COzR

4 1 R 1 \~ R

RZ ~CO2H

Rl IV B

Scheme IVC

F~X RO2C~ co2R F~ ~CO2R

IV A4 .8 OEt N~
42 Rl OEt O
F~lD~N~co2R ~ o R2 ~J F ~3~C4 3 2 R

F~,O~NJ~co2H

R2i~

WO 96/39407 PCTrUSg~ 991 Scheme VA

L L , L
~CH3 F~ ~F~ N H R

F~$ - ~O F. ~
~¦~ CO2R 51 ~¦~ 2 steps F~CO2R X~co2F~ F~F

~¦, 49 NHR EtO CO2R

R2X~co2R 48 C02R

54 ~ O RR2~co2R F~3~3~Co2H

R2~co2H 50 NHR VA1 OR

Scheme VB

IVA2 F~C~ F~

F ~X

62 E~COzR ~ F~ \5s5 N

~1~ CO2R 61 ~ 2 steps F~ F~C02R F'~$R

~¦ X NHR EtO CO2R

R2~co2R 58 CO2R

X OR O

R2~ R2 F~ Jb~C02H 60 X NHR
R2~ V B1 X OR

-CA 02222322 1997-11-2~

W O 96/39407 PCT~U596/D~931 Scheme Vl F~F F~CH3 F~ 67 R02C~¢C02R

8 OEt F o F
F~N J~CO2R F~J~F CO2R

F~ FJ'N ~CO2R
F R1 69 68 R1 OEt R2 X~E~co2R R2~CO2H

Vl pcTrus96lo8 Scheme~l V AZ CH3 ~ ~

7, R F~ O H
~ 73 R

F~' F~C02R

F~CO2H R2 ~CO2R

WO 96139407 PCT~US9~'~5391 Scheme vm 0 1~l F CO2R
FCH2COR + HCOR ~ + ~ NH2 HCI
H O~ Na+-- NH 4 3 ~ R1 is not cyclopropyl Re X~ R 1 ~N J~_ R 1 ~ ~_ R

~OC2H5 O

R2~ R2 ~N~

F ~ ~CO2R F~NJ~cO2R F~ J~rco2R

R2 NJ~ 2 steps Cl N~ HO
10b R1 10~ Rl 78 R

2 steps\~

F~ J~CO2H

W O 96/39407 PCTrUSg~G~331 Scheme ~X

R3 NH+CI-FCH2COOR+ X-Co-R3 ~D ~0 +H2N4Q

79 4 (Q=H) or 6 (Q=COOEt) H O~N~cooEt or H O~N~H

via Schemes 1, Il, or Vlll R3 o o R2~N~

I

W O 96139407 PCTrUS96~'C~9~1 Scheme X

R2M + FCH2COX
82 ~1, 83 FC H2COR2 + HCOOR
84 ~ 2 O~Na+ NH+CI-F ~ Jl + H2N ~rQ
R2_~o R1 4 (Q=H) or 6 (Q=COOEt) ~ N F~ N
R2J~N~CooEt or R2~bN~H

via Schemes 11 or Vlll o o 2 ~J~O H

I

W O 96/39407 PCT~J'3~ 8931 Scheme XI

FCH2COOR + R2COX O R
88 ~o R2 ~0 O R NH+CI
F~o + H2N J~r R2 o R1 91 4 (Q=H) or 6 (Q=COOEt) OH OH

Fl2~N~COOEt or F2~N~H

R2 '~N~COOEt or F 2 '~N~H

via Scheme X~

W O 96/39407 PCTrUS96/08991 Scheme XT~

F)¢Y'F t-bu-O)¢~F t-bu-O~F t-bu-O~F

F~ t-bu-O~ t-bu-O~F

F~I~N F~N F~&~ONoEt COOEt ,~COOEt Cl~ Cl~

CA 02222322 1997-11-2~

W O 96/39407 PCT~US96/08991 Scheme~ m F F F

t-bu-O~F t-bu-O$F t-bu-O~F
OH oR7 s Scheme~nrV

F$~ F t-bu-O~ F t-bu-O~ F
F F F

-7 PCTrUS96,'t~3~1 Scheme XV

F ~ R16 F~

R~ R~

OH OH

O O O O

R2~ ~ R2~ , R2~~ H
~ R16 ~ R16 ~ R16 CA 02222322 l997-ll-25 W O 96/3~407 PCTrUS9~ 991 Scheme XVI

X~OH

t-BuO~O H t-BuO~ t-Bul ~7R1J60~oEt N~OEt N5~OEt H O~J Cl~ -~--~ R16 ~--'' R16 O O O O
X;.~OEt F~

PCT~US9G/0~931 Scheme XVII

F R~N,R R~N,R o R3~N R3~N R3~N~CooEt t-bu-O~F t-bu-O~F R2 NH2 ~ NH2 ~
R3~NJ~CooEt R3~NJ~Co2R4 R2 ~ R2 WO 96/39407 PCTrUS96/08991 Scheme xvm R~ o R5 o R o~C02Et Rs o ''RO~CO2Et Rs o Rs o O R ~NJ~co2Et R3~,~NJ~,Co2R4 R 0~ W 2AR~
(CH2)n~¦ R6 R1 ~ (CH2)n--¦ R6 R1 (CH2)m l 26 / (CH2)m 1 27 Rb Rb In accordance with reaction Scheme I, illustrated above, an alpha-halo acetate derivative of for;nula 1, such as ethyl 2-fluoro~cet~te, is cond~n~ed wit'n a formate ester of formula 2 in the presence of a suitable base, as for example sodium ethoxide, in an inert solvent such as diethyl ether to to give an enolate compound of formula 3. Compounds of formula 3 are, in turn, converted to compounds of formula 5 by condensation with an ~mi~ine derivative of formula 4, in which Rl is an electron withdrawing group such as phenyl, trifluoromethyl, cyano, perfluoroaL~cyl, vinyl, substituted vinyl, fluorine, nitro, acetylene, ~.ub..~i~uled acetylene, aLlcoxycarbonyl, or a nitrogen-cont~ining aromatic heterocycle. Compounds of formula 5 are reacted with an aLkoxymethylene malonatederivative of forrnula 8 in the presence of a suitable strong base, for example lithium 15 diisopropylamide (LDA) or n-butyl lithium, preferably at a temperature below 0~C, and conveniently at -78~C to afford the compounds of formula 9A.
The compounds of formula 9A are cyclized in the presence of a base, as for example DBU or piperidine, or in the presence of an acid, such as sulfuric acid, in a - solvent such as toluene, THF, ethanol or chlorobenzene, or by heating the compound in a CA 02222322 1997-11-2~

W O 96/39~07 PCT~US96/08991 solvent, as for example xylene, diglyme, triglyme, sulfolane or Dowtherm A~ (a eutectic mixture of biphenyl and diphenyl ether) at a Lc~ greater than 120~C, to give the compounds of formula lOC. The esters lOC are converted into the esters 1 lA via transesterification with an alcohol suitable for selective hydrolysis, such as benzyl alcohol S or 2-(trimethylsilyl)ethanol (TMSE), in the presence of a catalyst, as for example lil;.,.il-~
tetraethoxide. t The 2-hydroxy compounds of formula 1 lA are converted to the cullcs~onding halo-derivatives of forrnula 12A by treatment with a halogenating agent, for example phosphorous oxychloride to afford the chlorû derivative, optionally in an inert solvent at a Lt;m~e1~LU1G between about 20~C and 145~C, depending on the halogenating agent and the boiling point of the solvent if one is used, and conveniently at room Lclll~ aLulc. The leaving group L in the compounds of formula 12A is then displaced by a nucleophile such as a nucleophilic amine, for example N-methylpiperazine or 2-meth~ ~ille, to give the compounds of formula 13A. The reaction may be conducted at a ~elll~ tulc from about 20~C to about 130~C in a suitable organic solvent such as pyridine, methylene chloride, chloroform or l-methyl-2-pyrrolidinone. It is desirable to carry out the reaction in the presence of an acid-acceptor such as triethylamine, potassium carbonate and the like, at a molar ratio of 1.0 to 2.0 moles of the acid acceptor per mole of compound of the formula 6.
The amine can also be used as an acid acceptor in which case two or more equivalents of this reagent are used.
The benzyl ester group of compounds of formula 13A is then removed by hydrogenolysis when R* is benzyl, or with tetrabutylammonium fluoride when R* isTMSE, to afford a compound of formula I.
In accordance with Scheme II above, the substituted act;LolliL,ile compounds of 2s formula 4B, where R 1 is an aL~cyl, cycloalkyl, halo(loweraL~yl) group or a (loweraLkyl)amino group protected with a protecting group such as benzyloxycarbonyl, or may be an electron withdrawing group as ~lescTibed above for Scheme I, are reacted with diethyl carbonate and sodium hydride in an inert organic solvent, such as toluene, THF or the like, to give the ~ubstitl~ted cyanoacetic acid ester of formula 5B. The cyano group of the compounds of formula SB is then reacted with an inorganic acid, such as hydrochloric acid, in the presence of one equivalent of anhydrous alcohol, such as ethanol, followed by reaction with arnmonia to give the substituted ~mi(lin~ ester of formula 6B, which is then conden~ed with an enolate compound of formula 7B, prepared in a manner similar to compounds of formula 3 in Scheme I, in the presence of a suitable base, for example 3s triethylarnine, in a polar solvent such as methanol to give the substituted hydroxy-pyrimidine ester compounds of formula 8B. The ester function of the compounds of CA 02222322 1997-11-2~

W O 96/39407 PCTAUS9C'~31 formula 8B is converted into an aldehyde function by reduction, for example with a hindered ~ minllm hydride, such as diisobutylaluminum hydride or LiAlH(O-t-butyl)3, or with N,N-dimethyl-chlo.ul,lt;Lhyl~nt~iminillrn chloride in pyridine or ~ rnino~lllmin~lm hydride to produce a compound of formula 9B. This reaction may be conducted at aS t~ ild~lllC below -20~C, and conveniently at -78~C in the presence of a aprotic solvent such as hexane, toluene, methylene chloride or THF.
The aldehyde compounds of formula 9B are reacted with a malonic acid diester, such as diethyl malonate, dibenzyl malonate, t-butyl m~l~ nz~te or di-t-butyl m,.lnn~t~, in the presence of a suitable base such as piperidine and a catalytic amount of an acid, such as lo acetic acid or sulfuric acid, in a polar solvent, such as ethanol, to afford the pyridopyrimitline compounds of formula IOB. The compounds of formula lOB are reacted with a suitable halogenating agent such as phosphoryl chloride at room temperature to afford the compounds of formula 1 lB. The halo group is displaced as discussed in reaction Scheme I to afford the compounds of formula 12B, which are in turn converted into the compounds of formula I as described in Scheme I for the conversion of compounds of formula 10 into compounds of formula I.
According to reaction Scheme m illustrated above, 2-picoline-N-oxide is cûnverted to a mixture of compounds of ft~rmlll~ 22 and 23 by Llt;at-llelll with a halogenating agent, for example phosphorus oxychloride, optionally in an inert solvent.
The reaction may be run at a ~-llpel~Lul~ between about 25~C and 125~C, depending on the halogenating agent selected. When the halogenating agent is phosphorus oxychloride the reaction ~ Ul~ is preferably between 60~C and 120~C. A compound of formula 23 is, in turn, reacted with an aLkoxymethylene malonate derivative of formula 8 in the presence of a suitably strong and hindered base, for example lithium diisopropylamide (LDA), preferably at a temperature below 0~C, and conveniently at -78~C to afford the compounds of formula 24. Compounds of formula 24 are cyclized by heating the compound in asolvent with a boiling point greater than 1 20~C, for example xylene, diglyme, triglyme, sulfolane or Dowtherm A(~) (a eutectic mixture of biphenyl and diphenyl ether), to afford compounds of formula 25. The leaving group in the 8-position of the quinolizinone compound of formula 25 is then displaced using 3-aminopyrrolidine with the primary amino group protected, for example with t-butoxycarbonyl. The protecting group is then removed to give the compounds of formula 26.
The esters of ~ormula 26 are than converted to the carboxylic acids of formula nI
as described in Scheme 1 for the conversion of compounds of formula 10 to compounds of 3s formula I.

CA 02222322 1997-11-2~

WO 96/39407 PCT~US96/08991 ~It~ n~t~ly, compounds of formula 23 are converted to compounds of formula 27, wherein Rl is alkyl, cycloaLkyl or carbocyclic aryl(loweralkyl), by Llcd~ ent with an alkyl, cycloalkyl or carbocyclic aryl(loweralkyl) halide in the presence of a suitable base such as LDA. Compounds of formula 23 are converted to compounds of formula 27, wherein R 1 is a phenyl group as defined herein or an alkylamino group by conversion to the corresponding halomethyl compound and Lled~ t1lt of the halomethyl compound with an aryl metal compound such as phenyllithillm as described above, or with an alkylamine such as methylamine as shown in reaction Scheme VA. The compounds of formula 27 are converted to the compounds of formula 29 by the sequence of reactions described above 10 for the conversion of compounds of formula 25. The leaving group in the 8-position of the quinolizinone compound of formula 29 is then displaced, for example by a nucleophilic amine such as N-methylpiperazine or 2-methylpiperazine, to give the the compounds of formula 30. The reaction may be conducted at a temperature from about 20~C to about 130~C in a suitable organic solvent such as pyridine, methylene chlnrille, chloroform or 1-15 methyl-2-pyrrolidinone. It is desirable to carry out the reaction in the presence of an acid-acceptor such as triethylamine, potassium carbonate and the like, at a molar ratio of 1.0 to 2.0 moles of the acid acceptor per mole of compound of the formula29. The amine can also be used as an acid acceptor in which case two or more equivalents of this reagent are used.
In the case where R2 is a phenyl group as defined herein, compounds of formula 30 are formed by coupling the compound of formula 29 with an aryl metal compound, for example phenyllithinm, to replace the 8-leaving group with an Imcubstit~lted phenyl group.
The coupling reaction is carried in a reaction-inert solvent, i.e., a solvent which does not in~ with the coupling reaction of the aryl metal compound with a compound of formula29. Suitable reaction-inert solvents include ethers, for example diethyl ether, dimethoxyethane and tetrah~uru,dll (THF). Co-solvents may be used with ethers ifdesired. These co-solvents may be benzene, toluene, ~eL,d,1,c;Ll1ylethyleneamine (TMEDA) and hexamethyl-phosphoramide (HMPA). The aryl metal compounds may be plt;pal~;d by known methods. For example, they may be prepared by direct lithium-halogen exchange of the cu1,e~onding aryl halide using n-butyl-, sec-butyl- or t-butyl-lithium followed by tra~m~t~ tion by a wide variety of salts by known methods such as described by E.
Negishi in "Organo-nçt~llics in Qrganic Sysnthesis", Vol. 1, page 104.
According to Scheme rv A illustrated above, a compound of formula 31 is treated with a malononic acid ester, for example diethyl malonate, in the presence of a suitable base such as sodium hydride in a polar nonprotic solvent such as an ether, for example diethyl ether or THF, to afford a compound of formula 32. Compounds of formula 32 are, in CA 02222322 1997-11-2~

W O 96/39407 PCTrUS~ 931 turn, decarboxylated, for example by heating them in strong mineral acid such as aqueous sulfuric acid, to afford the compounds of formula 33. The nitro-compound of formula 33 is reduced to the corresponding amino-compound of formula 34. The nitro group may be reduced by catalytic hydrogenation using standard techniques or by any of a variety of 5 known reducing agents such as using a metal, for example zinc, tin or iron, in the presence if a mineral acid, usually hydrochloric acid. The amino-compound of formula 34 is converted to the corresponding fluoro-compound of formula 35 by ~ ."~-t with ethyl nitrite and tetrafluoroboric acid, followed by ll~at,.l~,nl with potassium fluoride. The compound of formula 35 is then converted into the corresponding N-oxide of formula 36 10 by oxidation, for example using peracetic acid. The reaction is carried out in the range from about 20~C up to the reflux ~c.ll~eldt~ of the solvent employed, preferably at about ~0~C. The compound of formula 36 is nitrated to afford compounds of formula 37. The nitration reaction can be carried out using a variety of known nitr~ting agents, for example a mixture of nitric acid and sulfuric acid or a mixture of sulfuric acid and potassium nitrate, 15 or by using nillunium salts such as nitronium trifluo~ ,lrlh~nesulfonate. The nitro compound of formula 37 is, in turn, converted to the corresponding halo compound of formula 38 by L..~ ~l ., IG~t with mineral acid at ~mhil-nt or elevated ~~ ,ld~Ul~ as desired.
For example, the col..~ou..d of formula 37 is treated with aqueous hydrochloric acid at a t~ p~ldture of about 100-120~C to afford the compound of formula 38 wherein L is Cl.
20 The compound of formula 38 is, in turn converted to the compound of forrnula IV A1 by reduction, for example using a metal such as iron or zinc in the presence of an acid such as acetic acid. The compound of formula IV A 1 is, in turn, converted to the compound of forrnula lV A2 by tre~tm~nt with a suitable base, such as LDA, followed by L-~;a~ e~-~ with a halogenating agent, for example N-chloro or N-bromo succinimi~le Alternately, the 25 compounds of formula IV A 1 are converted to compounds of formula IV A3, wherein R
is alkyl, cycloaL~yl or carbocyclic aryl(loweralkyl), by tre~tm~ont with an aL~cyl, cycloaLkyl or caubocyclic aryl(loweraL~cyl) halide in the presence of a suitable base such as LDA. The conl~oL,..ds of formula IV A3 are further treated with a a suitable base, such as LDA, followed by ~ ,nt with a halogenating agent, for example N-chloro or N-bromo 30 succinimide to afford the compounds of formula lV A4. Compounds of formulae IV A l -rv A4 are key interm~rlizltt-s used in the synthesis of quinolizinone compounds.According to Schemes IV B and rv c illustrated above, the compounds of formulae IV A3 and IV A4 are converted to the quinolizinone compounds of formula IV B
and IV C, respectively, by the following series of reactions: (I) reaction with an - 35 aL~coxymethylene CA 02222322 1997-11-2~

W O 96/39407 PCTrUS96/08991 malonate derivative of formula 8 in the presence of a suitably strong and hindered base, for example lithium diisopropylamide (LDA), preferably at a temperature below 0~C, and conveniently at -78~C, to afford the compounds of formulae 39 and 42, respectively (2) cyclization as discussed in reaction Scheme m, to afford the compounds of formulae 40 and 43, respectively (3) displ~ççm~nt of the leaving group in the 8-position as discussed in reaction Scheme m to afford the compounds of formulae 41 and 44, respectively and (4) hydrolysis or hydrogenolysis as discussed in reaction Scheme m of the carboxylic acid ester to the corresponding carboxylic acids of formulae IV B and IV C, respectively.
According to Scheme V A illustrated above, compounds of formula IV A1 are 10 treated with a halogenating agent under suitable conditions for g~ ,.I;ng halogen radicals, for example using N-bromo- or N-chlorosuccinimi~l~ in the presence of a free radical initiator such as AIBN to afford the compounds of formula 45. The halogen on the alpha carbon atom is then displaced by a nucleophile, for example an alkoxide to give the compounds of formula 51 or an amine to give the compounds of formula 46. The amine 15 function is plulcclcd during synthesis by converting it to the corresponding ~~ lin~
function affording compounds of formula 47. Compounds of formula 47 are reacted with an alkoxymethylene malonate derivative of formula 8 in the presence of a suitably strong and hindered base, for example lithium diiso~lupylamide (LDA), preferably at a G~alLI~c below 0~C, and conveniently at -78~C. The fc,l"-~",;~line group is then20 removed by reaction with hydrazine and acetic acid to afford the compounds of formula 48. The compounds of formula 48 are cyclized as discussed in reaction Scheme m, to afford the compounds of formula 49. The leaving group, L, is then displaced as discussed in reaction Scheme m to afford the compounds of formula 50. The compounds of formula 50 are, in turn, converted to the compounds of formula V Al as discussed in reaction 25 Scheme 1.
The compounds of formula 51 are converted to the compounds of formula V A2 by the following series of reactions: ( 1 ) reaction with an aLIcoxymethylene malonate derivative of forrnula 8 in the presence of a suitably strong and hindered base, for example lithium diisopropylarnide (LDA), preferably at a temperature below 0~C, and conveniently at-78~C, to afford the compounds of formula 52 (2) cyclization as discussed in reaction Scheme III, to afford the compounds of forrnula 53 (3) displacement of the leaving group in the 8-position as discussed in reaction Scheme III to afford the compounds of formula 54 and (4) conversion of the carboxylic acid ester to the corresponding carboxylic acids of formula V A2.

CA 02222322 1997-11-2~

W O 96~9407 PCT~US96/08991 According to reaction Scheme V B illustrated above, compounds of forrnula IV
A2 are converted to compounds of formulae V B 1 and V B2 by the same procedures discussed in reaction Scheme V A for the conversion of compounds of formula IV A 1 to compounds of formulae V Al and V A2.
S According to reaction Scheme VI illustrated above, perfluoroinated pyridine is converted to the compound of formula 66 by the procedures described in reaction Scheme IV A for the ~lc~dLion of compounds of formula 33. Compounds of formula 66 are, in turn, converted to the compounds of formula VI A and VI B by the series of reactions cus~erl in reaction Scheme l~I for the conversion of compounds of forrnula 23 tocompounds of formula III.
According to reaction Scheme VlI illustrated above, compounds of formula IV A2 are reacted with a ~ te.,~cd alcohol of formula 71, in the presence of a suitable base such as LDA, to afford compounds of formula 72. The hydroxy l~lutec~illg group is preferably a THP (tetrahydopyranyl) ether group. The compounds of formula 72 are, in turn, dep-u~, ~d by standard methods to afford the compounds of formula 73. The compounds of formula 73 are cyclized, in the presence of a suitable non-nucleophilic base such as sodium hydride, to afford the compounds of formula 74. The compounds of formula 74 are then comverted to the compounds of formula 77 by the series of reactions described in reaction Scheme IV B for the conversion of the compounds of formula IV A3 to thecompounds of formula IV B.
Compounds of forrnula I, wherein R2 contains a free primary an~ino group are synthesized according to reaction Scheme vm illustrated above. In accordance with reaction Scheme VIII, an alpha-halo acetate derivative of formula 1, such as ethyl 2-fluoro~l~et~te, is condenced with a formate ester of formula 2, in the presence of a suitable base, for example sodium ethoxide, in an inert solvent such as diethyl ether to give an enolate compound of formula 3. Compounds of formula 3 are, in turn, converted tocompounds of formula 5 by conden~tion with an ~mi~iine derivative of formula 4, in the presence of a suitable base, for example triethylamine, in a polar solvent such as methanol.
The hydroxy-substituted compounds of formula S are converted to the corresponding halo-derivatives of formula 6 by tre~tment with a halogenating agent, for exa;nple phosphorus oxychloride to afford the chloro derivative, optionally in an inert solvent at a ~ e~
~ ,n about 20~C and 145~C, depending on the halogenating agent and the boiling point of the solvent if one is used. When phosphorus oxychloride is the halogenating agent, the reaction Lc;l~ ,.dLulc iS preferably between about 80~C and 100~C. The leaving group in the CA 02222322 1997-11-2~

W O 96/39407 PCTAUS~ 8~1 5-position of the pyrimi~line ring of compounds of formula 6 is then cli~pl~ed by a nucleophile such as a nucleophilic amine, for example N-methylpiperazine or 2-methyl~iy~ ,e, to give the the compounds of formula 7. The reaction may be c~-nd~ t at a temperature from about 20~C to about 130~C in a suitable organic solvent such as s pyridine, methylene chloride, chlolu~-m or l-methyl-2-pyrrolidinone. It is desirable to carry out the reaction in the presence of an acid-acceptor such as triethylamine, potassium carbonate and the like, at a molar ratio of 1.0 to 2.0 moles of the acid acceptor per mole of compound of the formula 6. The amine can also be used as an acid acceptor in which case two or more equivalents of this reagent are used.
The compounds of formula 7 are reacted with an aLlcoxymethylene malonate derivative of formula 8 in the presence of a suitably strong hindered base, for example lithium diisopropylamide (LDA), preferably at a tcnl~LldLu.c below 0~C, and conveniently at -78~C to afford the compounds of formula 9. The compounds of formula 9 are cyclized in the presence of a suitable hindered base, for example DBU, in an aprotic solvent, such 15 as toluene, THF or chlorobenzene to give the compounds of formulalO. The cyclization is carried out at a temperature in the range of about 30~C to about 130~C, preferably at the reflux Lclll~;lLulc of the reaction mixture. The compounds of formula 10 are hydrolyzed in the presence of a suitable base such as sodium or potasium hydroxide to afford the compounds of formula 78. The compounds of formula 78 are, in turn, chlorinated to 20 afford the coll",oullds of forrnula lOa using an aL ~lu~flate chlorinating agent such as phosphorus oxychloride. The leaving group in the 8-position of the quinolizinonecompound of formula lOa is then displaced using a nucleophilic amine such as 3-aminopyrrolidine (with the primary amino group protected, for example with t-butoxycarbonyl). The l,lotc.;Lillg group is then removed to give the compounds of formula 25 lOb. The esters of formula lOb are then converted to the carboxylic acids of formula I.
The conversion may be achieved by conventional hydrolysis or by converting a compound of formula lOb to the cu,.~ onding ester, via transesterification with an alcohol suitable for selective hydrolysis, such as benzyl alcohol or 2-(trimethylsilyl)ethanol (TMSE), in the presence of a catalyst, for example ~ .n tetraethoxide, and then, in turn, removing the 30 alcohol group by hydrogenolysis when R* is benzyl or tetrabutylammonium fluoride when R* is TMSE to afford a compound of formula I.
Compounds of formula I where R3 is loweralkyl or halo(loweraLl~yl) are synthe~i~ed according to reaction Scheme IX. In accordance with reaction Scheme IX
illustrated above, an alpha-halo acetate derivative of formula 1, such as ethyl 2- -3~ fluoroacetate, is cnn-lçn~ecl with a compound of formula 78, where X may be a halogen or alkanoyl and R3 may be loweraL~yl or halo(loweralkyl), for example acetyl chloride or -W O 96/39407 PCT~US9~/~8931 ethyl trifluoro~cet~t~, in the presence of a sui~able base, for example sodium methoxide or sodium ethoxide, and in a suitable solvent, such as methanol, ethanol or ether, to give an alpha-fluoro beta-keto ester compound of formula 79. Co~ oullds of formula 79 are then reacted with ;lmi~linç compounds of formula 4 or formula 6, in which R1 is an alkyl, halo(loweralkyl) or cycloaL~cyl group, or may be an electron withdrawing group such as t phenyl, trifluoromethyl, cyano, perfluoroaL~cyl, vinyl, substituted vinyl, fluorine, nitro, acetylene, substituted acetylene, aLkoxycarbonyl, or a nitrogen-cont~inin~ aromatic heterocycle, in the presence of a suitable base, such as sodium methoxide or sodiurn ethoxide, in the presence of a suitable solvent, such as methanol or ethanol, to give 0 compounds of formulae 81 or 80, lGs~e~,lively. Compounds of formula 80 may besubstit-lted for compounds of formula 8B in Scheme II and converted via the reactions in that Scheme, described above, into compounds of formula I. Compounds of formula 81 may be substituted for compounds of formula 5 in Scheme I and converted into compounds of formula I via the reactions of Scheme I described above. Alternatively, the compounds of formula 81 may be sub ,liLuled for compounds of formula 5 in Scheme VIII and converted via the reactions in that scheme, described above, into compounds of formula I.
Compounds of formula I where R2 is loweraL~cyl, cycloaLkyl, carbocyclic aryl(loweralkyl), cycloaLkyl(loweraL~cyl), phenyl, nitrogen-co~ g aromatic heterocycle, or nitrogen-cv~ ;..;..g heterocycle are syntll~ci7~cl according to reaction Scheme X. In 20 accordance with reaction Scheme X illustrated above, an organo-metallic derivative of formula 82, such as phenyl m~gnesillm bromide, cyclopentyl m~n~chlrr~ brornide, or N-methylpiperidin-~yl m~..f.~il..n bromide is con-len.ced with an alpha-haloacet~te derivative of forînula 83, where X may be a halogen or a~oxy group, such as ethyl 2-fluoroacetate or 2-fluoroacetyl chloride, in an anhydrous solvent, for example ether or THF, to produce the 2~ alpha-fluoro compounds of formula 84. Compounds of formula 84, may in turn be reacted with a formate ester of formula 2, in the presence of a suitable base, for example sodium ethoxide, in an inert solvent such as diethyl ether to give an enolate derivative of formula 85. The compounds of formula 85 are in turn converted to compounds of formula 86 or 87 by cond~n.c~tion with an ~mi-lin~ derivative of formula 4 or 6, in which Rl is loweraLkyl, 30 halo(loweralkyl) or cycloaLkyl, or is an electron withdrawing group such as phenyl, trifluoromethyl, cyano, perfluoroaLIcyl, vinyl, substituted vinyl, fluorine, nitro, acetylene, substituted acetylene, aL~coxycarbonyl, or a nitrogen-cont~ining aromatic heterocycle, in the presence of a suitable base, for example triethylamine, in a polar solvent such as methanol.
Compounds of forrnula 87 may be substi~lted for compounds of formula 7 in Scheme35 vm, and converted via the reactions in that scheme, described above, into compounds of formula 1. Compounds of formula 86 may be substituted for compounds of formula 9B in CA 02222322 1997-11-2~

W O 96/39407 PCTrUS96/08991 Scheme II and, by reaction with a malonic acid diester as described for Scheme II above, converted directly into compounds of formula 12B and, thence, into compounds of formu'la I.
Alternatively, compounds of formula I, where R2 is loweralkyl, cycloaLkyl, carbocyclic aryl(loweralkyl), cycloalkyl(loweralkyl), phenyl, nitrogen-containing aromatic ,~
heterocycle, or nitrogen-cont~ining heterocycle are synthç~i7tod according to reaction Scheme XI. An alpha-h~lo~et~te derivative of formula 1 is con~lensed with an acid halide or ester derivative of formula 88, for example acetyl chloride, benzoyl chloride, isonicotinoyl chloride, or 2,6-dimethylisonicotinoyl chloride, in an anhydrous solvent, for 10 example ether, THF, anhydrous methanol or an hydrous ethanol, in the presence of a suitable base, such as sodium methoxide or NaN(TMS)2, to produce the beta-ketoester derivative of formula 91, which is converted into compounds of formula 92 in the presence of a suitable base, such as sodium methoxide or sodium ethoxide, in the presence of a suitable solvent, such as methanol, ethanol or ether, to give the hydroxy-s~hstit-lted 15 compounds of formulae 92 or 93. These compounds, in turn, are converted into the corresponding halo- derivatives of formulae 94 and 95 under conditions as described for conversion of compounds of formula S to compounds of formula 6 in Scheme VIII. The compounds of formulae 94 and 95 are then reacted with reducing agents such as zinc in acetic acid or hydrogen in the presence of catalytic agents such as Ni, Pd, or Pt in suitable solvents such as ethanol or methanol to produce the compounds of formula 86 and 87, which are converted as described in Scheme X into compounds of formula I.
In addition, the non-fluorinated derivatives of formula 90, where R2 is as described above, may be converted to the beta-ketoester derivatives of formula 9 l using a reagent such as N-fluoropyritlinium triflate, N-fluorosulfonyl amide, cesium fluorooxysulfate, or acetyl hypofluoride.
ln accordance with Scheme XII, which illustrates a process for ~ l~p~uing the desired compounds of formula Ic wherein R l is cyclopropyl, co~ ;ially available 3-chloro-2,4,5,6-tetrafluoropyridine (compound 88) is reacted with an alkali salt of t-butanol, such as for example, sodium t-butoxide or lithium t-butoxide, in a polar organic solvent such as THF, first at from 10~C to -78~C for 1-4 hours, then at room temperature for 2-72 hours, to give the compound of formula 89 (isolated from a mixture of products by ch,ulllaLugraphy). The compound of formula 89 is then reacted with hydrogen over a noble catalyst, such as Pd/C in a sodium acetate buffer, to remove the chlorine and give the compound of formula 90 (also isolated from a mixture of products by clllullla~c)graphy). In the instance where R6 is alkyl, the compound of formula 90 is then reacted with a suitable alkyl halide, for example methyl halide or the like, in the ~,.,ence of a suitably strong and CA 02222322 1997-11-2~

W O 96/39407 PCTrU~96/08991 hindered base, for example lithium diisopropylamide (LDA), preferably at a t~ dLulG
below 0~C, and conveniently at -78~C to afford the compounds of formula 91. In the inct~nre where R6 is haloalkyl, for example fluoroaL~cyl, the compound of formula 90 is first reacted with a suitably strong and hindered base, for example lithium diisopropylamide 5 (LDA), preferably at a lGm~ dLulG below 0~C, and conveniently at -78~C followed by reaction with formaldehyde to give the compound where R6 is hydroxyrnethyl which is then reacted with diaminosulfur trifluoride (DAST) in a non-polar solvent such as methylene chloride to give the compound of formula 91. Alt~m~t~.ly, when the R~ group is to be a difluoromethyl, for example, the compound of formula 90 is first reacted with a 10 suitably strong and hindered base, for example lithium diusopropylamide (LDA), preferably at a lel~l~Gldt~llG below 0~C, and conveniently at -78~C followed by reaction with DMF to form ~he i~ l..ecliate compound wherein R6 is CHO, and this il~L~ cdia~ is then reacted with DAST to prepare the compound of formula 91, wherein R6 is difluoromethyl. The compounds of forrnula 91 are then reacted with hydrazine under nitrogen at reflux 15 temperature for 2-8 hours, and after removal of excess hydrazine the residue is dissolved in an organic solvent, such as methanol or bell~enc, for example, and air is then passed through the solution of the hydrazino product for 8-16 hours to give the compounds of formula 92. he compounds of formula 92 are then con~len~ed with cyclopropyl acetonitrile in a polar organic solvent, such as THF, for example, in the presence of strong base, such 20 as lithium diethylamide (LDA) or lithium diisopropylamide, at -78~C for 1-4 hours and then at 0~C for 1-4 hours or NaNH2 at -5~C to -10~C for 1 to 8 hours in order to prepare compounds of formula 93. The compounds of formula 93 are then reacted with trifluoroacetic acid under nitrogen for 1-4 hours at ~mbient LG.l.~Gld~uuG to removed the lJlot~Li~lg t-butoxide group, and the ull~ G~;LGd m~t.-ri~l is then reacted with POC13 in a 25 suitable organic solvent, such as DMF or methylene chloride, for example, at ambient Lul~ for 8-24 hours in order to prepare the compounds of formula 94.
In an improved ~n,~udLi~/e method, regarded as a part of the present invention, the compounds of formula 89 may be converted directly to the compounds of formula 9 l by Lle~nllt llt with a strong base, such as t-butyllithil-m or s-butyllithiu-m--~ for example, in a 30 polar solvent such as THF or the like for a period of from 0.5 to 3 hours, followed by reaction with methyl iodide at a ~Glll~ldlUlG firstly below -50~C then at ~mhient temperature for a period of from 4 to 20 hours. The compounds of formula 91 may then be converted to the compounds of formula 92 by ~IGatu~elll with a hydride reducing agent, such as LAH
or sodium bis-(2-methoxyethoxy)~ min--m hydride (Red-AlTM), for example, at from 0~C
z 35 to ambient lGllllJGldlulc for a period of from 8-24 hours. The resulting compounds of formula 93 are then reacted with POC13 in an organic solvent such as DMF or methylene CA 02222322 1997-11-2~

WO 96/39407 PCTAUS96~8991 chloride, for example, at ambient temperature for a period of from 6-20 hours in order to prepare directly the compounds of formula 94.
The cyano compounds of formula 94 are converted to esters of formula 95 by L ~,aLlnell~ with anhydrous ethanolic HCl followed by LIGdLIIl~,.lt with H20. The ester 5 compounds of formula 95 are then reduced to the aldehyde compounds of formula 96 by reaction with lithium alul.li,lul.. hydride in THF at reduced te~ .,.dtures for 0.5 -2 hours, followed by reaction with oxalyl chloride and DMS0 in the presence of triethyl amine at -78~C for 0.25-1.0 hours. The compounds of formula 96 are reacted with with a m~l~ nir acid diester, such as diethyl malonate, dibenzyl malonate, t-butyl malonate or di-t-butyl m~lnnz~:, in the ~-~,sence of a suitable base such as piperidine and a catalytic amount of an acid, such as acetic acid or sulfuric acid, in a polar solvent, such as ethanol, followed by isolation of the i l~lr.l ~e~ te compounds of formula 97 with subsequent llGdLlllellt thereof by heating in a polar, high-boiling solvent such as DMF or DMS0 at reflux telll~cldt~ue or in Do~Lh~,llll ATM for a period of from 0.5 to 4 hours to form the pyridopyrimidinecompounds of formula 98. The chloro group of the compounds 98 is displaced as discussed in reaction Scheme I to afford the compounds of formula 99, which are in turn converted into the compounds of formula Ic as described in Scheme I for the conversion of compounds of formula 13A into compounds of formula I.
In accordance with Scheme xm, trifluoropyridine ether of formula 90 is reacted with a suitable strong base, for example, LDA, preferrably at a ~el~ Gldture below 0~C and convenientyly at -78~C, in an inert solvent such as THF, for example. The anion thus ge.lGlaLed is then reacted with an alkyl borate, such as, for example, trimethylborate or triethylborate, followed by oxidation with hydrogen peroxide in the presence of base such as sodium hydroxide in situ to give the compound of formula 100, wherein R7 is lower a~cyl. Compound 100 is then aL~ylated with a suitable alkylating agent, such as an alkyl iodide or aLkyl sulfate, for example methyl sulfate or ethyl iodide or the like, in the presence of a base such as sodium hydroxide, barium hydroxide, potassium carbonate, lithium carbonate, or the like, in a polar solvent, such as acetone, ethanol, DMF, THF, or the like, within a tGnl~ dLulG range of room Lelllp~ ure to reflux LGIII~G1dLU1G of the solvent, to give the compound of formula 101. Alternately, compound 101 can be obtained by treating compound 100 with an alcohol of the formula R70H, wherein R7 is as described above, triphenylphosphine and diethyldiazocarboxylate in a solvent such as THF at a temperature in the range of 0~C to room ~Glll~JGlLulG.
In accordance with Scheme Xl~/, conllllG--;ially available pentafluoropyridine of 3S formula 102, is reacted with an alkali metal salt of t-butanol, for example, sodium t-butoxide or potassium t-butoxide, in an anhydrous organic solvent such as THF, at a WO 96/39407 PCT/U',.~tO~991 temperature in the range of -78~C to room ~e~ aLul~, to give the compound of formula 103. Compound 103 is then reacted with hydrazine at a Lt;~ el~ule in the range of room temperature to reflux temperature, and in a solvent such as methanol, iso-propanol, ether, or the like, followed by bubbling air through the solution of the int~rrnP~ te in a solvent s such as benzene of toluene, in the presence of a base such as sodium hydroxide to give to compound of formula 104.
In accordance with Scheme XV, the penL~[luoropyridine of formula 102 is disso~ved in a solvent, such as for example, THF or methylene chloride, and reacted with a cyclic a~une of the formula R2H, wherein R2 is as defined above, or, when R2 is 10 sllhstitl-t~d with a reactive group such as an amino group, a cyclic amine with suitably protected reactive s~lb~ in the presence iof a suitable base, such as a tertiary amine, such as for example triethylarnine, at a lelll~el~Lul~ in the range of 0~C to room telllp~,la~ul~.
The reactant of formula 106, wherein R16 is as defined above and TBS represents a tributylsilyl group, is ~ç~ from the corresponding iodide starting m~t~ri~l by reaction with t-butyl lithium in ether at -78~C, and is reacted with compound 105 in a solvent such as THF or ether at -78~C to give the compound of formula 107. The plo~.;Lillg TBS group is removed from compound 107 by reaction with tetrabutylallllllol-iulll fluoride in THF at room ~ d~Ul~ to give the compound of formula 108. The trifluoro compound 108 is converted into the difluoro compound 109 by reacting co",~ound 108 with hydrazine at reflux ~Ill~ Ul~ in a solvent such as ether, propanol, or methoxymethyl ether, followed by Lle~ l of an i--l. . . - .ç~ t~-. hydrazino product with CuS04 in a solvent such as methanol, ethanol, or toluene, or ~lt~rn~tely by reaction with air in the presence of a base such as NaOH. The monocyclic compound 109 is then converted into the bicyclic compound of formula 110 by reaction with NaH at reflux t~ LLU~; in a solvent such as dioxane or THF. Compound 110 is then treated with a strong base, such as LDA at -78~C, for example, and con(len~l with diethyl ethoxymethylenemalonate to give an illLc;~ ediate product which is cyclized in the presence of a base such as DBU or piperidine/acetic acid, in a solvent such a ethanol or aqueous THF, at a ~elllp~,la~u~e from room ~elnpG,dture to 60~C, to give the tricyclic ester of fonnula 111. The ester 111 is hydrolyzed to the acid of formula 112 with an aL~ali metal hydroxide in aqueous THF, for example. Any protecting groups remaining onthe R2 or R 16 groups may conveniently be removed at this point to give the desired compound of Formula I.
In accu,dance with Scheme XVI, an alternate method of preparing compounds 112 is given. Compound 103 (from Scheme XIV) is reacted with compound 106 (from 3s Scheme XV) in a solvent such as THF or ether at -78~C to give a TBS-~lu~c~d .e~ compound, from which theTBS group is removed by reaction with WO 96/39407 PCTrUS9C/'~

tetrabutylammonium fluoride in THF at room ~C~ dLulc to give the compound of formula 113 The trifluoro compound 113 is converted into the difluoro compound 114 by reaction with hydrazine at reflux ~e~ ,ldtuuc in a solvent such as ether, propanol, or methoxymethyl ether, followed by llcdllnellt of an intermediate hydldzillo product with CuS04 in a solvent such as methanol, ethanol, or toluene, or ~lt~orn~tely by reaction with air in the presence of a base such as NaOH The monocyclic compound 114 is then converted into the bicyclic compound of formula 115 by reaction with NaH at reflux ~e.ll~,ldlulc in a solvent such as dioxane or THF. Compound 115 is then treated with a strong base, such as LDA at -78~C, for example, and con~ n~ecl with diethyl 10 ethoxymethylenemalonate to give an int~rrn~Ai~te product which is cyclized in the presence of a base such as DBU or piperidine/acetic acid, in a solvent such a ethanol or aqueous THF, at a L~ c.d~ulc from room ~CIllp~ldtUUC to 60~C, to give the tricyclic ester of formula 116. The protecting t-butoxy group is removed from compounds 116 by reaction with an acid, such as HCl or trifluoroacetic acid at room ~elllpcld~uuc, and optionally in a suitable 1~ solvent, such as methylene chloride or dioxane to give compound s 117 The free hydroxy group of compounds 117 is then reacted with POC13/DMF in a suitable solvent such as methylene chloride at room t~nllJ~,-dluuc to give the chloro compounds of formula 118.
Compounds 118 are reacted with a cyclic amine of the formula R2H, wherein R2 is as defined above, or, when R2 is sub~ ul~d with a reactive group such as an amino group, a cyclic amine with suitably ~lu~c~,d reactive substihl.Qntc, in the presence of a suitable base, such as a tertiary amine, such as for example triethylamine, in a suitable solven, such as ~cetonitrile or pyridine, at a reflux temperature to give the compounds 111. The ester group is hydrolyzed, and optional additional protecting groups removed, as described in Scheme XV
In accordance with Scheme XVII are pic~,d desired compounds of Formula I
wherein R5 is amino Compounds of formula 91 are reacted with HN-P, wherein P areamino plu~e~;Lhlg groups, for example benzyl and p-methoxybenzyl groups, in a solvent such as ethanol or toluene, at elevated ~el,l~,cld~ulc to give compounds of formula 119 Compounds of formula 119 are treated according to the procedures as described inSchemes XII, XV and XVI above to provide compounds of formula 120. Deprotection of protected arnino compounds of formula 120 by catalytic hydrogenation such as Pd-C in ethanol or m~th~nol at room Lclll~cldtulc, or by oxidation if R is p-methoxybenzyl with ammnnillm cerium nitrate, and the resulting compounds of formula 121 are hydrolyzed by a base such as LiOH or NaOH to give compounds of formula 122 In accordance with Scheme xvm are prepared compounds of Formula I wherein the R2 group is a ring group ~che~l via a carbon atom Compounds of formula 123, W O 96~9407 PCT~US96/08991 wl~ eill X is a leaving group such as chlo3ide, brornide, iodide, fluon~le or sulfonate, for example, is treated with an aL,plopliately sub~LiLuLt;d malonate, wherein R, R' could be the same or different) are aLlcyl groups, such as diethyl and di-t-butyl malonate, in a polar solvent such as DMF, DMSO, or the like, in the presence of a strong base such as NaH, at a temperature between 0 to 60~C, to give compounds of formula 124. Decarboxylation of compounds of formula 124 under acidic conditions, such as trifluoroacetic acid and hydrogen chloride in a solvent such as me~hylene chloride, ethanol, wa~er, or the like, followed by protection of the il~Lllllediate acid with an ester such as diphenylmethyl ester by tre~ting with diphenyl ~i~7o~ Ll.~n~ in a solvent such as methylene chloride or THF, 0 gives the compounds of formula 125. Compounds of formula 125 are then cyclized to compounds of formula 126 by reaction with Br(CH2)nB(CH2)mBr or I(CH2 )nB(CH2)mI
or Rb substituted iodide or bromide, for example, wherein B is CH2, N, O or S, in the presence of a base such as NaH and in a solvent such as DMF, DMSO, or the like, at room L.ll~eldLult or elevated Ln.~ ture. Alternately, conversion of compounds of formula 125 15 to the methylenyl int~rm~ t~ by reacting with aqueous form~lclehyde with a base such as sodium bicarbonate in a solvent such as DMF, followed by reacting with meth~neslllfonyl chloride and triethylamine. The methylenyl compound is then converted to compound 126 by cycli7~ti- n or dipolar addition with a suitable reagent, such as trimethylsulfonium iodide or dia:zomethane for cyclopropyl compound, in a solvent such as DMF, DMSO, or the like at 0 to 60~C in the presence of a suitable base such as NaH. Selective d~,~.rote-,-Lion of the ester 'lROCO, such as using trifluoroacetic acid and anisol at room L~ ature fordiphenylmethyl ester, followed by alkaline hydrolysis of the other ester provides the desired compounds of formula 127, and followed by Curtius realTangement when 'R2 is NH2. In the compounds of formulas 126 and 127, n and m may be from 0-4, n+m=1-4 B may be CH2, N, O or S; Rb may be hydrogen, alkyl, amino, aminoaLkyl, hydroxyl or alkoxyl groups, for exarnple, or other substituents as described for substituent Y in subformula Ic above.
R~sG.~Li~/e of the ch~mi~l i"~. . ."e~ tes which are useful in the above synthçses, and which are regarded as a further aspect of the present invention, are the following compounds:
4-t-butoxy-3 -chloro-2,5,6-trifluoropyridine;
4-t-butoxy-2,3,6-trifluoropyridine;
4-t-butoxy-2,3,6-trifluoro-5-methylpyridine;
4-t-butoxy-2,5 -difluoro-3 -methylpyridine;
2-(4-t-butoxy-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetonitrile;
2-(~chloro-5-fluoro-3-methyl-2-pyridinyl)cyclo~l upalleacetonitrile;

-CA 02222322 1997-11-2~

W O 96/39407 PCTAUS96~'~E931 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetic acid;
ethyl 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cycloprop~n.o~ret~tt~
2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cycloprop~ne~c et~ld~hyde;
2-(4-chloro-5-fluoro-3 -methyl-2-pyridinyl)cyclopropaneethanol;
2-(2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylet'nylidinyl)- 1,3-prop~ne lic~rboxylic acid, diethyl ester; and 8-chloro- 1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4h-quinolizine-3-carboxylic acid ethyl ester.
The foregoing may be better understood from the following examples, which are presented for the purpose of illustration and are not intencl~d as a limit~tion upon the scope of the invention.

F.xam~le I
3-nuoro-9-(4-fluorophenyl)-2-(4-methylpiperazin- 1 -yl)-6H-6-oxo-pvridor 1.2-alpyrimidine-7-carboxylic acid Ste~ 5-Fluoro-2-(4-fluorobenzyl)-4-hydroxypvri nidine Sodium hydride (4.36 g of 60% NaH in mineral oil, 107.6 mmol) was suspended, under a nitrogen atmosphere, in 125 mL of anhydrous diethyl ether in a 500 mL round-bottom flask fitted with a mechanical st*rer, a thermometer and a condenser. To this mixture, with vigorous stirring, was slowly added 6.28 mL (107.6 mmol) of anhydrous ethyl alcohol. After tne evolution of gas ceased, a mixture of ethyl 2-fluoroacetate (10 mL, 102.5 mrnol) and ethyl formate (12.5 mL, 153.7 mmol) was added, dropwise, to the ethoxide solution. The reaction mixture was cooled when necessary in 2s order to m~int~in the reaction ~~ ; belvv~n 18~C and 20~C. The reaction mixture was stirred, under a nitrogen atmosphere, at 18-20~C for 4.75 hours. The solvent was removed under aspirator pr~ .u,e, fresh anhydrous diethyl ether was added to the residue and the ether solution was concentrated under reduced pr~s~.u,t; to afford, as a solid residue, the sodium enolate of ethyl 2-fluoro-3-oxo-2-propanecarboxylate, as described by E.Elkik and M. Imbeaux-Oudotte in ~Q~ Chim, 1165-1169, 1975. To this residue was added 20.3 g (107.6 mmol) of 4-fluorobenzylamidine hydrochloride, followed by 250 mL of methanol and 28.8 mL (205 mmol) of triethylamine (TEA). The reaction mixture was heated, with stirring, at reflux ~Illp~.a~UlG for 16 hours and then concentrated in vacuo. The residue was LliLul~t;d with hexane and the hexane was dec~ntecl Water was 3s added to the residue and the aqueous mixture was ~ci~ified with glacial acetic acid and extracted with 4 X 150 mL of methylene chloride. The combined organic extract was W O 96/39407 PCT~U~,G,!~6~91 washed with 200 mL of water and concentrated in vacuo. The residue was recryst~lli7ed twice from ethyl acetate CO~ ~llg Norite~) charcoal to afford the title compound, m.p.
169-170~C; MS DCI-NH3 M/Z: 223 (M+H)+; lH NMR (DMSO-d6) d 3.87 (s, 2H), 7.14 (m, 2H), 7.33 (m, 2H), 7.98 (d, lH). Analysis calculated for Cl lH8F2N2O: C, 59.46;
H, 3.63; N, 12.61. Found: C, 59.08; H, 3.70; N7 12.57.
Step 2: 4-Chloro-5-fluoro-2-(4-fluorobenzyl)-pyrimidine A mixture of 1.93 g (8.7 mrnol) of 5-fluoro-2-(4-fluorobenzyl)-4-hydroxypyrimidine, from Step 1, and 15 mL of phosphorus oxychloricle was heated in an oil bath at 90~C for 1.5 hours and then concelll,dlc;d in vacuo. The residue was l~ ed with 75 mL of ice water and the aqueous rnixture was adjusted to pH 8 - 9 by the addition of solid sodium bicarbonate. The mixture was extracted with 3 X 70 mL of methylene chlolide. The combined organic ex~racts were dried over anhydrous rn~gnesillm sulfate, filtered and conc~ , dt ,d in vacuo to a light brown residue. The residue was purified by flash cl~ol~alography on a 230-400 mesh silica gel column (4.8 X 14.6 cm) eluted with hexalle.mGlllylene chloride (1:1 v/v) to afford 1.94 g (90% yield) of the title compound; MS
DCI-NH3 M/Z: 241 (M+H)+; lH NMR (CDC13) d 4.22 (s, 2H), 7.00 (m, 2H), 7.30 (m, 2H), 8.48 (s, lH).

Step 3: 5-Fluoro-2-(4-fluorobenzyl)-4-(4-"1~ll,yl~ zin-l-yl)-pyrirni~in~
A mixture of 0.48 g (2 rnmol) of 4-chloro-5-fluoro-2-(4-fluorobenzyl)-pyrimi~line from Step 2 and 1.53 mL (14 mmol) of 4-meth~lpiy~ le in 10 mL of methylene chloride was stirred at ambient ~nly~ ulG for 1.5 hours. The reaction mixture was concen~T~ted in vacuo and the residue was dissolved in methylene chloride. The resultant solution was washed with 4 X 3~) mL of water, dried over anhydrous m~gnesium sulfate, filtered and 2s concentrated in vacuo to give 0.59 g (95% yield) of the title compound as an oil; 1 H NMR
(CD~C13) d 2.32 (s, 3H), 2.47 (t, 4H), 3.78 (t, 4H), 3.99 (s, 2H), 6.97 (m, 2H), 7.29 (m, 2H), 7.97 (d, lH). The product was calTied on to the next step without purification.
Step 4: Diethyl 2-ethoxy-3-(~fluorophenyl)-3-[5-fluoro-4-(4-meth~ ,G,~in- I -yl~pyrimidin-2-yll-propane- 1.1 -dicarboxylate A solution of 0.35 mL (2.5 mmol) of diisopropylamine in 5 mL of anhydrous tetrahydrofuran (THE~) was prepared under a nitrogen atmosphere and cooled in anice/water bath. To this solution was added via syringe, 1.0 mL of a 2.5 ~I solution of n-butyllithium (2.5 mmol) in hexane. The solution was stirred for 15 ~ ules at 0~C and then -CA 02222322 1997-11-2~

W O 96/39407 PCTrUS96/08991 cooled to -78~C. To the mixture at -78~C, was added a solution of 0.7 g (2.3 mmol) of 5-fluoro-2-(4-fluorobenzyl)-4-(4-methylpiperazin-1-yl)-pyrimi~line, from Step 3, in 5 mL of anhydrous THF and a dark red-colored solution was formed. The solution was stirred at -78~C for 1 hour and then 0.46 mL ~2.3 mmol) of ethyl 2-carboethoxy-3-ethoxy-2-s propenecarboxylate was added. Stirring was continlled at -78~C for 3 hours and the reaction mixture turned a light yellow color. The reaction mixture was poured into 30 mL
of water, with 6 g of solid ~mmonillm chloride. The aqueous mixture was extracted with 4 X 50 mL of methylene chloride. The combined organic extract was dried over m~gnesillm sulfate, filtered and concentrated in vacuo. The residue was dissolved in 300 mL of methylene chloride. The resultant solution was washed with a 50 mL portion of water, followed by a 75 mL portion of water, dried over anhydrous m~ ;iulll sulfate, filtered and concentrated in vacuo to afford the title compound; MS DCI-NH3 M/Z: 521 (M+H)+;
lH NMR (CDC13) d 0.84 (2 X t, 3H), 1.18 (t, 3H), 1.28 (t, 3H), 2.33 (s, 3H), 2.50 (m, 4H), 3.36-3.53 (m, 2H), 3.83 (s, 4H), 3.96-4.22 (m, 4H), 4.42 (t, lH), 4.98 (dd, lH), 6.95 (m, 2H), 7.48 (m, 2H), 7.99 (d, lH).
Step 5: Ethyl 3-fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin-1-yl) -6H-6-oxo-~yridor 1.2-alpyrimidine-7-carboxylate A solution of 0.57 g (1.1 mmol) of diethyl 2-ethoxy-3-(4-fluoruphenyl)-3-[5-fluoro-4-(4-meth~pi~ d~in-1-ylpyrimidin-2-yl]-propane-1,1-dicarboxylate, from Step 4, and 0.2 mL of 1,8-~ 7~bicyclo[5.4.0]undec-7-ene (DBU) in 200 mL of toluene was heated at reflux Lc;llllu~ tu~, with stirring, for 20.5 hours. During the first 0.5 hours, 125 mL of toluene was removed via Dean Stark trap and 100 mL of fresh toluene was added through a dropping funnel. Water (75 mL) was added to the reaction mixture and stirring was continued at ambient tGll~eldLulc; for 3 honrs. The organic layer was s~u~Lt;d and washed with 75 mL of water. The combined aqueous layers were extracted with 3 X 75 mL of toluene. The organic layers were all combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue (0.32 g) was puri~led on a 70-230 mesh silica gel column (2.4 X 43 cm) eluted with ethyl alcohol:chloroform (1: 10 v/v) to afford 0.26 g (56% yield) of the title compound, m.p. 202-204~C; MS DCI-NH3 M/Z: 429 (M+H)+; lH NMR (CDC13) d 1.40 (t, 3H), 2.33 (s, 3H), 2.51 (m, 4H), 3.93 (m, 4H),4.40 (q, 2H), 7.08 (t, 2H), 7.50 (m, 2H), 8.43 (s, lH), 9.20 (d, IH).

W O 96/39407 PCT~U'._~'~331 Step 6: Benzyl 3-fluoro-9-(4-fluorophenyl)-2-(4-l-lt;~hylL,i~,~lazin-l-yl) 6H-6-oxo-pyridorl.2-alpyrLm. i~1ine-7-~rboxylate A mixture of 0.11 g (0.26 mmol) of ethyl 3-fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin-l-yl)-6H-6-oxo-pyrido[1,2-a]pyrimi-iine-7-carboxylate, from Step 5, 50 mL of dry benzyl alcohol and 0.05 mL of ~ tetraethoxide was heated. with stirring, at 100~C for 22 hours. The benzyl alcohol was removed by ~licti~ on under reduced IJ11,5'71LUC and the residue was dissolved in 75 mL of methylene chloride. To this solution was added S mL of sadluldt~;d aqueous lithium fluoride solution and the resultant mlixture was stirred at ~mbjent t.Clll~ Ul~, for 20 minllt~s The layers were s~ud~,d and the 0 organic layer was diluted with 75 mL of methylene chlorirlç and washed with 20 mL of water. The aqueous layer was extracted w~th 25 mL of methylene chloride and the methylene chlnri~ layer from this extraction was comhin~c~ with the organic layer. The combine~i organic layers were dried over anhydrous m~nesi~lm sulfate, filtered and concentrated. The residue (0.18 g) was cl~l~"l,a~ographed on a 70-230 mesh silica gel column (1.8 X 34 cm) eluted with ethanol:c'nloroforrn (1:13 v/v) to afford 87 mg (67%
yield) of the title compound; IH NMR (CDC13) d 2.33 (s, 3H), 2.52 (m, 4H), 3.94 (m, 4H), 5.40 (s, 2H), 7.08 (s, 2H), 7.27 (m, SXI), 8.44 (s, lH), 9.21 (d, lH). The product was carried on to the next step without further purific ~tion Step '7: 3-Fluoro-9-(4-fluorophenyl)-2-(4-meth~ - l-yl)-6H-6-oxo-~yridorl.2-al~yrimidine-7-c:~rboxylic acid Benzyl 3-fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin- 1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (87 mg, 0.177 mmol), from Step 6, was dlissolved in 20 mL of ethyl acetate. To this solution was added 20 mg of 10% p~ rlillm on carbon and the resultant mixture was hydrogenated at a"-b;~ G~ under 4 atmospheres of hydrogen, for approximately 19 hours. The catalyst was removed by filtration and washed with 400 mL of ethyl acetate The filtrate was concentrated in vacuo to give 65.2 mg of solid. The solid was purified by ch-o--.a~ography on a 70-230 mesh silica gel column (1.8 X 18.5 cm) eluted with chl-~rofu~ l-anol:acetic acid:water (100:25:5:2.5 v/v/v/v). The fractions con~ the desired product were combined and concentrated. Toluene was added to the residue and e~ u.~ted in vacuo. Chloroform was then added to the residue and evaporated in vacuo to afford the ti~e compound as a yellow solid, m.p. 225-230~C;
MS DCI-NH3 M/Z: 401 (M+H)+; lH NMR (CDC13) d 1.68 (brs, lH), 2.33 (s, 3H), 2.53 - (brs, 4H), 3.98 (brs, 4H), 7.10 (t, 2H), 7.48 (m, 2H), 8.57 (s, lH), 9.08 (d, 2H).
35 Analysis calculated for C20Hl8F2N4o3+o.7sH2o: C, 58.03; H, 4.75; N, 13.54. Found:
C, 57.98; H, 4.32; N, 13.22.

WO 96/39407 PCTrUS96/~B9~l Fx~m~le 2 3-Fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin- l -yl)-6H-6-oxo-pyridorl.2-alpyrimidine-7-carboxylic acid Step 1: Ethyl 3-fluoro-9-(4-fluorophenyl)-2-hydroxy-6H-6-oxo-pyridor 1 .2-alpyrimidine-7-carboxylate To a stirred solution of 0.87 g (2.05 mmol) of ethyl 3-fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin- l -yl)-6H-6-oxo-pyrido[ 1 ,2-a]pyrimidine-7-carboxylate, the product of Step S of Example l, in 54 mL of THF/water ( l: l ) was added 6 mL of ~ N aqueous 10 sodium hydroxide solution. The reaction mixture was sti~red at z~mhient temperature for 6 hours and then was allowed to stand overnight at ~mhient te~ dlulc. The solid was ltered and dried to give the title compound; lH NMR (d6-DMSO) d 1.23 (t, 3H), 4.15 (q, 2H), 7.17 (m, 2H), 7.52 (m, 2H), 7.91 (s, lH), 8.77 (d, lH).
Step 2: Ethyl 2-chloro-3-fluoro-9-(4-fluorophenyl)-fiH-6-oxo-pvridor 1 .2-alpvrimidine-7-carboxylate A mixture of 55.7 mg of ethyl 3-fluoro-9-(4-fluorophenyl)-2-hydroxy-6H-6-oxo-pyrido[ 1,2-a]pyrimidine-7-carboxylate from Step 1 and 0.5 mL of phosphorus oxychloride was stirred and heated at 90~C for 1.25 hours. The mixture was evaporated under reduced 20 p~S~ulc to yield the title compound which can be reacted with amines without purification.
A pure sample of the title compound is obtained by l1C~ of the crude product with aqueous sodium bicarbonate solution and extracting the aqueous mixture with methylene chl-~ncle The organic solution is conc~ a~ and chromatographed on silica gel eluting with ethyl acetate.
Step 3: Ethyl 3-fluoro-9-(4-fluorophenyl)-2-(4-methyl~i~c~ -1-yl)-6H-6-oxo-pyndor 1 .2-alpyrimidine-7-carboxylate Following the procedures described in Step 3 of Example 1, ethyl 2-chloro-3-fluoro-9-(4-fluorophenyl)-6H-6-oxo-pyrido[ 1,2-a]pyrimidine-7-carboxylate from Step 2 is 30 reacted with 4-l~ llyl~ erazine to afford the title compound.

W O 96139407 PCTrUS~C/'~9~1 Step 4: Benzyl 3-fluoro-9-(~fluorophenyl)-2-(4-~ l- 1-yl)-6H-6-oxo-pyridor 1.2-al~vnmidine-7-carboxylate ~ A mixture of 0.11 g (0.26 mmol) of ethyl 3-fluoro-9-(4-fluorophenyl)-2-(4-methyl~ ,,hl-l-yl)-6H-6-oxo-pyrido[1,2-a]pyrimi~lin~-7-carboxylate, from Step 3, S0 t 5 rnL of dry benzyl alcohol and O.OS mL of !;I;~ lll tetraethoxide was heated, with stining, at 100~C for 22 hours. The henzyl alcohol was removed by ~ tillzltio~ under reduced ~,S~ ; and the residue was dissolved in 75 mL of methylene chlorit1ç To this solution was added S mL of sdlula~d aqueous lithium fluoride solution and the resultant Iruxture was stirred at ~mhient ~I~ tUl~ for 20 Illi~ , The layers were se~ ~ and the organic layer was diluted with 75 mL of methylene c~llori~e and washed with 20 mL of water. The aqueous layer was extracted with 25 mL of methylene chkrid~ and the methylene chloride layer from this extraction was cornhin~.-l with the orgaluc layer. The combined organic layers were dried over anhydrous m~necium sulfate, filtered andconcenl~rd~d. The residue (0.18 g) was ch-umdtographed on a 70-230 mesh silica gel 15 colunnn (1.8 X 34 cm) eluted with eth~nol chlo,or~ 13 v/v) to afford 87 mg (67%
yield) of the title compound; lH NMR (CDC13) d 2.33 (s, 3H), 2.52 (m, 4H), 3.94 (m, 4H), 5.40 (s, 2H), 7.08 (s, 2H), 7.27 (m, SH), 8.44 (s, lH), 9.21 (d, lH). The product was carried on to the next step without fur~er purification.
20 Step 5: 3-Fluoro-9-(~fluc,lv~hc.~yl)-2-(4-methyl~ -1-yl)-6H-6-oxo-pyridorl.2-al~yrimidine-7-carboxylic acid Benzyl 3-fluoro-9-(~fluorophenyl)-2-(4-methyl~ ,.d~in-1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (87 mg, 0.177 mmol), from Step 4, was dissolved in 20 mL of ethyl acetate. To this solution was added 20 mg of 10% p~ m on carbon 25 and the resultant mixture was hydrogenated at ambient L~ ule, under 4 atmospheres of hydrogen, for approximately 19 hours. The catalyst was removed by filtration and washed with 400 mL of ethyl acetate The fil~ate was con~e ~ d in vacuo to give 65.2 mg of solid. The solid was purified by ~IIlunla~ography on a 70-230 mesh silica gel column (1.8 X 18.5 cm) eluted with chlo~ methanol:acetic acid:water (100:25:5:2.5 v/v/v/v). The 30 fractions co.,l;.i,~ the desired product were combined and concentrated. Toluene was added to the residue and evaporated in vacuo. Chloroform was then added to the residue and ev~o.a~d in vacuo to afford the title compound as a yellow solid, m.p. 225-230~C;
MS DCI-NH3 M/Z: 401 (M+H)+; lH NMR (CDC13) d 1.68 (brs, lH), 2.33 (s, 3H), 2.53 (brs, 4H), 3.98 (brs, 4H), 7.10 (t, 2H), 7.48 (m, 2H), 8.57 (s, lH), 9.08 (d, 2H).
35 Analysis calculated for C20Hl8F2N4o3~o.7sH2o: C, 58.03; H, 4.75; N, 13.54. Found:
C, 57.98; H, 4.32; N, 13.22.

WO 96/39407 PCTAJSg~'033~1 Fxamples 3-38 By following the procedures described in Example 2 and using the a~ ol~liate amine, Examples 3-20, as disclosed in Table 1, may be ~lc~ ,d which have the general s formula O

R2~N ~--F

Likewise, Examples 21-38, as also disclosed in Table 1, may be prepared by using the al,~,op.iate amine and 2,4-difluorobenzylamidine instead of 4-fluoro-10 benzyl~mi-line to produce the general formula F~o~ N J~COOH
R2~NJ~
~F

W O 96/39407 PCT~US9G, ~ablç 1 Fxan~DleNos. B2 F~n~le Nos. R2 3, 21 N'~ 12, 30 N'~
~ NH~ ~,O

4, 22 ~N~CH3 13, 31 N~CH2NH~CH3 N--I N
5,23 I~,N 14,32 N--~ \
6, 24 ~r CH3 ~NH2 7j 25 ~ ~CH3 ~NH2 CH3 ~NCH3 8, 26~ ,~CH2F 17, 35 CH
I~,NH ~ N

9, 27~N ~NH2 18, 36 ~NH2 ~J Cl 10, 28 Nl~ 19, 37 ~NH2 NH2 ~

11, 29~N~s 20, 38 ~NH~ET

* The amines are protected and deprotected as described in Example 58 CA 02222322 1997-11-2~

W 096/39407 PCTrUS96/08991 RY~le 39 9-Cyclopropyl-3-fluoro-2-(4-methylpiperazin- 1 -yl)-6H-6-oxo-pvridorl~2-alpvrimidine-7-carboxylic acid s Step 1. 2-Cyclopropvl-3-hydroxyacrylic acid A 1.1 ~ solution of diethylzinc (350 mL) in an oven-dried system under positive nitrogen atmosphere is coled in an ice bath. Vinyl acetic acid (17 mL, 200 mmol) is added dropwise with stirring, followed by 24 mL (300 mmol) of diiodol~lbLllane. The reaction mixture is stirred overnight at ambient tel,~ dture. The reaction mixture is then cautiously 10 poured into 500 mL of 1 N aqueous hydrochloric acid solution and the aqueous mixture is extracted with diethyl ether. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated. The residue is vacuum distilled to give cyclopropylacetic acid.
The cyclopropylacetic acid ( 15 g, 150 mmol) in a flask protected from moisture is cooled in an ice bath and 13.2 mL ( 180 mmol) of thionyl chloride is added dropwise with 15 stirring. After the addition is complete, the reaction mixture is warmed to ambient temperature and then to 50~C. The reaction mixture is heated at 50~C for 1 hour and then cooled in an ice bath. Absolute ethanol (26 mL, 450 mmol) is added dropwise with stirring to the reaction mixture. After the ad-ii~-on is complete, the reaction mixture is stirred at ~mhi~nt temperature overnight. The reaction mixture is diluted with 500 mL of methylene chlori~le and then washed with 200 mL of 5% aqueous sodium bicarbonate solution. The organic layer is dried over anhydrous sodium sulfate, filtered and the ethyl ester of cyclopropylacetic acid is obtained by fli~till~tion 2-Cyclopropyl-3-hydroxyacrylic acid (12.8 g, lO0 mmol), from Step 1, is dissolved in 150 mL of dry dimethoxyethane in an oven-dried system under positive 25 nitrogen atmosphere. The resultant solution is cooled in an ice bath and 4.4 g of 60%
sodium hydride in mineral oil is added. The mixture is stirred for several hours at approximately 0~C and then for several hours at amb;ellt ~el--~ at~;. The reaction mixture is cooled in an ice bath and 8.9 mL (110 mmol) of ethyl formate in 90 mL of dry dimethoxyethane is added dropwise with stilTing. After the addition is complete, the 30 reaction mixture is stirred overnight at ambient temperature. The reaction mixture is then cautiously poured into 300 mL of saLuld~ed aqueous ammoninm chloride solution and extracted with ethyl acetate. The ethyl acetate solution is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound.

W O 96~9407 PCT~US96/08991 Step 2. Ethyl 5-Cyclopropyl-2.6-dihv-lroxy-nicQtinic acid A solution of 11.5 (88 mmol) of monoethyl malonate monoamide in 25 mL of dry THF is cooled in an ice bath and is treated with 10.7 g (95 mmol) of potassium t~butoxide.
The reaction rnixture is stirred at 0-5~C for 1 hour. A solution of 12.5 g (80 rnmol) of 2-5 cyclopropyl-3-hydroxyacryllic acid, from Step 1, in 20 mL of dry THF is added dropwise with stirring. The reaction mixture is then warmed to ~mbi~.nt temperature and then heated at reflux overnigh~ The reaction mixture is poured into brine and is extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to af~ord the title compound.

Ste~ 3. F~thyl 5-cvclo~ropyl-2.6-dichloro-nicotinic acid Ethyl 5-cyclopropyl-2,6-dihydroxy-nicotinic acid (15.6 g, 70 mmol) from Step 2, 1,2-dichloroethane (25 rnL), anhydrous DMF (2 mL) and phosphoryl chloride (14.3 rnL, 150 mmol) are combined in a system under positive nitrogen atmosphere, The reaction 15 mixture is stirred at ambient ~e~y~a~u-e for 24 hours then diluted with 1,2-dichloroethane.
The reaction mixture is then washed with 5% aqueous sodium bicarbonate solution and brine. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated in vac~4o to afford the title compound.
Step 4. 2-Chloro-5-cyclopropyl-6- N-((4,5dimethoxy-2-nitro-phenyl)methoxycarbonyl)amino-nicotinic acid Ethyl 5-Cyclopropyl-2,6-dichloro-nicotinic acid ( 1 1.2 g, 50 mmol) from Step 3 is dissolved in 15 mL of anhydrous DMF. To this solution is added 25 mL of concentrated arnmonium hydroxide and the reaction mixture is heated at reflux overnight. The reaction mixture is cooled to ambient ~~ t;lalLuG, diluted with water and extracted with 1,2-dichloroethane. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is dissolved in 250 mL of 1,2-dichloroell-alle and 200 mL of 10% aqueous sodium carbonate solution. The reaction mixture is cooled in an ice bath and 16.5 g (60 rnrnol) of 3,4-dimethoxy-6-nitrobenzylchlulo~l---at~ is added. The reaction mixture is stirred at 0-5~C for 1 hour. The layers are separated and the aqueous layer is extracted with 1,2-dichloroethane. The combined organic layers are dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.

CA 02222322 1997-11-2~

W 096/39407 PCT/U',~"~9~1 Step 5: 2-Chloro-5-cyclopropyl-6- N-((4,5dimethoxy-2-nitro-~henyl)methoxycarbonvl)-N-(2-fluoroacetyl)amino-nicotinic acid 2-Chloro-5-cyclopropyl-6- N-((4,5dimethoxy-2-nitro-phenyl)methoxycarbonyl)-amino-nicotinic acid (14.4 g, 30 mmol) from Step 4 is dissolved in 20 mL of dry THF in an oven-dried system under positive nitrogen atmosphere. The reaction mixture is cooled v in an ice bath and 1.3 g of 60% sodium hydride in mineral oil is added. The reaction mixture is stired at 0-5~C for 1 hour and 3.2 g (33 mmol) of alpha-fluoroacetyl chloride in 5 mL of dry THF is added dropwise with stirring. After the addition is complete, the reaction mixture is slowly warmed to ambient temperature and stirred overnight at ambienl L~nl~CldLu~e. The reaction mixture is then poured into brine and extracted with ethyl acetate. The ethyl acetate solution is dried over anhydrous sodium sulfate, filtered and conce.llldt~d in vacuo. to afford the title compound.
Step 6: 2-Chloro-5-cyclopropyl-6- N-((4,5dimethoxy-2-nitro-phenyl)methoxy-carbonvl)-N-(2-fluoro-3-hydroxy-1-oxo-1-prop-2-enyl)amino-nicotinic acid Sodium hydride ()880 mg of 60% NaH in mineral oil) is suspended in 10 mL of dry THF. The suspension is cooled in an ice bath and 10.7 g (20 mmol) of 2-chloro-5-cyclopropyl-6- N-((4,5~1im~thoxy-2-nitro-phenyl)methoxycarbonyl)-N-(2-fluoroacetyl)-amino-nicotinic acid, from Step 5, in 150 mL of dry THF is added dropwise with stirring.
20 After the addition is complete, the reaction mixture is stirred at 0-5~C for 1 hour. Ethyl formate (1.78 mL, 22 mmol) in 25 mL of dry THF is added dropwise with stirring. After the addition is complete, the reaction is stirred overnight at ambient l~,...pcldthle and then poured into 10% aqueous ammonium chloride solution. The aqueous mixture is extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, filtered and conc~ontTated in vacuo to afford the title compound.
Step 7: Ethyl 9-cyclopropyl-1-((4,5dimethoxy-2-nitro-phenyl)methoxycarbonyl)3-fluoro-2-hydroxy-6H-6-oxo-pyridor 1.2-alpyrimidine-7-carboxylate A solution of 8.5 g (15 mmol) of 2-Chloro-5-cyclopropyl-6- N-((4,5dimethoxy-2-nitro-phenyl)methoxycarbonyl)-N-(2-fluoro-3-hydroxy- 1 -oxo- 1 -prop-2-enyl)amino-nicotinic acid, from Step 6, is dissolved in 200 mL of dioxane/water (1: 1). To this solution is added 4.1 g (30 mrnol) of potassium carbonate. The reaction mixture is heated at reflux with stirnng overnight and then cooled to ambient Lt;lll~ dLulc;. The reaction mixture is then diluted with water and extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound.

W O 96/39407 ' PCTrUS96/08991 Step 8: Ethyl 9-cyclopropyl-3-fluoro-2-chloro-6H-6-oxo-pyridor 1 .2-al~yrimidine-7-carboxylate " Ethyl 9-cyclopropyl-1-((4,5dimethoxy-2-nitro-phenyl)methoxy-carbonyl)3-fluoro 2-hydroxy-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (5.3 g, 10 mrnol) from Step 7 is dissolved in 75 mL of 2:1 clioxane:water and the resultant solution is ill~ d with 320 nm light for 30 min. The reaction mixture is extracted with ethyl acetate. The orgaLnic layer is dried over anhydrous sodium sulfate, filtered and concel~tlal~d in vacuo.
The residue is purified by silica gel chromatography to afford the product of Step 7 with the nitrogen ~lO~c~ lg group removed. This product is dissolved in 1,2-dichloroethane and 10 tretaRd with phosphorous oxychloride at ambient temperature for 18 hours. The reaction mix ~ure is diluted with 1,2-dichloroethane and is washed with saturated aqueous sodium bicarbonate solution and brine. The organic layer is dried over anhydrous sodium sulfate, filtered and concelllldted in vacuo to afford crude title compound which is purified by recrystallization from ethyl alcohol.

Step 9: Ethyl 9-cyclopropyl-3-fluoro-2-(4-methylpiperazin- l-yl)-6H-tS-oxo-pyridorl.2-al~"yrimidine-7-carboxylic acid Following the procedures described in Step 3 of Example 1, ethyl 9-cyclopropyl-3-fluoro-2-chloro-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate from Step 8 is reacted 20 withl 4 methylpiperazine to afford the title compound.
Step 10: 9-Cyclopropyl-3-fluoro-2-(4-meth~l~iye.d~in-1-yl)-6H-6-oxo-pyridorl.2-alpyrimidine-7-carboxylic acid Following the procedures described in Steps 5 - 7 of Example 1, Ethyl 9-25 cyclopropyl-3-fluoro-2-(4-methylyiy~,l d~in- 1 -yl)-6H-6-oxo-pyrido[ 1 ,2-a]pyrimidine-7-carbloxylic acid is converted to the title compound.
Examples 40-57 By following the procedures described in Example 39 and replacing 4-metlhyl~.iy~,.dzil,e in Step 4 with the ayyl~yliate amine, Examples 40 - 57 may be prepared as disclosed in Table 2 wherein the compounds have the general formula ,.
~;, COOH

Table 2 FY~n1~1e NO. ~2 FX~rnPIe N~ R2 ~, ~, NH ~ ~, 41 N ~CH3 N I~cH2NHcH3 NH ~ l~o 42 ~N 51 N--I N
43 ~I,N~ 52 ~--NH

CH3 \N
44 ~N ~CH3 ~--~H2 ~,NH ~ \ CH3 CH3 N ~
~ N ~CH2F 54 CH3~ NH2 ~,NH ~ N
46 N NH2 ~ 55 ~NH2 Cl ~ NH ~ 56 ~NH2 48 N--I 57 ~NHET
~_S

* The amines are protected and deprotected as described in Example 58 - g3 -CA 02222322 1997-11-2~

W O 96/39407 PCTrUS96/a-931 F~nple 58 8-(3-Amino-1-pyrrolidinyl)-4H-quinolizin-4-one-3-carboxylic acid hydrochloride Step 1. 4-Chloro-2-picoline To 34.5 mL (0.37 mol) of phosphorus oxychloride, under a nitrogen atmosphere, was added 20.0 g (0.19 mol) of 2-picoline-N-oxide (commercially available from Aldrich Chemical Company) in small portions. The reaction ~cnll~cldture slowly increased during the addition to ~60~C. After the ~d~1ition was complete, the reaction mixture was a homogeneous dark red solution and the reaction ~wll~eld~ulc; was 80~C. This solution was lo heated at 120~C for 1.5 hours. The reaction mixture was concentrated under reduced pressure in order to remove most of the phosphorus oxychloride and the conç~ntr~te was poured into ice water. The aqueous mixture was allowed to stand for 2 hours at ambient dtlllC and then was extracted witn diethyl ether. The ether extract was discarded.
The aqueous layer was adjusted to pH 8.0 with potassium carbonate and then extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced ~JlCS' UlC. The liquid concentrate was distilled to afford 8.737 g of a mixture of the title compound and the isomeric 6-chloro-2-picoline as a clear colorless liquid, b.p. 70~C (25 mm Hg). This product was combined with another sample of the same mixture ~l~palc;d separately by the same procedure. The isomeric products were inseparable by ~ till~tion. The combined products (12.905 g) were dissolved in 750 mL of ethyl alcohol. To the resultant solution was added, dropwise, concentrated nitric acid solution until a white precipitate forrned and the pH of the supr~ solution was 1.
The pl~ci~iLa~ was removed by filtration and dissolved in water. The resultant aqueous solution was adjusted to neutral pH with sodium bicarbonate and then extracted with 2s methylene chloride. The organic extract was dried over anhydrous sodium sulfate, filtered and conce"ll~ted under reduced pressure to afford 7.487 g of the title compound.lH NMR (CDC13) d 2.55 (s, 3H), 7.12 (dd, IH, J=3 Hz, 6 Hz), 7.18 (d, IH, J=3 Hz), 8.40 (d, IH, J=6 Hz).
Step 2. Diethyl 2-etboxv-3-(5-fluoropyridin-2-yl)-propane- l . l -dicarboxylate T ithillm diisopropylamide (LDA: 16 mL of a 1.5 M solution in hexane) was added to 8 mL of dry THF, under a nitrogen atmosphere, and the resultant solution was cooled to -70~C in a isopropyl alcohoVdry ice bath. To the cooled solution of LDA, was added dropwise, over a 30 minute period, a solution of 2.5 g (19.6 mmol) of 4-chloro-2-picoline, from Step 1, in 20 mL of dry THF. The solution turned a very dark red color.

CA 02222322 1997-11-2~

W O 96/39407 PCT~US96/~8~1 After stirring the dark red solution for 0.5 hours at -70~C, a solution of 4.04 mL (19.6 mrnol) of ethoxymethylenemalonate in 18 mL of dry THF was added dropwise over a 30 minute period. The reaction solution turned from dark red to orange. After stirring for 0.5 hours at -70~C, the reaction solution was allowed to warm to -20~C and was stirred at -20~C
S for 1 hour. The reaction was quenched at -20~C by the addition of 1.3 mL of glacial acetic acid and the cooling bath was removed. After 20 minutes the reaction solution was poured into 5% aqueous sodium bicarbonate solution. The aqueous mixture was extracted with methylene chloride and the organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced ples~ e. The residue (8.03 g) was purified by lo chromatography on a silica gel column (-120 g of SiO2) eluted with 0.5% methanol in methylene chloride to afford 4.59 g (68% yield) of the title compound.

Step 3. Ethyl 8-chloro-4H-~uinolizin-4-one-3-carboxylate 80 mL of Dowtherm A(~) in a 3-neck flask equipped with a thermometer, an addition funnel and an air-cooled conden~t~r was heated to 235~C, under nitrogen, using a heating mantel. A solution of 4.26 g (12.4 mmol) of diethyl 2-ethoxy-3-(5-fluoropyridin-2-yl)--propane- 1, l-dicarboxylate, from Step 2, in 45 mL of Dowtherm AtE9 was added, dropwise over a 1.5 hours period, through the addition funnel to the heated stirring Dow~herm A(~. After the addition was complete, the resultant solution was heated at ~200~C for 1 hour and then was cooled to ambient ~~ d~ . The black-green-coloredsolution was then poured into 500 mL of hexane and a precipitate formed. The ~.~,ci,oi~le was collected by filtration, washed with 5 X 100 mL of hexane and dried to afford 1.487 g (48% yield) of the title compound.

Step 4. Ethyl 8-(3-(N-t-butoxycarbonyl)amino-.l-pyrrolidinyl)-4H-quinolizin-4-one-3-carboxvlate Ethyl 8-chloro-4H-quinolizin-4-one-3-carboxylate (1.0 g, 3.97 mmol), from Step 3, was dissolved in 20 mL of dry pyridine under a nitrogen atmosphere. To the resultant solution was added a solution of 1.85 g (9.92 mmol) of 3-(N-t-butoxycarbonylamino)pyrrolidine in 5 mL of dry pyridine and the reaceion mixture was heated at 70~C for 4.5 hours. The reaction mixture was then concentrated in vacuo in order to remove all of the pyridine. The dry residue (3.124 g) was purified by chromatography on siIica gel eluted with 2% methanol in methylene chloride to afford 0.889 g (56% yield) c of the title compound.

,, CA 02222322 1997-ll-2~

W 096/39407 PCTrUS96/08991 Step 5: 8-(3-Amino-l-pyIrolidinyl)-4H-quinolizin-4-one-3-carboxylic acid hydrochloride A solution of 0.889 g (2.2 mmol) of ethyl 8-(3-(N-t-butoxycarbonyl)amino-1-pyrro~idinyl)-4H-quinolizin-4-one-3-carboxylate, from Step 4, in 20 mL of trifluoroacetic acid ~I'FA) was stirred for 2 hours at ambient temperature. The TFA was evaporated in vacuo and the residue was dissolved in 200 rnL of methanol. To the resultant solution was added 4.5 g of strongly basic ion exchange resin and the mixture was stirred at ,.mhient L~,mpe,~u,c; for 1 hour. The mixture was filtered and the filtrate was con~entr,.t.-d under reduced pl~,SsLIl~ to afford crude ethyl 8-(3-amino-1-pyrrolidinyl)-4H-quinolizin-4-one-3-carboxylate as a residue. The residue was dissolved in 5 mL of THF and 11 mL of a 1 M
aqueous solution of sodium hydroxide was added. The reaction mixture was heated at 60~C for 1 hour and then the reaction ~nl~wdt~ was increased to 85~C in order toevaporate the THF. The concentrated reaction solution was diluted with 20 mL of water and the pH of the resultant solution was adjusted to 1 - 2 with conct;.~LIdted hydrochloric acid. The aqueous solution was concentrated in vacuo. The residue was crystalli~d from ethyl alcohol:isopropyl alcohol:water (4:4: I v/v/v) and recrystallized from ethyl alcohoVwater to afford 0.388 g (57% yield) of the title compound, m.p.225-230~C; MS
DCI-NH3: 274 (M-Cl)+ 90%, 230 ((M-CI)-C02H)+ base; ~ (KBr): 3420 (OH), 1650 (C=O) cm~l; lH NMR (TFA) d 2.8-3.1 (m, 6H), 4.62 (m, lH), 7.06 (s, lH), 7.4 (d, 2H, J=9 Hz), 8.14 (d, lH, J=9 Hz), 9.06 (d, lH, J=9 Hz). Analysis calculated for C14H16ClN3O3+1/3H2O: C, 53.21; H, 5.10; N, 13.30. Found: C, 53.58; H, 5.38; N, 13.30.

Fx~mple 59 8-(3-(N-Norvalvl)amino-pyrrolidinyl)-4H-ql-inolizin-4-one-3-carboxylic acid 3-Amino-l-benzylpyrrolidine (I. Sumio and T. Matsuo, Japanese Kokai JP
5328161, published March 16, 1978) is coupled to N-t-butoxycarbonyl norvaline (Boc-nVal) using conventional N-hydroxysuccinimide coupling procedures. The l-benzyl group is removed by hydrogenolysis in methanol using palladium on carbon catalyst. The 3-(N-30 Boc-norvalyl)aminopyrrolidine is then reacted with ethyl 8-chloro-4H-quinolizin-4-one-3-carboxylate, the product of Step 3 of Example 58, as described in Step 4 of Example 58, replacing 3-(N-t-butoxycarbonylamino)pyrrolidine with 3-(N-Boc-norvalyl)aminopyrrolidine, to give 8-(3-(N-norvalyl)amino-pyrrolidinyl)-4H-quinolizin~-one-3-carboxylic acid with the nitrogen of the amino acid protected with a Boc group. The W O 96J39407 PCTrUS96/08991 Boc plotc~ g group is remo~ed by standard hydrolysis using trifluoroacetic acid and dilute aqueous hydrochloric acid.
Using the procedure outlined in Example 59, or any of the other convçntion~l con-l~nc~lion methods listed above, other amino acid derivatives of the compounds of this i~ s invention having an amino group can be prepared. Examples of amino acids which can be coupled, either alone or in combination with one and other, include naturally o~c~lrrin~
amino acids such as glycine, alanine, leucine, isoleucine, methionine, phenylz~l~nine, valine, and the like, as well as synthetic amino acids such as cyclohexyl~ nin~,cyclohexylglycine, aminopentanoic acid. and the ~ike.

R~mple 60 8-Chloro-4-H-quinolizin-4-one-3-carboxylic acid Step 1: Ethyl 8-chloro-4H-quinolizin-4-one-3-carboxylate 35 mL of Dowtherm A~ in a 3-neck flask equipped with a thernnometer, an addition funnel and an air-cooled con-len~rr was heated to 230-235~C, under positive nitrogen plGS~llle, using a heating mantel. A solution of 2.7 g (7.85 mmol) of diethyl 2-ethoxy-3-(5-fluoropyridin-2-yl)-propane-1, l-dicarboxylate, the product of Step 2 of Example 58, in 45 mL of Dowtherm A~ was added, dropwise over a 1.5 hours period,through the addition funnel to the heated stirring Dowtherm A(~. After the addition was complete, the resultant solution was heated at ~200~C for 40 minutes and then was cooled to amb:_.lt ~cl~ "dture. The black-green-colored solution was then poured into 600 mL of hexane and a ~lcci~i~te formed. The precipitate was collected by filtration, washed with 2 X 150 mL of hexane and dried to afford 1.15 g (58% yield) of the title compound, m.p.
2s 1 53- 1 54~C.

Step 2: 8s-Chloro-4-H-quinolizin-4-one-3-carboxylic acid Ethyl 8-chloro-4H-quinolizin~-one-3-carboxylate (125 mg, 0.5 mrnol) was suspended in 5 mL of 0.5 N aqueous sodium hydroxide solution. The reaction mixture was heated to 65~C and 2 mL of THF was added. After the reaction mixture was stirred at t 65~C for 1 hour, the THF was distilled from the mixture. Stirring was continued for 2 hours at 65~C and then the reaction mixture was allowed to cool to ambient Lclll~c~ re.
The aqueous mixture was adjusted to pH 2 with 3 mL of 1.0 N aqueous hydrochloric acid solution and diluted with 10 mL of water. The precipitate was collected by filtration, CA 02222322 1997-11-2~

W O 96/39407 PCTrUS96/08991 washed with 2 X 15 mL of water and dried in vacuo to afford 100 mg (89% yield) of the title compound, m.p. 229-230~C. The product was recrystallized from ethyl alcohol and dried in vacuo to afford 50 mg (44.5% yield) of the title compound, m.p. 237-238~C; MS
DCI-NH3: 224 (M+H)+, 241 (M+NH4)+; IR (KBr): 3430 (OH), 1740 (C=O) cm~l; lH
s NMR (CDCl3) d 6.89 (d, lH, J=6.9 Hz), 7.30 (dd, lH, J=2.1 Hz, J=6.6 Hz), 7.71 (d, lH, J=2.1 Hz), 8.64 (d, lH, J=6.9 Hz), 9.25 (d, lH, J=6.6 Hz). Analysis calculated for CloH6ClNO3: C, 53.71; H, 2.70; N, 6.26. Found: C, 54.27; H, 2.86; N, 6.23.

Fxample 61 8-(4-methylpiper~7in- 1-yl)-4H-quinolizin-4-one-3-carboxylic acid hydrochloride Step l: Ethyl 8-(4-methylpiperazin-l-yl)-4H-quinolizin-4-one-3-~rboxylate Ethyl 8-chloro-4H-quinolizin-4-one-3-carboxylate (755 mg,3.0 mmol), the product of Step 3 of Example 58, was suspended in 12 mL of dry pyridine under a nitrogen atmosphere. To the resultant solution was added 6.0 mL (6.0 mmol) of N-methylpiperazine and the reaction mixture was heated at 70~C for 8 hours. The reaction mixture was then con-,e.ll,d~ed in vacuo in order to remove all of the pyridine. The dry residue (3.124 g) was dissolved in 125 mL of methylene chloride and the methylene chloride solution was washed with 125 mL of ~a~uldt~,d sodium chloride solution (brine).
The aqueous layer was extracted with 125 mL of methylene chloride and the combined methylene chloride solutions were dried over anhydrous sodium sulfate, filtered and concentrated and dried in vacuo to afford 1.01 g of the title compound.

Step 2: 8-(4-methyl~ n-1-yl)-4H-quinolizin-4-one-3-carboxylic acid hydrochloride A mixture of 0.865 g (2.75 mmol) of ethyl 8-(4-methyl~ ,.azi---1-yl)-4H-quinolizin-4-one-3-carboxylate, from Step 1, in 12 mL of THF and 16.5 mL of a 0.5 N
aqueous solution of sodium hydroxide was heated, with stirring, at 75~C for 8 hours. The THF was removed from the reaction mixture by ~ t~ tion during the reaction. The 30 conct;.lL~d~d reaction mixture was cooled to abien~ temperature and adjusted to pH 2.0 with 10.5 mL of 1 N aqueous hydrochloric acid solution. The aqueous solution wasconcentrated in vacuo to remove ~80% of the water and the concentrate was diluted with 50 mL of 95% ethyl alcohol. The solid was collected by filtration, washed with 2 X S mL of ethyl alcohol and dried in vacuo to afford the desired product.The product was recryst~lli7e~ from ethyl alcohoVwater (3: 1 v/v) to afford 0.332 g (37% yield) of the title CA 02222322 1997-11-2~

wo 96/39407 PCTtUss ~ ~. ~ 3~1 compound, m.p.257-258~C; MS DCI-NH3: 288 (M-Cl)+ 90%, 244 ((M-Cl)-C02H)+
base, 270 (M-Cl-H20)+; IR (KBr): 3420 (OH), 1645 (C=O) cm~l; lH NMR (TFA) d 3.20 (m, 3H), 3.52 (dd, 2H, J=10 Hz), 4.02 (m, 4H), 4.63 (d, 2H, J=12 Hz), 7.41 (m, 2H), 7.65 (d, lH, J=7.5 Hz), 8.26 (d, lH, J=9 Hz), 9.18 (d, lH, J=7.5 Hz). Analysis calcLlated for C1sHlgClN3O3+0.5H2O: C, 54.14; H, 5.75; ~, 12.62. Found: C, 54.23;
H, 5.54; N, 12.64.
Example 62 8-(3-Amino-l-pyrrolidinyl)-l-ethyl-4H-quinolizin-~one-3-carboxylic acid hydrochloride Step 1: 4-Chloro-2-propyl-pyridine A 1.5 M solution of LDA in hexane (100 mL, 150 mmol) was cooled to -60~C in an isopropyl alcohoVdry ice bath. To the stirred LDA solution, under nitrogen, was added, dropwise over a 0.5 hours period, a solution of 17.466 g (137 mlTIol) of 4-chloro-2-picoline (the product of Step 1 of Example 58) in 80 mL of dry THF. The reaction mixture was stirred for 0.5 hours at -60~C and then a solution of 10.95 mL (137 mmol) of ethyl iodide in 30 mL of dry THF was added, dropwise over a 20 minute period. After the reaction mixture was sti~red at -60~C for 0.5 hours, the cooling bath was allowed to slowly (1.5 hours) warm to -30~C. According to TLC analysis on silica gel eluted with 5%
m~th~nol in methylene chloride, the reaction had gone to completion. The reaction mixture was poured into cold brine and the aqueous mixture was extracted with methylene chloride.
The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was ~ tille~ to afford 12.667 g (60% yield of the title compound, b.p.
77-80~C (10 mm Hg).

Step 2. Diethyl 2-ethoxy-3-r~chloro-2-pyridyll-pentane-1.1-dicarboxylate A solution of 12.6 mL (89.9 mmol) of diisopropylamine in 20 mL of anhydrous tetrahydrofuran (~IF) was prepared under a nitrogen atmosphere and cooled in an ice/water bath. To this solution was added, dropwise over a 30 minute period, 36 mL of a 2.5 ~1 solution of n-butyllithil-m (90 mmol) in hexane. The solution was stirred for 30 minutes at 0~C and then cooled to -60~C. To the amine solution at -60~C, was added, dropwise over a 30 minute period, a solution of 12.66 g (81.9 mmol) of 4-chloro-2-propyl-pyridine, from Step 1, in 100 mL of anhydrous THF and a dark red-colored solution was formed. The solution was stirred at -60~C for 0.5 hours and then 16.55 mL
(81.9 mmol) of ethyl 2-carboethoxy-3-ethoxy-2-propenecarboxylate was added, dropwise over a 30 minu~e period. Stirring was continued at -60~C for 0.5 hours and at -20~C for CA 02222322 1997-11-2~

WO 96~9407 PCT~US96/08991 1.5 hours. The reaction mixture was poured into cold brine and the aqueous mixture was extracted with methylene chloride. The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 35.48 g of the title compound. The product was carried on to the next step without purification.

Step 3. Ethvl 8-chloro-1-ethvl-4-H-quinolizin-4-one-3-~rboxylate A solution of 35.48 g (99.2 mmol) of diethyl 2-ethoxy-3-[4-chloro-2-pyridyl]-pentane-1,1-dicarboxylate, from Step 2, in 1 L of xylene was heated at 150~C, with stirring, for 24 hours and then concentrated in vacuo. The residue was washed with a lo mixture of hexane and cyclohexane to afford 14.867 g (54% yield) of the title compound as a green solid; MS DCI-NH3 M/Z: 280 (M+H)+, 246 (M-Cl)+, 217 (M-Cl-Et)+; lH NMR
(CDC13) d 1.31 (t, 3H, J=7.5 Hz), 1.43 (t, 3H, J=7.2 Hz), 2.78 (q, 2H, J=7.5 Hz), 4.43 (q, 2H, J=7.2 Hz), 7.10 (dd, lH, J=2.4 Hz, 8.1 Hz), 7.70 (d, lH, J=2.4 Hz), 8.32 (s, lH), 9.40 (d, lH, 8.1Hz).

Step 4. Ethyl 8-(3-(N-t-butoxycarbonyl)amino-l-pyrrolidinyl)-I -ethvl-4H-quinolizin-4-one-3-carboxylate Ethyl 8-chloro-1-ethyl-4H-quinolizin-4-one-3-carboxylate (1.20 g, 4.3 rnmol), from Step 3, was dissolved, under a nitrogen atmosphere, in 15 mL of dry pyridine. To the resultant solution was added 1.04 g (5.59 mmol) of 3-(N-t-butoxycarbonylamino-pyrrolidine) and 1.8 mL (12.9 mmol) of dry triethylamine and the reaction mixture was heated at 60~C for 12 hours. The reaction mixture was then concentrated in vacuo in order to remove all of the pyridine. Ethyl alcohol (4 mL) was added to the dry residue. The mixture was filtered to give 0.421 g of the desired product as a solid. The filtrate was 2s concentrated and the residue purified by flash chromatography on silica gel eluted with 2%
methanol in methylene chloride, followed by 5% methanol in methylene chloride to afford an additional 1.273 g of the desired product. The title compound was obtained in 92%
yield (1.694 g) as a yellow solid and taken on to the next step.

Step 5. 8-(3-Amino- I -pyrrolidinyl)- 1 -ethyl-4H-quinolizin-4-one-3-carboxylic acid hvdrochloride A solution of 1.694 g (3.94 mmol) of ethyl 8-(3-(N-t-butoxycarbonyl)-amino-l-pyrrolidinyl)- 1 -ethyl-4H-quinolizin-4-one-3-carboxylate, from Step 4, in 25 mL of trifluoroacetic acid (TFA) was stirred for 2 hours at ambient ~IIIytl~t~c. The TFA was 3s evaporated in vacuo and the residue was dissolved in 200 mL of methanol. To the resultant W O 96~9407 PCTrU~ 9~1 solution was added 25 g of strongly basic ion exchange resin and the mixture was stirred at a",b;_nt Lt;lllpCl~ lllG for 2 hours. The mixture was filtered and the filtrate was conc~
under reduced ~ ,S~ulG to afford 1.146 g (88% yield) of ethyl 8-(3-amino-1-pyrrolidinyl)-l-ethyl-4H-quinolizin-4-one-3-carboxylate as a residue. The residue was dissolved in 6 s rnL of THF and 10.5 rnL of a 1 M aqueous solution of sodium hydroxide was added. The reaction mixture was heated at 60~C for 2 hours and then the reaction ~GIll~ LulG was increased to 90~C for 2 hours, in order to evaporate the THF. The conce~ ed reachon solution was poured into water and the pH of the resultant solution was adjusted to ~2 with conce"hd~d hydrochloric acid. The solid was filtered tO afford 0.365 g (31% yield) of the title compound, m.p.l96-198~C; MS DCI-NH3: 302 (M-Cl)+ base. 258 ((M-Cl)-C02H)+
25%; IR (KBr): 3440 (OH), 2960, 1650 (C=O), 1500, 1360, 1280 cm~l; lH NMR (TFA~
d 1.41 (t, 3H, J=7.5 Hz), 2.39 (q, 2H, J=7.5), 2.70 (m, 3H), 4.0 (m, 3H), 4.53 (m, lH), 6.93 (d, lH, J=1.5 Hz), 7.33 (dd, lH, J=9 Hz, 1.5 Hz), 7.93 (s, lH), 9.08 (d, lH, J=9 H2). Analysis calculated for C16H20clN3o3: C, 56.98; H, 5.97; N, 12.44. Found:
C, 56.83; H, 6.00; N, 11.93.

Fxample 63 8-(3-(Alanyl)amino-pyrrolidir~yl)-l-ethyl4H-quinolizin-4-one-3-carboxylic acid 3-A nino- l-benzylpyrrolidine (I. Surnio and T. Matsuo, Japanese Kokai JP
5328161, p~lbli~h~A March 16, 1978) is coupled to N-t-butoxycarbonyl alanine (Boc-Ala) using conventional N-hydroxysuccinimide coupling procedures. The l-benzyl group is removed by hydrogenolysis in methanol using p~ linm on carbon catalyst. The 3-(N-Boc-alanyl)arninopyrrolidine is then reacted with ethyl 8-chloro- 1-ethyl-4H-quinolizin-4-2s one-3-carboxylate, the product of Step 3 of Example 62, as described in Step 4 of Example 62 replacing 3-(N-t-butoxycarbonylaminopyrrolidine) with 3-(N-Boc-alanyl~a.~ o~"/rrolidine, to give 8-(3-(N-alanyl)amino-pyrrolidinyl)-4H-quinolizin-4-one-3-carboxylic acid with the nitrogen of the amino acid protected with a Boc group. The Boc IJlo~ g group is removed by standard hydrolysis using hifluoroacetic acid and dilute aqueous hydrochloric acid.
Using the procedure outlined in Example 63, or any of the other convenhonal conc~çn~tion me~ods listed above, other amino acid derivatives of the compounds of this t invention having an arnino group can be prepared. Examples of amino acids which can be coupled, either alone or in combination with one and other, include naturally occuning amino acids such as glycine, ~l~nine~ leucine, isoleucine, methionine, phenyl~l~nine, >

CA 02222322 1997-11-2~

WO 96/39407 PCTrUS9G/~3~1 valine, and the like, as well as synthetic amino acids such as cyclohexy~ nin~
cyclohexylglycine, aminopentanoic acid, and the like.

Fx~ le 64 1-Ftl~yl-8-(3-methvl-l-piperazillyl)-4H-quinolizin-4-one-3-~rboxylic acid hydrochloride Step 1. F.tllyl l-ethyl-8-(3-methyl-1-~iperazinyl)-4H-quinolizin-4-one-3-carboxylate Ethyl 8-chloro- 1-ethyl-4H-quinolizin-4-one-3-carboxylate (558 mg, 2.0 mmol), the product of Step 3 of Lxample 62, was dissolved in 10 mL of dry pyridine under a nitrogen atmosphere. To the resultant solution was added 600 mg (6.0 mmol) of 2-methyl~ zi"e and the sti~Ted reaction mixture was heated at 65~C for 3 hours. The reaction mixture was allowed to cool to ~mbient It;nl~JGl~UlG and then co~çe~ in vacuo in order to remove all of the pyridine. The residue was dissolved in 60 mL of methylene chloride and the methylene chloride solution was washed with 60 mL of water. Theaqueous layer was extracted with 2 X 60 mL of methylene chloride and the combined methylene chloride solutions were dried over anhydrous sodium sulfate, filtered and con~,ç"l,~f ~ and dried in vacuo to afford 690 mg of the title compound. The product was carried on to the next step without pllnfi~ *on Step 2. 1-Ethyl-8-(3-methyl-1-pi~ yl)-4H-quinoli7in-4-one-3-~rboxylic acid hydrochloride To a suspension of 0.686 g (2 mmol) of ethyl 1 -ethyl-8-(3-methyl- 1 -e.d;cinyl)-4H-quinolizin-4-one-3-carboxylate, from Step 1, in 8 mL of THF was added 8.0 mL of a 1.0 N aqueous sodium hydroxide solution and the reaction mixture washeated, with stirring, at 65~C for 3 hours. The THF was removed from the reaction mixture by ~ ti11~tion during the reaction. The concentrated reaction mixture was cooled to ambient lelll~lalulG and adjusted to pH 1-2 with 16 mL of 1 N aqueous hydrochloric acid solution. The aqueous solution was conce~ at~d in vacuo to remove the water and the residue was suspended in 10 mL of water. The solid was collected by filtration and dried in vacuo to afford the 385 mg (55% yield) of the title compound. m.p.>295~C; MS DCI-MH3: 316 (M-Cl)+; IR (KBr): 3420 (OH), 1720 (C=O) cm~l; lH NMR (TFA) d 1.50 (t, 3H, I=7.5 Hz), 1.70 (d, 3H, J=6 Hz), 3.00 (q, 2H, J=7.5 Hz), 3.70-4.10 (m, 6H), 4.55 (m, lH), 4.60 (m, lH), 7.40 (d, IH, J=3.0 Hz), 7.68 (dd, lH, J=3.0 Hz, 8.4 Hz), 8.18 (s, lH), 9.19 (d, lH, J=8.4 Hz). Analysis calculated for C17H22ClN3O3+H2O: C, 3S 55.21; H, 6.54; N, 11.36. Found: C, 55.19; H, 6.07; N, 11.34.

W O 96/39407 PCT~US96/08991 Fxample 65 1-Fthyl-8-(4-m~ y~ A~ -vl)-4H-quinQlizin-4-one-3-carboxylic acid hydrochloride S Ste~ 1. Ethyl l-ethyl-8-(4-methylpil~l~ill-1-yl)-4H-quinolizin-4-one-3-~rboxylate Ethyl 8-chloro- 1-ethyl-4H-quinolizin-4-one-3-carboxylate (279 mg, 1.0 mmol), the product of Step 3 of Example 62, was dissolved in 5 mL of dry pyridine under a nitrogen atmosphere. To the resultant solution was added 2 mL (2.0 mmol) of N-methylpiperazine and the stirred reachon mixture was heated at 85~C for 2.5 hours. The 10 reaction mixture was allowed to cool to ~mbient ~e~ a~ and then conc~ d in vacuo in order to remove all of the pyridine. The residue was dissolved in 50 mL of methylene chloride and the methylene chloride solution was washed with 50 mL of 5~ aqueoussodium bicarbonate solution. The aqueous layer was extracted with 3 X 50 mL of methylene chloride and the combined methylene chloride solutions were dried over15 anhydrous sodium sulfate, filtered and concenLIdted and dried in vacuo to afford 343 mg of the title compound, m.p. 94-96~C; MS DCI-NH3: 344 (M+H)+.

Step 2. 1-Ethyl-8-(4-llleLllyl~ ~in-l-yl)-4H-Quinolizin-4-one-3-carboxylic acid hydrochloride To a solution of 171 mg (0.5 mmol) of ethyl 1-ethyl-8-(4-methylpiperazin-1-yl)-4H-quinolizin-4-one-3-carboxylate, from Step 1, in 4 mL of THF was added 4.0 mL of a 1.0 N aqueous sodium hydroxide solution and the reaction mixture was heated, with stirring, at 75~C for 4.5 hours. The reaction mixture was cooled to ambient ~lll~ alule and adjusted to pH 2 with 5 mL of 1 N aqueous hydrochloric acid solution. The aqueous solution was concentr~tç~l in vacuo to ~5 mL and the solid was collected by filtration and dried in vacuo to afford 120 mg (68% yield) of the title compound, m.p. 293-294~C (dec);
MS DCI-NH3: 316 (M-Cl)+ 90%, 272 ((M-Cl)-C02H)+ base; IR (KBr): 3420 (OH), 1695 (C=O), 1640 (C=O) cm~l; IH NMR (TFA) d 1.47 (t, 3H, J=7.5 Hz), 3.00 (q, 2H,J=7.5 Hz), 3.23 (s, 3H), 3.55 (dd, 2H, J=9 Hz), 4.12 (m, 4H), 4.65 (d, 2H, J=15 Hz), 7.40 (s, lH), 7.67 (d, IH, J=9 Hz), 8.18 (s, IH), g.20 (d, IH, J=7.5 Hz). Analysis calculated for C17H22ClN3O3: C, 56.59; H, 6.42; N, 11.64. Found: C, 56.86; H, 6.19;
N, 11.60.
-CA 02222322 1997-11-2~

W O 96~9407 PCTrUS9~ 8391 F.xample66 4-Chloro-5-fluoro-2-picoline Step 1 2-(5-Mtro-2-pvridvl)-1.3-propanedicarboxylate Sodium hydride (20.2 g of NaH suspended in hexane, 0.504 mol) was suspended, under a nitrogen atmosphere, in 600 mL of anhydrous THF in a 3-neck 2 L
round-bottom flask equiped with an addition funnel and a mechanical stirrer. Thesu~pe~l~ic n was cooled to 0~C in an ice bath. A solution of 71.8 mL (0.473 mol) of diethyl m~ n~l~ in 60 mL of anhydrous THF was added dropwise to the sodium hydride suspension over a I hour period. After the addition and the evolution of hydrogen gas were complete, the reaction mixture was stirred for 20 min at 0~C. A solution of 50 g (0.315 mol) of 2-chloro-5-nitropyridine in 150 mL of anhydrous THF was added dropwise to the mixture, over a 25 min period. The ice bath was removed and the deep red-colored solution was stirred at ambient temperature for 48 hours. These procedures were repeated on the same scale. The two solutions containing the product were concentrated to ~ 500 mL and poured into a mixture of 1 L of 10% aqueous sodium bicarbonate solution and 1 L
of brine. The aqueous mixture was e~L~ ,d with 3 X 500 mL of methylene chloride. The combined organic extract was dried over anhydrous sodium sulfate, filtered and conce..lla~d in vacuo to a solid residue. The residue was cryst~lli7~d from ethyl alcohol and the crystals were washed with hexane to yield 140 g (79% yield) of the title compound as a bright yellow solid; MS DCI-NH3 M/Z: 283 (M+H)+ base, 253 ((M+H)-C2Hs)+
base; lH NMR (CDCl3) d 1.30 (t, 6H, J=7.5 Hz), 4.26 (q, 2H, J=6.0 Hz), 4.29 (q, 2H, J=6.0 Hz), 5.08 (s, lH), 7.77 (dd, lH, J=9.0 Hz, 0.6 Hz), 8.49 (dd, lH, J=3.0 Hz, 9.0 Hz), 9.38 (dd, lH, J=3.0 Hz, 9.0 Hz).
2s Step 2. 5-Nitro-2-~icoline A suspension of 102.0 g (0.361 mol) of 2-(5-nitro-2-pyridyl)-1,3-propanedicarboxylate, from Step 1, in 600 mL of 20% aqueous sulfuric acid solution was heated at 95~C for 24 hours. The resultant solution was poured onto 1 kg of ice and the aqueous mixture was adjusted to a pH within the range pH 10 - 12 with 50% aqueous sodium hydroxide solution. The precipitate was filtered and dissolved in ethyl acetate. The ethyl acetate solution was dried over anhydrous sodi~lm sulfate, filtered and concentrated to a solid residue. The residue was washed with hexane. The hexane was removed by filtration and the solid was dried to afford 45.86 g (92% yield) of the title compound; lH
, WO 96/3~407 PCTrUS96i'~9~1 NMR (CDC13) d 2.71 (s, 3H), 7.36 (d, lH, J=9.0 Hz), 8.37 (dd, lH, J=3.0 Hz, 9.0 Hz), 9.33 (d, lH, J=3.0 Hz).

Step 3. 5-Amino-2-picoline " 5 The product of Step 2, 5-nitro-2-picoline (45.86, 0.332 mol), was dissolved in 200 mL of rneth~nol and 1.15 g of 10% p~ dillm on carbon was added to the resultant solution. The reaction mixture was hydrogenated at ambient Lwll~ dLu~ under 4 atmospheres of hydrogen. The p~ m catalyst was removed by filtration through a 45 Millipore(~ filter and the filtrate was conce.lLlalcd in vacuo to afford 33.96 g (9~% yield) of the title compound as a tan solid; lH NMR (CDC13) d 2.42 (s, 3H), 3.54 (brs, 2H), 6.91 (m, 2H), 8.00 (m, lH).

Step 4. 5-Fluoro-2-picoline A solution of S-amino-2-picoline (20 g, 0.185 mol), from Step 3, in 105 mL of ethyl alcohol was cooled to 0~C. Tetr~flucroboric acid (55 mL of a 48% solution in water) was added to the cold 5-aminopicoline solution and the flask con~ g the resultant solution was weighed. Ethyl nitrite was bubbled through the cold solution un~il 13.88 g (0.185 mol) had been added. The addition took place over a 1.25 hours period. After the addition was complete the reaction solution was allowed to sit at 0~C for 15 ~un, during which lime, the excess ethyl nitrite evaporated from the sollltinn Diethyl ether (120 mL) was added to the reaction mixture to ensure complete L,lcici~ ion of the tetrafluoroborate salt. After 30 minutes at 0~C, the mixture was filtered. The filter cake was washed with 200 rnL of diethyl ether, followed by 300 mL of hexane. The solid was transferred to a 1 L beaker co~l;-;..i..~ approximately 300 mL of hexane and 10.75 g (0.185 mol) ofpotassium fluoride. The mixture was heated to 40~C over a 4.5 hours period. The orange-colored solid was converted to a black oily solid. The hexane was dec~nted and the residue was cooled to 0~C. The cold residue was triturated with applo~ ately 200 mL of 50%
sodium hydroxide. The mixture was combined with m~ltf~rizll obtained from duplicate runs of the preceeding procedures and the combined aqueous Il~ix~Lul~S were steam ~ tillçri. The aqueous ~li.Cti~ tt~. collected ~lv~n 92~C and 100~C was extracted with two portions of methylene chloride. The combined methylene chloride extract was dried over anhydrous sodium sulfate, filtered and added to the (hexane) t~ tilklte~ which was collected between 62~C and 65~C. The product was carried on to the next step in solution.

CA 02222322 1997-11-2~

W 096/39407 PCT~US~ 9991 Step 5. 5-Fluoro-2-picoline-N-oxide To the solution of 5-fluoro-2-picoline obtained in Step 4, at 0~C, was added, with vigorous stirring, a cold solution of 40% peracetic acid (prepared by carefully adding 50 mL of 30% hydrogen peroxide solution to 150 mL of glacial acetic acid). The reaction mixture was heated at reflux ~e",~ dture (50~C) for 4 days and then poured into 600mL of ice water. The aqueous mixture was adjusted to pH 9 by the addition of pot~cciumcarbonate and then was stirred at ~mhient ~CIll~ dlUlG for 4 hours. The aqueous solution was continuously extracted with methylene chloride for 24 hours and the methylene chloride extract was dried over anhydrous sodiurn sulfate, filtered and concentrated in vacuo to afford 30.8 g (22% yield) of the title compound; MS DCI-NH3 M/Z: 128 (M+H)+ base; lH NMR (CDC13) d 2.48 (s, 3H), 7.00 (ddd, lH), 7.22 (dd, lH), 8.22 (dd, 1 H).

Step 6. 5-E;luoro-4-nitro-2-picoline-N-oxide The reaction was carried out in a flask vented to a gas scrubber cont~ining aqueous sodium hydroxide solution. The product of Step 5, 5-fluoro-2-picoline-N-oxide (1.0 g, 7.86 mmol) was cooled to 0~C and con~;e.~LId~cd sulfuric acid (4.2 mL) was slowly added, with stirring. Solid potassium nitrate (1.27 g, 12.5 mmol) was then added to this mixture at 0~C, in small portions over a 45 minute period. The reaction mixture was allowed to warm to amhient IcllllJe~a~ulc and was stirred at ambient ~cm~c~ c for 1 hour.
Not all of the potassium nitrate had dissolved and the reaction mixture was heated at 50~C
for 0.5 hours and then at 100~C for 18 hours. The homogeneous reaction solution was poured over ice and the resultant aqueous solution was adjusted to pH 9 with solid potassium carbonate. The aqueous solution was then extracted with 3 X 80 mL of methylene chloride. The combined organic extract was dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to give 1.084 g (80% yield) of the title compound as a yellow solid, m.p. 107-108~C; MS DCI-NH3 M/Z: 190 (M+NH4)+ 10%, 173 (M+H)+ 30%, 157 (M-O)+ 50%; 1H NMR (CDC13) d 2.48 (s, 3H), 8.05 (d, lH, J=9.0 Hz), 8.31 (d, lH, J=6.0 Hz).
Step 7. 4-Chloro-5-fluoro-2-picoline-N-oxide The product of Step 6, 5-fluoro-4-nitro-2-picoline-N-oxide (3.56 g, 20.6 mmol) was dissolved in 30 mL of concentrated (37.5%) aqueous hydrochloric acid. The resultant solution was heated, with stirring, at 110~C for 48 hours and then concentrated in vacuo.

, WO 96ng407 PCT~US96/08991 Water (30 rnL) was added to the residue and the resultant aqueous solution was adjusted to pH 9- 10 with sodium carbonate. The aqùeous solution wa~. then extracted with 3 X 50 mE
of metlhylene chloride and the comhin~d organic extract was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was crystzllli7ed from hexane to s afford 1.8 g (55% yield) of the title compound, m.p. 92-93~C; MS DCI-NH3 M/Z: 179 ., (M+NI~)+ 30%, 162 (M+H)+ base, 146 (M-O)+ 60%; lH NMR (CDC13) d 2.46 (s, 3H), 7.30 (d, lH, J=9.0 Hz), 8.26 (d, lH, J=4.5 Hz); IR (chloroform solution) 1605 (N-O), 1180 (C-F) cm~l . Analysis calculated for C6HsClFNO: C, 44.61; H, 3.12; N, 8.62.
Found: C, 44.89; H, 3.25; N, 9.40.
Ste,,~ 8. 4-Chloro-5-fluoro-2-"icoline 4-Chloro-5-fluoro-2-picoline-N-oxide (12.43 g, 76.93 mmol), from Step 7, was dissolved in 52 mL of glacial acetic acid in a 3-necked flask equiped with a m~çh~nit~
stirrer, a condenser and a thermometer. Iron powder (6.45 g, 115.5 mmol) was added to the solution at ~mhi~nt Lt;~ 1G and ~he reaction mixture was carefully heated to 35-40~C. After lO min at 30~C, an exothermic reaction took place which caused the reaction L~ LU1e to rise to 120~C and the reaction mixture became a very dark brow~i-colored solution. The flask was ~ra~Ç~ ed to a cold water bath and the IC . I I11GI ~ of the solution brought down to ~mbierlt The reaction mixture was then poured over ice. The resultant aqueous mixture was adjusted to pE~ 9 with potassiurn carbonate and steam distilled. The aqueous dictill~t~ collected at 92-96~C was extracted with three portions of methylene cnloride. The combined organic extract was dried over anhydrous sodiurn sulfate, filtered and rli.ctillt~tl to afford 15.91 g (71% yield) of the title compound, b.p. 138-140~C; MS GC-MS M/Z:146 (M+H)+; lH NMR (CDC13) d 2.53 (s, 3H), 7.23 (d, lH, J=6.0 Hz), 8.37 z5 (s, 1 H).

Fxaml7le 67 3.4-Dichloro-5-fluoro-2-picoline To 0.87 g (6 mmol) of 4-chloro-5-fluoro-2-picoline, the product of Example 66, in 20 mL of chlolurc,,l,l cooled to -45~C, is added 0.75 mL of t-butylhypochlorite. The reaction rnixture is stirred at -45~C for 2 hours and at 0~C for 2 hours. The reaction mixture is then poured into water and the resultant aqueous mixture is extracted with methylene - chloride. The organic solution is dried over anhydrous m~gnesium sulfate, filtered, concentrated under reduced ~l~;S~ulc and rlictillt~d to afford the title compound.

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W O 96/39407 PCT~US~ 83~1 Fx~mple 68 3-Bromo-4-chloro-5 -fluoro-2-picoline 4-Chloro-5-fluoro-2-picoline, the product of Example 66, is treated with bromine5 in fuming sulfuric acid containing 65% sulfur trioxide for 7 hours at 80~C as described by L. van der Does and H.J. Hertog in Rec Trav Chim 81: 864 (1965) to afford the title compound.
F.xample 69 4-Chloro-3~-difluoro-2-picoline 4-Chloro-5-fluoro-2-picoline is treated with 1.1 equivalents of acetyl hypofluorite as c~escribed by O. T Rrrn~n )l et al. I Org Chem, 49: 806-813 (1984) to afford the title compound.

Fxample 70 4-Chloro-5-fluoro-2-propyl-pyridine Diisopropylamine (924 ~LL, 6.59 mmol) was dissolved in 9 mL of dry THF and the resultant solution was cooled to 0~C in an ice bath. n-Butyllithillm (3.07 mL of a 2.05 20 M solution in THF, 6.29 mmol) was added via syringe to the amine solution and the resultant solution was s~irred for 30 minutes at 0~C. The lithium diisopropylamide (LDA) solution was then cooled to -50~C in an isopropyl alcohoVdry ice bath. To the cold LDA
solution was added, dropwise from an addition funnel, over a 15 min period, a solution of 4-chloro-5-fluoro-2-picoline (435 IlL, 3.0 mrnol), the product of Example 64, in 9 mL of 25 THF. The reaction solution turned dark orange-brown in color. The reaction solution was stirred at a t~ LulG in the range -50~C to -45~C for S hours and then was cooled over a 15 min period to -78~C. Ethyl iodide (792, LL, 9.9 mmol) was added in one portion and the reaction solution was stirred at -78~C for 20 min. The reaction was then quenched by pouring the reaction solution into 60 mL of 10% aqueous ammonium chloride solution.
30 The aqueous mixture was extracted with 2 X 50 mL of methylene chloride. The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated in vacllo and the residue was distilledto afford the title compound, b.p. 80-82~C (12 mm Hg); MS
DCI-NH3 M/Z: 174 (M+H)+ 40%; lH NMR (CDC13) d 0.96 (t, 3H, J---7.5 Hz), 1.73 (spt, 2H, J=7.5 Hz), 2.73 (t, 2H, J=7.5 Hz), 7.21 (d, lH, J=6.0 Hz), 8.38 (s, lH).

WO 96/39407 PCTAJ~6~5331 F.x~rnple 71 3 ~4-Dichloro-~-fluoro-2-provvl-pyridine By following the procedures described in Example 67 and replacing 4-chloro-5-5 fluoro-2-picoline (the product of Example 66) with 4-chloro-S-fluoro-2-propyl-pyridine (the product of Example 70), the title compound can be ~ d.
F.xam~le 72 3-Bromo-4-chloro-S-fluoro-2-~ropyl-pvridine By following the procedures described in Example 68 and replacing 4-chloro-5-fluoro-2-picoline (the product of Example 66) with 4-chloro-S-fluoro-2-propyl-pyridine (the product of Example 70), the title compound can be ~ ar~.

F.xample 73 IS 4-Chloro-3.5-difluoro-2-1~ropvl-pyridine By following the procedures described in Example 69 and replacing 4-chloro-S-fluoro-2-picoline (the pr~ uct of Exar.plc 66) with A ChlOrO-S-..UOrO-2-prOpyl-py.idirle (the product of Example 70), the title compound can be plCL~al'~.
F.xam.I?le 74 l -Ethyl-7-fluoro-8-(~meth~lyi~eld~ -1 -yl)-4H-quinoli7.in-4-one-3-carboxylic acid hvdrochloride By following the procedures described in Step 2 of Example 62 and in Example 65 and replacing 4-chloropicoline with 4-chloro-S-fluoro-picoline (the product of Example ~6), the title cornpound can be ~ ,d.

Fxample 75 1-Ethyl-7-fluoro-8-(3-methyl- 1 -piperazinyl)-4H-quinoli7.in~one-3-carboxylic acid hydrochloride By following the procedures described in Step 2 of Example 62 and in Example 65 and replacing 4-chloropicoline with 4-chloro-S-fluoro-picoline (the product of Example - 35 66), and replacing N-methylpiperazine with 2-methylpiperazine, the title compound can be ,d.

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W O 96/39407 PCTrUS96~ 9~1 F~ le 76 8-(3-Amino- 1 -pyrrolidinyl)- 1 -ethyl-7-fluoro-4H-quinoli7in-4-one-3-carboxylic acid hydrochloride s Following the procedures described in Example 62, replacing 4-chloropicoline with 4-chloro-5-fluoro-picoline (the product of Example 66), the title compound is ,d.

F~rnple 77 9-Chloro- 1-ethyl-7-fluoro-8-(4-methylpi~ 1-yl)-4H-quinoli7in-4-one-3-carboxylic acid hydrochloride Following the procedures de~cn~d in Step 2 of Example62 and in Example 65, replacing 4-chloropicoline with 3,4-dichloro-5-fluoro-picoline (the product of Example s 67), the title compound is ~.c~cd.

F.xample 78 9-Chloro- 1 -ethyl-7-fluoro-8-(3-methyl- 1 -pip~ yl)-4H-ql-inolizin-4-one-3-carboxylic acid hydrochloride Following the procedures des~nbed in Step 2 of Example 62 and in Example 65, replacing ~chloropicoline with 3,4-dichloro-5-fluoropicoline (the product of Example 67), and replacing N-meth~ d4i,le with 2-methylpiperazine, the title compound is prepared.

Fx~rnple 79 8-(3-Amino- 1 -pyrrolidinyl)-9-chloro- 1 -ethyl-7-fluoro-4H-quinolizin-4-one-3-carboxvlic acid hydrochloride Following the procedures described in Example 62, replacing 4-chloropicoline with 3,4-dichloro-5-fluoropicoline (the product of Example 67), the title compound is p,~,~cd.

Fx~mple 80 9-Bromo- 1 -ethyl-7-fluoro-8-(4-methyl~ ~in- I -yl)-4H~ inolizin-~one-3-carboxylic acid hydrochloride s Following the procedures described in Step 2 of Example 62 and in Example 65, " replacing ~chloropicoline with 3-bromo-~chloro-5-fluoropicoline (the product of Example 68, the title compound is p~ ~Gd.

F.x~le 8 1 lo 9-Bromo-1-ethyl-7-fluoro-8-(3-methyl-1-pi~ a~ yl)-4H-quinolizin-4-one-3-carboxylic acid hydrochloride Following the procedures described in Step 2 of Example 62 and in Example 65, replacing 4-chloropicoline with 3-bromo-4-chloro-5-fluoro-picoline (the product of Example 68), and replacing N-methyl~ le with 2-methyl~ e, the title compound is prepared.

F.xample 82 8-(3-Amino- 1 -pyrrolidinyl)-9-bromo- 1 -ethyl-7-fluoro-4H-quinoli7in-4-one-3-carboxylic acid hydrochloride Following the procedures described in Example 62, replacing 4-chloropicoline with 3-bromo-4-chloro-~-fluoro-picoline (the product of Example 68), the title compound is p~ ar,d.
F.xan~le 83 7,9-Difluoro- 1 -ethyl-8-(4-methyll,ipe~ ,-1 -yl)-4H-quinoli7in-4-one-3-carboxylic acid hydrochloride Following the procedures described in Step 2 of Example 62 and in Example 65, - replacing 4-chloropicoline with 4-chloro-3,5-difluoropicoline (the product of Example 69), the title compound is ~

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WO 96~9407 PCTrUS96i'~991 F.xample 84 7,9-Difluoro- 1 -ethyl-8-(3-methyl- 1 -pi~el azirlyl)-4H-quinolizin-4-one-3-c~rboxylic acid hydrochloride s Following the procedures described in Step 2 of Example 62 and in Example 65, replacing 4-chloropicoline with 4-chloro-3,5-difluoropicoline (the product of Example 69), and replacing N-methylpiperazine with 2-methylpiperazine, the title compound is p~ d.

Fxample 85 108-(3-Amino- 1 -pyrrolidinyl)-7,9-difluoro- 1 -ethyl-4H-~uinolizin-~one-3-carboxylic acid hydrochloride Following the procedures described in Example 62, replacing 4-chloropicoline with 4-chloro-3,5-difluoropicoline (the product of Example 69), the title compound is 15prepared.

Fx~n~le 86 l-Cyclopropyl-7-fluoro-8-(4-methylpiperazin- l-yl)-4H-quinoli7in-~one-3-r~rboxylic acid hydrochloride Following the procedures described in Steps I and 2 of Example 62 and in Example 65, replacing 4-chloropicoline with ~chloro-S-fluoropicoline (the product of Example 66), and replacing ethyl iodide with cyclopropyl iodide, the title compound is prepared.
2s F.x~ le 87 1 -Cyclopropyl-7-fluoro-8-(3-methyl- 1 -~ip~,~d~nyl)-4H-~uinolizin-4-one-3-carboxylic acid hydrochloride 30Following the procedures described in Steps 1 and 2 of Example 62, replacing 4-chloropicoline with 4-chloro-5-fluoropicoline (the product of Example 66) and replacing ethyl iodide with cyclopropyl iodide, and the procedures described in Example 65, replacing N-methylpiperazine with 2-methylpiperazine, the title compound is plC~)al~d.

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WO 96/39407 PCTrUS~Gi~91 Fx~rnple 88 ; 8-(3-Amino- 1-pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-~uinolizin-4-one-3-carboxy'lic acid hydrochloride Fo'llowing the procedures described in Example 62, replacing 4-chloropicoline with 4-c'moro-5-fluoropicoline (the product of Example 66), and replacing ethyl iodide with cyclopropyl iodide, the tiltle compound is prepared.

Fxample 89 9-ChloIo- l-cyclopropyl-7-fluoro-8-(4-methylpiperazin-1-yl)-4H quinolizin-4-one-3-carboxvlic acid hydrochloride Following the procedures described in Steps 1 and 2 of Example 62, replacing 4-cnloropicoline with 3,4-dichloro-5-fluoropicoline (the product of Example 67) and 15 replacing ethyl iodide with cyclopropyl iodide, and the procedures described in Example 65, the title compound is plc~al~d.

F.x~ le 90 9-Chloro- 1 -cyclopropyl-7-fluoro-8-(3-methyl- 1-piv~ inyl)-4H-quinolizin-4-one-3-carboxy'lic acid hydrochloride Following the procedures described in Steps 1 and 2 of Example 62, replacing 4-chloropicoline with 3,4-dichloro-5-fluoropicoline (the product of Example 67) and replacing ethyl iodide with cyclopropyl iodide, and the ~luc~lules described in Example 25 65, replacing N-methylpiperazine with 2-methylpiperazine, the title compound is ~lcpa~,d.

Fx~le 91 8-(3-Amino- l-pyrrolidinyl)-9-chloro- l-cyclopropyl-7-fluoro-411-quinolizin-4-one-3-carboxylic acid hydrochloride Following the procedures described in Example 62, replacing 4-chloropico'line with 3,4-dichloro-5-fluoropicoline (the product of Example 67) and replacing ethyl iodide with cyclopropyl iodide, Ithe title compound is prepared.
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W O 96/39407 PCTAUSS~ 931 F.Y~mple92 9-Bromo- 1 -cyclopropyl-7-fluoro-8-(4-methylpiperazin-l-yl)-4H-quinolizin-4-one-3-carboxylic acid hydrochloride S Following the procedures described in Steps 1 and 2 of Example 62, replacing 4-chloropicoline with 3-bromo-4-chloro-5-fluoropicoline (the product of Example 68) and rep~ ing ethyl iodide with cyclopropyl iodide, and the procedures described in Example 65, the title compound is ~ ,d.

0 F~y~m~le 93 9-Bromo- l-cyclopropyl-7-fluoro-8-(3-methyl- 1-Pi~er~7ir~yl)-4H-quinolizin-4-one-3-carboxylic acid hydrochloride Following the procedures described in Steps 1 and 2 of Example 62, replacing 4-chloropicoline with 3-bromo-4-chloro-5-fluoropicoline (the product of Example 68) and replacing ethyl iodide with cyclopropyl iodlde, and the procedures described in Example 65, replacing N-methyl~ip~ e with 2-methyl~ ine, the title compound is prepared.
F.Y~nu?le 94 8-(3-Amino- l-pyrrolidinyl)-9-bromo- 1 -cyclopropyl-7-fluoro-4'~-qninoli7in-4-one-3-~rboY~ylic acid hvdrochloride Following the procedures described in Example 62, replacing 4-chloropicoline with 3-bromo-4-chloro-5-fluoropicoline (the product of Example 68) and replacing ethyl iodide with cyclopropyl iodide, the title compound is prepared.

F.xarr~le 95 1 -Cyclopropyl-7,9-difluoro-8-(4-methylpiperazin- 1 -yl) -4H-~uinolizin-4-one-3-carboxvlic acid hydrochloride Following the procedures described in Steps 1 and 2 of Example 62, replacing 4-chloropicoline with 4-chloro-3,5-difluoropicoline (the product of Example 69) and repl~ing ethyl iodide with cyclopropyl iodide, and the procedures described in Example 65, the title compound is prepared.

.
CA 02222322 1997-11-2F.

- Fxample 96 l-Cyclopropyl-7,9-difluoro-8-(3-methyl- l-piperazinyl)-4H-ql,linoli7in-4-one-3-carboxy~ic acid hvdrochloride S Following the procedures desçriked in Steps 1 and 2 of Example 62, replacing 4-., chloropicoline with 4-chloro-3,5-difluoropicoline (the product of Example 69) and replacing ethyl iodide with cyclopropyl iodide, and the procedures c~esc~ibe~i in Example 65, replacing N-methylpiperazine with 2-methyl~ ,d~i"e, the title compound is pn,~cd.

0 F.xample 97 8-(3-Amino- 1 -pyrrolidinyl)- 1-cyclopropyl-7,9-difluoro-4H-quinolizin-4-one-3-carboxylic acid hydrochloride Following the procedures described in Example 62, replacing 4-chloropicoline 15 with 4-cnloro-3,5-difluoropicoline (the product of Example 69) and repl~-~ing ethyl iodide with cyclopropyl iodide, the title compound is plc~ ed.

F~arr~le 98 7-Fluoro- 1 -methylamino-8-(4-methylpiperazin- 1 -yl)-4H-q~linoli7in-4-one-3-t~rboxvlic acid hy~lrochloride Step 1. 4-Chloro-S-fluoro-~7ha-bromo-2-picolin~
4-Chloro-5-fluoro-2-picoline (2.9 g, 20 mmol), the product of Example 66, was dissolved in 50 mL of 1,2-dichloroethane in a dry flask. The resultant solution was heated, 25 with stirring, to 75~C and 4.09 (23 Irunol) of N-bromosuccinimide was added, followed by 100 mG (0.7 mrnol) of 2,2-azobisisobutyronitrile (AIBN), a free radical initiator. After the reaction mixture was s~red at 75~C for 24 hours, it was diluted with 450 mL of methylene chloride and washed with 3 X 400 mL of water. The organic layer was se~c,~d and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pl~,ssule. The 30 residue was dried in vacuo to give 3.5 g (69% yield) of the title compound as an amber oil;
lH NMR (CDCl3) d 4.50 (s, 2H), 7.54 (d, lH), 8.44 (s, lH).
Stev 2. 4-Chloro-5-fluoro-2-(N-methylaminomethyl)-pYridine ~Chloro-5-fluoro-alpha-bromo-2-picoline (1.37 g, 6.1 mmol), from Step 1 was 35 dissolved in 15 rnL of rn~th~nol in a pressure tube. Methylamine (3 mL of 40% aqueous solution) was added to the tube and the tube was sealed. The reaction mixture was stirred CA 02222322 1997-11-2~

W O 96/39407 PCTrUS~'C3331 at ambient tc~ .b~ e for 26 hours and then the solvent was removed under reducedpl~,S~7UlC. To the residue was added 50 mL of 10% aqueous sodium carbonate solution and the resultant aqueous mixture was extracted with 3 X 50 mL of methylene chloride. The organic combined extract was dried over anhydrous sodium sulfate, filtered and s concel.l.d~d under reduced pressur. The residue was dried in vacuo to give 754 mg g (70% yield) of the title compound; MS DCI-NH3 M/Z: 175 (M+H)+ base; lH NMR
(CDC13) d 2.50 (s, 3H), 3.90 (s, 2H), 7.47 (d, lH), 8.42 (s, lH).

Step 3. N-(4-chloro-5-fluoro-2-pyridyl)methyl-N-methyl-N-('~'~-dimethylethvl)-r~----a--~idine 4-Chloro-S-fluoro-2-(N-methylaminomethyl)-pyridine (650 mg, 3.72 mmol), from Step 2 was dissolved in 15 mL of toluene. To the resultant solution was added 2.3 mL (15 mmol) of N,N-dimethyl-N-(2,2-dimethylethyl)-fol."~,-.i(le, followed by 40 mg (0.3 mmol) of ammonium sulfate. The reaction mixture was heated at reflux le~ Jt;ldtul~, 15 with stirring, for 28 hours and then allowed to cool to ambient temperature. The solvent was removed under reduced pressure and the residue dried in v acuo to give 560 mg (59%
yield) of the title compound; MS DCI-NH3 M/Z: 175 (M+H)+ 73%, 203 ((M+H)-Cl-F)+
base; lH NMR (CDC13) d 1.17 (s, 3H), 1.19 (s, 9H), 2.83 (d, 2H), 4.47 (s, lH), 7.43 (d, lH, J=3 Hz), 8.40 (dd, lH), J=3 Hz, 1.5 Hz).
Step 4. Diethyl 2-ethoxy-3-(5-fluoropyridin-2-yl)-3-[N-methyl-N-(2" ~"-dimethylethyl)methylaminol-propane- 1.1 -dicarboxylate Lithium diisoL,lu~ylan--de (LDA: 16 mL of a 1.5 M solution in hexane) is added to 8 mL of dry THF, under a nitrogen atmosphere, and the resultant solution is cooled to 25 -70~C in a isopropyl alcohol/dry ice bath. To the cooled solution of LDA, is added dropwise, over a 30 minute period, a solution of 3.41 g (19.6 rnmol) of N-(4-chloro-5-fluoro-2-pyridyl)methyl-N-methyl-N-(2,2-dimethylethyl)-form~mirline, from Step 3, in 25 mL of dry THF. After stirring the solution for 0.5 hours at -70~C, a solution of 4.04 mL
(19.6 mmol) of ethoxymethylenem~lonate in 18 mL of dry THF is added dropwise over a 30 30 minute period. The reaction solution turns from dark red to orange. After stirring for 0.5 hours at -70~C, the reaction solution is allowed to warm to -20~C and is stirred at -20~C
for 1 hour. The reaction is quenched at -20~C by the addition of 1.3 mL of glacial acetic acid and the cooling bath is removed. After 20 minutes the reaction solution is poured into 5% aqueous sodium bicarbonate solution. The aqueous mixture is extracted with 35 methylene chloride and the organic extract is dried over anhydrous sodium sulfate, filtered W O 96~9407 PCTrU5~ 3~91 and concentrated under reduced lJlCS~UlC. The residue is purified by ch,o"ldLography on a silica gel column to afford the title compound.

Step 5. Diethyl 2-ethoxy-3-(5-fluoropyridin-2-yl)-3-- s methvlammo-propane- 1. I -dicarboxvlate A solution of 2 mmol (0.8 g) of diethyl 2-ethoxy-3-(5-fluoropyridin-2-yl)-3-[N-methyl-N-(2",2"-dimethylethyl)methylamino]-propane-1,1-dicarboxylate, from Step 4, 16 mmol of hydrazine and 6 mml of glacial acetic acid in 20 mL of 95% ethyl alcohol is heated at 50~C under nitrogen for aL~ imdlely 15 hours. Upon cooling, the solvent is removed in vacuo and the residue extracted with diethyl ether. The ether solution is washed with s~Luldted aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and conCeLlLIdt~,d in vacuo to afford the title compound.

Step 6. Ethyl 8-chloro-7-fluoro-1-methvlamino-4H-quinolizin-4-one-3-c~bo~cvlate 80 mL of Dowtherm A(~ in a 3-neck flask e~luiL,~ed with a thermometer, an addition funnel and an air-cooled concl~n~er is heated to 235~C, under nitrogen, using a heating mantel. A solùtion of 3.9 g (12.4 mrnol) of diethyl 2-ethoxy-3-(5-fluoropyridin-2-yl)-3-methylarnino-propane-1,1-dicarboxylate, from Step 5, in 45 mL of Dowtherm A(~) is added, dropwise over a 1.5 hours period, through the addition funnel to the heated stirring Dowtherm A~. After the addition is complete, the resultant solution is heated at ~200~C
for 1 hour and then is cooled to ambient ~III~Cl~tUlC. The solution is then poured into 500 mL of hexane and a ~-ccipi~ forms. The precipitate is collected by filtration, washed with S X 100 mL of hexane and dried to afford the title compound.

2s Step 7. Ethyl7-~luoro-1-methylamino-8-(4-~ llylpipcl~,ill-l -vl)-4H-quinolizin-4-one-3-carboxylate Ethyl 8-chloro-7-fluoro- 1 -methylamino-4H-quinolizin-~one-3-carboxylalte (899 mg, 3.0 mmol), the product of Step 6, is suspended in 12 mL of dry pyridine under a nitrogen atmosphere. To the rçs~llt~nt solution is added 6.0 mL (6.0 mmol) of N-methyl~ azine and the reaction mix~ure is heated at 70~C for 8 hours. The reaction mixture is then conce"l,~led in vacuo in order to remove all of the pyridine. The dry residue is dissolved in 125 mL of methylene chloride and the methylene chloride solution is washed with 125 rnL of brine. The aqueous layer is extracted with 125 mL of methylene r chl--~ide and the comhined methylene chloride solutions are dried over anhydrous sodium sulfate, filtered and concentrated and dried in vacuo to afford the title compound.

W O 96/39407 PCT~US96/08991 Step 8. 8-(4-methylpiperazin-1-yl)-4H-quinolizin-4-one-3-~rboxylic acid hydrochloride A mixture of 1 g (2.75 mmol) of ethyl 7-fluoro-1-methylamino-8-(4- ~, s methylpiperazin-l-yl)-4H-quinolizin-4-one-3-carboxylate, from Step 7, in 12 mL of THF
and 16.5 mL of a 0.5 N aqueous solution of sodium hydroxide is heated, with stirring, at 75~C for 8 hours. The THF is removed from the reaction mixture by rlictill~tinn during the reaction. The conce~ ed reaction mixture is cooled to ambient ~t;lll~JCldtLllC; and adjusted to pH 2.0 with 10.5 mL of 1 N aqueous hydrochloric acid solution. The aqueous solution 10 is concentrated in vacuo to remove ~80% of the water and the concentrate is diluted with 50 mL of 95% ethyl alcohol. The solid is collected by filtration, washed with 2 X 5 mL of ethyl alcohol and dried in vacuo to afford the desired product.

Fxam~les 99-1 16 By following the procedures described in Example 98 and replacing N-methyl~ zi"e in Step 7 with the al l,lu~,ia~ amine as shown, Examples 99-1 16 are ,d as disclosed in Table 3 wherein the compounds have the general formula o F~ N J~ COOH
R2 J~

~VO 96/39407 PCT~US~ 9~1 Ta~le 3 .
Fxample No. R2 Example No. f~2 ~, NH ~ ~,O

100 N~;CH3 109 N~CH2NHCH3 10 1 ~N 110 N--I N
1 02 ~1' ~CH3 111 ~NH2 103 ~N ~ ,CH3 112 '~ NH
I~NH ~ ~ CH3 104 N ~CH2F 1 13 CH
I~,NH ~ N

1 05 ~N~NH2 11 4 ~NH2 106 NI~NH2 ~ 115 ~NH2 107 ~N~s 1 16 ~}~NHET ~

* The amines are protected and deprotected as described in Example 58 ~r W O 96t39407 PCTtUS9~i~fi391 Fxample 117 7,9-Difluoro- 1 -methylamino-8-(4-methylpiperazin- l-yl)-4H-quinolizin-4-one-3-carboxylic acid hydrochloride By following the procedures described in Example 98 and replacing 4-chloro-S-fluoro-2-picoline (the product of Example 66) with 4-chloro-3,~-difluoro-2-picoline (the product of Example 69), the title compound is prepared.

F.xamples 1 18-135 By following the procedures described in Example 98, replacing ~chloro-S-fluoro-2-picoline (the product of Example 66) with 4-chloro-3,5-difluoro-2-picoline (the product of Example 69) and replacing N-methylpi~e~ e with the ~ u~liate amine asshown, Examples 118-135 are lVlG~J~lfel as disclosed in Table 4 wherein the compounds have the general formula o F~ N J~COOH
R2 J~

UtO 96/39407 PCTrUS96/08991 Ta,k~

FxamDle No. R2 Exam~le No. R2 11 8 N--~ 1 27 ~N--1 ~,NH ~ ~,O

11 9 N~c~H3 1 28 N~CH2NHCH3 A

120 ~N 128 N--12 1 ~1' CH3130 ~--NH

122 ~N--~C~3 131 p--NH2 "
~NH ~
~ CH3 123 ~N--~CH2F 132 CH3~--~H
I~_NH

124 ~N~NH2 ~ 133 ~--NH2 12~; N~NH2 ~ 134 ~NH

126 ~N~s 135 ~NHET~

* The amines are protected and deprotected as described in Example 58 WO 96/39407 PCT~US961'C~

Fxam~le 136 1 -Ethyl-8-(4-methylpiperazin- 1 -yl)-6,7,9-tnfluoro-4H-quinoli7in-4-one-3-carboxylic acid hy~lrochloride Step 1. 3.4~5~6-Tertrafluoro-2-picoline 2,3,4,5,6-Pent~fll1oropyridine (commercially available from Aldich (~hemi~
Co.) is oxidized to the corresponding N-oxide following the procedures described in Step 6 of Example 66. The 2,3,4,5,6-pçnt~fllloropyridine N-oxide is treated at ambient Lc~n~ dLul~i with one equivalent of methylm~gnçcium iodide in diethyl ether as described lo by F. Binns and H. Suschitsky in Chemical Communications~ 750-751 (1970) and I Chem $oc (C), 1223-1231 (1771). The reaction mixture is treated with aqueous ammoniumchloride and extracted with diethyl ether. The ether solution is dried over anhydrous m~gnesium sulfate, filtered and conc~nt~teA under reduced ~JlC5~:~UlC and the crude product is chromatographed on silica gel to afford 2-methyl-3,4,5,6-tetrafluoropyridine N-oxide (3,4,5,6-tetrafluoro-2-picoline). The N-oxide is then reduced to afford the title compound by the procedures described in Step 8 of Example 66.

Step 2. 2-P~opvl-3.4.5~6-tetrafluoropyridine A 1.5 ~ solution of LDA in hexane (100 mL, 150 mmol) is cooled to -60~C in an isopropyl alcohoVdry ice bath. To the stirred LDA solution, under nitrogen, is added, dropwise over a 0.5 hours period, a solution of 22.617 g (137 mmol) of 3,4,5,6-tetrafluoro-2-picoline, the product of Step 1, in 80 mL of dry THF. The reaction mixture is stirred for 0.5 hours at -60~C and then a solution of 10.95 mL (137 mmol) of ethyl iodide in 30 mL of dry THF is added, dropwise over a 20 minute period. After the reaction mixture is stirred at -60~C for 0.5 hours, the cooling bath is allowed to slowly (1.5 hours) warm to -30~C. The reaction mixture is poured into cold brine and the aqueous mixture is extracted with methylene chloride. The organic extract is dried over anhydrous sodium sulfate, filtered and concellLIdLcd in vacuo. The residue is distilled to afford the title compound.
Step 3. Diethyl 2-ethoxy-3-[3,4,5,6-tetrafluoro-2-pyridyll-pentane- 1.1 -dicarboxylate A solution of 12.6 mL (89.9 mmol) of diisopropylamine in 20 mL of anhydrous tetrahydrofuran (TEIF) is ~lc~dlcd under a nitrogen atrnosphere and cooled in an ice/water bath. To this solution is added, dropwise over a 30 minute period, 36 mL of a 2.5 M

wo 96/39407 PCTrUS96/08991 solution of n-butyllithillm (90 mmol) in hexane. The solution is stirred for 30 minutes at 0~C and then cooled to -60~C. To the amine solution at -60~C, is added, dropwise over a 30 minute period, a solution of 15.82 g (81.9 mmol) of 2-propyl-3,4,5,6-tetrafluoropyridine, from Step 2, in 100 mL of anhydrous THF. The resultant solution is stirred at -60~C for 0.5 hours and then 16.55 mL (81.9 mmol) of ethyl 2-carboethoxy-3-e:thoxy-2-plupellec~lJoxylate is added, dropwise over a 30 minute period. Stirring is continued at -60~C for O.S hours and at -20~C for 1.5 hours. The reaction mixture is poured into cold brine and the aqueous mixture is extracted with methylene chloride. The combined organic extract is dried over anhydrous sodium sulfate, filtered and con~ L.d~d 10 in vacuo to afford 35.48 g of the title compound. The product is carried on to the next step without pllrific~lion.

Step 4. Ethyl l-ethyl-6.7.8.9-tetrafluoro-4-H-quinolizin-4-one-3-~rbox~ylate A solution of 40.61 g (99.2 mmol) of diethyl 2-ethoxy-3-[4-chloro-2-pyridyl]-15 pentane-l,l-dicarboxylate, from Step 3, in 1 L of xylene is heated at 150~C, with stirring, i~or 24 hours and then concenL.a~d in vacuo. The residue is washed with a mixture of hexane and cyclohexane to afford the title compound.

Step 5: Ethyl l-ethyl-8-(4-methylpiperazin-1-yl)-6,7,9-t~ifluoro-4H-quinolizin-4-one-3-carboxylate Ethyl 8-chloro-1-ethyl-6,7,8,9-tetrafluoro-4H-quinolizin-4-one-3-carboxylate (317 mg, 1.0 mmol), from Step 4, is dissolved in 5 mL of dry pyridine under a nitrogen ;ltmosph~re. To the resultant solution is added 2 mL (2.0 mmol) of N-methylpiperazine and the stirred reaction mixture is heated at 85~C for 2.5 hours. The reaction mixture is 25 allowed to cool to ambient ~ pc;~dtule and then conce.~ d in vacuo in order to remove all of the pyridine. The residue is dissolved in 50 mL of methylene chloride and the mlethylene chloride solution is washed with 50 mL of 5% aqueous sodiurn bicarbonate solution. The aqueous layer is extracted with 3 X 50 mL of methylene chloride and the comhine~l methylene chloride solutions are dried over anhydrous sodium sulfate. filtered 30 ;and conce~ d and dried in vacuo ~o afford the title compound.

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W O 96/39407 PCT~US96/08991 Step 6. 1-Ethyl-8-(4-methylpipeld~ 1-yl)-6,7,9-trifluoro-4H-quinolizin-4-one-3-carboxylic acid hydrochloride To a solution of 199 mg (0.5 mmol) of ethyl 1-ethyl-8-(4-nl~lhyll~ip~-d~ yl)-6,7,9-trifluoro-4H-quinolizin-4-one-3-carboxylate, from Step 5, in 4 mL of THF is added s 4.0 mL of a 1.0 N aqueous sodium hydroxide solution and the reaction mixture is heated, with stirring, at 75~C for 4.5 hours. The reaction mixture is cooled to ambient tell~,.dLulc;
and adjusted to pH 2 with 5 mL of 1 N aqueous hydrochloric acid solution. The aqueous solution is concenLldted in vacuo to ~S mL and the solid is collected by filtration and dried in vacuo to afford the title compound.

Fxample 137 8-(3-Amino- 1-1 -pyrrolidinyl)- 1 -ethyl-6,7,9-trifluoro-4H-quinoli7in-4-one-3-n~rboxylic acid hvdrochloride Step 1. Ethyl 8-(3-(N-t-butoxycarbonyl)amino-l-pyrrolidinyl)-l -ethyl-6.7~9-trifluoro-4H-quinoli7in-4-one-3-carboxylate Ethyl 6,7,8,9-tetrafluoro- 1 -ethyl-4H-quinolizin-4-one-3-carboxylate ( 1.26 g, 3.97 mmol), from Step 3 of Example 136, is dissolved in 20 mL of dry pyridine under a nitrogen atmosphere. To the reslllt~nt solution is added a solution of 1.85 g (9.92 mmol) 20 of 3-(N-t-butoxycarbonylamino)pyrrolidine in 5 mL of dry pyridine and the reaction mixture is heated at 70~C for 4.5 hours. The reaction mixture is then concentrated in vacuo in order to remove all of the pyridine. The dry residue (3.124 g) is purified bycll.~",atc,gld~lly on silica gel to afford the title compound.

2s Step 2. 8-(3-Amino- 1 -pyrrolidinyl)- 1 -ethyl-6,7,9-trifluoro-4H-quinoli7in-4-one-3-carboxvlic acid hydrochloride A solution of 1.11 g (2.2 mmol) of ethyl 8-(3-(N-t-butoxycarbonyl)amino- 1-pyrrolidinyl)- l-ethyl-6,7,9-trifluoro-4H-quinolizin-4-one-3-carboxylate, from Step 1, in 20 mL of trifluoroacetic acid (TFA) is stirred for 2 hours at ambient telll~ atule. The TFA
is evaporated in vacuo and the residue is dissolved in 200 mL of methanol. To the resultant solution is added 4.5 g of strongly basic ion exchange resin and the mixture is stirred at ambient temperature for 1 hour. The mixture is filtered and the filtrate is concentrated under reduced p,c;s~ to afford crude ethyl 8-(3-amino- l-pyrrolidinyl)- 1 -ethyl-6,7,9-trifluoro-4H-quinolizin-4-one-3-carboxylate as a residue. The residue is dissolved in 5 mL
3s of THF and 11 mL of a 1 M aqueous solution of sodium hydroxide is added. The reaction -mixture is heated at 60~C for 1 hour and then the reaction ~ ,lllC iS increased to 85~C
in order to evaporate the THF. The conce.,~ ~d reaction solution is diluted with 20 mL of water and the pH of the resultant solution is adjusted to 0 with concentrated hydrochloric acid. The aqueous solution is con(~el~ l~ in vacuo. The residue is crystalli~d from ethyl 5 alcohol:isopropyl alcohol:water (4:4: 1 v/v/v) and recrystallized from ethyl alcohol/water to afford the title compound.
Example 138 1-Fthyl-8-(3-(N-norvalyl)amino-pyrrolidinyl)-4H-quinoli7in-4-one-3-carboxylic acid 3-Amino-l-benzylpyrrolidine (I. Sumio and T. Matsuo, J~panese Kokai JP
5328161, published March 16, 1978) is coupled to N-t-butoxycarbonyl norvaline (Boc-nVal) using conventional N-hydroxysuccinimide coupling procedures. The l-benzyl group is removed by hydrogenolysis in methanol using p~ Aillm on carbon catalyst. The 3-(N-]Boc-norvalyl)aminopyrrolidine is then reacted with ethyl 6,7,8,9-tetrafluoro- 1 -ethyl-4H-quinolizin-4-one-3-carboxylate, as described in Step I of Example 137, replacing 3-(N-t-butoxycarbonylamino)pyrrolidine with 3-(N-Boc-norvalyl)aminopy~Tolidine, to give 1-ethyl-8-(3-(N-norvalyl)amino-pyrrolidinyl)-4H-quinolizin-4-one-3-carboxylic acid with the nitrogen of the amino acid protected with a Boc group. The Boc p~ lg group is r emoved by standard hydrolysis using trifluoroacetic acid and dilute aqueous hydrochloric acid.
Using the procedure outlined in F~c~mpl~ 138, or any of the other conventional conclçn~tiQn methods listed above, other amino acid derivatives of the compounds of this i~nvention having an amino group can be ~ d. Examples of amino acids which can be coupled, either alone or in combination with one and other, include naturally occurring 2s amino acids such as glycine, ~ nine~ leucine, isoleucine, methionine, phenyl7~l~ninç
valine, and the like, as well as synthetic amino acids such as cyclohexyl~l~nin~, cyclohexylglycine, aminopentanoic acid, and the like.
Fxamples 139- 155 By following the procedures described in Example 136 or Example 137 and replacing N-methyl~ ine or 3-(N-t-butoxycarbonylamino)pyrrolidine with the u~liate amine as shown, Examples 139-155 are prepared as disclosed in Table 5 inwhich the compounds have the general formula W O 96/39407 PCT~U~,Ci'~8~1 F~COOH

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W O 96J39407 PCT~US96/08991 Table5 ExamDle No. R2 Example No. R2 139 N--l 148 N'~
~_ NH ~ I~,o 140 ~ ~CH3 149 N~CH2NHCH3 141 ~N 150 N ~ N
142 ~r ~CH3 15 1 ~--NH
CH3 \ CH3 143 N ~CH3 152 N~
~NH ~ CH

144 ~ ~CH2F 153 <~NH
~, NH ~ Cl 145 NIJNH2 ~ 1 54 \ NH2 146 NI~NH2 ~ 155 ~NHET

N--I
, 47 I~,s * The amines are protected and deprotected as described in Example 58 CA 02222322 1997-11-2~

Fxample 156 11,12-Dihydro-7-fluoro-12-methyl-8-(4-methyl-1-piperazinyl)-4H-pyranoriJlquin-olizin-4-one-3-carboxylic acid 5 Step 1. 4-Chloro-3.5-difluoro-2-(1-(2-tetrahydro"yranyl)oxy-2-propyl)~"yridine A solution of 12.8 g (150 mmol) of 2-chloro-1-propanol is dissolved in 200 mL
of acetone. To the resultant solution are added 40 g of anhydrous ferric chloride and 30 g (200 mmol) of sodium iodide. The reaction mixture is stirred at room ~CIIIpt;ld~UlC for 24 hours and then filtered to remove sodium chloride. The solvent is evayu-dLcd to afford the corresponding 2-iodo-1-propanol. The iodo alcohol is dissolved in 200 mL of methylene chloride and is treated with 20.5 mL (225 mmol) of 3,4-dihydro-2H-pyran and 50 mg of p-to]uenes-llfonic acid. The reaction mixture is stirtred atroom Lclllluc;ldLulc for several hours and then poured into 200 mL of 5% aqueous sodium bicarbonate solution. The aqueous mixture is extracted with methylene chloride. The methylene chloride solution is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the THP-ylutc~,Lcd 2-iodo-1-propanol.
A solution of 4-chloro-3,5-difluoro-2-methylpyridine (16.5 g, 100 mmol) in 150 mL of dry THF under a positive nitrogen atmosphere is treated with 73 mL of 1.5 M
lithium dusopropylamine (LDA) at -78~C. After stirring at -78~C for 30 minutes, a solution of 27.0 g (100 mmol) of the THP-ylote~ d l-iodo-2-propanol in 150 mL of THF is added dropwise with stirring. The reaction mixture is stirred at -78~C for several hours and then is slowly warmed to -20~C. The reaction is quenched by pouring the reaction mixture into 400 mL of saturated aqueous arnmonium chloride solution. The aqueous layer is s~ated and extracted with methylene chloride. The combined organic layers are dried over anhydrous sodium sulfate, filtered and concentrated under in vacuo to afford the title compound.

Step 2. 4-Chloro-3.5-difluoro-2-(1-hydroxy-2-propyl)pyridine The product of Step 1 is dissolved in 200 mL of 2: 1 THF:water and to this solution is added 6 mL of acetic acid. The reaction mixture is heated at 45~C for approximately 5 hours. The THF is removed under reduced pressure and the aqueousreaction mixture is adjusted to a pH in the range of 8 to 9 with 10% sodium carbonate and is then extracted with methylene chloride. The organic layer is dried over anhydrous sodiurn sulfate, filtered and concenLl~L~d in vacuo to afford the title compound.

W O 96/39407 PCT~US96/08991 Step 3. 8-Chloro-3~4-dihvdro-7-fluoro-3-methyl-2H-~yranor3.2-blpyridine The product of Step 2 (lS.S g, 75 mmol) is dissolved in 100 mL of dry THF in an oven-dried system under positive nitrogen atmosphere. The reaction mixture is cooled in ice and 3.2 g (80 mmol) of 60% sodium hydride is added. The reaction mixture is warmed to room temperature and then heated at reflux ~,~ dL~I.e overnight with stirring.
The reaction ~ is cooled to room ~~ alulc and poured into brine. The aqueousmixture is extracted with ethyl acetate. The organic layer is dried over anhydrous n-~nesillm sulfalte, filtered and concentrated in vacuo to afford the title compound.

Step 4. Diethyl 2-(8-chloro-3,4-dihydro-7-fluoro-3-methyl-2H-~yranor3.2-blpyridin-4-yl)-2-ethoxy- 1.1 -ethanedicarboxylate Following the procedure described in Step 2 of Example 62, the product of Step 3is treated with ethyl 2-carboethoxy-3-ethoxy-2-propenecarboxylate and LDA to afford the 15 title compound.

Step S. Ethyl 8-chloro-1 1,12-dihydro-7-fluoro-12-methyl-4H-~vranori jl~uin-olizin-4-one-3-~rboxylate Following the procedures described in Step 3 of Example 62, the product of Step 20 4 is heated in refluxing Dowtherm A(!~ to afford the desired cyclized product.

S tep 6. Ethyl 1 1,1 2-dihydro-7-fluoro- 1 2-methyl-8-(4-methyl- 1 -viyerazinyl)-4~-pyranori jlguin-olizin-4-one-3-carboxvlate Following the procedures described in Step I of Example 65, the product of Step 25 5 is reacted with N-methyl~ Gine to afford the title compound.

Sltep 7. 11,12-Dihydro-7-fluoro-12-methyl-8-(4-methyl-1-piperazinvl)-4H-pvranorijl~uin-olizin-4-one-3-carboxylic acid Following the procedures described in Step 2 of Example 65, the tile compound 30 is l"G~,a,t;d.
.

~, ~ , CA 02222322 1997-11-2~

W O 96/39407 PCTrUS9G~ 391 Fxam~lel57 2-(3-Aminopyrrolidin- l-yl)-9-cyclopropyl-3-fluoro-6H-6-oxs-pyridorl.2-alpyrimidine-7-carboxylic acid hydrochloride salt 5 Step 1. 2-Cvclo~ropyl-2-ethoxycarbonylacetamidine hydrochloride Into a stilred solution of 38.72 g (0.253 mol) of ethyl 2-cyano-2-cyclopropylacetate (,u~p~Lion described by R.W.J. Carney and J. Wojtkunski, Org.Prep. Proced. Int., ~i, 25 (1973)) in 17.7 mL (0.303 mol) of anhydrous ethanol under a dry N2 atmosphere was introduced 10.0 g (0.274 mol) of gaseous hydrogen chloride with 10 ice cooling. The mixture was allowed to warm to room L~lnpt;l~Lule and stand for 72 hours. The reaction was diluted with 100 mL of anhydrous ethanol, 70 mL of ammoni~ in ethanol (4.17 M) was added slowly at room temperature and the reaction was stirred for 3 hours. The reaction mixture was filtered to remove the ammonium chloride, and the solvent was removed to afford the title compound as a viscous off-white oil, which was 15 taken directly to the next step.

Step 2. 2-Cyclopropyl-2-(5-fluoro-4-hydroxypyrimidin-2-yl)acetic acid methyl ester and 2-cyclopropyl-2-(5-fluoro-~hy-lroxypyrimidin-2-yl)acetic acid ethyl ester A mixture of 0.253 mol of the compound from Step 1,0.254 mol of the sodium salt of ethyl 2-fluoro-3-hydroxy-2-propenoate (ple~td as described by E. EL'Icik and M.
Imbeaux-Oudotte, Bull. Soc. Chim. Fr., 5-6 pt 2. 1165 (1975)) and 37.0 ml (0.265 mol) of triethylamine in 250 mL of anhydrous methanol was heated at reflux under a dry N2 atmosphere for 17 hours. The solvent was removed, 200 mL of water added and the residue acidified to pH 5 with acetic acid. This mixture was then extracted with methylene chloride. The extract was washed with water, dried over anhydrous m~gnesillm sulfate, and the solvent was removed by evaporation under vacuum to give a dark brown oil. The product was purified by column cl~ullla~ugraphy on silica gel eluting with 1: 1 ethyl ~et~t~-hexane to afford 22.8 g of the methyl ester title colll~oulld as a pale yellow viscous oil and 6.45 g of the ethyl ester title compound as a pale yellow viscous oil.
Methyl ester: MS M/Z: 227 (M+H). NMR (CDC13): d 0.43 (lH, m), 0.52 (IH, m), 0.65 (lH, m), 0.77 (lH, m), 1.42 (lH, m), 2.97 (lH, d, J=10 Hz), 3.80 (3H, s), 7.88 (lH, d, J=3 Hz), 11.8 (lH, b). IR: (neat) 1740, 1690, 1615 cm~l. Analysis calculated for CloHl lFN203-1/4 H2O: C, 52.06; H, 5.02; N, 12.14. Found: C, 52.45;
3~ H, 4.94; N, 11.76.

~0 96/39407 PCT~US9~'~a~31 Ethyl ester: MS MlZ: 258 (M+NH4). NMR (CDCi3): d 0.47 (lH, m), 0.54 (lH, m), 0.66 (lH, m), 0.74 (lH, m), 1.31 (3H, t, J=7 Hz), 1.34 (lH, m), 2.96 (lH, d, J=10 Hz), 4.27 (2H, m), 7.83 (lH, d, J=3 Hz), 11.0 (lH, b): IR: (neat) 1735, 1682, 1605 cm~l. Analysis calculated for Cl lH13FN203-0.3 H20: C, 53.78 H, 5.58; N, s 11.40. Found: C, 54.05; H, 5.59; N, 11.11.

Step 3. 2-Cvclopropyl-2-(5-fluoro-4-hydroxypyrirrudin-2-yl)acetaldehyde To a solution of 4.960 g (21.9 mmol) of the methyl ester compound from Step 2 in 40 mL of toluene stirred at -70~C under a dry N2 atmosphere was added 46.0 mL of lN
10 diisobutylaluminnm hydride in toluene (46 mmol). The reaction was stirred for 40 min and then quenched by the addition of S mL of acetic acid. The mixture was allowed to waIm to room ~e."~ u,c;, and the reaction was extracted with ethyl acetate. The extract was washed with water (3x), dried over anhydrous m~gnecium sulfate and conce~ L~ under vacuum to afford 2.230 g of the title compound as a white solid. This compound was used 15 directly in the next step.
M[S M/Z: 214 (M+NH4). NMR:(CDC13) d 0.48 (m, 2H), 0.91 (m, 2H), 1.35 (m, lH0, 7.40 (d, lH, J=10 Hz), 7.75 (d, lH, J=4 Hz), 9.61 (br s, lH), 13.64 (d, lH, J=10 lHz). IR (KBr) 1695, 1660, 1635 cm~l.

20 Step 4. 9-Cyclopropyl-3-fluoro-2-hydroxy-6H-6-oxo-pyridorl.2-alpyrimidine-7-carboxylic acid benzyl ester A 2.230 g (11.37 mmol) sample of the compound from Step 3 was dissolved in 100 mL of anhydrous ethanol. To this was added 3.5 mL (14.00 mmol) of dibenzyl malonate, 2.5 mL of piperidine and 0.25 mL of acetic acid. This reaction mixture under a 25 dry N~ atmosphere was heated under reflux conditions for 3 hours and stirred at room temperature overnight. The solvent was removed by evaporation, the residue was dissolved in methylene chloride which was washed with water and dried over anhydrous m~gnesium sulfate. The solvent was removed by evaporation under vacuum to give ayellow oil, which was purified by column chlo-..alography on silica gel, eluting with 30 1 :5: 100 acetic ~Cifi m.oth~nol:methylene chloride. Removal of the solvent afforded 1.800 g of the ~itle compound as a pale yellow solid, mp 225.5-226.5~C. MS M/Z 355 (M~H).
- NMR:(CDC13) d 0.64 (m, 2H), 1.08 (m, 2H), 1.62 (m, lH), 5.37 (s, 2H), 7.35-7.48 (rn, 5H[), 8.28 (s, lH), 9.00 (d, lH, J=6 Hz). lR (KBr) 1720, 1700, 1690 cm~l.
Analysis calculated for ClgHlsFN204-1/4 H2O: C, 63.60; H, 4.35; N, 7.81. Found: C, 35 63.54; H, 4.08; N, 7.78.

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W O 96/39407 PCTrUS9~931 Step 5. 2-Chloro-9-cyclopropyl-3-fluoro-6H-6-oxo-pyridorl.2-alp~rimidine-7-carboxylic acid benzyl ester A mixture of 0.200 g (0.564 mmol) of the compound from Step 4, O.S0 mL of DMF, 0.60 mL of phosphorous oxychloride and 10 mL of methylene chloride was stirred S under a dry N2 atmosphere at room t~lllyGlalulG for 4 hours. Ice was added to react with the excess phosphorous oxychloride. The mixture was extracted with methylene chloride, which was washed with water, then the solvent was dried over anhydrous m~,,f~il,,,, sulfate and the solvent was removed by evaporation under vacuum to yield the title compound as an orange residue. This compound was taken directly to the next step.

Step 6. 2-(3-(N-t-butoxycarbonyl)aminopyrrolidin- 1 -yl)-9-cyclopropyl-3-fluoro-6H-6-oxo-pyTidorl~2-alpyrimidine-7-carboxylic acid benzyl ester The 0.564 mmol sample of the compound from the previous step was dissolved in S mL of dry methylene chloride and cooled to 0~C. To this solution was added 0.45 g of lS 3-(N-t-butoxycarbonyl)aminopyrrolidine, and the reaction mixture was stirred at room temperature overnight. The solvent was removed by evaporation under vacuum, and the product was purified by column cluomalography on silica gel, eluting with 10% methanol in methylene chloride to afford 0.295 g of the title compound as a yellow solid, mp 159-160~C. MS M/Z 523 (M+H). NMR:(CDC13) d 0.60 (m, 2H), 0.87 (m, 2H), 1.46 (s, 9H), 1.90-2.40 (m, 2H), 3.70-4.45 (m, SH), 4.94 (br s, lH), 5.37 (s, 2H), 7.29 (m, lH), 7.37 (m, 2H), 7.50 (m, 2H), 7.99 (br s, lH), 9.10 (d lH, J=10 Hz). IR (KBr)1715, 1685, 1660 cm~ 1. Analysis calculated for C2gH31FN4O5- 1/2 H2O: C, 63.44; H, 6.08; N, 10.57. Found: C, 63.39; H, 6.13; N, 10.83.

Step 7. 2-(3-(N-t-butoxycarbonyl)aminopyrrolidin-l-yl)-9-cyclopropyl-3-fluoro-6H-6-oxo-pyridor 1 ~2-al~yrimidine-7-carboxylic acid To a 0.135 g (0.259 mrnol) sample of the benzyl ester from Step 6 in 20 mL of methanol and 2 mL of THF was added 2.0 mL of 98% formic acid and O.OS g of 10%
Pd/C. This mixture was stirred under a dry N2 atmosphere at room ~llly~l~lule for 37 min. The catalyst was removed by filtration, and the solvent was removed under vacuum.
The crude product was purified by column cluulllatography on silica gel, 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 product was taken directly to the next step.

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~0 96/39407 PCTAJS9G~ 931 Step 8. 2-(3-Aminopyrrolidin-l-yl)-9-cyclopropyl-3-fluoro-6H-6-oxo-pyridorl.2-alpyrimidine-7-carboxylic acid hy(lrochloride ~lt The sample of the compound from the previous step was reacted with 10 mL of 4N HCl in dioxane under a dry N2 atrnosphere at room temperature 3 hours. The solvent 5 was removed, the yellow solid was dissolved in distilled water. The yellow solution was filtered and freeze-dried to afford 0.0681 g of the title compound as a yellow solid, mp 234~C, (dec.). MS M/Z 333 (M-Cl). NMR: (CDC13) d 0.64 (m, 2H), 0.96 (m, 2H), 2.20-2.65 (m, 3H), 3.58-4.35 (m, SH), 7.80 (d, lH, J=10 Hz), 9.05 (br s, lH), IR(KBr) 1665, 1620 cm~ 1.

Fxample 158 2-(3-Aminopyrrolidin- 1 -yl)-9-cyclopropyl-3-fluoro-6H-6-oxo-~vridorl.2-alpyrimidine-7-carboxylic acid Step 1. 9-Cyclopropyl-3-fluoro-2-hydroxy-6H-6-oxo-pyridorl.2-alpyrimidine-7-carboxylic acid t-butyl ester A 0.247 g (1.262 mmol) sample of 2-cyclopropyl-2-(5-fluoro-4-hydroxypyrimidin-2-yl)acet~l(lehyde, from Example 157 Step 3 above, was dissolved in 20 mL of ethanol, and 0.290 mL of ethyl t-butyl malonate, 0.5 mL of piperidine and 0.05 mL of acetic acid were added. The reaction was heated under a dry N2 atmosphere at reflux for 25 hours, the solvents were removed by evaporation and the product was purif~ed by column chru-~-a~ugraphy on silica gel, eluting with 1: 10: 100 acetic ~ri(l m~th~nol methylene chloride. Removal of the solvent afforded 0.287 g of the title compound as a pale yellow solid, mp >265~C. MS M/Z 321 (M+H). NMR: (CDC13 +
CD3OD) d 0.61 (m, 2H), 1.06 (m, 2H), 1.58 (s, 9H), 1.72 (m, IH), 8.07 (s, lH), 8.93 (d, lH, J=6 Hz). IR (KBr)1720, 1525 cm-l.

Step 2. 2-Chloro-9-cyclopropyl-3-fluoro-6H-6-oxo-pyridorl.2-alpyrirnidine-7-carboxylic acid t-butyl ester A mixture of 0.100 g (0.312 mmol) of the compound from Step 1, 0.29 mL of DMF, 0.33 mL of phosphorous oxychloride and 10 mL of methylene chloride was stirred under a dry N2 atmosphere at room ~"",~.~ture for 1 hour. After workup as described in Example 157 Step 5, the title compound was obtained as a orange solution in methylene chloridle. This compound was taken directly to the next step.

CA 02222322 1997-11-2~

WO 96/39407 PCTAU~9f'~991 Step 3. 2-(3-(N-t-buto~y~al bonyl)aminopyrrolidin- 1 -yl)-9-cyclopropyl-3-fluoro-6H-6-oxo-pyridor 1.2-alpyrimidine-7-carboxylic acid t-butyl ester To the 0.312 mrnol sarnple in methylene chlnri-le from the previous step at roomly~,~dLulG was added several small portions of 3-(N-t-butoxycarbonyl)arninopyrrolidine s until the color of the reaction turned from orange to light yellow. The solution was concentrated to leave a yellow residue. The product was purified by column chlul~lal~graphy on silica gel, eluting with 10:100 methanol: methylene chloride to afford 0.132g of the title compound as a yellow solid after removal of the solvent. This compound was taken directly to the next step.

Step 4. 2-(3-aminopyrrolidin- 1 -yl)-9-cyclopropyl-3-fluoro-6H-6-oxo-pyridorl~2-alpyrinlidine-7-r~rboxylic acid The boc-protected t-butyl ester from Step 4 was hydrolyzed by reacting the 0.132g sample with 1 mL of 4N HCl in dioxane under a dry N2 atmosphere . The solvent was removed, the yellow solid was dissolved in water and the solution adjusted to pH 7-8, and extracted with methylene chloride. The reaction was incomplete at this point, so the solid was redissolved in S mL of trifluoroacetic acid and the reaction stirred at room LGll~y.,,aLLllG
overnight. The solvent was removed by evaporation. The residue was redissolved and extracted as above, then the product was purified by column ~-I.-ol-laLugraphy on silica gel, eluting with 2:5:20:100 water:acetic ari~ metll~ncll:methylene chloride to afford 0.0515 g of the title compound as a yellow solid.
.

F.xamRle 159 9-(2,4-Difluorophenyl)-3-fluoro-2-(4-methylpil)c.~ - l-yl)-2s 6H-fi-ûxopvridorl~2-alpvrimidine-7-carboxylic acid Step 1. 2-(2.4-Difluorophenyl)-acetamidine h~vdrochloride Into a solution of 49.44 g (0.323 mol) of 2,4-difluorophenylacetonitrile (col,l",elcially available) in 20.8 mL (0.354 mol) of ethanol cooled to 0~C in an ice bath and stirred under a dry N2 atmosphere was added 14.61 g (0.400 mol) of gaseous HCl. After 20 min the reaction mixture solidified, this was then allowed to warrn to room LGIllpcldtlllG
and held at this ~c~ Je~dLulG for 72 hours. To the mixture was then added 140 mL of ethanol, followed by 150 mL (0.42 mol) of 4.2 M ammonia in ethanol. This mixture was stirred for an :~Aditi~n~l 3 hours at room temperature and filtered. The solvent was removed from the filtrate by evaporation to afford 65.7 g of the title compound as a white solid, mp 163-164~C. NMR: (DMSO-d6) d 3.72 (s, 2H), 7.16 (m, lH), 7.33 (m, lH), 7.50 (m, lH), 8.95 (broad, 4H). This compound was taken directly to the next step.

Step 2. 2-(2.4-D;fluorobenzyl)-5-fluoro-4-hydroxypyrimidine S A mix LLI1G of 68.0 g ( 0.33 mol) of the compound from Step 1, 0.34 mol of the sodiurn salt of ethyl 2-fluoro-3-hydroxy-2-propenoate (p-c~c;d as described by E. ELcik and M. rm~e~llx-Oudotte, Bull. Soc. Chim. ~r., 5-6 ~t 2. 1165 (1975)), 300 mL ofanhydrous meth~nnl and 50 mL of triethylamine was heated at reflux under a dry N2 atmosphere for 23 hours. The solvent was removed by evaporation under vacuum, 200 0 mL of water added and the m~xture ~idifie~ to pH 3-4 with 10% HC1. This rnixture was then extracted with methylene chloride. The solvent was washed with water, dried over anhydrous rn~g-.esi--.-- sulfate, and the solvent was removed by evaporation under vacuum to give a dark oil which solidified upon st~n-lin~ The solid was washed with ethyl acetate, e~hyl acetate/hexane and hexane to af~ord 29.8 g of the title compound as a white solid, mp 1S 155-156~C. A second crop of 10.2 g of product was obtained from the filtrates after clL~ .Ia~lgraphy on silica gel, eluting with 2.5% methanol in methylene chloride. MS M/Z:
2S8 (M=NH4), 241 (M+H). NMR: (CDC13) d 4.02 (s, 2H), 6.88 (m, 2H), 7.33 (m, lH), 7.89 (d, lH, J=3 Hz). IR (KBr): 1690, 1605 cm -1. Analysis calculated for C11H7F3N2O: C, 55.00; H, 2.94; N, 11.67. Found: C, 54.63; H, 2.98; N, 11.50.
S tep 3. 4-Chloro-2-t2.4-difluorobenzyl)-5-fluoropvrimidine A mixture of 1.000 g (4.16 mmol) of the compound from Step 2, 3.40 mL (43.7 mmol) of DMF and 3.90 mL (43.7 mmol) of phosphorous oxychloride in 15 mL of methylene chloride was stirred under a dry N2 atmosphere at ambient Ltil~ ulc for 2 hours, then q~l~nrhed with water and ice. The mixture was then extracted with methylene chloride, which was washed with water, dried, filtered and concentrated to yield the title compound as a yellow oil. MS M/Z: 259 (M+H). NMR: (CDC13) d 4.27 (s, 2H), 6.83 (m, 2H), 7.27 (m, lH), 8.48 (s, lH). This compound was taken directly to the next step.

Scep 4. 2-(2.4-Difluorobenzvl)-5-fluoro-4-(4-methylpiperazin-1-yl)pyrimidine To the 4.16 mmol of the compound from Step 3 in 10 mL of methylene chloride was added 3 mL of N-methylpiperidine and the mixture was stirred under a dry N2 atmosphere at room ~ lp~,ldLule for 1 hour. The solvent was removed by evaporation, and the product was purified by column clll~,lllaLography on silica gel eluting with ~% meth~n()l CA 02222322 1997-11-2~

W O 96/39407 PCT~US96/08991 in methylene chloride. The solvent was removed by evaporation to afford 1.229 g of the title compound as a pale yellow oil, MS M/Z: 323 (M+H). NMR: (CDC13) d 2.32 (s, 3H), <, 2.46 (t, 4H, J+7 Hz), 3.75 (t, 4H, J=7 Hz), 4.05 (s, 2H), 6.80 (m, 2H), 7.25 (m, lH), 7.99 (d, lH, J=7 Hz). Analysis calculated for C16H17F3N4: C, 59.61; H, 5.32; N, 17.38. Found: C, 59.63; H, 5.31; N, 17.31.
Step 5. 3-(2,4-Difluorophenyl)-2-ethoxy-3-(5-fluoro-4-(4-methylpiperidin-I-yl)vyrimitlin-2-yl)yro~ane-1.1-di~zlrboxvlic acid diethyl ester Following the procedure of Step 4 Example 1 the compound from Step 4 above (0.74 g, 2.3 mmol), 1.0 mL (2.5 mmol) of a 2.5 M solution of n-butyllithium in hexane and 0.35 mL of diisopropylamine was reacted with 0.46 mL ethyl 2-carboethoxy-3-ethoxy-2-propenecarboxylate, to afford after work-up 1.22 g of the title compound as an oil. This material was further purified by column chlo,l,aLography over silica gel, eluting with 5%
ethanol in ethyl acetate to give 0.774 g of an oil; MS M/Z: 539 (M+H). NMR: (CDC13) d 0.87 (m, 3H), 1.22 (m, 6H), 2.34 (s, 3H), 2.50 (m, 4H), 3.52 (m, 2H), 3.81 (m, 4H), 4.16 (m, 5H), 4.82 (m, lH), 4.99 (m, lH), 6.78 (m, 2H), 7.59 (m, lH), 8.01 (m, lH).

Step 6. 9-(2,4-Difluorophenyl)-3-fluoro-2-(4-methyl~ipc.d~ - l-yl)-6H-6-oxopvridorl.2-alpyrimidine-7-carboxylic acid ethyl ester To a 1.847 g (3.43 mmol) sample of the compound from Step 5 dissolved in 40 mL of anhydrous ethanol was added 1.5 mL of piperidine and 0.05 mL of acetic acid, and the reaction was heated at reflux conditions under a dry N2 atmosphere for 3 hours. The solvent was removed by evaporation to leave a yellow solid which was purified by column chromatography over silica gel, eluting with 0.5:10:100 28% aq.
NH40H:methanol:methylene chloride to afford after removal of the solvent 1.282 g of the title compound as a yellow solid, mp 193-195~C. MS M/Z: 447 (M+H). NMR: (CDC13) d 1.40 (t, 3H, J=7 Hz), 2.33 (s, 3H), 2.50 (m, 4H), 3.89 (m, 4H), 4.39 (q, 2H, J=7 Hz), 6.91 (m, 2H), 7.33 (m, lH), 8.37 (s, lH), 9.16 (d, lH, J=10 Hz). lR (KBr): 1725, 1685, 1660 cm~l. Analysis calculated for C22H21F3N4O3-0.5 H2O: C, 58.02; H, 4.87; N, 12.30. Found: C, 58.15; H, 4.70; N, 12.15.

Step 7. 9-(2,4-Difluorophenyl)-3-fluoro-2-(4-methyl~ip~,ld,in- l-yl)-6H-6-oxopyridorl.2-al~yrimidine-7-carboxylic acid benzyl ester A mixture of a 1.166 g (2.61 mmol) sample of the ethyl ester compound from Step 1, 150 mL of d~y benzyl alcohol and 0.5 mL of titanium tetramethoxide was heated -.
WO 96/39407 PCT~US9~'C~931 under a dry N2 atmosphere with sti;ling at reflux conditions for 17 hou;s. The solvent was removed by ~ till~tion at 100~C under reduced ~ S~uuc in a kugelrohr ay~ us.The product was purified by colurnn chromatography on silica gel, eluting with 0.5:10:100 28% aq. NH40H:methanol:methylene chloride to afford after removal of the solvent 0.895 ~ 5 g of the title compound as a yellow solid, mp 207-208~C. MS M/Z: 509 (M+H). NMR:
~CDCl3) d 2.33 (s, 3H), 2.50 (m, 4H), 3.88 (m, 4H), 5.38 (s, 2H), 6.90 (m, 2H), 7.30-'7.50 (m, 6H), 8.37 (s, lH), 9.17 (d, lH, J=10 Hz). IR (KBr): 1730, 1685, 1660 cm~l.
$tep 8. 9-(2,4-Difluorophenyl)-3-fluoro-2-(4-methylpiperazin- 1 -yl)-6H-6-oxopyridorl.2-alpyrimidine-7-carboxylic acid A 0.300 g (0.590 mmol) sample of the benzyl ester from Step 7 was dissolved in 40 mL of dry methanol and 0.1 g of 10% Palladium on carbon was added. Four mL of98% formic acid was added and the rnixture stirred under a dry N2 atmosphere for 20 min.
I'he catalyst was removed by filtration through ~ tom~ceous earth, and the solvent was removed under vacuum. The product was purified by column ~;lllulllalcgraphy on silica gel, eluting with 1:10:100 acetic aci~ r~ ol:methylene chloride give a yellow solid.
This material was washed with pH 7.5 sodium bicarbonate solution, followed by water inse ~:o afford 0.178 g of the title compound as a yellow solid, mp 246-248~C (dec.). MS
419 (M+H). NMR: (CDC13 + CD30D) d 2.34 (s, 3H), 2.53 (m, 4H), 3.85-4.00 (m, 4H), 6.90 (m, 2H), 7.32 (m, lH), 8.49 (s, lH), 9.07 (d, lH, J=9 Hz). IR (lKBr):
]L720, 1660 cm~1. Analysis calculated for C20H17F3N4O3: C, 57.42; H, 4.10; N, 13.39.
E~ound: C, 57.21; H, 4.08; N, 13.21.

Fxample 160 2-(3-(N-t-butoxycarbonyl)aminopyrrolidin- l-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyridorl.2-alpyrimidine-7-carboxylic acid Step 1. 3-(2,4-Difluorophenyl)-2-ethoxy-3-(5-fluoro-4-hydroxypyrimidin-2-yl)propane-1.1-dicarboxylic acid diethyl ester A 4.804 g (20.0 mmol) sample of 2-(2,4-Difluorobenzyl)-5-fluoro-4-hydroxypyrimidine (pl~,pa,~d as described in Step 2 Example 159 above) was dissolved in 150 mL of dry THF and cooled to -78~C with stirring under a dry N2 atmosphere. To this was slowly added 16.40 mL of 2.5 N n-butyllithium in hexane, and the mixture was stirred for 30 min. Then 4.85 mL (24 mmol) of diethyl ethoxymethylenemalonate was added and 35 the mixture stirred for an additional 30 nin at -78~C. The reaction mixture was quenched with 10% HCl until the mixture was at pH 3, wllGlGu~lon it was then extracted with ethyl W O 96/39407 PCT~US9~ 9 acetate. This was dried over anhydrous magnesium sulfate and the solvent was removed by evaporation under vacuum to afford the title compound as a yellow oil. This m~t.o.ri~l was taken directly to the next step.

Step 2. 9-(2,4-Difluorophenyl)-3-fluoro-2-hydroxy-6H-6-oxopyridorl.2-alpyrimidine-7-calboxylic acid ethyl ester The compound from Step 1 was dissolved in 80 ml of ethanol, 2 mL of piperidine and 0.2 mL of acetic acid was added and the mixture heated at reflux (bath ~~ dt~ ; at 90~C) for 16 hours under a dry N2 atmosphere. The solvent was removed by evaporation, and the residue was washed with methanol and methylene chloride to give 4.794 g of a pale yellow solid. The washings were conce.ltld~ed and the residue was purified by column chlum;l~ography on silica gel, eluting with 2: 10: 100 acetic acid:methanol:methylene chloride to afford an additional 2.220 g of the title compound as a pale yellow solid, mp 239-240~C. MS M/Z: 382 (M+NH4), 365 (M+H). NMR:(DMSO-d6) d 1.23 (t, 3H, J=7 Hz), 4.14 (q, 2H, J=7 Hz), 7.08 (m, lH), 7.21 (m, lH), 7.40 (m, lH), 7.83 (s, lH), 8.74 (d, lH, J=8 Hz). ~R (KBr) 1710, 1675, 1620 cm~l.

Step 3. 9-(2,4-Difluorophenyl)-3-fluoro-2-hydroxy-6H-6-oxopyridolrl.2-al~yrimi-linP-7-carboxylic acid benzyl ester To a 7.000 g sample of the ethyl ester compound from Step 2 dissolved in 200 mL of benzyl alcohol was added 0.70 mL of ~ ,i..l" tetraethoxide and the mixture heated with stirring at 100~C fûr 2.5 hours under a dry N2 atmosphere. The reaction was diluted with methylene chloride, then washed once with 1 N HCl and three times with water, and the solvent was dried over anhydrous m~gneSillm sulfate and removed by evaporation 2s under vacuum to leave a yellow solid. This m~t~ri~l was washed with ether and dried under vacuum to afford 6.655 g of the title compound as a yellow solid, mp 218-219~C.
MS M/Z 427 (M+H). NMR:(DMSO-d6) d 5.26 (s, 2H), 7.15-7.45 (m, 8H), 8.00 (s, lH), 9.00 (d, lH, J=7 Hz). IR (KBr) 1710, 1675, 1620 cm~l.

Step 4. 2-(3-(N-t-butoxycarbonyl)aminopyrrolidin-l-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyridorl.2-alpyrimidine-7-carboxvlic acid benzyl ester A 1.200 g (2.815 mmol) sample of the compound from Step 3 was dissolved in !t 45 mL of methylene chloride and 2.50 mL of DMF and 2.95 mL of POCl3 were added.
The reaction was stirred under a dry N2 atmosphere at room temperature for 2.5 hours, 3s then qu~nch~-d with ice and water. The mixture was extracted with methylene chloride, and the solvent was washed with water until the acidity of the rinse water was above pH 3.
The solvent was then dried with m~gne~ m sulfate and an excess of 2-(N-t-..
butoxycarbony-lamino)pyrrolidine was added and allowed to react. The solution was then concenLIdL~;;d and the product was purified by column ~;hlumalography over silica gel eluting with 0.5:5: 100 conc. ~mmnnillm hydroxi~e-methanol:methylene chloride. The solvent was removed to afford 1.579 g of the title compound as a light yellow crystalline solid, mp 103-104~C. MS M/Z: 595 (M+H). NMR: (CDC13) d 1.45 (s, 9H), 1.85-2.30 ~m, 2H), 3.42-4.35 (m, SH), 4.65 (br s, lH), 5.38 (s, 2H), 6.89 (m, 2H), 7.30-7.50 (m, 6H), 8.35 (s, lH), 9.15 (d, lH, J=9 Hz), 9.16 (d, lH, J=9 Hz). IR (KBr): 1735, 1710, 1660 cm~1.

Step 5. 2-(3-(N-t-butoxycarbonyl)aminopyrrolidin- 1 -yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxo~yridorl.2-al~ynmidine-7-carboxylic acid A 1.769 g sample of the compound from Example 160 Step 4 was dissolved in 80 mL of dry methanol, and the benzyl ester was removed by reacting with 4.0 mL of 98%
~ormic acid in the presence of 0.200 g of 10% Pd/C under a dry N2 atmosphere . After Eiltration and evaporation of the solvent, the product was purified by column ~-hlullla~ography on silica gel, eluting with 1:10:100 acetic z3~i~ m~th~nol met~ ylene chlnride to afford, after removal of the solvent, 1.125 g of the title compound as a yellow solid, mp 209.5-210.5~C. MS M/Z: 505 (M+H). NMR: (CDC13/CD30H) d 1.45 (s, 9H), 1.90-2.30 (m, 2H), 3.50-4.35 (m, 5H), 6.91 (m, 2H), 7.32 (m, lH), 8.44 (s, lH), 9.03 (d, lH, J=8 Hz), 9.04 (d, lH, J-8 Hz). IR (KBr): 1714, 1662, 1620 cm~l.

Fxarrll?le 161 2-(3-Arninopyrrolidin- I -yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopvridorl~2-alpyrimirline-7-carboxvlic acid ,..
A 0.100 g, (0.198 mmol) sample of 2-(3-(N-t-butoxycarbonyl)-aminopyrrolidin-I-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylic acid, ~rom Example 160 Step 5, was dissolved in a small volume of 4 N HCl in dioxane and stirred at room L~ cld~ulci for 3 hours under a dry N2 atmosphere. The solvent was removed by evaporation under vacuum to yield a yellow solid, which was dissolved in water and neutralized to pH 7 with 5% sodium bic~bon~Le solution. The resulting ~l~,ci~uiLdte was filtered off, washed with water and dried to afford 0.075 g of the title 3s compound as a yellow solid, mp >250~C. MS M/Z: 405 (M+H). NMR: (DMSO) d 1.90-:2.30 (m, 2H), 3.00-4.10 (m, 5H), 7.16 (m, 2H), 7.30 (m, lH), 8.18 (s, lH), 9.17 (d, -CA 02222322 1997-11-2~

WO 96/39407 PCT~US96,'~89~1 lH, J=8 Hz), 9.18 (d, lH, J=8 Hz). IR (KBr): 1715, 1660 cm~l. Analysis calculated for ClgH15F3N4O3-1.25 H2O: C, 53.46; H, 4.07; N, 13.12. Found: C, 53.64; H, 3.70;
N, 12.80.

Example 162 2-(3-Aminopyrrolidin- 1 -yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyridorl.2-alpyrimidine-7-carboxylic acid trifluoroacetic acid salt A 0.879 g (2.174 mmol) sample of 2-(3-aminopyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrirnidine-7-carboxylic acid, from Example 161, was dissolved in 10 mL of trifluoroacetic acid, then the excess acid was removed by evaporation under vacuum. The yellow residue was dissolved in 600 mL of water with cont~ining 1 mL of trifluoroacetic acid, the solution was filtered through sintered glass and freeze dried to afford 0.876 g of the title compound as a light yellow solid; mp 191-192~C (dec.). MS M/Z: 405 (M+H). NMR (CD30H): a 2.102.55 (m, 2H), 3.75-4.20 (m, 5H), 7.05 (m, 2H), 7.50 (m, lH), 8.30 (s, lH), 9.19 (d, lH), J=8 Hz). IR (KBr): 1720, 1660, 1620 cm~l. Analysis calculated for C21H16F6N4~5-H20:
C, 47.02; H, 3.38; N, 10.45. Found: C, 47.36; H, 3.07; N, 10.36.

F~mple 163 9-Cyclopropyl-3-fluoro-2-(4-methylpiperazin- l-yl)-6H-6-oxo-pyridor l 2-alpyrimidine-7-carboxylic acid Step 1. 2-Chloro-9-cyclopropyl-3-fluoro-6H-6-oxo-pyridorl.2-alpyrimidine-7-carboxylic acid benzyl ester To a 0.100 g (0.282 mmol) sample of 9-cyclopropyl-3-fluoro-2-hydroxy-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylic acid benzyl ester, prc~ d as described in l~xample lS7 Step 4, was added 5 mL of methylene chloride, 0.275 mL of DMF and 0.33 mL of phosphorous oxychloride, and the reaction was stirred S hours at room temperature 30 under a dry N2 atmosphere. The solution was cooled to 0~C, and ice was added to destroy the excess phosphorous oxychloride. This mixture was then extracted with methylene chloride which was dried over anhydrous magnesium sulfate The solvent was removed by evaporation under vacuum to afford the title compound as an orange solid. NMR (CDCl3):
d 4.27 (s, 2H), 6.83 (m, 2H), 7.27 (m, 2H), 8.48 (s, lH). This material was taken 35 directly to the next step.

V~O 96/39407 PCT~US96/08991 Step 2. 9-Cyclopropyl-3-fluoro-2-(4-meth~ yl)-6H-6-oxo-p,vridor 1.2-alpvnmidine-7-carboxylic acid benzvl ester The compound from the previous step was dissolved in 2.5 mL of methylene chloride and 0.5 mL of N-methylpi~ e was added with cooling. The reaction was 5 stirred at room L~ urG overnight. The solvent was removed by evaporation and the product was purified by column cll,onlaLugraphy on silica gel, eluting with 10% meth~nol in methylene chloride. The solvent was removed to afford 0.107 g of the title compound as a yellow solid. Recryst~lli7~tion from methanol gave yellow needles, mp 194-195~C. MS
M/Z 437 (M+H). NM[R:(CDC13) d 0.62 (m, 2H), 0.88 (m, 2H), 2.12 (m, lH), 2.57 (s,3H), 2.~9 (t, 4H, J=7 Hz), 4.07 (t, 4H, J=7 Hz), 5.38 (s, 2H), 7.28 (m, lH), 7.36 (m, 2H), 7.51 (m, 2H), 8.04 (s, lH), 9.16 (d, lH, J=10 Hz). IR (KBr): 1715, 1685, 1660 cm~l. Analysis calculated for C24H2sFN4O3-1/4 H2O: C, 65.37; H, 5.83; N, 12.70.
Pound: C, 65.21; H, 5.53; N, 12.59.

1~ S,tep 3. 9-Cyclopropyl-3-fluoro-2-(4-methyl~ ,.d~ -1-yl)-6H-6-oxo-pyridorl.2-al~yrimidine-7-carboxylic acid To a 0.050 g (0.115 mmol) sample of the benzyl ester compound from the previous step was added 10 mL of methanol, 1 rnL of 98% formic acid and 0.04 g of 10%
Pd/C, and the mixture was stirred under Argon for 30 min at room temperature. The 20 solution was diluted with methylene chloride, filtered through fli~t~m~reous earth and the sDlvent was removed to leave a yellow residue. The product was purified by column chromatography on silica gel, eluting with 1: 10: 100 acetic ~Ci~l m~th~nol:methylene chloride. After removal of the solvent, 0.0345 g of the title compound was obtained as a yellow solid, mp 219-220~C. MS M/Z 347 (M+H). NMR:(CDC13) d 0.67 (m, 2H), 0.95 (Im, 2H), 2.18 (m, lH), 2.39 (s, 3H), 2.65 (t, 4H, J=6 Hz), 4.13 (m, 4H), 8.11 (s, lH), 9.02 (d, lH), J=10 Hz). IR (KBr): 1720, 1660, 1620 cm~l. Analysis calculated iFor C17HlgFN4O3-0.6 CH3COOH: C, 57.17; H, 5.64; N, 14.65. Found: C, 57.60; H, 5.79; N, 14.13.

CA 02222322 1997-11-2~

W O 96/39~07 PCTrUS96~ 31 F.xample 164 9-Cyclopropyl-3-fluoro-2-(piperazin- 1-yl)-6H-6-oxo-pvridorl~2-al~yrimidine-7-carboxylic acid Step 1. 2-Chloro-9-cyclopropyl-3-fluoro-6H-6-oxo-pyridor1.2-alpyrimidine-7-carboxylic acid t-butyl ester A mixture of 0.100 g (0.312 mmol) of 9-cyclopropyl-3-fluoro-2-hydroxy-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylic acid t-butyl ester from Example 158 Step 1, 0.29 mL of DMF, 0.33 mL of phosphorous oxychloride and 10 mL of methylene chloride was stirred under a dry N2 atmosphere at room temperature for 1 hour. After workup as described in Example 157 Step 5, the title compound was obtained as a orange solution in methylene chloride, which was taken directly to the next step.

Step 2. 9-Cyclopropyl-3-fluoro-2-(piperazin- 1 -yl)-6H-6-oxo-pvridorl.2-al~,~vrimidine-7-carboxylic acid t-butyl ester The sample from Step 1 in 5 mL of methylene chloride was added dropwise to a solution of 0.289 g pi~c;l~ine in 10 mL of methylene chloride stirred under a dry N2 atmosphere. The resulting yellow solution was concentrated to give a yellow residue, which was purified by column chlullla~ugraphy on silica gel, eluting with 0.5: 10: 100 conc. ammoninm hydroxide:meth~nol mPthylene chll~ricle, to afford after removal of the solvent 0.068 g of the title compound as a yellow solid. This m~tf ri,.l was taken directly to the next step.

Step 3. 9-Cyclopropyl-3-fluoro-2-(piperazin- 1 -yl)-6H-6-oxo-~ yridorl.2-al~yrimiriin~-7-carboxylic acid The sample of the compound from the previous step was reacted with 10 mL of 4N HCl in dioxane under a dry N2 atmosphere at room ~ Jt;lalulc; overnight. The solvent was removed, the yellow solid was dissolved in distilled water, adjusted to pH 7-8 with saturated sodium carbonate solution, and the solution extracted with methylene chloride.
The extracts were washed with water, dried, concentrated, and ~,I.,~,Il,atographed on silica gel to afford 0.043 g of the title compound as a yellow solid, mp 198-199~C. MS M/Z 333 (M+H). NMR:(CDC13) d 0.67 (m, 2H), 0.94 (m, 2H), 2.19 (m, lH), 3.08 (t, 4H, J=6 "
Hz), 4.08 (m, 4H), 8.11 (s, lH), 9.01 (d, lH, J=10 Hz). IR (KBr): 1710, 1660 cm~l.
Analysis calculated for C16H17FN4O3-0.1 H2O: C, 57.36; H, 5.20; N, 16.72. Found:C, 57.69; H, 5.22; N, 16.31.

UIO 96/39407 PCTrUS96/08991 Fxam~ple 165 9-Cyclopropyl-3-fluoro-2-(morpholin- 1-yl)-6H-6-oxo-~yridorl.2-alpyrimid~e-7-carboxylic acid -~ 5 Step 1. 9-Cyclopropyl-3-fluoro-2-(morpholin-1-yl)-6H-6-oxo-pvridorl~2-al~yrimidine-7-carboxylic acid benzyl ester To a 0.150 g (0.396 mmol) sample of 2-chloro-9-cyclopropyl-3-fluoro-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylic acid benzyl ester, pl~,pal~l as in Example 164 Step 1, dissolved in anhydrous methylene chloride and cooled to 0~C and stirred under a dry N~ atmosphere was added 0.042 mL (0.483 mmol) of morpholine dropwise. The color changed from orange to yellow, and the reaction was complete in 15 min. The solvent was removed by evaporation, and the product was purified by column chromatography on silica gel, eluting with 2:10:100 acetic ~ l m~thanol:methylene chloride. The solvent was removed to afford the title compound as a yellow solid. This was taken directly to the next step. NMR:(CDC13) d 0.62 (m, 2H), 0.89 (m, 2H), 2.11 (m, lH), 3.87 (t, 4H), J=6 Hz), 4.07 (t, 4H, J=6 Hz), 5.39 (s, 2H), 7.29 (m, lH), 7.37 (m, 2H), 7.51 (m, 2H), 8.07 (s, lH), 9.19 (d, lH, J=10 Hz).

Step 2. 9-Cyclopropyl-3-fluoro-2-(morpholin- 1-yl)-6H-6-oxo-pyridorl.2-alpyrimidine-7-~rboxy'lic acid The benzyl ester product from the previous step was dissolved in 20 mL of anhydrous methanol and stirred with 0.020 g of 10% Pd/C catalyst under 1 atm. Hydrogen at room ~e ~ dLulc for S hours. The catalyst was removed by filtration, and the solvent was removed under vacuum to afford 0.100 g of the title compound as a yellow solid, mp >260~C. MS M/Z 334 (M+H). NMR:(CDC13) d 0.68 (m, 2H), 0.95 (m, 2H), 2.19 (m, lH), 3.90 (t, 4H, J=6 Hz), 4.10 (t, 4H, J=6 Hz)., 8.15 (s, lH), 9.06 (d, lH, J=10 Hz).
IR 1720, 1660, 1620 cm~l. Analysis calculated for C16H16FN3O4-H2O: C, 54.70; H, S.16; N, 11.96. Found: C, 55.01; H, 4.71; N, 11.62.

CA 02222322 1997-11-2~

~xample 166 9-(2,4-Difluorophenyl)-3-fluoro-2-(3-(N-(S)-norvalyl)aminopyrrolidin- 1 -yl)-6H-6-oxopyridorl.2-alpyrimidine-7-carboxylic acid hydrochloride salt Step 1. 2-(3-Aminopyrrolidin-l-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxo~yridorl.2-alpyrimidine-7-carboxylic acid benzyl ester A 1.579 g (2.655 mmol) sample of the 9-(2,4-difluorophenyl)-3-fluoro-2-(3-(N-t-butoxycarbonyl)aminopyrrolidin- 1 -yl)-6H-6-oxopyrido[ l ,2-a]pyrimi~iin~-7-carboxylic acid benzyl ester, from Example 160 Step 4, was dissolved in 5 mL of trifluoroacetic acid and stirred at room temperature for 1 hour under a dry N2 atmosphere. The solvent was removed by evaporation under vacuum to yield the d~,u~ecL~d title product as a yellow solid, which was taken directly to the next step. Mp 185-186~C. NMR (CDC13): d 1.75-2.19 (m, 2H), 3.33-4.07 (m, SH), 5.38 (s, 2H), 6.87 (m, 2H), 7.32 (m, 4H), 7.48 (m, 2H), 8.33 (s, lH), 9.13 (~paltint d, lH, J=9 Hz).
Step 2. 2-(3-(N-(N-Benzyloxycarbonyl)norvalyl)aminopyrrolidin-l-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyridorl.2-alpvrimidine-7-carboxylic acid benzyl ester The sample from the previous step was suspended in 50 mL of THF and diisopropylethylamine was added with stirring at room ltlllp.,ldlulc until a homogeneous solution resulted. Then 0.885 g (2.66 mmol) of the N-benzyloxycarbonyl protected (s)-norvaline succin~mirle was added and stirred at room k;lll~)~,ld~lllt; for 1 hour under a dry N2 atrnosphere. Another 0.050 g of the protected norvaline was added, and the solution was stirred for another 0.5 hours. The reaction was diluted with methylene chloride, washed with water (4x), and the organic solvent dried over anhydrous m~gnecium sulfate and removed by evaporation under vacuum. This product was purified by column u~a~ography on silica gel, eluting with 5% methanol in methylene chloride, to afford 1.678 g of the title compound as a yellow crystalline solid after removal of the solvent. Mp 103-105~C. MS M/Z: 728 (M+H). NMR: (CDC13) d 0.90 (t, 3H, J=7 Hz), 1.39-2.30 (m, 6H), 3.30-4.40 (m, SH), 4.85-5.40 (m, SH), 6.75-7.40 (m, 13 H), 8.15-8.80 (m, 2H). IR (KBr): 1700, 1660 cm~l. Analysis calculated for C3gH36F3N5O6-0.25 H20:
C, 63.97; H, 5.02; N, 9.56. Found: C, 64.19; H, 5.11; N, 9.50.

CA 02222322 l997-ll-25 W 0 96/39407 PCT~US96/08991 Step 3. 9-(2,~Difluorophenyl)-3-fluoro-2-(3-(N-(S)-norvalyl)aminopyrrolidin- 1-yl)-6H-6-oxopvridol l.2-al~vnmidine-7-carboxy'~ic acid hydrochlonde salt A 1.515 g sample (2.0822 mmol) sample of the compound from the previous step was dissolved in 80 mL of methanol, and 4.0 mL of 98% for nic acid and 0.2 g of 10%
J Pd/C was added. The mixture was stirred at room temperature for 1.7 hours under a dry N2 atmosphere, filtered and conce~ d~ed to leave a yellow solid residue. Tnis solid was dissolved in methanol and filtered through sintered glass, then the solvent was removed to leave a yellow solid. This solid was dissolved in 50 mL of m~th~nol, 3 mL of conc. HCI
was added and the solvent evaporated off. The residue was dissolved in 200 rnL of water, filtered again through sintered glass, and the solution was freeze-dried to afford 0.969 g of ~e title product as a yellow solid, mp 192-194~C. MS MlZ: 504 (M+H). NMR: (CD30D) d 0.96 (m, 3H), 1.90-2.35 (m, 6H), 3.50-4.60 (m, SH), 7.02 (m, 2H), 7.48 (m, lH), 8~22 (br s, lH), 8.35 (br s, 2H), 9.09 (m, lH). IR (E~Br): 1710, 1665, 1610 cm~l.
A.nalysis calculated for C24H2sF3NsO4-2 H2O: C, 50.05; H, 5.07; N, 12.16. Found:C, 50.00; H, 4.56; N, 12.03.

FY~m~le 167 2-(3-(N-(S)-Alanyl)aminopyrrolidin- 1 -yl)-9-(2,4-difluuioph~nyl)-3-fluoro-6H-6-oxopyridorl.2-alpyrimidine-7-carboxylic acid hvdrochloride Step 1. 2-(3-(N-(N-Benzyloxycarbonyl)alanyl)aminopyirolidin-1 -yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[ l ,2-alpy~midine-7-carboxylic acid benzyl ester A 0.982 g (1.986 mrnol) sample of 9-(2,4-difluorophenyl)-3-fluoro-2-(3-aminopyrrolidin-l-yl)-6~I-6-oxopyrido[1,2-a]pyrimi-lin~-7-carboxylic acid benzyl ester, prepared as described in Example 166 Step 1, was suspended in 40 mL of THF and 0.700 g (2.196 mmol) of the N-benzyloxycarbonyl protected (S)-alanine succin~mi~e was added.The mixture was stirred at room temperature for 2 hour under a dry N2 atmosphere.
'l'he reaction solvent was evaporated off, then the residue was dissolved in methylene chloride, which was washed with water (3x). The organic solvent was dried over anhydrous m~ ci..." sulfate and removed by evaporation under vacuum. This product was purified by column chlu",a~ugraphy on silica gel, eluting with 5% methanol in methylene chloride, to afford, after removal of the solvent, 1.318 g of the title compound as a yellow crystalline solid, mp 104- 107~C. MS M/Z 700 (M+H). NM[R: (CDC13) d 1.43 (m, 3H), 1.95-2.30 (m~ 2H), 3.40-4.40 (m, 5H), 4.75-5.35 (M, 5H), 6.77 (m, 2H), ~, W O 96/39407 PCT~US9'/~ a~ 1 7.10-7.40 (m, lH), 8.18-8.40 (m, 2H). IR (KBr): 1720, 1660 cm -1. Analysis calculated for C37H32F3N5O6-1/2 H2O: C, 62.71; H, 4.69; N, 9.88. Found: C, 63.04; H, 4.49;
N, 9.92 Step 2. 2-(3-(N-(S)-Alanyl)aminopyrrolidin-l-yl)-9-(2,4-difluuluphenyl)-3-fluoro-6H-6-oxopyridorl.2-alpyrimidine-7-carboxylic acid hydrochloride A 1.262 g (1.804 mmol) sample of the compound from the previous step was suspended in 80 mL of methanol and 4.0 mL of 98% formic acid and 0.200 g of 10% Pd/C
was added with stirring. The mixture was stirred at room temperature for 1.7 hours, then 40 ml of THF was added and the mixture stirred for 0.3 hours longer under a dry N2 atmosphere, filtered and concentrated to leave a yellow solid residue. This was dissolved in 500 mL of water and 4 mL of conc. HCl was added, then the solution was filtered through sintered glass and freeze-dried to afford 0.877 g of the title compound as a yellow solid, mp 198-200~ C (dec). MS M/Z476 (M-Cl). NMR: (DMSO-d6) d 1.33 (ap~a,tllt 1S t, 3H, J=7 Hz), 1.90-2.30 (m, 2H), 3.35-4.40 (m, 6H), 7.17 (m, lH), 7.32 (m, lH), 7.58 (m, lH), 8.20 (d, lH), 9.19 (m, lH), 13.45 (br, lH). IR (KBr): 1715, 1665, 1620 cm~ 1. Analysis calculated for C22H21 ClF3NsO4~ 1.5 H2O: C, 49.03; H, 4.48; N, 12.99. Found: C, 49.18; H, 4.17; N, 12.53.

Example 168 2-(3-(N-(S)-Alanyl-(S)-alanyl)aminopyrrolidin- l-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyridorl.2-alpyrimidine-7-carboxylic acid hydrochloride Step 1. 2-(3-(N-(N-Benzyloxycarbonyl)-(S)-alanyl-(S)-alanyl)aminopyrrolidin- 1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyridorl.2-alpyrimidine-7-carboxylic acid benzyl ester A 0.905 g (1.830 mmol) sample of 9-(2,4-difluorophenyl)-3-fluoro-2-(3-aminopyrrolidin-l-yl)-6H-6-oxopyrido[1,2-a]pyrimi~ine-7-carboxylic acid benzyl ester, plG~Gd as described in Example 166 Step 1, was suspended in 10 mL of DMF and 0.700 g (2.196 mmol) of the N-benzyloxycarbonyl p,ote~;lGd (S)-alanyl-(S)-alanine. The mixture was stirred at 0~C and 0.530 g of 1-ethyl-3-[3-dimethylaminopropyl]carbodiumide hydrochloride (EDAC) and 0.370 g of l-hydroxybenzotriazole hydrate (HOBT) was added. The mixture was stirred for 30 min at 0~C, then at room temperature for 2 hours.
The solvent was removed in a kugelrohr apl~al~us, then the residue was dissolved in methylene chloride, washed 2x with water, washed 2x with saturated sodium bicarbonate solution. then 2x again with water and dried over m~gnç~ rn sulfate. The solvent was W O 96~9407 PCTrUS96/08991 removed by evaporation, and the product was purified by column ~ u~atography on silica gel, eluting with 10% methanol in methylene chloride to afford 1.187 g of the title product asyellowcrystals,mpl23-126~C. MSM/Z771(M+H). NMR:(CDC13) d 1.37(m, 6H), 1.92-2.18 (m, 2H), 3.58-4.48 (m, SH), 4.76-5.00 (m, 2H), 5.30 (s, 2H), 5.32 (s, ,'H), 6.80 (m, 2H), 7.10-7.45 (m, lH), 8.23 and 8.30 (two s, lH), 8.87 and 8.93 (two d, 1 H,J=8Hz). IR(KBr): 1720, 1660cm~1. AnalysiscalculatedforC40H37F3N607-1/2 E~2O: C, 61.62; H, 4.91; N, 10.78. Found: C, 61.51; H, 4.71; N, 10.75.

Step 2. 2-(3-(N-(S)-Alanyl-(S)-alanyl)aminopyrrolidin- 1 -yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-~-oxopyr~dorl.2-alpyrimidine-7-carboxylic acid hydrochloride A 1.131 g (1.467 mmol) sample of the compound from Step 1 was dissolved in 80 mL of m~tll~nol and 4.0 mL of 98% formic acid and 0.2 g of 10% Pd/C was added.
l'he mixture was stirred 1 hour at room ~ lL)eldLulc under a dry N2 atmosphere, filtered, and conce~ al-;l to leave a yellow residue. This was dissolved in 500 mL of ~ led water and 3 mL of conc. HCl was added, then the solution was filtered though sintered glass, and freeze-dried to afford 0.729 g of the title compound as a pale yellow solid, mp 217-21L9~C (dec). MS M/Z 547 (M-Cl). NMR: (DMSO-d6) d 1.24 (m, 3H), 1.32 (d, 3H, J=7 Hz), 1.80-2.20 (m, 2H), 3.40-4.50 (m, 7H), 7.17 (m, lH), 7.31 (m, lH), 7.57 (m, lH), 8.20 (br, 4H), 8.47 (m, lH), 8.66 (m, lH), 9.19 (m, lH), 13.45 (br, lH). IR
(KBr): 1710, 1660, 1630 cm~l.

FY~mple 169 2-((2S,4S)-4-~cet~ 1o-2-methylpyrrolidin- 1 -yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopvridorl.2-a~ yrimidine-7-~rboxvlic acid S tep 1. 2-((2S,4S)-4-Acet~mi~- -2-methylpyrrolidin- 1 -yl)-9-(2,4-D difluoru~hel-yl)-3-fluoro-6H-6-oxopyrido[1,2-alpyrimidine-7-carboxvlic acid benzvl ester A 0.200 g (0.469 mmol) sample of 9-(2,4-difluorophenyl)-3-fluoro-2-hydroxy-6H-6-oxopyrido[1,2-a]pyrimiriine-7-carboxylic acid benzyl ester, from Example 160 Step 3, was dissolved in 5 mL of methylene chloride and 0.42 mL of DMF and 0.49 mL ofPOC13 were added. The reaction was stirred under a dry N2 atmosphere at room d~ ; for 3.5 hours, then quenched with ice and water. The rnixture was extracted- 35 with methylene chloride, and the solvent was washed with water until the acidity of the rinse water was above pH 3. The solvent was then dried with magnesium sulfate and 0.120 g (0.656 mmol) of (2S,4S)-4-acet~misk~-2-lllc;tllyl~yrrolidine (~ ,d as described CA 02222322 1997-11-2~

W O 96/39407 PCT~US96/08991 by Rosen, T., et al., J. Med. Chem., ~, 1598-1611 (1988)) in 10 mL of methylene chloride and 2 mL of triethylamine was added and allowed to react. The solution was then ,.
concellLIdted and the product was purified by column cl~olllatography over silica gel eluting with 1:10:100 acetic acid:methanol:methylene chloride. The solvent was removed to afford 0.205 g of the title compound as yellow crystals, mp 117-119~C. [a]=-122.6~
(25~C, D, c=0.05, CHC13). MS M/Z 551 (M+H). NMR: (CDC13) d 1.10 (d, 3H, J=7 Hz), 1.85-2.25 (m, 2H), 2.10 (s, 3H), 4.05 (m, 2H), 4.23 (m, lH), 4.80 (m, IH), 5.06 (d, lH, J=13 Hz), 5.27 (d, lH, J=13 Hz), 6.79 (m, 2H), 7.20-7.40 (m, 6H), 7.76 (br, lH), 8.21 (s, lH), 8.80 (d, lH, J=9 Hz). IR (KBr): 1725, 1660 cm~1. Analysis 10 calculated for C2gH2sF3N4O4-H2O: C, 61.26; H, 4.79; N, 9.85. Found: C, 61.59; H, 4.37; N, 9.72.

Step 2. 2-((2S,4S)-4-Acet~mido-2-methylpyrrolidin- 1 -yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxo~yridorl~2-alpyrimidine-7-carboxylic acid To a 0.198 g (0.359 mmol) sample of the compound from Step l in 20 mL of methanol was added 1 mL of 98% formic acid and 0.1 g of 10% Pd/C. The mixture was stirred at room lelll~ ture under a dry N2 atmosphere for 1.25 hours. The rnixture was filtered, and the filtrate conc~ L~d to leave a yellow residue. The product was purified by column c}~o,l,a~ography on silica gel, eluting with 1: 10: 100 acetic aciA mtqth~nol:methylene chloride to afford 0.126 g of the title compound as a yellow solid, after removal of the solvent, mp 163-164~C. [a]=-50.2~ (23~C, D, c=0.5, CHCl3). MS M/Z 461 (M+H).
NMR: (CDC13 + CD30D) d 1.09 and 1.39 (two d, 3H, J=6 Hz), 1.92-2.15 (m, 2H), 2.00 (s, 3H), 3.97 (m, lH), 4.16 (m, lH), 4.32 (m, lH), 4.72 (m, lH), 6.90 (m, 2H), 7.25 (m, lH), 8.17 and 8.31 (two s, lH), 8.93 and 8.97 (two d, lH, J=8 Hz). IR (KBr):
1720, 1660, 1035 cm~l. Analysis calculated for C22HlgF3N4O4-H2O: C, 55.23; H, 4.42; N, 11.71. Found: C, 55.25; H, 4.20; N, 11.21.

Exa~le 170 9-(2,4-Difluorophenyl)-3-fluoro-2-(3-hydroxypyrrolidin- 1 -yl)-6H-6-oxopyridorl.2-alpvrimidine-7-carboxylic acid Step l. 9-(2,4-Difluorophenyl)-3-fluoro-2-(3-hydroxypyrrolidin-1-yl)-6H-6-oxopyridorl.2-a~yrimidine-7-carboxylic acid benzyl ester A 0.200 g (0.469 mmol) sample of 9-(2,4-difluorophenyl)-3-fluoro-2-hydroxy-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylic acid benzyl ester, from Example 160 Step 3, was dissolved in 5 mL of methylene chloride and 0.42 mL of DMF and 0.49 mL of W 0 96/39407 PCTrUS~ra991 POCl3 were added. The reaction was stirred under a dry N2 atmosphere at room ~c~ a~ule for 3.5 hours, then quenched with ice and water. The mixture was ex~racted with methylene chloride, and the solvent was washed with water until the acidity of the Iinse water was above pH 3. The solvent was then dried with m~gne~ rn sulfate and 0.1 s rnL of 3-pyrrolidinol was added and allowed to react. The solution was then concellll~d aLnd the product was purified by colu nn cl~ull~a~ugraphy over silica gel eluting with 1:10:100 acetic acid:methanol:methylene chloride. The solvent was removed to afford 0.183 g of the title compound as yellow crystals, mp 105-107~C. MS M/Z 496 (M+H).
NMR: (CDC13) d 2.00-2.16 (m, 2H), 3.55-3.68 (m, 2H), 3.96-4.16 (m, 2H), 4.18 and4.55 (m, lH), 5.36 and 5.38 (two s, 2H), 6.90 (m, 2H), 7.30-7.48 (m, 6H, 8.33 (s, lH), 9.08 and 9.14 (two d, lH, J=6 Hz). IR (KBr): 1725, 1690, 1660 cm~l. Analysis calculated for C26H20F3N3o4-3/4 H2O: C, 61.36; H, 4.26; N, 8.26. Found: C, 60.97;
H, 3.67; N, 7.98.

Step 2. 9-(2,4-Difluorophenyl)-3-fluoro-2-(3-hydroxypyrrolidin-1-yl)-6H-6-oxopyridorl.2-alpyrirnidine-7-carboxylic acid To a 0.166 g (0.334 mmol) sample of the compound from Step 1 in 20 mL of rn~th~nol and 15 mL of DMF was added 2 mL of 98% formic acid and 0.12 g of 10%
Pd/C. The mixture was stirred at room le-llpela~ under a dry N2 atmosphere for 1.33 2û hours. The mixture was filtered, and the filtrate conce,~ ~d, removing the DMF in a k.ugelrohr ~,u~lus, to leave a yellow residue. The product was purified by column cll~u~alugraphy on silica gel, eluting wi~ l: 10: 100 acetic ;~ci~l m~th~nol:methylene chloride to afford 0.088 g of the title compound as a yellow solid, after removal of the solvent, mp 168- 170~C (dec). MS M/Z 406 (M+H). NMR: d 2.00-2.15 (m, 2H), 3.55-3.70 (m, 2H), 3.97-4.12 (m, 2H), 4.50-4.60 (m, lH), 6.93 (m, 2H), 7.35 (m, lH), 8.43 (s, lH), 9.01 and 9.04 (two d, lH, J=4 Hz). IR (KBr): 1715, 1665, 1625 cm~l.
Analysis calculated for ClgH14F3N3O4-1/2 H2O: C, 55.08; H, 3.65; N, 10.14. Found:
C, 55.10; H, 3.53; N, 10.04.
Fxample 171 2-((2S,4S)-4-An~ïno-2-methylpyrrolidin- 1 -yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyridorl.2-alpyrimidine-7-carboxylic acid hydrochloride Step 1. (2S.4S)-4-acetamido-2-methylpyrrolidine A 6.000 g (24.760 mrnol) sample of (2S, 4S)-4-acetamido-1-(t-butoxy-3s carbonyl)-2-methylpyrrolidine, prepared as described by Rosen, T., et al., J. Med. Chem., CA 02222322 1997-11-2~

W O 96/39407 PCT~US96/08991 31, 1598- 1611 (1988~, was dissolved in 3Q mL of 4N HCl in dioxane and stirred at room y~ tul~ for 24 hours to remove the boc group. The solvent was removed by evaporation to give the hydrochloride salt of this compound as a white solid, which was .
taken directly to the next step.
S
Step 2. (2S. 4S)-4-acetamido-1-benzyl-2-n.~lllylyyllulidine This salt from the previous step was suspended in 27 mL of methylene chloride, 8.4 mL of triethylamine was added and the mixture stirred for 10 min. Next was added 3.2 mL (26.9 mmol) of benzyl bromide and the mixture heated at reflux for 5 hours. The 10 mixture was diluted with methylene chloride, which was washed 3x with water, dried over m~gn~ m sulfate, and evaporated to leave the l-benzyl ploLe~;led ~;on-~ou--d as a white solid, which was taken directly to the next step.

Ste~ 3. (2S. 4S)-4-amino-1-benzyl-2-methyhpyrrolidine hydrochloride The acetyl group was removed from the compound from the previous step by heating at reflux for 6 hours in 6N HCl. Removal of the solvent gave the solid product which was taken directly to the next step.

Step 4. (2S. 4S)- 1 -benzvl-4-t-butoxycarbonylamino-2-methylpyrrolidine The sample from the previous step was dissolved in 10 mL of water and 35 mL
of methanol. To this solution stirred at 0~C was added 5.2 mL of triethylamine and 4.21 g of di-t-butyl dicarbonate. The reaction was stirred for 2 hours at 0~C and then at room temperature for 19 hours. The solvent was removed by evaporation, the residue dissolved in methylene chloride, which was washed with water and concentrated. The product was purified by column chromatography on silica gel, eluting with 0.5:5: 100 conc. ammoniurn hydroxiden~blllanol:methylene chloride to give the title compound as a white solid after removal of the solvent. This material was taken directly to the next step.

Ste~ 5. (2S. 4S)-4-t-butoxycarbonylamino-2-methylpyrrolidine The sample from the previous step was dissolved in 150 mL of methanol, 0.90 g of 10% Pd/C was added and the mixture shaken under 4 atm of hydrogen at room le~ ; for 13 hours. The mixture was concentrated, the catalyst was removed by filtration, and the solvent removed to afford 3.081 g of the title compound as a white solid.

WO 96/39407 PCTAJS9G~'G8 MS M/Z 201 (M+H). NMR (CDC13): d 1.15 (d, 3H, J=6 Hz), 1.44 (s, (H), 1.54-1.63 ~m, 2H), 1.75 (m, lH), 2.64 (dd, lH, J=5, J=12 Hz), 3.26 (m, lH), 3.38 (dd, lH, J--7, J=12 Hz), 4.12 (br, lH), 4.63 (br, lH). IR (KBr): 1685 cm~l.

$tep 6. 2-((2S,4S)-4-t-butoxycarbonylamino-2-methylpyrrolidin- l -yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6~oxopyridorl.2-alpyrimidine-7-carboxylic acid benzyl ester A 1.500 (3.518 mmol) sample of 9-(2,4-difluorophenyl)-3-fluoro-2-hydroxy-6H-6-oxopyrido[1,2-a]pyrimi~line-7-carboxylic acid benzyl ester, from Example 160 Step 10 3, was dissolved in 40 mL of methylene ~hll~ri~l~ and 3.20 înL of DMF and 3.70 mL of ]POC13 were added. The reaction was stirred under a dry N2 atmosphere at room ul~ for 2.25 hours, then quen~hecl with ice and water. The rnixture was extracted with methylene chloride, and the solvent was washed with water until the acidity of the rinse water was above pH 3. The solvent was then dried with m~gnecillm sulfate and 1.06 15 g (0.656 mmol) of (2S,4S)-4-t-butoxycarbomylamino-2-methylpyrrolidine, from Step 5 above, in 50 rnL of methylene chlori~1e and 7 mL of triethylamine was added and allowed to reac~ The solution was then concentrated and the product was pulirled by column cluulllalography over silica gel eluting with 0.5:10:100 conc. ~oul~olliulll hydro~ le ~ nol methylene chloride. The solvent was removed to afford 1.856 g of the 20 r,itle compound as yellow crystals, mp 106-107~C. [a]=+13.4 (23~, D, c=0.5, CH[C13).
MS M/Z 609 (M[+H). NMR: (CDC13) d 1.11 (two d, 3H, J=7 Hz), 1.45 and 1.55 (two s, 9H), 1.90-2.10 (m, 2H), 3.60-4.60 (m, SH), 5.39 (s, lH), 6.89 (m, 2H), 7.34-7.50 (m, 6H), 8.34 and 8.36 (two s, lH), 9.16 and 9.19 (two d, lH, J=9 Hz). IR (KBr): 1715, 1690, 1660 cm~1. Analysis calculated for C32H31F3N4Os-1/2 H2O: C, 62.23; H, 5.22;
25 'N, 9.07. Found: C, 62.44; H, 5.20; N, 9.16.

Step 7. 2-((2S ,4S)-4-Amino-2-nnethylpyrrolidin- 1 -yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopvridorl.2-alpyrimidine-7-carboxylic acid To a 1.814 g (2.981 mmol) sample of the compound from Step 6 dissolved in 80 30 mL olF methanol and 10 mL of THF was addled 8 mL of 98% formic acid and I g of 10%
Pd/C. The mixture was stirred at room temperature under a dry N2 atmosphere for 2.3 hours. The mixture was filtered, and the filtrate conct;~ dted to leave a yellow residue.
The product was purified by column clllonla~ography on silica gel, eluting with 1: 10: 100 - acetic acid:methanol:methylene chloride to afford 1.513 g of the title compound as a yellow 35 solid, after removal of the solvent. The compound was taken directly to the next step.
r CA 02222322 1997-11-2~

WO 96/39407 PCTrUS96iG~931 Step 8. 2-((2S ,4S)-4-Amino-2-methylpyrrolidin- 1 -yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyridorl.2-alpyrimidine-7-carboxylic acid hy-lrochloride The 1.528 g sample of the compound from the previous step was dissolved in 20 mL of 4N HCl in dioxane and stirred at room temperature for 3.5 hours. The solvent was 5 removed, the residue redissolved in 500 mL of water, 0.5. mL of conc. HCl was added, and the solution freeze-dried to afford 1.147 g of the title compound as a yellow solid, mp 204~C (dec). [a]=+35.4~ (22~C, D, c=0.5, CH30H). MS M/Z 419 (M-Cl). NMR:
(CD30D) d 1.16 and 1.41 (two d, 3H, J=7 Hz), 2.15-2.31 (m, 2H), 3.75-4.40 (m, 4H), 7.04 (m, 2H), 7.46 (m, lH), 8.25 and 8.30 (two s, lH), 9.11 and 9.21 (two d, lH, J=9 Hz). IR (KBr): 1710, 1660, 1630 cm~l. Analysis calculated for C20H18F3CIN4O3-H2O: C, 50.80; H, 4.26; N, 11.85. Found: C, 50.98; H, 4.10; N, 11.85.
Example 172 2-(3-Aminopyrrolidin- 1 -yl)-3-fluoro-9-(2,3,4,5,6-pentafluorophenyl)-6H-6-oxopyridorl.2-alpyrimidine-7-carboxylic acid hydrochlonde salt Step 1. 2-(? ~.4.5.6-Pentafluorophenvl)-acetamidine hvdrochloride Into a solution of 26.72 g (0.129 mol) of pentafluoroace~ul.iL,;Ie (~;u~ln~ cially available) in 8.30 mL of anl.ydlo~ls ethanol cooled to 0~C and stirred under a dry N2 atmosphere was introduced gaseous HCl, until the mixture solidified. The reaction was allowed to stand for 96 hours, then 60 mL of ethanol and 30.7 mL of 4.2 N HCl in ethanol (0.124 M) was added, and the slurry was stirred at room temperature for 2 hours. The mixture was filtered through sintered glass, and the filtrate was concentrated under vacuum to afford the title compound as a brownish solid, which was taken directly to the next step.
Step 2. 5-Fluoro-4-hydroxy-2-(2.3.4.5.6-pentafluorobenzyl)pyrimidine A mixture of the compound (0.129 mol) from Step 1, 0.135 mol of the sodium salt of ethyl 2-fluoro-3-hydroxy-2-propenoate (plcpa ed as described by E. ELlcik and M.
Imbeaux-Oudotte, Bull. Soc. Chim. Fr., 5-6 pt 2~ 1165 (1975)), 150 mL of anhydrous methanol and 25 mL of triethylamine was stirred under a dry N2 atmosphere for 24 hours.
The solvent was removed by evaporation under vacuum and the residue was dissolved in methylene chloride and washed (lx) with 10% HCl and (lx) with water, then dried over anhydrous m~gn~cium sulfate, and the solvent was removed by evaporation under vacuum to give a dark oil which solidified upon st~n-ling This solid was washed with 1 :2 ethyl acetate:hexane to afford 4.843 g of the title compound as a white solid, mp 161-162~C.

VVO 96/39407 PCT~US96/08~1 The filtrate was concentrated and extracted with 1:4 ethyl acetate:hexane to leave a second crop of 4.454 g of product. Additional product was obtained by cl.r~,.naLography of the r esidue,foratotalyieldofl9.20gofproduct. MSM/Z312(M+NH4). NMR(CDC13):
d 4.15 ~a~ Gn~ s, 2H), 7.80 (d, lH, J=3 Hz), 13.38 (br s, lH). IR (KBr): 3440, 1685, 1660, 1610 cm~l .

Step 3. 2-Ethoxy-3-(5-fluoro-4-hydroxy-3-(2,3,4,5,6-pentafluorophenyl)propane- 1. I -dicarboxylic acid diethyl ester The compound from Step 2 above (0.294 g, 1.00 mmol) was dissolved in 10 mL
10 of THF and cooled to -78~C with stirring, then 0.82 mL (2.05 mmol) of a 2.5 M solution of n-butyllithium in hexane was added and the resulting yellow solution was stirred for 30 ~mn. To this was added 0.243 mL ( 1.2 mmol) of ethyl 2-carboethoxy-3-ethoxy-2 propenecarboxylate with stirring for 15 rnin. The reaction was quenched with 10% HC1, allowed to warm to room te~ cl~Lule and extracted with ethyl acetate. The extract was washed (2x) with brine, and the solvent dried over m~gnesil-m sulfate and concentrated to afford the title compound as an oil, which was ta'Ken directly to the next step.
Step 4. 9-(2,3,4,5,6-pe..li1fhlorophenyl)-3-fluoro-2-hydroxy-6H-6-oxopyridorl.2-alpyrimidine-7-carboxvlic acid ethyl ester The compound from Step 3 above was dissolved in 10 mL of ethanol, 0.2 mL of conc. sulfuric acid was added and the solution was heated at reflux for 18 hours. The solvent was removed and the residue washed with ether to afford 0.222 g of the title compound as a yellow solid, mp 235-236C. MS M/Z 419 (M+H), 436 (M+NH4). IR
(E~Br): 3440 (br), 1710, 1680, 1615 cm~l. NMR (CDC13) d 1.38 (t, 3H), J=7 Hz), 4.37 2~ (q, 2H, J=7 Hz), 8.23 (s, lH), 9.05 (d, lH, J=6 Hz).

Step 5. 3-Fluoro-2-hydroxy-9-(2,3,4,5,6-pentafluorophenyl)-6H-~-oxoDyridorl.2-alpyrimidine-7-carboxylic acid benzyl ester A 1.000 g (2.391 mmol) sample of the compound from Step 4 was dissolved in 25 mL of benzyl alcohol, 0.09 rnL of tit~ninm tetraethoxide was added and the mixture was slirred at 90~C for 20 hours. The reac~on was diluted with methylene chloride, washed (lx) with 10% HCl and concentrated in a rotary evaporator. The crude product waspurified in a kugelrohr a~palaLus to yield a yellow solid, which was washed with ether and , dried to afford 0.457 g of the title compound, which was taken directly to the next step.

- 1~3-CA 02222322 1997-11-2~

WO 96/39407 PCT~US96J05~1 Step 6. 2-(3-(N-t-Butoxycarbonyl)aminopyrro'~idin- 1 -yl)-3-fluoro-9-(2,3,4,5,6-pentafluorophenyl)-6H-6-oxopyridorl~2-alyyrimidine-7-carboxylic acid benzyl ester A 0.400 g (0.833 mmol) sample of the compound from Step 5 was dissolved in ~, s 10 mL of methylene chloride and 0.746 mL of DMF, and 0.870 mL of POC13 were added and stirred under a dry N2 atmosphere at room temperature for 1.7 hours. The reaction was quenched with ice and the mixture çxtr~ct~d with methylene chloride which was washed (2x) with water. The organic layer was added to a stirred solution of 0.235 g (1.2 mmol) of 2-(N-t-butoxycarbonylamino)pyrrolidine in 4 mL of triethylamine. The solvent was removed by evaporation, and the product was purified by column chlu-,la~ography on silica gel, eluting with 2.5: 100 methanol:methylene chloride . Removal of the solvent afforded 0.353 g of the title product as a yellow crystalline solid, mp 107-108~C. MZ M/Z
649 (M+H). NMR (CDC13) d 1.44 (s, 9H), 1.90-2.30 (m, 2H), 3.40-4.65 (m, SH), 5.38 (s, 2H), 7.35 (m, 3H), 7.48 (m, 2H), 8.34 (s, lH), 9.14 and 9.1S (two d, lH, J=9 Hz).

Step 7. 2-(3-(N-t-Butoxycarbonyl)aminopyrrolidin-1-yl)-3-fluoro-9-(2,3,4,5,6-pentafluuluvhe,lyl)-6H-6-oxopyridorl.2-alpvrimidine-7-~rboxylic acid A 0.335 g ( 0.516 mmol) sample of the compound from Step 6 was dissolved in 40 mL of dry methanol, and the benzyl ester was removed by reacting with 2.0 mL of 98%
formic acid in the presence of 0.100 g of 10% Pd/C, stirring under a dry N2 atmosphere for Ø25 hours. After filtration and evaporation of the solvent, the product was purified by column cluu--.a~ography on silica gel, eluting with 1: lS: 100 acetic acill meth~nol:methylene chloride to afford, after removal of the solvent, the title compound as a yellow solid, which was taken directly to the next step.

Step 8. 2-(3-Aminopyrrolidin- 1 -yl)-3-fluoro-9-(2,3,4,5,6-pentafluorophenyl)-6H-6-oxopyridorl.2-a~vnmidine-7-carboxylic acid hydrochloride C:~lt The compound from the previous step was dissolved in 10 mL of 4 N HCl in dioxane and stirred at room temperature for 0.7 hours, after which the solvent was removed under vacuum. The residue was dissolved in water which was filtered through sintered glass and freeze-dried to afford 0.232 g of the title compound as a yellow solid, mp 202-204~C. MS M/Z 459 (M-Cl). l~MR (CD30D): d 2.12-2.54 (m, 2H), 3.70-4.36 (m, SH), 8.42 (s, lH), 9.21 (d, lH, J=9 Hz). IR (KBr): 1715, 1660, 1630 cm~l.

-- l44 CA 02222322 1997-11-2~

W O 96139407 PCT~US9~"~931 A,nalysis calculated for ClgH12F6N403-HCl-O.SH20: C, 45.30; H, 2.80; N, 11.12.
Found: C, 45.46; H, 2.39; N, 10.57.
Example 173 ~? 5 2-((2S, 4S)-4-(N-(S)-Alanyl-(S)-alanyl)amino-2-methylpyrrolidin- I -yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyridorl.2-alpyrimidine-7-carboxylic acid hydrochloride S-tep 1. 2-((2S,4S)-4-amino-2-methylpyrrolidin-1-yl)-9-(2,4-difluorophenyl)-0 3-iluoro-6H-6-oxopyridorl.2-alpyrimidine-7-carboxylic acid benzyl ester Following the procedure described in Example 166 Step 1, replacing the boc-protected benzyl ester compound with a 2.345 mmol sample of 2-((2S,4S)-4-t-butoxycarbonylamino-2-methylpylrolidin- 1 -yl)-9- (2,4-difluorophenyl)-3 -fluoro-6H-6-oxopyrido[1,2-a~pylirrudine-7-carboxylic acid benzyl ester, from Example 171 Step 6, the 15 boc protecting group was removed to afford 1.06 g of the title compound.

Scep 2. 2-((2S,4S)-4-(N-(N_Benzoyloxycarbonyl)-(S)-alanyl-(S)-alanyl)amino-2-me~hylpyrrolidin- 1 -yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyridorl~2-alpyrimidine-7-carboxylic acid benzyl ester Following the procedure of Exarnple 168 Step 1, replacing the benzyl ester compolmd of that example with 1.06 g of the compound from Step 1 above, 0.98 g of the title compound was ~lep~ed.

Step 3. 2-((2S, 4S)-4-(N-(S)-Alanyl-(S)-alanyl)amino-2-methylpyrrolidin- 1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyridor 1 ~2-alpyrimidine-7-carboxylic acid hydrochloride Following the procedure of Example 168 Step 2, replacing the boc-protected be:nzyl ester compound of that example with the compound fiom Step 2 above, 0.66 g of the title compound was L~l~ P~- Mp 198-200~C. MS M/Z 561 (M-Cl). NMR (CD30D):
d 1.14 and 1.40 (two d, 3H, J=7 Hz), 1.34 and 1.35 (two d, 3H, J=7 Hz), 1.50 and 1.51 (two d, 3H, J=7 Hz), 1.96-2.11 (m, 2H), 3.50-4.60 (m, 6H), 7.40 (m, 2H), 7.47 (m, IH), 8.26 and 8.29 (two s, IH), 9.12 and 9.16 (two d, lH, J=9 Hz).

CA 02222322 1997-11-2~

WO 96/39407 PCT~US96/~8991 Fx~n~le 174 9-(2,4-Difluorophenyl) -3 -fluoro-2-hydroxy-4-methyl-6H-6-oxopyridorl.2-al~yrinlitline-7-carboxylic acid ethyl ester Ste~ 1. 2-(2.4-Difluorobenzyl)-5-fluoro-4-hydroxy-6-methylpvrimi-lin~
A mixture of 8.6 g (0.0445 mmol) of 2-(2,4-difluorophenyl)-~et~mi-line hydrochloride, L,.G~ued as in Example 159 Step 1, and 6.1 g (0.0405 mmol) of ethyl 2-fluoro-3-oxo-butanoate (prepared as described by E. O. Beiglnallll, S. Cohen, and I.
Shahak, J. Chem .Soc.., 3278 (1959)), in 30 mL of anhydrous meth~nol and 10.1 mL of a 2.5% solution of sodium methoxide was heated at reflux under a dry N2 atmosphere for 16 hours. The solvent was removed by evaporation under vacuum, and the residue was washed with water, then 200 mL of water added and the mixture was acidified and the resulting ~u,~il,i~t; was filtered off. The aqueous solution was then extracted (3x) with methylene chloride. The solvent was washed with water, dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation under vacuurn to give a dark solid. The solid was washed with ethyl ether and dried, then combined with the earlier l,l~i~i~t~ which was recrystalli~d from methanol:ether to afford 4.51 g of the title compound. MS M/Z 272 (M+NH4). NMR: (CDC13) d 2.22 (d, 3H, J=4 Hz), 3.92 (s, 2H), 6.92 (m, 2H), 7.30 (m, lH).
Step 2. 3-(2,4-Difluorophenyl)-2-ethoxy-3-(5-fluoro-4-hydroxy-6-methyl~yrimidin-2-yl)~ropane- l .1 -dicarboxylic acid diethyl ester A 0.615 g (2.42 mmol) sample of the compound from Step 1 above was dissolved in THF and cooled to -78~C with stirring under a dry N2 atmosphere. To this was slowly added 1.98 mL of 2.5 N n-butyllithium in hexane, and the mixture was stirred for 30 min. Then 0.586 mL (2.9 mmol) of diethyl ethoxymethylenemalonate was added at -78~C and the mixture stirred for an additional 15 min at room ~",~w~ e. The reaction mixture was quenched with 10% HCl until the mixture was about pH 3, whereupon it was then extracted with ethyl acetate. This was dried over anhydrous m~gnesillrn sulfate, and the solvent was removed by evaporation under vacuum to afford 1.6 g of the titlecompound as a yellow oil. This m~tt~ l was taken directly to the next step.

, W O 96~9407 PCTAUS9C/08991 Step 3. 9-(2,4-Difluorophenyl)-3-Jluoro-2-hydroxy~-methyl-6H-6-oxopyridorl.2-alpyrimidine-7-carboxylic acid ethyl ester " The compound from Step 2 was dissolved in toluene, 0.62 mL of DBU was added and the mixture heated at reflux in a flask equipped with a Dean-Stark condenser for 16 hours under a dry N2 atmosphere. The mixture was removed from the heat and stirred with 70 mL of water for 2 hours. After separation, the organic phase was dried over magnesioum sulfate, and the solvent was removed by evaporation. The residue was purified by column chlulllalography on silica gel, elu~ng with 1 :5: 100 ace~ic l rnethzlnol methylene chloride to afford 0.175 g of the title compound as a yellow o solid. MS M/Z: 379 (M+H). NMR:(DMSO-d6) d 1.21 (t, 3H, J=7 Hz), 2.07 (d, 3H, J--~l H[z), 4.10 (q, 2H, J=7 Hz), 7.03 (m, lH), 7.16 (m, lH), 7.38 (m, lH), 7.66 (s, lH).
Fxarnples 175- 178 By following the procedures described in Example 174 and sub~ lg the ul)liate ester for ethyl 2-fluoro-3-oxobutyrate, Examples 175-178 may be ~JlGpalGd as disclosed in Table 6 (where R = ethyl and R 1 = 2,4-difluorophenyl).

Table 6 Rs o O

HO~

Fx~rnple NQ. B5 Fxamples 179- 195 By following the procedures described in Example 160 Steps 3, 4 and 5 and Example 161, and replacing 2-(N-t-butoxycarbonylamino)pyrrolidine in Step 4 with the al,l,.upliate N-methyl- or boc-protected amine, Examples 179-195 may be prepared as disclosed in Table 7 (where R 1 = 2.4-difluorophenyl).

W O 96/39407 PCT~US96/08991 Table 7 R5 0 o ~NJ~OH 9 R2~bNJ~

F.~am~le No. B2_ B5 rN

N

N

~' ~' .

~VO 96/39407 PCTrU~96i'~931 ~, 186 Cl 12NHCH2CH3 -CHF2 ~--N

CH3 N~

CH3 N~

191 NHz -CF3 WO 96/39407 PCT~US96/08991 Fx~ml?les 196-24Q
By following the procedures described in Example 160 Steps 3, 4 and 5 and Example 161, replacing 2-(N-t-butoxycarbonylamino)pyrrolidine in Step 4 with thea~,~,~liate substituted or boc-protected amine and replacing 9-(2,~difluoro-phenyl)-3-S fluoro-2-hydroxy-6H-6-oxopyrido[1,2-a]pyrimi~lin~-7-carboxylic acid benzyl ester with the compound cont~ining the ~plopliate Rl group (as described in Examples 2 and 39), Examples 196-240 may be ~,G~ed as disclosed in Table 8.1 to 8.3 in which: Rl is 4-fluorophenyl (Table 8.1), 2,4-difluorophenyl (Table 8.2) or cyclopropyl (Table 8.3); and R5 is hydrogen.

-WO 96/39407 PCT~US96~'a~931 Table 8. 1 R5 O o ~ N J~OH
R2 ~N J~
R1 = ~fluoro~henyl~ RS = H:

F~am~le No.R2 Example NoR2 196 HO-N N-- 205 NH2>CN~

197 H2N~N 3 206 CH3NH~N--199 2 207 NH2~$N--208 NH2~N--201 HN~N d--202 cH3~<cH3 209 CH~O~;N--203NaSCSNH~N- 210NH2CH2-$N-204NH2~N--Table8.2 Rs ~ ~

R2~
B1 = 2.4-di~uorophenvl.R5 = H:
s F~mDle No. R2 Example NoR2 21 1 H0-N N-- 220 NH2>CN~

212 H2N~N--22 1 CH3NH~N-2 13 CH3--N~ZN--214 HN~ZN-- 222 ~o, 2 15 CH3--N~N--223 NH2~N--2 16 HN~N - ~_ 217 HN N-- 224 NH2~, 2 18NaSCSNH--CN- 225NH2CH2~N-219NH2~,N-U'O 96~9407 . PCTrUS9f'~931 Table 8.3 ~ ~OH

gl = cyclQ~ropYh R5 = H:

F~rnr)le No. R2F~mple No R2__ 226 H 0- N N-- 235CH3>CN--227 H2N~N-228 CH3 - N~N--229 H N~N-- 237 ~0 230 CH3 N~N
238NH2 ~ N--231 HN~N-- d--232 H N N 239NH2 ~, 233NaSCSNH~N-- 240NH2CH2~N--234NH2~N~

Examples 241-250 By following the procedures of Example 157 Steps 2-8, replacing 2-cyclopropyl-2-ethoxycarbonyl~et~mi~linto hydrochlori-le in Step 2 with the compound cont~ining the 10 a~ o~liate Rl group (refer to compound 6B in Scheme II), and replacing the 3-(N-t-butoxycarbonyl)aminopyrrolidine in Step 6 with the a~plul,liately protected amine, examples 241-250 may be ~lep~ed as disclosed in Table 9, above, (in which R5 is hydrogen).

W O 96/39407 PCT~US96,~ 91 Table 9 Rs o O
~ N ~OH
R2 ~N J~

Exam~le No. RZ R

242 ~N- CH3 NH2~/ CCHH~3_ 243 ~N- CH3 244 ~N - F3C--246 N~ N-248 N N- CH~

249 N~_~N- F3C--250 ~ FCH2CH2--W O 96/39407 . PCTrUS9G~991 Examples 251-252 By following the procedures of Example 157, steps 2-8, replacing replacing 2-cyclopropyl-2-ethoxycarbonylacet~rnic~ine hydrochloride in Step 2 with 2-(N-s benzoylo~y~;~l,onyl-N-methylatnino)-2-ethoxycarbonyl~cetz~millin~ hydrochloride, and replacing the 3-(N-t-butoxycarbonyl)aminopyrrolidine in Step 6 with the a~Iuuliately protected amine, Examples 251-252 may be prepared as disclosed in Table 10 (in which R5 H).
Table 10 Rs ~ ~
~ N J~OH
R2 J;:~N J~
R
l~x~r,l~le No. R2 R1 251 ,~ CH3NH-252 HN~ N- CH3NH-Example 253 8-(3-Amino- 1 -pyrrolidlinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-41~-quinolizine-3-carboxylic acid S tep 253a. 4-t-Butoxy-3-chloro-2.5 ~6-trifluoropyridine To 250 mL of a THF solution containing 106 g (0.571 mmol) of a mixture of 4-chloro-tetrafluoropyridine and 3-chloro-tetrahydropyridine (approx 70:30 ratio, from Aldrich C~hçmic ~1 Co.) at -78~C was added a solution of 38.3 g (0.399 mmol) of sodium t-butoxide in 350 mL of THF, and the solution was stirred for 2 hours at -78~C and at ambient ~e~ d~ule for 16 hours. The mixture was poured into 500 mL of hexane, and this mixture was filtered through celite and the filtrate concentrated. The residue was purified by flash chromatography, eluting first with hexane, then ethyl acetate:hexane (1:4), to sep~r~t~ the desired title product from the mixture of products. MS 238, 240 (M+H)+;
lH N~IR (CDC13) a 1.52 (d, J-2Hz); 19F NMR (CDC13, CFC13 as reference) a 73.75 (dd, Jl=14.2, J2=23.2 Hz), 89.71 (dd, Jl=14.2, J2=21.98 Hz); 152.42 (apparent t, J=22 Hz).

CA 02222322 1997-11-2~

WO 96/39407 PCTAUS96,'~8331 Step 253b. 4-t-Butoxy-2.3.6-trifluoro~yridine To the product from Step 253a above (24.92 g, 0.104 mmol) in 100 mL of methanol was added 2.5 g of Pe~rlmz~n~s catalyst (Aldrich Chemical Co.), and the mixture s was stirred at ambient Lw~ dture for 14 hours under and atmosphere of hydrogen. An additional 2.5 g of catalyst was added, and the mixture was stirred for another 22 hours.
The mixture was filtered, the filtrate was c~lncç.,l.AI~, and the residue was extracted with hexane/ether. After filtration, the solvent was removed by evaporation, and the residue was purified by flash cl.l.JIllatography (ethyl acetate:hexane 1:16) to yield 12.05 g of the 10titleproduct. MS 206 (M+H)+, 233 (M+18)+; lHNMR (CDC13) a 1.52 (s, 9H), 6.51 (m, lH); 19F NMR (CDC13, CFC13 as reference) a 72.60 (dd, Jl=14.3, J2=21.0 Hz), 89.74 (dd, Jl=14.3, J2=21.0 Hz), 164.68 (dt, Jl=4.2, J2=21.0 Hz).

SteD 253c. 4-t-Butoxv-2 ~6-trifluoro-5-methyl~yridine 15A freshly ~lc~a- ,d solution of lithium diethylamide (LDA) (58.21 mmol) in 30 mL of THF at -78~C was added to 10.0 g (48.74 mmol) of the product from Step 253b in 50 mL of THF at -78~C, and the reaction was stirred for 50 min. To the reaction mixture was added 4.3 mL (69.07 mmol) of methyl iodide, and the mixture was stirred at -78~C for 1 hour and stirred at ambient Lcnl~GldLulc for 16 hours. The reaction was quenched with 20 saturated NH4Cl solution, extracted with hexane, and the extracts washed with water, dried over MgSO4 and conce..l,aLcd to give the title product as a pale yellow Oil, which was taken directly to the next step. MS (220) (M+H)+; lH NMR (CDC13) a 1.47 (m, 9H), ~
2.12 ~m, 3H). 19F NMR (CDC13, CFC13 as reference) a 75.91 (dd app~,lL,J1=15.0, J2=22-1 Hz), 93.17 (dd ~palellt, Jl=15.0, J2=22.1 Hz), 156.54 (m).
2s Step 253d. 4-t-Butoxv-2.5-difluoro-3-methylpvridine A sample of the product from Step 253c above (48.74 mmol) and 13.5 mL of hydrazine monohydrate were dissolved in 150 mL of n-propanol. The reaction was stirred at reflux Le~ dLulc under nitrogen for 4 hours. The volatiles were removed, and the 30 residue was dissolved in methylene chloride, which was washed with water and dried over MgSO4. The solvent was removed to give the intermediate hydrazine product as a yellow liquid, which was dissolved in 110 mL of methanol. To this was added 20 mL of 20% ,, NaOH and air was passed through the solution for 16 hours. The solvents were removed at 30~C under vacuum. The residue was dissolved in methylene chloride, which was , W O 96~39407 PCTAJS9~ 931 washed with water and dried over MgSO4. The solvent was removed and the crude product purified by flash ~ ullla~ugraphy~ eluting with ethyl acet~t~:hexane 1: 16 to give the title prûduct as a colorless liquid after removal of the solvents. MS (202) (M[+H)+; lH
NMR (CDC13) ~: 1.43 (d, 9H, J=1.5 Hz), 2.18 (d, 3H, J=1.5 Hz), 7.85 (br s, lH); 19F
NMR. (CDCl3, CFCl3 as reference) a 73.37 (d, J=24.5 Hz), 142.17 (d, J=24.5 Hz).

Step 253e. 2-(4-t-Butoxy-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetonitrile A sample of the product from Step 253d above (40.8 mrnol) was dissolved in 50 mL of THF and cooled to -78~C. To this was added a freshly ~lc~ ,d solution of LDA
(0.103 mmol) in 50 mL of THF at -78~C, and the reaction was stirred for 1 hour. The reaction was then stirred at 0~C for 1 hour, quenched with saturated NH4Cl solution and extracted with ether. The extracts were washed with ~ d NaCl solution, dried over MgSO4, and conce.,L,~d. Tihe residue was purified by flash cl-l o".a~ography, eluting witlh 1 :4 ethyl acetate hey~n~, to yield 10.33 g of the title product after removal of the solvent. MS 263 (M+H)+; lH NMR (CDCl3) a o.so (m, 2H), 0.63 (m, lH), 0.73 (m, lH), 1.60 (m, lH), 1.43 (d, 9H, J=2 Hz), 2.29 (s, 3H), 3.76 (d, lH, J=8 Hz), 8.30 (d, lH, J=3 Hz). lR (neat) 2240, 1580, 1470 cm~l.

Step 253f. 2-(4-Chloro-5-fluoro-3-methyl-2-pyridinyl)cyclo~ ne;~lcelQ,lil,ile A sample of the product from Step 253e above (5.21 g, 19.86 mmol) was dissolved in 50 mL of trifluoroacetic acid, the reaction was stirred under nitrogen for 1 ;hour at ambient lenl~lC~d~Ult, and the rnaterial CO~ r~l to dryness. The residue was dissolved in a mixture of 15.6 mL of DMF and 90 mL of methylene chloride. This solution was cooled in a water bath as 18.8 mL (19.86 mmol) of POCl3 was added, then 2s the reaction was stirred at ~mhi~nt t~ LulG for 16 hours. The reaction was quenched by pouring it into ice water, and the mixture was extracted with methylene chloride. The ~queous solution was adjusted to pH7 with NaOH and re-extracted with methylene chloride. The extracts were combined and washed with water, dried over MgSO4 andconcc~ a~d. The residue was purified by flash chromatography with 1 :4 ethyl acetate:hexane to give 3.26 g of the title product as a colorless liquid after removal of the solvents. MS 225, 227 (M+H)+; lH NMR (CDC13) a 0.48 (m, lH), 0.59 (m, lH), 0.66 ~m, lH), 0.77 (m, lH), 1.50 (m, lH), 2.48 (s, 3H), 3.80 (d, lH, J=8 Hz), 8.39 (s, lH).
IR (neat) 2240, 1570, 1460 cm~ 1.

CA 02222322 1997-11-2~

WO 96/39407 PCTrUS96/08991 Ste~ 253~. Ethyl 2-(4-chloro-5-fluoro-3-methyl-2-pyri~ yl)cyclopropaneacetate A sample of the product from Step 253f above (3.26 g, 14.51 mmol) was dissolved in 10 mL of ethanol, and gaseous HCI was introduced until 4 g had beendissolved. The solution was heated to reflux, and 0.36 mL of water was added, then the mixture was stirred for 1 hour. The reaction was cooled, then poured into water, and the t mixture was adjusted to pH7 with NaHCO3. The mixture was then extracted with methylene chloride, which was washed with water, dried over MgSO4 and concentrated.
The residue was Ll;LuldLcd with 1:4 ethyl acetate h~Y~ne, and filtered. The filtrate was con~cl.L~dLGd and the residue was purified by flash cl-lu.,-aLography with 1:4 ethyl acetate:hexane to give 2.262 g of the title product after removal of the solvent. MS 272, 274 (M+H)+; lH NMR (CDCl3) a 0.12 (m, lH), 0.38 (m, lH), 0.53 (m, lH), 0.76 (m, lH), 1.20 (t, 3H, J=7 Hz), 1.67 (m, lH), 2.40 (s, 3H), 3.23 (d, lH, J=9 Hz), 4.16 (q, 2H, J=7 Hz), 8.36 (s, lH).

Ste~ 253h. 2-(4-Chloro-5-fluoro-3-methvl-2-~yridinyl)cvclopropane-acetaldehyde A sample of the product from Step 253g above (1.73 g, 6.37 mmol) was dissolved in 10 mL of THF and stirred with water bath cooling and 3.2 mmol of LiAlH4 (LAH) was added. The mixture was stirred at ambient Lc.ll~ dlulG for 1 hour, then poured into water. This mixture was extracted with ether, the extracts were washed, dried and con~,cn~,dted to give 1.48 g of a colorless oil. This oil was dissolved in 10 mL of methylene chloride and added to a solution of 3.8 mL (7.6 mmol) of oxalyl chloride and 1.1 mL of DMSO (15.5 mmol) in 15 mL of methylene chlori~l.o stirred at -78~C. The solution was stirred for 15 min, and 4.4 mL (31.6 mmol) of triethylamine was added. The stirring was continl-ecl at -78~C for S min and at -10~C for 10 min. The reaction was quenched with water, and extracted with methylene chloride. The extract was washed, dried and concentrated to give 1.49 g of the crude title product, which was taken directly to the next step without further purification. MS 228, 230 (M+H)+; lH NMR (CDC13) ~:
0.25 (m, lH), 0.35 (m, lH), 0.60 (m, lH), 0.75 (m, lH), 1.53 (m, lH), 2.38 (s, 3H), 3.19 (dd, lH, J=3, J=9 Hz), 8.37 (s, lH), 9.86 (d, lH, J=3 Hz).
Step 253i. 8-Chloro-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinoli7ine-3-carboxylic acid ethyl ester A sample of the product from Step 253h above (6.37 mmol) was dissolved in 50 mL of ethanol, and to this were added 1.5 mL of piperidine, 1.5 mL of acetic acid, and 5 W O 96~39407 PCT~US96/08991 mL of diethyl malonate (32.9 mmol). The reaction was heated at reflux under nitrogen for 4 hours. The solvents were then removed, and the residue was dissolved in ether. The ether was washed with water and brine, then dried over MgSO4 and concentrated Purification in a kugelrohr ap~dld~us gave 2.4 g of the crude con-len~*on produce. This 5 interm~ t~ product was dissolved in 20 ML of of Dowtherm ATM, and this solution was added to 100 mL of Dowtherrn ATM heated to 235~C. The reaction was then stirred at 220~C for 45 rnin. After cooling, the product was ~d~d from the solvent by flashchromatography, eluting with hexane to remove the solvent and then with 1 :4 ethyl acetate hexane to remove the product. In this manner 1.065 g of the title product was obtained after removal of the solvent. MS 324, 326 (M+H)+; lH NMR (CDC13) ~: 0.75 (m, 2H), 1.07 (m, 2H), 1.42 (t, 3H, J=7 Hz), 2.31 (m, lH), 3.08 (s, 3H), 4.42 (q, 2H, J=7 Hz), 8.40 (s, lH), 9.44 (d, lH, J=6 Hz).

3tep 253j. 8-(3-(N-BOC-amino)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl~-oxo-4H-quinolizine-3-carboxylic acid ethyl ester A sample of the product from Step 253i above (0.500 g, 1.544 mmol) was dissolved in 20 mL of anhydrous ac;~,~ol iL.ile, and 0.600 g of sodiurn bicarbonate and û.600 g (3.22 mmol) of 3(S)-(BOC-arnino)pyrrolidine were added. The mixture was heated at reflux under nitrogen for 7 hours, then the solvent was removed and the residue 20 was redlissolved in methylene chloride. This solution was washed with water,5% HCl, ~,vater, and concentrated.. The residue was purified by flash chromatography, eluting with 100:10 methylene chlori(le ll~r~ nol~ followed by 100:10:0.5 methylene chlonde:
methanol:NH4OH. Removal of the solvent gave 0.778 g of the title product, which was taken directly to the next step.
Step 253k. 8-(3-(N-BOC-amino)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methy1-4-oxo-4H-quinolizine-3-carboxylic acid A sample of the product from Step 253j above (0.778 g, 1.645 mmol) was dissolved in 20 mL of THF, 0.570 g of LiOH-H20 and 10 mL of water were added, and 30 the mixture was stirred under nitrogen for 3 hours. The THF was removed under vacuum, and the residue was adjusted to a pH between 2 and 4 with 1 N HCl. The solid wascollecte~l, and the filtrate was extracted with methylene chloride and washed and concentrated to give additional product. The combined solids were purified by flash cluunlaL~graphy eluting with 100:5: 1 methylene chk~n~l~ m~th~n~ cetic acid to yield CA 02222322 1997-11-2~

WO 96/39407 PCT~US96~'ae931 0.698 g of the title product after removal of the solvent. This m~t~ri~l was taken directly to the next step.

Step 2531. 8-(3-aminopyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxvlic acid hydrochloride A sample of the product from Step 253k above (0.697 g, 1.564 mmol) was dissolved in 17 mL of anhydrous methylene chloride, 5.0 mL of 4 N HCl in dioxane was added, and the reaction was stirred for 1.75 hours. Ether was added, and the p-~,ci~
was collected by filtration and washed with ether. The solid was dissolved in water, 10 ~lltered through a sintered glass funnel, and freeze-dried to give the title product as a yellow solid. mp 230-232~C (dec). MS 346 (M-Cl)+; lH NMR (DMSO) ~: 0.58(m, 2H), 0.99 (m, 2H), 2.15 (m, lH), 2.31 (m, 2H), 2.63 (s, 3H), 3.77 (m, 2H), 3.99-4.06 (m, 3H), 7.94 (s, lH), 8.39 (br s, 3H), 9.10 (d, lH, J=ll Hz), 13.85 (br s); IR 3440, 1695, 1610 cm~
Fxam~le 254 8-(3-(aminomethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-qllin--li7in~-3-~rboxylic acid hvdrochloride The 3-(BOC-amino)pyrrolidine of Step 253j above was replaced by 3-BOC-aminome~l.ylpyllolidine and the reaction product was carried forward as in Steps 253K and 2531, above, to prepare 0.085 g of the title compound. MS 360 (M-Cl)+; IH NMR
(DMSO) ~: 0.60 (m, 2H), 0.99 (m, 2H), 1.81 (m, lH), 2.18 (m, lH), 2.30 (m, IH), 2.60 (s, 3H), 2.98 (m, 2H), 3.66-3.81 (m, SH), 7.90 (s, lH), 8.09 (br s, 3H), 9.06 (d, lH, J=l l Hz), 13.85 (br s, lH).

Fxaml?le 255 8-(2S,4S-4-amino-2-methylpyrrolidinyl)- l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinoli7ine-3-~rboxylic acid hydrochloride The 3-BOC-aminopyrrolidine of Step 253j above was replaced by (2S,4S)-4-(BOC-amino)-2-methylpyrrolidine and the reaction product was carried forward as in Steps 253K and 2531, above, to prepare 0.071 g of the title compound. MS 360 (M-Cl)~; lH
NMR (DMSO) ~: 0.51 (m, lH), 0.63 (m, lH), 0.90 (m, lH), 1.09 (m, lH), 1.17 (d, 3H, J=6 Hz), 2.01 (m, lH), 2.40 (m, 2H), 2.64 (s, 3H), 3.40 (m, lH), 3.98 (m, lH), 4.31 (m, lH), 4.61 (m, lH), 8.00 (s, lH), 9.17 (d, lH, J=l l Hz).

_ ~VO 96/39407 PCTrU59''~9~1 Fxample256 8-(3-~minoa7~tidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride The 3-BOC-aminopyrrolidine of Step 253j above was replaced by 3-(BOC-amino)~7etirline and the reaction product was calTied forward as in Steps 253K and 2531, above, to prepare 0.094 g of the title compound. MS 332 (M-Cl)+; lH NMR (DMSO) a0.61 (m, 2H~, 1.00 (m, 2H), 2.30 (m, lH), 2.61 (s, 3H), 4.15 (m, lH), 4.56 (m, 2H), ~486 ~m, 2H), 7.89 (s, lH), 8.51 (br s, 3H), 9.13 (d, lH, J=10 Hz).

Exam~le 257 8-(3(S)-arninopyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride The 3-BOC-aminopyrrolidine of Step 253j above was replaced by 3(S)-(BOC-amino)pyrrolidine and the reaction product was carried forward as in Steps 253K and 2531, above, to prepare 0.087 g of the title compound. MS 346 (M-Cl)+; lH NMR (DMSO) a0.59 (m, 2H), 0.99 (m, 2H), 2.14 (m, lH), 2.31 (m, 2H), 2.63 (s, 3H), 3.76 (m, 2H), 3.98-4.07 (m, 3H), 7.94 (s, lH), 8.36 (br s, 3H), 9.11 (d, lH, J=ll Hz).

Fxample 258 1 -cyclopropyl-7 -fluoro-9-methyl-4-oxo-8 -(3 -methyl-yl)-4H-quinoli*n~o-3-~rboxylic acid hydrochloride 2s The 3-BOC-aminopylTolidine of Step 253j above was replaced by 2-melhylpiperazine (Aldrich ~hemi~l Co.), and the reaction product was carried ~orward as in Steps 253K and 2531, above, to prepare 225 mg of the title compound. mp > 300~C.
[R (KBr): 3420, 1720, 1650 cm~l. MS 360 (M-Cl)+. lH NMR (CD30D) ~: 0.75 (m, 2H), 1.10 (m, 2H), 1.40 (d, 3H, J=7.5 Hz), 2.90 (s, 3H), 3.45 (m, 3H), 3.71 (m, 4H), 8.23 (s, lH), 9.40 (d, lH, J=12 Hz). Calc. for ClgH23ClFN3O3-1.25 H2O: C, 54.55;H, 6.14; N, 10.04; Found: C, 54.78; H, 5.78; N, 10.05.

CA 02222322 1997-11-2~

WO 96~9407 PCT~US96/08991 F~sam~le 259 1 -cyclopropyl -7 -fluoro-9-methyl-4-oxo-8-piperazinyl-4H-qllinoli7in~-3-carboxylic acid hydrochloride S The 3-BOC-arninopyrrolidine of Step 253j above was replaced by piperazine (Aldrich (~hemil~l Co.), and the reaction product was carried forward as in Steps 253K
and 2531, above, to prepare 75 mg of the title compound. mp = 279-280~C. IR (KBr):
3420, 1710, 1650, 1610 cm~ l . MS 346 (M-Cl)+. l H NMR (CD30D) a 0.72 (m, 2H), 2.43 (m, lH), 2.92 (s, 3H), 3.43 (m, 4H), 3.72 (m, 4H), 8.25 (s, lH), 9.30 (d, lH, J=12 Hz). Calc. for C1gH21ClFN3O3-1.5 H2O: C, 55.32; H, 5.67; N, 10.75; Found: C, 55.52; H, 5.49; N, 10.59.

Exam~le 260 1 -cyclopropyl-7-fluoro-9-methyl-8-(2-((N-methyl)aminomethyl)-IS 4-morpholinyl)-~oxo-41I-~uinolizine-3-carboxvlic acid hvdrochloride Step 260a. l -N-benzyl-3-(chloromethvl)morpholine A mixture of l.S g (10 mmol) of N-benzyl-ethanolamine (Aldrich Ch~mic~l Co.) and 7.8 mL of epichlorohydrin was heated at 40~C for 30 min. The reaction was cooled, 20 and the excess epichlorohydrin was removed with a rotary evaporator. The residue was dried under vacuum, dissolved in 30 mL of conc. H2SO4, and the mixture heated at 150~C
for 30 min. The reaction was quenched by pouring onto ice, and the pH was adjusted with NaOH to pH 13. The basic solution was extracted with toulene (3x), and the extracts were dried over Na2SO4, filtered, and the solvent remove under vacuum. The residue was dried 2s under vacuurn to yield 193 mg of the title product.

Step 260b. 1 -N-benzyl-3-((N-methylamino)methyl)-morpholine A thick-walled glass tube was charged with 8.83 g of N-benzyl-3-(chlc,lor-oLl-yl)morpholine, from step 260a above, dissolved in 15 mL of methanol. The 30 tube and its contents were cooled and 25 mL of anhydrous methylamine was added. The tube was sealed and heated at 100~C for 24 hours. The seal was broken, and the solvent was removed under vaccum. The residue was diluted with 100 rnL of 10% Na2C03, then extracted 3x with methylene chloride. The extract was dried over Na2SO4, f1ltered, and the solvent was removed on a rotary evaporator to yield 8.6 g of the title product.

-W O 96/39407 PCTrU5~ h931 Step 260c. 1 -N-benzvl-3-((N-BOC-N-methylamino)methyl)-mor~holint ~ To a dry flask under positive N2 atmosphere was added 8.6 g (39 mmol) of the l-N-ben~yl-3-((N-methylamino)methyl)-morpholine, from step 260b above, in 100 mL of ~- dry methylene chloride. The solution was cooled in an ice bath and 8.6 mL (64.3 mmol) of s triethylamine and 12.7 g (58.5 mmol) of di-t-butyldicarbonate was added. The reaction mixture was stirred at 0-5~C for 30 min, then wanned to room temperature and stilTed for 'J2 hours. The reaction contents were diluted with 100 mL of methylene chloride, which was then washed with water and dried over Na2SO4. The solution was filtered, thesolvent was removed on a rotary eva~ dlo~, and the residue dried under vacuum to afford 10 12.4 g of crude title product. The product was purified by column clLlu..,atography to yield '7.4 g of the title product as a colorless oil. Anal Calc. for Cl lH22N203: C, 67.47; H, 8.81;,N, 8.74; Found: C, 67.00; H, 8.53; N, 8.66.

Step 260d. 2-(N-BOC-N-methyl-aminomethvl)morpholine A 1.10 g (3.43 mmol sample of I -N-benzyl-3-((N-BOC-N-methylarnino)methyl)-morpholine, from step 260c above, was dissolved in 100 mL of methanol. To this was added 500 mg of 20%Pd/C, and the mixture was stirred at room Lulc; under 4 atm of H2 for 16 hours. The catalyst was removed by filtration, the solvent was removed with a rotary e~,~ol~ûl, and the residue was dried under vacuum to yield 794 mg of the title product as a colorless oil.

Step 260e. 1-cyclopropyl-7-fluoro-9-methyl-8-(2-((N-methyl)~minornethyl)-4-mor~holinyl)-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride The 3-BOC-aminopyrrolidine of Step 253j above was replaced by 2-(N-BOC-N-methyl-aminomethyl)morpholine (from step 260d above)and the reaction product wascarried forward as in Steps 253K and 2531, above, to prepare 280 mg of the titlecompound. mp = 208-210~C. IR (KBr): 3420, 1720, 1700, 1650 cm~l. MS 390 (M-Cl)+. lH NMR (CD30D) a 0.70 (m, 2EI), 1.10 (m, 2H), 2.38 (m,lH), 2.78 (s, 3H).2.90 (s, 3H), 3.10-3.30 (m, 2H), 3.50-4.15 (m, 7H), 8.12 (s, lH), 9.20 (d, lH, .1=14 Hz). Calc. for C20H2sClFN3O4-2H2O: C, 52.01; H, 6.33; N, 9.10; Found: C, :51.90; H, 5.92; N, 9.09.

CA 02222322 1997-11-2~

WO 96/39407 PCTrUS96/08991 Ex~ml71e 261 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(1,2,3,4-tetr~l~ydro-2-iso~linolinvl)-4H-~uirloli7ine-3-carboxylic acid - .
The 3-BOC-aminopyrrolidine of Step 253j above was replaced by 1,2,3,4-tetrahydroisoquinoline (Aldrich ('hemir~l Co.), and the reaction product was carried forward as in Steps 253K and 2531, above, to prepare 315 mg of the title compound. mp =
214-215~C. IR (KBr): 3420, 1730, 1680cm~l. MS 393 (M+H)~. IH NMR (CDC13)~:
0.70 (m, 2H), 1.08 (m, 2H), 2.30 (m,lH), 2.85 (s, 3H),3.10 (dd, 2H, J=6 Hz), 3.75 (m, 2H), 4.60 (s, 2H), 7.28 (m, 4H), 8.40 (s, lH), 9.22 (d, lH, J=12 Hz). Calc. for C23H21FN2O3~1.25 H2O: C, 66.58; H, 5.71; H, 6.75; Found: C, 66.56; H, 5.26; N, 6.62.
Fx~ ple 262 1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-amino-1-~ dillyl)-4H-q~linoli7in~-3-e~rboxylic acid hydrochloride Step 262a. N-ben7yl-4-(N-hydroxyimino)pi~eri-line A 3.78 g (20 mmol) sample of N-benzyl-4-oxo-piperidine (Aldrich Chemcial Co.) was dissolved in 50 mL of methanol. To this solution was added 4.16 g (60 mmol) of hydroxylamine hydrochloride and 5.2 g NaHCO3 (62 mmol) (Dissolved in 80 mL ofwater and added in 5 mL portions). The mixture was then stirred at room temperature for 18 hours. The mixture was filtered, and the solvent was removed from the filtrate on a rotary evaporator to give 3.05 g of the title product. mp 127- 128~C.
Step 262b. 1-N-benzyl-4-aminopiperidine A 2.04 g (9.98 mmol) sample of the oxime from step 262a above was dissolved in 200 mL of methanol and reduced with 10 g of ~aney nickel under 4 atmosphere of H2 at room ~ )e~ U1C; for 4 hours. The catalyst was removed by filtration, and the solvent was removed on a rotary e~/apol~tol. The residue was dried under vacuum to yield 1.79 g of the title product. MS M/Z: 191 (M+H)+.

Step 262c. 1-N-benzyl-4-BOC-aminopiperidine In a dry system under N2 pressure was introduced 1.78 g of the 1-N-benzyl-4-3s aminopiperidine, from step 262b above, dissolved in 9 mL of dry methylene chloride. To -CA 02222322 1997-11-2~

W O 96/39407 PCTAU~96/08991 this was added 1.6 mL (12 mmol) of triethylamine and 2.45 g (11.2 mmol) of di-t-butyldicarbonate. The reaction mixture was stiIred at room lwll~ dLult; for 96 hours. The contents were diluted with 125 mL of methylene chloride and washed with water. The organic layer was dried over Na2S04, filtered, and the solvent removed on a rotary S evaporator. The residue was dried under vacuum to yield 2.45 g of the title product as an off-white solid. The crude product was purified by column ~Llulllalugraphy on silica gel, eluting with 2% methanol in methylene chloride. Removal of the solvent gave 1.74 g of product, which was the ~ ly~l~lli7tod from ethanol, and dried under vacuum. mp. 121-122~C. Anal. calc. for C17H25N202: C, 70.31; H, 9.02; N, 9.65; Found: C, 70.26; H, 9.02; N, 9.55.

Ste~ 262d. 4-BOC-~minopiperidine The benzyl group was removed from the product of step 262c by the procedure descIibed for Example 260d above, to afford the title product.
Step 262e. 1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-amino-1-yiy~dillyl)-4H-quinolizine-3-carboxylic acid hydrochloride The 3-BOC-aminopyrrolidine of Step 253j above was replaced by 4-(BOC-amino)-methylpiperidine, from step 262d above, and the reaction product was carried forward as in Steps 253K and 2531, above, to prepare 480 mg of the title compound. mp =
231-232~C. IR (E~Br): 3420, 1700, 1610 cm~1. MS 360 (M-Cl)+. IH NMR (CD30D) a 0.70 (m, 2H), 1.08 (m, 2H), 1.85 (m,lH), 2.10 (m, lH), 2.18 (m, 2H), 2.35 (m, 2H), 2.87 (s, 3H), 3.50 (m, 2H), 3.70 (m, lH), 8.16 (s, lH), 9.22 (d, 2H, J=9 Hz). Calc. for ClgE~23ClFN303-0.75 H2O: C, 55.75; H, 6.03; H, 10.26; Found: C, 55.70; }I, 6.07; N, 2s 10.36.

Fx~rnple 263 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-amino- 1 -piperdinyl)-4H-quinolizine-3-carboxylic acid hydrochloride The 3-BOC-aminopyrrolidine of Step 253j above was replaced by 3-amino-piperidine hydrochloride (Aldrich Chemical Co.), which was neutralized with triethylamine, and the reaction product was carried forward as in Steps 253K and 2531, above, to prepare 250 mg of the title compound. mp = 222-223~C. 1~ (KBr): 3400, 1700, 3s 1680 cm~l. MS 360 (M-Cl)+. lH NMR (CD30D) ~: 0.70 (m, 2H, J=6 Hz), 1.10 (m, CA 02222322 1997-11-2~

2H, J=6 Hz), 1.70 (m,2H), 2.05 (m, 3H), 2.30 (m, 2H), 2.40 (m, 2H), 2.87 (s, 3H), 3.90 (m, lH), 8.18 (s, lH), 9.20 (d, lH, J=9 Hz). Calc. for ClgH23ClFN3O3-2 H2O:C, 52.84; H, 6.30; H, 9.73; Found: C, 52.62; H, 6.62; N, 9.36.

Fxample 264 1 -cyclopropyl-7-fluoro~9-methyl-4-oxo-8 -(4-(aminomethyl)-1-piperdinvl)-4H-quinolizine-3-carboxylic acid hydrochloride The 3-BOC-aminopyrrolidine of Step 253j above was replaced by 4-(amino-methyl)piperidine (Aldrich Chemical Co.), and the reaction product was carried forward as in Steps 253K and 2531, above, to prepare 157 mg of the title compound. mp > 300~C. IR
(KBr): 3410, 1720, 1660 cm~l. MS 374 (M-Cl)+. lH NMR (CD30D) a 0.70 (m, 2H), 1.08 (m, 2H), 1.55 (m, lH), 1.95 (m, 2H), 2.42 (m, 2H), 2.83 (s, 3H), 2.95 (m, 3H), 3.40 (m, 2H), 3.60 (m, 2H), 8.18 (s, lH), 9.22 (d, lH, J=9 Hz). Calc. for C20H25clFN3o3-l.75 H2O: C, 54.42; H, 6.51; H, 9.52; Found: C, 53.92; H, 6.85; N,9.73.

F~mple 265 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(5-amino- 1,2,3,4-ttqtr~h~y~lro-2-;~oquinolinyl)-4H-quinoli7ine-3-~rboxylic acid hydrochloride Step 265a. 5-amino-1 ~ ~.4-tetrahydroisoquinoline A 1.0 g (0.69 mmol) sample of 5-aminoisoquinoline (Aldrich Chemical Co.) was dissolved in 100 mL of m~th~nol and reduced with 250 mg PtO2 catalyst at 25~C under 4 2~ atmospheres of H2 for 8 hours. The catalyst was removed by filtration, the solvent was removed on a rotary evaporator, and the residue was dired under vacuum to give 1.01 g of crude product. The material was crystallized from i-propanol and dried under vacuum, yield 602 mg. mp = 153- 154~C. MS M/Z: l 49 (M+H)+, 166 (M+NH4)+.

Step 265b. 1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(5-amino-1,2,3,4-tetr~llydro-2-isoquinolinyl)-4H-q~linoli7in~-3-c~rboxylic acid hvdrochloride The 3-BOC-aminopyrrolidine of Step 253j above was replaced by 5-amino-1,2,3,4-tetrahydroisoquinoline, ~l~pal~d in step 265a above, and the reaction product was carried forward as in Steps 253K and 2531, above, to prepare 507 mg of the title3~ compound. mp = 185-187~C. IR (KBr): 3380, 1710, 1650 cm~l. MS 408 (M-CI)+, 390 (M+NH4-CI)+. lH NMR (CD30D) a 0.72 (m, 2H, J=6, J=3 Hz), 1.10 (m, 2H, J=3 W O 96/39407 PCTrUS96/08991 Hz), 2.40 (m, lH), 2.90 (s, 3H), 3.07 (dd, 2H, J=7.5 Hz), 3.90 (dd, 2H, J=7.5, J=3 Hz), 4.74 (s 2H), 7.28 (m, 2H), 7.35 (m, lH, J=9 Hz), 8.17 (s, lH), 9.25 (d, lH, J=12 Hz). Calc. for C23H23ClFN3O3~0.75 H20: C, 60.39; H, 5.40; H, 9.19; Found: C, 60.38; H, 5.16; N, 9.10.
~- 5 F.x~rnple 266 l-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-(1-pyrrolyl)-l-p~eridinyl)-4H-quinolizine-3-carboxylic acid The 3-BOC-aminopyrrolidine of Step 253j above was replaced by 4-(1-lo pyrrrolyl)piperidine (~lGpaled from N-benzyl 1-hydroxypiperidine by mesylation followed by displacing the mesyl group with pyrrole and removing the benzyl group), and the reaction product was carried ~lw~rd as in Steps 253K and 2531, above, to prepare 386 mg of the title compound. mp = 268-269~C. IR (KBr): 3420, 1720, 1660 cm~l. MS 427 (M+NH4)+, 410 (M+H)+. lH NMR (CD30D) ~: 0.70 (m, 2H), 1.03 (m, 2H), 2.14 (m, 15 4H), 2.40 (m, lH), 2.90 (s, 3H), 3.60 (m, 4H), 4.18 (m, lH), 6.08 (dd, 2H, J=3 Hz), 6.84 (dd, 2H, J=3 Hz), 8.37 (s, lH), 9.25 (d, lH, J=12 Hz). Calc. for C23H24FN3O3Ol.25 H2O: C, 63.95; H, 6.18; H, 9.73; Found: C, 63.60; H, 6.61; N, 9.43.

Fxamvle 267 l-cyclopropyl-8-(cis-3.5-dimethyl- 1-pi~ d~ yl)-7-fluoro-9-methyl-4-oxo-4H-~uinoli7into-3-~rboxylic acid hydrochloride The 3-BOC-aminopyrrolidine of Step 253j above was replaced by cis-3,5-25 dimethy-lpiperazine (Aldrich Chemical Co.) and the reaction product was calTied forward as in Steps 253j and 253k, above, to prepare 0.46 g of the title compound. IR (KBr):
3450, 1720, 1650, 1610 cm~l. MS 374 (M-Cl)+. IH NMR (D6DMSO) a 0.70 (m, 2H), 1~04 (m, 2H), 1.30 (d, 6H, J=7 Hz), 2.41 (m, lH), 2.80 (s, 3H), 3.40-3.65 (m, 6H), 8~03 (s, lH), 9.26 (d, IH, J=9Hz), 9.60 (br s, lH). Calc. for C20H2sclFN3o3oo~7sH2O: C, 56.74; H, 6.31; N, 9.92; Found: C, 56.66; H, 6.21; N, 9.74.

FY~rnple 268 l-cyclopropyl-8-(2,7-diazabicyclo[3.3.0]oct-2-yl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride The 3-BOC-aminopyrrolidine of Step 253j above was replaced by 7-BOC-2,7-di,aza~3.3.0]octane (~ d according to US Patent 5,071,999) and the reaction product ~!

CA 02222322 1997-11-2~

WO 96/39407 PCT~US96/08991 was carried ru~ wdld as in Steps 253j, k, and 1, above, to prepare 0.34 g of the title compound. IR (KBr): 3400, 1700, 1650, 1605 cm~l. MS 372 (M-Cl)+. lH NMR
(D6DMSO) ~: 0.60 (m, 2H), 0.91 (m, lH), 2.03-2.10 (m, 3H), 2.36 (m, lH), 2.68 (s, 3H), 3.19 (m, lH), 3.49 (m, 2H), 4.15 (m, lH), 5.50 (m, lH), 7.98 (s, lH), 9.14 (d, s lH, J=10 Hz), 9.40 (br s, lH). Calc. for C20H24cl2FN3o3: C, 54.06; H, 5.44; N, 9.46; Found: C, 53.86; H, 5.48; N, 9.63.

Fx~ le 269 1 -cyclopropyl-8-(2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-9-methvl-4-oxo-4H-qllinoli7in~-3-~rboxylic acid hydrochloride The 3-BOC-aminopyrrolidine of Step 253j above was replaced by 8-BOC-2,8-diaza[4.3.0]nonane (p.~,pdr~,d according to US 5,059,597), and the reaction product was carried forward as in Steps 253K and 2531, above, to prepare 0.50 g of the title compound.
lR (KBr): 3400, 1690, 1650, 1600 cm~l. MS 386 (M-Cl)+. lHNMR (D6DMSO)~:
0.56 (m, lH), 0.62 (m, lH), 0.93 (m, lH), 1.07 (m, lH), 1.60-1.80 (m, 4H), 2.28-2.32 (m, 2H), 2.67 (s, 3H), 2.72 (m, lH), 2.94 (m, lH), 3.70 (m, 2H), 3.91 (m, lH), 4.03 (m, lH), 4.35 (m, lH), 7.93 (s, lH), 8.90 (br s, lH), 9.10 (d, lH, J=l l Hz), 9.48 (br s, lH), 13.85 (br s, lH). Calc. for C21H26C12FN3O3: C, 55.03; H, 5.72; N, 9.17; Found:
C, 54.75; H, 5.82; N, 9.38.
Fx~m~le 270 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3(S)-( l -pyrrolyl)-l-pyrrolidinvl)-4H-quinolizine-3-carboxylic acid 2s A mixture of 25 mg 8-(3(S)-aminopyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochll nfle (from Example 257) and 40 mg of sodiurn acetate in 0.7 mL of ethyl acetate was heated to 100~C. To this solution was added 0.009 mL of dimethoxytetrahydloruldn dropwise, and the reaction was stirred at 110~C for S min, then quenched by addition of water. The mixture was ~ ed twice with methylene chloride, and the extract was washed with water, dried over MgSO4 and concentrated. The residue was purified by IJ,c~dlive TLC, eluting with 100: 10 chlorofnrm methz~nol, to give 13.6 mg of the title product as a yellow solid after removal of the solvent. MS 395 (M-Cl)+. 1 H N~IR (CDC13) a 0.67 (m, 2H), 1.00 (m, 2H), 2.20(m, lH), 2.46 (m, lH), 2.56 (m, IH), 2.66 (s, 3H), 3.89 (m, lH), 3.99 (m, 2H0, 4.15 3s (m, lH), 4.86 (m, lH), 6.23 (t, 2H, J=2 Hz), 6.79 (t, 2H, J=2 hz), 8.32 (s, lH), 9.15 (d, lH, J=10 Hz), 13.83 (br, lH).
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~VO 96/39407 PCT~U~96tO8991 Fx~mple 271 l-cyclopropyl-7-fluoro-8-(3-hydroxy- 1 -pyrrolidinyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride - s The 3-BOC-aminopyrrolidine of Step 253j above was replaced by 3-hydroxy-pyrrolidine (Aldrich ~h~mic~l Co.), and the reaction product was carried forward as in Steps 253j and 253k above, to prepare 0.15 g of the title compound. IR (KBr): 3425, 1690, 1650, 1600 cm~l. MS 346 (I~/I+H)+. lH NMR (DMSO-d6) ~: 0.59 (m, 2H), 0.93 (m, lH), 1.03 (m, lH), 1.96-2.01 (m, 3H), 2.29 (m, lH), 2.49 (s, 3H), 3.43 (m, lH), 10 3.69 (m, lH), 4.01 (m, 2H), 4.42 (m, lH), 5.15 (d, lH, J=3 Hz), 7.89 (s, lH), 9.05 (d, lH, J=l l Hz), 13.86 (br s, lH). Calc. for ClgHlgFN2O4: C, 62.42; H, 5.53; N, 8.09;
Found: C, 62.20; H, 5.55; N, 8.09.

F~zlrnple 272 1-cyclopropyl-7-fluoro-8-(4-methyl- 1 -pi~ inyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hvdrochloride The 3-BOC-arninopyrrolidine of Step 253j above was replaced by 1-rnethylpipera_ine (Aldrich C~hem~ Co.), and the reaction product was carried forward as 20 in Steps 253j and 253k, above, to prepare 0.15 g of the title compound. mp = 210-216~C
(dec). MS 360 (M-CI)+. lH NMR (CDC13) ~: 0.70 (m, 2H), 1.02 (m, 2H), 2.28 (m, LH), 2.40 (s, 3H), 2.60 (m, 4H), 2.79 (s, 3H), 3.48 (m, 4H), 8.37 (s, IH), 9.21 (d, lH, J=9 H[z).

2s F~xample 273 1 -cyclopropyl-9-chloro-7-fluoro-8-(3-amino- 1 -pyrrolidinyl)-4-oxo-4H-quinolizine-3-carboxylic acid trifluoroacetic acid salt The 4-t-butoxy-2,3,6-trifluoro-5-methylpyridine of Step 253d above was 30 replaced by 4-t-butoxy-3-chloro-2,5,6-trifluoropyridine (from step 253a above), and the methanol solvent was replace by ben7.~ne, and the reaction product was carried forward as in Steps 253d-1 above, and the 4N HCI in dioxane of Step 2531 was replaced with triflucroacetic acid. to prepare 0.13 g of the title compound. MS 366 (M-CF3CO2)+. 1 H
NMR (D6-DMSO) ~: 0.58 (m, 2H), 0.97 (m, 2H), 2.11 (m, lH), 2.31 (m, lH), 2.44 (m, 35 IH), 3.83 (m, lH), 3.97 (m, 2H), 4.!0 (m, lH), 4.20 (m, lH), 8.09 (s, lH), 8.09 (br, 3H), 9.18 (d, lH, J=l l Hz). Calc. for C17H17CIFN3O3:-CF3COOH-0.5 H2O: C, 46.69; H, 3.92; N, 8.60; Found: C, 46.62; H, 3.64; N, 8.45.

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W O 96/39407 PCT~US~6~9~1 F.xan~le 274 8-(3-amino- 1-pyrrolidinyl)- 1-cyclopropyl-7,9-difluoro-4-oxo-4H-quinolizine-3-carboxvlic acid hydrochlonde Step 274a. 4-t-butoxy-2~3.5~6-tetrafluoropyridine A 15B.5 g (0.938 mmol) sample of pentafluoropyridine (Aldrich ~h~mi~l Co.) was dissolved in 600 mL of THF and cooled to -78~C. To this was added 88.29 g (0.919 mmol) of sodium-t-butoxide in 800 mL of THF over a 30 min period, with stirring and 10 while m~ ;ig the t~,~n~ dLulG at -78~C. The mixture was stirred for another 30 rnin at this te~ dl~.e~ then the ~~ d~UlG of the bath was raised to -20~C, and the reaction was stirred at this ~ Gld~ulG for 64 hours. The reaction mixture was removed from the cold bath and diluted with 1.5 L of ether, then filtered through a di~tQm~reous earth filter aid.
The solvent was removed under vacuum to leave a yellow oil. The oil was purified by vacuum rli~till~tion to afford 141.34 g of the title product.

Step 274b. 4-t-butoxy-'7 ~.5-trifluoropyridine A 20.0 g (0.089 mmol) sample of the product from step 274a above was dissolved in 100 mL of absolute ethanol, and 26.08 mL (0.538 mol) of hydrazine monohydrate was added. The reaction was stirred for 1 hour at room ~GIll~tla~ulG and I
hour at reflux. The solvent was removed under vacuum. The residue was dissolved in ether and washed with water and brine. The organic phase was dried over MgSO4, and the solvent was removed under vacuum to yield a yellow solid. This m~t~ l was dissolved in 120 mL of toluene, 60 mL of 20% sodium hydroxide was added, and air was bubbled through the stirred solution for 18 hours. To the reaction was added 100 mL of ether, and the organic phase was sG~ ed, washed with water and brine, and dried over MgSO4.Removal of the solvent, and purification of the residue with flash clhollla~ography on silica gel, eluting with 1:16 ethyl acetate:hexane, gave 14.6 g of the title product as areddish liquid.
Step 274c. 8-(3-amino- 1 -pyrrolidinyl)- 1-cyclopropyl-7,9-difluoro-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride Replacing the 4-t-butoxy-2,5-difluoro-3-methylpyridine of step 253e with the 4-t-butoxy-2,3,5-trifluoropyridine from step 274b above, and carrying the product forward 3s according to the procedures of Steps 253e-1,76 mg of the title compound was prepared.

-VVO 96/39407 PcT~us96/~&~3l MS l~ 350 (M-CI)+. lH NMR (D6-DMSO) a 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, lH), 8.46 (br, 3H), 9.17 (d, lH, J=9 Hz).
_ Example 275 8-(3-amino- 1-pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methoxv-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride Step 275a. 4-t-butoxv-2.3.6-trifluoro-5-hydroxypyridine A 11.16 g (54.39 mrnol) sample of 4-t-butoxy-2,3,6-trifluoropyridine, from kxample 253 step b above, was dissoved in 50 mL of THF, and the solution was cooled to ~78~C. To this solution was added LDA (65.6 mmol) with stirring for 30 min, during which a solid precipL~d. To this mixture was added 7.5 mL of trimethoxyborane, with stirring for 25 min at -78~C. To this rnLxture was added 10 mL of acetic acid, and the 15 mixture was stirred and allowed to warm to room ~ u~e~ Next was added 100 mL of 30% hydrogen peroxide and 100 mL of 2N sodium hydroxide while cooling in an ice bath.
The mixture was then stirred at room temperature for 16 hours, and quenched withsalu~led NH4Cl solution. The mixture was extracted with ether, and the extract was washed with brine and dried over MgSO4. The solvent was removed under vacuum, and 20 I:he residue was purified by flash chl~,lllatography on silica gel, eluting with 1:8 ethyl ;~cet~te:heY~ne. Removal of the solvent gave 9.769 g of the title product as a colorless llquid.

Step 275b. 4-t-butoxy-2.3.6-trifluoro-5-methoxypyridine To a solution of 237 mg (1.07 mmol) of 4-t-butoxy-2,3,6-trifluoro-5-hydroxypyridine, from step 275a above, in 3 mL of anhydrous THF was added 335 mg~1.277 rnmol)of triphenyl phosphine and 0.060 mL (1.48 mrnol) of methanol. To this solution was added 0.200 mL (1.270 mmol) of DEAD dropwise at room temperature. The reaction was complete in 10 min, so the solvents were removed under vacuum and the 30 residue was purified by flash ~ nlalugraphy on silica gel, eluting with 1: 16 ethyl acetate:hexane to give 215.6 mg of the title product as a colorless liquid after removal of the solvent.

..

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Step 275c. 8-(3-amino- l-pyrrolidinyl)- I -cyclopropyl-7-fluoro-9-methoxy-4-oxo-4H-quinoli7in~-3-carboxylic acid hydrochloride Replacing the 4-t-butoxy-2,3,6-trifluoro-5-methylpyridine of F.x~mple 253 step cwith the 4-t-butoxy-2,3,6-trifluoro-5-methoxypyridine of step 275b above and carrying the product forward according to the procedures of Steps 253d-1, 120 mg of the title compound was ~l~pal~,d. MS M/Z: 362 (M-Cl)+. IR (KBr): 3440, 1799, 1650, 1610 cm~l. lH
NMR (D6-DMSO) ~: 0.62 (m, 2H), 0.91 (m, 2H), 2.12 (m, lH), 2.29 (m, lH), 2.39 (m, lH), 3.62 (s, 3H), 3.81 (m, lH), 3.94 (m, 2H), 4.06 (m, 2H), 7.79 (s, lH), 8.30 (br, 3H), 9.13 (d, lH, J=10 Hz), 13.79 (br, lH). Calc. for Cl8H2oFN3o4-2Hcl-o.sH2o:
C, 48.77; H, 5.23; N, 9.48; Found: C, 48.65; H, 5.19; N, 9.56.

F.x~le 276 1 -cyclopropyl-7-fluoro-9-methyl-8-(3(S)-I,ltLllyla~i--o-l-~yrrolidinyl)-4-oxo-4H-quinoli7.ine-3-carboxylic acid hydrochloride Ste~ 276a. 1 -N-benzyl-3(S)-(BOC-amino)-l~yrrolidine A 4.2 g sample of (3S)-3-BOC-a..~..opyrrolidine (TCI America) and 4.7 mL of triethylamine were dissolved in 75 mL of methylene chlori-1e at room temperature. To this solution was added 2.95 mL of benzyl bromide dropwise, and the reaction was heated at 20 reflux for 6 hours. ~fter cooling, the solution was washed with water, and the solvent was dried and e~,dl,u.dltd to give 5.10 g of the title product as a white solid.

W O 96/39407 PCT~US9~ 931 Step 776b. 1-~-benzyl-3(5)-(methvlamino~-pyrrolidine The 5.10 g sample of 1-N-benzyl-3(S)-(BOC-amino)-pyrrolidine, from step 276a above, was dissolved in 25 mL of THF, and 55.6 g of LiAlH4 (1.0 M in THF) was added.
The mixture was stirred and heated at reflux for 4 hours. The reaction was quenched with 5 water, and the mixture was extracted with methylene chloride. The solvent was washed with water, dried over MgSO4, and removed on a rotary evaporator to yield 2.43 g of the title product.

Step 276c. 1 -N-benzyl-3(S)-(N-BOC-N-methylamino)-~yrrolidine A 2.43 g sample of 1-N-benzyl-3(S)-(methylamino)-pyrrolidine, from step 276b above, was dissolved in 100 mL of a 4: 1 methanol:water mixture, and 3.34 g of di-t-butyl dicarbonate was added in portions. The reaction was stirred at room ~ ,.atul~ for 6 hours. The methanol was removed under vacuum, and the aqueous residue was extracted with methylene chloride. The solvent was washed with water, dried over MgSO4 and15 removed under vacuum. The residue was purified by clm~ at~graphy over silica gel, eluting wtih 100:5:0.5 methylene chlori-le~ n- l:NH4OH to give 3.23 g of the title product.

Ste~ 276d. (S)-(N-BQC-N-methylamino)-pylTolidine The product from step 276c was treated according to the procedure of Example 171 step 5 to remove the benzy ~ e~ g group and afford 2.24 g of the title product as a white solid.

Step 276e. 1-cyclopropyl-7-fluoro-9-methyl-8-(3(S)-methylamino-2s 1-pyrroli(linyl)-4-oxo-4H-~uinolizine-3-carboxvlic acid hvdrochloride Following the procedure of Example 253 step j, replacing the 3-BOC-aminopyrrolidine of that example with the 3(S)-(N-BOC-N-methylamino)-pyrrolidine from step 276d above, and carrying the reaction product forward according to the procedures of Example 253 steps k and 1, a 452 mg sample of the title product was obtained. MS: 360 30 (M-CI)+. ~R (KBr): 3450, 1710, 1650, 1610 cm~l. lH NMR (d6-DMSO): 0.62 (m, 2H), 1.00 (m, 2H), 2.26 (m, lH), 2.33 (m, 3H), 2.65 (s, 6H), 3.75 (m, lH), 3.90 (m, 7.H), 4.05 (m, 2H), 7.94 (s, lH), 9.12 lH, J=10 Hz), 9.18 ( br s, 2H), 13.86 (br s, lH).
- Anal. Calc. for ClgH22FN3O3-HCl-H2O: C, 55.14; H, 6.09; N, 10.15; Found: C, S5.29; H, 5.99; N, 10.18.

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WO 96/39407 PCTnJS96~a~31 F~ le 277 l-cyclopropyl-7-fluoro-9-methyl-8-(3(R)-amino- 1 -pyrrolidinyl)-4-oxo-4H-quinolizine-3-carboxylic acid hvdrochloride s Step 277a. 1-N-benzyl-3(R)-(BOC-amino)-~yrrolidine Following the procedure of Example 276 step a, replacing the (3S)-3-BOC-aminopyrrolidine of step 276a with (3R)-3-BOC-aminopyrrolidine (TCl America), the title compound was ~ ~ed.

Step 277b. 3(~)-(BOC-amino)pyrrolit1ine The benzyl group was removed from the product of step 277a by the procedure of step 276d above, to give the title product.

Step 277c. 1-cyclopropyl-7-fluoro-9-methyl-8-(3(E~)-amino-l-pyrrolidinyl)-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride Following the ~ocedu,c of Example 253 step j, replacing the 3-(BOC-amino)pyrrolidine of that example with the 3(R)-(BOC-amino)-pyrrolidine from step 277b above, and carrying the reaction product froward according to the procedures of Example 253 steps k and 1, a 452 mg sample of the title product was obtained. MS: 346 (M-Cl)+.
IR (KBr): 3440, 1700, 1650, 1610 cm~l. IH NMR (d6-DMSO): 0.59 (m, 2H), 1.00 (m, 2H), 2.15 (m, lH), 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, lH, J=l l Hz). ClgH20FN3O3-HCl-H2O: C, 54.07; H, 5.~0; N, 10.51; Found: C, 54.19; H, 5.65; N, 10.37.
FY~m~?le 278 (3R)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-2H 3H,6H-6-oxo-~vranor2.3.4-ijlquinolizine-5-carboxylic acid hydrochloride Step 278a. (S)-l-bromo-2-methyl-3-(t-butyldimethy1~ilyloxy)~ro~ne To a 9.59 g (62.67 mmol) sample of (S)-(+)-3-bromo-2-methyl- l-propanol (Aldrich Chemical Co.) in 40 mL of DMF was added 4.27 g (62.720 mmol) of imid~7Qle, and the solution was cooled to 0~C. To this cooled solution was added 9.45 g (62.69 .
mmol) of t-butyldimethylsilyl chloride, and the solution was stirred at room temperature for W 0 96/39407 PCT~US~6/~991 16 hours. The reaction solution was poured into water, which was extracted with hexane.
The organic layer was washed with water, satd. brine, dried over MgSO4, and concentrated. The residue was ~ ;lle~ in a kugelrohr ~atus (0.2 mrn Hg, 50~C) toyield 15.00 g of the title product as a colorless liquid.

Stev 278b. (S)- l -iodo-2-methyl-3 -(t-butvldimethylsilyloxy)propane A 15.00 g sample of the product from the precee-ling step was dissolved in 100 mL of acetone, and 42.00 g (5 eq) of NaI was added. This mixture was heated at reflux under N2 for 9 hours. The n~ixture was cooled, filtered, and the filtrate was concentrated.
lo The residue was dissolved in hexane, and the solution was again filtered and concentrated to yield 16.62 g of a colorless liquid. This m:~t~ri~l was ~i.ctilled in a kugelrohr ~)~dlaLuS
(0.2 nnm Hg, 60~C) to give 16.479 g of the title product as a colorless liquid. MS: 315 (M+H[)+. lH NMR (CDC13) a 0.07 (s, 6H), 0.90 (s, 9H, 0.95 (d, 3H, J=7 Hz), 1.65 (m, 11:~), 3.29 (m, 2H), 3.40 (m, lH), 3.54 (m, lH).
Step 278c. 1-f2~3.5~6-tetrafluoro-4-pyridyl)-4-methvly~
A 25.10 g sarnple (0.148 mmol) of p~ n uolopylidine (Aldrich (~h~o.mi~l Co.) and 23.0 mL (0.165 nnrnol) of triethylarnine were dissolved in 150 mL of HPLC grade methylene chloride. To this solution 17.3 mL (0.156 mmol) of N-methylpiperazine were 20 added slowly dropwise at 0~C. The solution was stirred for 16 hours at 0~C, then washed with water, dried over MgS04 and conceni.~tecl to give 36.95 g of the title product as a colorless oil, which solidifed upon standing. MS: 250 (M+H)+. lH NMR (CDC13) a 2.36 (s, 3H), 2/53 (m, 4H), 3.52 (m, 4H).

25 Step 278d. (R)-2-methyl-3-(4-(4-rnethyl~ yl)-3,5,6-trifluoro-2-pyridinyl)- I-pro~anol A 5.03 g (16.00 rnmol) sample of (S)-l-iodo-2-methyl-3-(t-butyldimethyl-silyloxy)propane, from step 278b above, was dissolved in 32 rnL of ether and cooled to -78~C. To this solution was added 19.8 mL (33.66 mmol) of t-buthyllithinm (1.7 M in 30 pentane), and the ~.~ Lul~ was "~i.,t~;"ed at -78~C while stirring for 40 min. The a~ulc was raised to 0~C, and stirring was continued for 30 min. This solution was de~i~n~h-ci the "lithium compound" and was utilized below. ~n a se~a a~e flask 3.99 g (16.01 mmol) of 1-(2,3,5,6-tetrafluoro-4-pyridyl)-4-methylpiperazine, from step 278c above, was dissolved in 50 mL of THF. To the latter solution at -78~C was added via ..

.

CA 02222322 1997-11-2~

WO 96/39407 PCT~US96~'a8991 cannula the solution of the lithium compound. The reaction was stirred at -78~C for 5 min and at room tcn~ldt~c for 30 rnin. The reaction was quenched by :~Ar~itil n of satd.
NH4Cl, and extracted with ether. The extract was washed with satd. brine, dried over MgSO4, and concentrated. The residue was dissolved in 30 mL of THF, and 16.5 mL of tetrabutly~mmonil-m fluoride (1 N in THF) was added. The mixture was stirred for 16 hours and concçntr~te-~ The residue was slurried with water and extracted with methylene chloride. The organic phase was washed wtih water, dried over MgSO4, and concen~ated. The residue was purified by flash ch-ollla~ography on silica gel, eluting with 100:5:0.5 methylene chloride:methanol:NH40H to give 4.037 g of the title product as a 10 colorless viscous oil. MS: 304 (M+H)+. lH NMR (CDC13) a o.ss (d, 3H, J=6.6 Hz), 2.11 (m, lH), 2.35 (s, 3H), 2.53 (m, 4H), 2.63 (m, lH), 2.71 (m, lH), 3.37-3.50 (m, 6H). Anal calc for C14H20F3N3O: C, 55.44; H, 6.65; N, 13.72; Found: C, 55.10; H,6.24; N, 13.72. [a]D=+7.80~ (26~, c=1.68, methylene chloride).

Step 278e. (R)-2-methyl-3-(4-(4-1llclhyll~iperazinyl)-3.5.-difluoro-2-pvridinyl)- 1 -~ropanol A 4.349 g (14.337 mmol) sample of 2-methyl-3-(4-(4-methylpiperazinyl)-3,5,6-trifluoro-2-pyridinyl)-1-propanol, from step 278d above, was dissolved in 20 mL of n-propanol, 3.50 mL (72.15 mmol) of hydrazine hydrate was added, and the reaction was heated at reflux under N2 for 17 hours. Another 1.5 mL of hydld~ e hydrate was added, and the reflux was continued for 15 hours. The solution was concc,,L,dtcd on a rotary evaporator, and the residue was slurried in water, then extracted with methylene chloride.
The solvent was washed with water, dried over MgSO4, and concentrated to give 4.60 g of the title product as a viscous oil. This intermediate hydrazino compound was dissolved in 300 rnL of water, and a solution of 29.78 g of CuS04 in 400 mL of water was added by pipet over a 15 min period. The reaction was then heated at reflux under N2 for 50 min The reaction was cooled to ambient t~ dllllc and the soultion was made basic with NH40H. The solution was extracted with methylene chloride, which was washed withwater, dried over MgSO4 and concentrated. The residue was purified by flash clllunlatography on silica gel, eluting with 100:5:0:5 methylene chloride meth~n~ l:NH40H, to give 3.605 g title product. MS: 286 (M+H)+. lH NMR
(CDC13) a 0.96 (d, 3H, J=6.6 Hz), 2.14 (m, lH), 2.35 (s, 3H), 2.52 (m, 4H), 2.80 (m, 2H), 3.35-3.41 (m, 5H), 3.51 (m, lH), 8.01 (d, lH, J=3.3 Hz). Anal. calc. for C14H21F2N3O: C, 58.93; H, 7.42; N, 14.73; Found: C, 58.59; H, 7.22; N, 14.31.

-W O 96/39407 PCTrUS96/08991 Step 278f. 3(R)-7-fluoro-3-methyl-8-(4-methyl- 1-pi~cldzi"vl)-2.3-dihvdro-4H-pvranor3.2-blpvridine A 3.557 g (12.465 mmol) sample of 2-methyl-3-(4-(4-methyi~ eldzinyl)-3,5,-difluoro-2-pyridinyl)-1-propanol, from step 278e above, was dissolved in 30 mL of s dioxane and added to a dispersion of 1.12 g (37.33 mmol) of NaH (50% dispersion) in 100 mL of dioxane. The mixture was heated at reflux for 19 hours, then conc~n~ tecl to dryness. The residue was slurried with water, and extracted with ether. The extract was ~ashed with satd. brine, dried over MgSO4, and collc~ a~;d. The residue was purified by flash ch~ la~ography on silica gel, eluting with 100:5:0:5 methylene chloride mPth~nol:NH4OH, to afford 2.299 g of the title product. MS: 266 (M+H)+. lH
NMR (CDC13) a 1.07 (d, 3H, J=6.6 Hz), 2.21 (m, lH), 2.38 (s, 3H), 2.49 (m, IH), :2.57 (m, 4H), 2.94 (m, lH), 3.37 (m, 4H), 3.67 (dd, lH, J=9.6, 10.3 Hz), 4.23 (m, IH), 7.90 (d, lH, J=3.3 Hz). Anal calc. for C14H20FN3O: C, 63.38; H, 7.60; N, 15.84; Found: C, 63.58; H, 7.60; N, 15.84.
Step 278g. 3(R)-9-fluoro-3-methyl- 10-(4-methyl- 1-piperazinyl)-2H 3H.6H-6-oxo-pyranor2.3.4-ijlquinolizine-5-carboxylic acid. ethvl ester A 132.7 mg (0.500 mmol) sample of 3(R)-7-fluoro-3-rnethyl-8-(4-methyl-1-lJi~,.d~inyl)-2,3-dihydro-4H-pyrano[3.2-b]pyridine, from step 278f above, was dissolved in 5 mL of THF and cooled to -78~C. To this solution was added 0.22 mL of n-butyl lithium (0.55 mmol, 2.5 M in hexane), and the reaction was stirred at -78~C for 30 min.
To the reaction vessel was added 0.120 mL (0.594 mmol) of diethoxy ethoxymethylen~ nate, and the reaction was stirred for S min at -78~C and at room IR~ cl~Lu~G for 15 min. The solvent was removed, and the residue was dissolved in ethanol. To this was added 1.0 mL of pir~ritlin~ and 0.2 mL of acetic acid, and the solution was heated at reflux for 16 hours. The solvents were removed, and the residue was dissolved in methylene chloride. This solution was washed with water, dried over MgSO4, and concentrated. The residue was hiLula~d with 50:50 ether:hexane, and the solid ~was Isolated, and the filtrate purified by chlull~aLugraphy on silica gel, eluting with 100:5:0:5 methylene chlor -le methanol:NH4OH, to afford a total of 88.9 mg of the title product. MS: 390 (M+H)+. IR 3440, 1710, 1630 cm~l. lH NMR (CDC13) ~: 1.34 (d, 3H, J=7 Hz), 1.42 (t, 3H, J=7 hz), 2.37 (s, 3H), 2.56 (m, 4H), 3.12 (m, lH), 3.55 (m, 4H), 4.02 (dd, lH, J=l l, 6 Hz), 4.28 (dd, lH, J=ll, 4 Hz), 4.41 (q, 2H, J=7 Hz), 8.03 ~s, lH), 9.06 (d, lH, J=9 Hz). Anal calc. for C20H24FN3o4: C, 61.69; H, 6.21; N, CA 02222322 1997-11-2~

W O 96/39407 PCT~US96/08991 10.79; Found: C, 61.42; H, 5.89; N, 10.65. [a]D=-37.14~ (25~C, c=0.28, methylenechloride).

Step 278h. 3(R)-9-fluoro-3-methyl- 10-(4-methyl- 1 -piperazinyl)-2H.3H~6H-6-oxo-pyranor2.3.4-ijlquinolizine-5-carboxylic acid A 657 mg (1.687 mmol) sample of 3(R)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylic acid, ethyl ester, from step 278g above, was dissolved in 6 mL of THF and 142 m~ of LiOH-H2O and 3 mL of water were added. The mixture was heated at 60~C under N2 for 80 min. The solvent was removed under reduced ~-c;s~u,c, and the aqueous residue was diluted with additional water and extracted with methylene chloride. The aqueous solution was then neuralized to ph& with 10% HCl, and extracted with methylene chloride. The extract was washed with water, dried over MgSO4 and conce.,lla~d to dryness. The residue wasdissolved in methylene chloride, which was then filtered through a sintered glass funnel.
The filtrate was concentrated to dryness, and the residue was L~ dl~d with 1: 1 ether:hexane to give 494.2 mg of the title product as a yellow solid after drying. MS: 362 (M+1)+. IR 3440, 1720, 1640, 1610 cm l. 1H NMR (CDCl3) a 1.37 (d, 3H, J=7 Hz), 2.39 (s, 3H), 2.60 (m, 4H), 3.19 (m, lH), 3.61 (m, 4H), 4.06 (dd, lH, J=6.3, 10.6 Hz), 4.34 (dd, lH, J=3.6, 10.6 Hz), 8.15 (s, lH), 8.94 (d, lH, J=8.8 Hz), 13.86 (br, lH).
Anal calc. for C18H20FN3o4 ~O.5H20: C, 59.09; H, 5.65; N, 11.48; Found: C, 59.25;
H, 5.59; N, 11.39.
Step 278i. 3(R)-9-fluoro-3-methyl- 10-(4-methyl- 1-piperazinyl)-2H,3H,6H-6-oxo-pyranor2.3.4-ijlquinolizine-5-carboxylic acid hydrochloride 2s A 200 mg sample of the free base from the previous step was dissolved in 15 mL
of methylene chloride, and 0.75 mL of 1 M HCl in ether was added. Additional ether was added to precipitate the product, which was collected by filtration. The solid was dissolved in water, and the solution was filtered through sintered glass. The filtrate was freeze-dried to give 213.1 mg of the title product as a yellow solid. MS: 362 (M-Cl)+. lR 3440, 1700, 1637, 1603 cm 1. 1H NMR (DMSO-d6) a 1.29 (d, 3H, j=7 Hz), 2.76 (s, 3H), 3.15-3.36 (m, 5H), 3.74 (m, 4H), 4.18 (dd, lH, J=5.7, 10.7 Hz), 4.38 (dd, lH, J=3.7, 10.7 Hz), 8.03 (s, lH), 9.02 (d, lH, J=8.8 Hz). Anal calc. for C18H20FN3o4 ~HCl-H2O: C, 51.99; H, 5.57; N, 10.08; Found: C, 51.91; H, 5.33; N, 10.03. [a]D=-24.2~ (24~C, 0.33, m~-th~nol).

-W 096r39407 PCTrUS96/08991 Fxample 279 3(S)-9-fluoro-3-methyl- 10-(4-methyl- 1 -piperazinyl)-2H ~H.6H-6-oxo-~yranor2.3.4-ijlquinoli7ine-5-carboxylic acid hydrochloride - 5 Ste~ 279a. 2(R)-3-ft-butyldimethylsilyl)oxy-2-methyl-1-~rovanol A 24.39 g (265 mmol) sample of (E~)-(-)-methyl 3-hydroxy-2-methylpropionate (Aldrich Chemical Co.) and 15.46 g (227 mmol) of imidazole were dissolved in 120 m~ of ~MF. The solution was stirred at 0~C under N2 and 34.23 g (227 mmol) of t-butyldimethyl-silyl chloride was added in several portions. The reaction was stirred at 0~C
o for 1 hour and room L~ a~ for 22 hours, then poured into water. The mixture was extracted with hexane, and the extract was washed with water, dried over MgSO4, and concentrated to give 52.51 g of the l lule-;L~d int~-~P~ te The intermediate was dissolved in 100 mL of THF and added via cannula to a flask cont~ining 475 mL of DIBAL in 200 mL of 1~ at -78~C, then stilTed for 15 rnin. The reaction was then warmed to 0~ rapidly 15 and stil~Ted for 2 hours. The reaction was quenched by slowly pouring it into 1 L of satd.
Na2SO4. The mixture was filtered through a filter aid. The organic phase was separated and reserved. The aqueous phase was extracted with ether. The organic phases were c(J~ ed, washed with satd. brine, dried over MgSO4 and conc~ aLed to give a yellow liquid. This m~t~ri~l was ~ tillÇd in a kugelrohr ~paldtus at 0.2 mmHg and 70~C ~o yield 20 19.50 g of the title product. [a]D=-8.12~ (26~C, c=2.02, CH2C12). 1H NMR (CDCl3) a 0.07 (s, 6H), 0.84 (d, 3H, J=7 Hz), 0.90 (s, 9H), 1.94 (m, lH), 2.81 (br, lH), 3.54-3.62 (m, 3H), 3.74 (m, lH).

Step 279b. 2(R)-3-(t-butyldimethyl~ilyl)oxy-1-iodo-2-meth~lvr~ allc A 19.50 g (95.41 mrnol) sample of 2(R)-3-(t-butyldimethylsilyl)oxy-2-methyl-1-propanol, from step 279a above, was dissolved in 100 mL of methylene chloride and 26.6 mL (191 mmol) of triethylamine was added. The solution was cooled to 0~C, 11.0 mL
(142 mmol) of methansulfonyl chloride was added, and the reaction was st~rred for I ho~r.
Slirring was discontinue~, and the reaction was held at -20~C for 16 hours. The reaction 30 was q~l~en~heci with 5% NaHCO3, then extracted with methylene chloride. The extract was washed with water, dried over MgSO4 and concentrated. The residue was chlul..atographed of silica gel, eluting with melthylene chloride, and the solvent was removed to give 25.95 g of the mesylated interme~ tlo This interlnet1i~te was dissolved in 100 mL of ~cetone~ and 55 g of NaI was added. The mixture was heated at reflux for 10 35 hours, then cooled, diluted with hexane, and filtered. The filtrate was conce.-Ll~ltd, the , CA 02222322 1997-11-2~

W O 96/39407 PCT~US96~'~E931 residue redissolved and refiltered, and again concentrated. The residue was distilled in a kugelrohr a~dLus at 0.2 rnmHg and 60~C to yield 18.22 g of the title product. [a]D=-9.39~ (25~C, c=2.46, CH2C12). MS: 332 (M+18)+, 315 (M+H)+. lH NMR (CDC13) a 0.07 (s, 6H), 0.60 (s, 9H), 0.96 (d, 3H, J=7 Hz), 1.64 (m, lH), 3.29 (m, 2H), 3.40 (m, lH), 3.53 (m, lH).

Step 279c. 3(S)-9-fluoro-3-methyl- 10-(4-methyl- 1-piperazinyl)-2H,3H,6H-6-oxo-pyranor2.3.4-ijl~uinolizine-5-carboxy'~ic acid hvdrochloride Following the procedure of Example 278d, substituting the 2(R)-3-(t-butyldirnethylsilyl)oxy-1-iodo-2-methylpropane of step 279b above for the 2(S)-3-(t-butyldimethylsilyl)oxy- 1-iodo-2-methyl~,rupane of step 278d, and calrying the product forward according to Example 278 steps f-i, the title product was prepared. MS 362 (M-Cl)+. IR (KBr): 3440, 1710, 1635, 1610 cm-1. lH NMR (DMSO-d6) ~: 1.29 (d, 3H, J=7 Hz), 2.82 (s, 3H), 3.18 (m, 2H), 3.27 (m, lH), 3.48 (m, 2H), 3.69 (m, 2H), 3.86 (m, 2H), 4.19 (dd, lH, J=6, 11 Hz), 4.49 (dd, lH, J=4, 11 Hz), 8.03 (s, lH), 9.03 (d, lH, J=9 Hz), 11.09 (br, lH), 13.96 (br, lH). Anal calc for ClgH20FN3O4-HCl-1.5H20: C, 50.89; H, 5.69; N, 9.89; Found: C, 50.50; H, 5.46; N,9.72.

Fx~ru; le 280 9-fluoro- 10-(1 -morpholinyl)-2H,3H,6H-6-oxo-pyrano-r2.3.4-ijlquinolizine-5-~rboxylic acid Step 280a. 3-(t-bu~yldimeth~y~ yloxy)-1-iodo~ropane A mixture of 44.28 g (175 mmol) sample of 1-bromo-3-(t-butyldimethylsilyloxy)-propane (pr~,pan,d according to Wilson and Zucker, J. Org. Chem, 33:2571 (1988)) and 100 g of Nal in 200 mL of acetone was heated at reflux for 20 hours, filtered and concl,." l ~ The residue was dissolved in hexane, re-filtered and concentrated. The residue was distilled in a kugelrohr apparatus (0.2-0.3 mm Hg, 60~C) to give 46.87 g of the title product. This m~teri~l was distilled under reduced l~rt~ illlG, and the pure product coming over at 53-57~C and 0.3 mrn Hg was collected. MS: 301 (M+H)+. lH NMR (CDC13) a 0.70 (s, 6H), 0.90 (s, 9H), 1.99 (m, 2H), 3.28 (t, 2H, J=7 Hz), 3.66 (t, 2H, J=6 Hz).

CA 02222322 1997-11-2~

WO 96~9407 PCTrUS96'Ç89~1 Step 280b. 9-fluoro-10-(1-morpholinyl)-2H,3H,6H-6-oxo-~yranor2.3.4-ijlquinolizine-5-.;~l,oxylic acid , Following the procedure of Example 278d, replacing the (2S)-3-(t-butyldimethyl-,; silyloxy)- 1 -iodo-2-methylpropane of that step with the 3-(t-butyldimethylsilyloxy)- l-iodo-5 propane from step 280a above, and carrying the product forward according to the procedures of Examples 278d-h, 20 mg of the title product was obtained. M[S: 335(M +JI)+. IR (KBr): 3440, 1705, 1630, 1610 cm-l. lH NMR (CDC13) a 3.13 (t, 3H, J=55 Hz), 3.58 (m, 4H), 3.85 (m, 4H), 4.42 (t, 2H, J=5.5 Hz), 8.08 (s, lH), 8.94 (d, lH, J=8.8 Hz). Anal. Calc. for C16H15FN2O4~1/8H20: C, 57.10; H, 14.57; N, 8.32;
10 Found: C, 57.07; H, 14.32; N, 8.23.

F~s~n~le 281 (3R)- 10-(3-amino- 1 -pyrrolidinyl)-9-fluoro-3-methyl-2H ~H.6H-6-oxo-pyranor2.3.4-ijlquinolizine-5-carboxvlic acid Ste~ 281 a. ~2R)-3-(4-t-butoxy-3 ~.6-trifluoro-2-pyridinyl)-2-methyl- 1 -prol?anol A 9.38 g (29.85 mrnol) of (S)-l-iodo-2-methyl-3-(t-butyldimethylsilyloxy)-propane, from Step 278b above, was dissolved in 50 mL of ether and reacted with 36.9 mL (1.7 M in pentane, 62.73 mmol) of t-butyl lithium at -78~C for 40 min and at 0~C for 30 20 min. This solution was cooled to -78~C again and added to a stirred solution of 6.70 g (30.02 mmol) sample of 4-t-butoxy-2,3,5,6-tetrafluoropyridine, from Example 274aabove, in 40 mL of ether at -78~C. The reaction was stirred for 5 min, the dry ice bath was removed, and the reaction was stirred at room temperature for 64 hours. The reaction was quenched with satd.NH4Cl, and the mixture was extracted with ether. The extract was 2s washed wtih satd. brine, dried over MgS04 and concen1T~te~ The residue was dissoved in 20 rnL of THF, and 30 mL of a lN solution of tetrabutylammonium fluoride was added.
The reaction was stirred for 5 hours and concc,ll,a~cd. The residue was dissolved in ether, which was washed with water, brine, dried over MgSO4, and concellL~d~ed to dryness.
The residue was flash cl~ol~latugraphed on silica gel, eluting with 1 :3 acetone:hexane to 30 give 5.21 g of the title product as a colorless liquid after removal of the solvent. MS: 278 (M+H)+. lH NMR (CDC13) ~: 0.93 (d, 3H, J=7 Hz), 1.44 (s, 9H), 1.83 (t, llH, J=7 Hz), 2.15 (m, lH), 2.67 (m, lH), 2.8 (m, lH, 3.50 (m, 2H). Anal. Calc. for C13E~IgF3NO2-l/4H20: C~ 55.41; H, 6.62; N, 4.97; Found: C, 55.17; H, 6.30; N, 4.61.

..

CA 02222322 1997-11-2~

WO 96/39407 PCTnUS96/08991 Step 281 b. (2R)-3-(4-t-butoxy-3.5-difluoro-2-pyridinyl)-2-methyl- 1 -propanol Following the procedure of Example 274b, replacing the reactant from step 278a with (2S)-3-(4-t-butoxy-3,5,6-trifluoro-2-pyridinyl)-2-methyl-1-propanol, from step 281a above, 3.44 g of the title product was ~lc~ared. MS: 260 (M+H)+. lH NMR (CDC13) ~:
00.93 (d, 3H, J=7 Hz), 1.42 (m, 9H), 2.16 (m, lH), 2.86 (m, 2H), 2.96 (t, lH, J=7 Hz), 3.40 (m, lH), 3.53 (m, lH), 8.21 (m, IH). Anal. Calc. for C13HlgF2NO2: C, 60.22; H, 7.39; N, 5.40; Found: C, 60.15; H, 7.46; N, 5.22.

Step 281c. 3(R)-7-fluoro-3-methyl-8-(t-butyloxy)-2, 3-dihy-lro-4H-~vranor3.2-blI~yridine A 3.29 g (12.69 mmol) sample of (2R)-3-(4-t-butoxy-3,5-difluoro-2-pyridinyl)-2-methyl-1-propanol, from step 281b above, was dissolved in 100 mL of dioxane and added to a dispersion of 0.570 g (19.00 mmol) of NaH (80% dispersion) in 100 mL of dioxane. The mixture was heated at reflux for 4 hours, then concentrated to dryness. The residue was slurried with water, and extracted with ether. The extract was washed with satd. brine, dried over MgSO4, and concentrated. The residue was purified by flash u~l-alugraphy on silica gel, eluting with 1:2 ethyl acetete h~x~n~, to afford 2.722 g of the title product. MS: 240 (M+H)+. lH NMR (CDC13) a 1.08 (d, 3H, J=6.5 Hz), 1.40 (d,9H, J=lHz), 2.22 (m, lH), 2.55 (m, lH), 2.99 (m, lH), 3.69 (dd, lH, J=9, 10 Hz),4.21 (m, lH), 8.01 (d, lH, J=l Hz). Anal calc. for C13HlgFNO2: C, 66.25; H, 7.58;
N, 5.85; Found: C, 66.35; H, 7.49; N, 6.04.

Step 281d. 3(R)-9-fluoro- 10-hydroxy-3-methyl-2H,3H,6H-6-oxo-pyrzlnor2.3.4-ulquinoli7ine-S-~rboxylic acid. ethvl ester A 400 mg (1.671 mmol) sample of 3(R)-7-fluoro-3-methyl-8-(t-butyloxy)-2,3-dihydro-4H-pyrano[3.2-b]pyridine, from step 281c above, was dissolved in 5 mL of THF
and cooled to -78~C. To this solution was added a solution of 0.80 mL of n-butyl lithium (2.0 mmol, 2.5 M in hexane) and 0.28 mL of LDA (2.00 mmol) (~lc~al~d at -78~C and warrned to 0~C for 15 min), and the reaction was stirred at -78~C for 30 min. To the reaction vessel was added 0.400 mL of diethoxy ethoxymethylenem~lonate, and the reaction was stirred for S min at -78~C and at room ~III,UCl~t~t; for 15 min. 1.7 mL of NNTMS2 (lN in THF) was added, the reaction was warmed to room temperature. then qllen~hed with satd. NH4CI. The mixture was extracted with ether, which was washed, dried over MgSO4 and concentrated. The solvent was removed, and the residue was dissolved in 10 mL of ethanol. To this was added 0.5 mL of DBU and thereaction was W 0 96/39407 PCTrUS96/08991 refluxed for 2 hours, then concentrated to dryness. The residue was dissolved inmethylene chloride, which was then washed with 10% citric acid, water, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel, eluting with 100:10 methylene chlori(le mPthanol. To the residue of the desired fraction s was added 3 mL of trifluoroacetic acid, and the mixture was conce~ tPd il"~ ly.
The residue was washed with ether to leave 307.4 mg of the title product as a yellow solid.
h~S: 308 (M+H)+. lH NMR (DMSO-d6) a 1.25 (d, 3H, J=7 Hz), 1.27 (t, 3H, J=7 hz), 3.19 (m, lH), 4.10 (dd, lH, J-5, 10 Hz), 4.22 (q, 2H, J=7 Hz), 4.33 (dd, lH, J-4, 10 Hz), 9.00 (d, lH, J=8 Hz).

Step 28 le. 3(R)- 10-chloro-9-fluoro-3-methyl-2H,3H,6H-6-oxo-~yranor2.3.4-ul~uinnli7ine-5-carboxylic acid. ethyl ester A 276.1 mg (0.899 mmol) sample of 3(R)-9-fluoro-10-hydroxy-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylic acid, ethyl ester, from step 281d above, was dissolved in 5 mL of methylene chloride, and 0.71 mL (9.17 mmol) of DMF and 0.85 mL of POC13 (9.12 mrnol) were added. The reaction was stilTed for 15 hours and qllPnched with water and ice. The mixture was extracted with methylenechloride, and the extract was washed with water, dried over MgSO4 and concenlla~d. The residue was purified by flash chromatography on silica gel, eluting with 10: 1 methylene chloride:mPth~nnl to afford 180.6 mg of the title product as a yellow solid after removal of the solvent. MS: 326, 328 (M+H)+. lH NMR (CDC13) a 1.40 (d, 3H, J=S hz), 1.43 (t, 3H, 7 Hz), 3.22 (m, lH), 4.21 (dd, lH, J=6, 10 Hz), 4.45 (m, 3H), 8.25 (s, lH), 9.09 (d, lH, J=6 Hz).

Step 281f. 3(R)-10-(3-(N-BOC)amino-1-pyrrolidinyl)-9-fluoro-3-methyl-2H ~H.6H-6-oxo-~vranor2.3.4-ijlquinolizine-5-carboxvlic acid~ ethyl ester A 130.9 mg (0.402 mînol) sample of 3(R)-10-chloro-9-fluoro-3-me~hyl-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylic acid, ethyl ester, from step 28 le above, was dissolved in 5 mL of acetonitrile. To this solution was added 0.24 mL of DBU and 120 mg (0.644 mmol) of 3-(N-BOC)aminopyrrolidine (TCI Arnerica, Inc.), and the reaction was heated at reflux for 8 hours. The solvent was removed, and the residue was dissolved in methylene chloride which was washed with water. The solvent wasremoved and the residue was purified by flash cluumatugraphy on silica gel, eluting with 100:10:0.5 methylene chl(lride:methanol:NH4OH to afford 187.6 mg of the title product as a yellow solid , CA 02222322 1997-11-2~

W 096/39407 PCTAJS~6~'C1~31 Step 28 lg. 3(R)- 10-(3-(N-BOC)amino- l-pyrrolidinyl)-9-fluoro-3-methyl-2H ~ 6H-6-oxo-pyranor2.3.4-ijlquinoli7in~-S-~rboxylic acid A 187.6 mg (0.394 mmol) sample of 3(R)-10-(3-(N-BOC)amino-l-pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylic acid, ethyl ester, from step 28 lf above, was dissolved in 4 mL of THF and 70 mg of LiOH-H2O in 2 mL of water was added. The mixture was stirred under N2 for 8 hours at 60~C. The pH
was adjusted to 6.5 with lN HCI, and the mixture was extracted wtih methylene chloride.
The extract was washed with water, dried over MgSO4 and concellLLdL~d. The residue was purified by flash cluo.na~ography on silica gel, eluting with 100:10:1 methylenechlori-le meth~nol:acetic acid to afford 144 mg of the title product as a yellow solid. MS:
448 (M+H)+. IR (E~Br): 3440, 1710, 1640, 1610 cm~l. IH NMR (CDC13) a 1.32 (d, 3H,J=7 Hz), 1.47 (s, 9H), 2.00 (m, lH), 2.18 (m, lH), 3.11 (m, lH), 3.85 (m, lH), 3/987 (m, 2H), 4.10-4.16 (m, 2H), 4.26 (m, lH), 4.32 (m, lH), 5.06 (m, IH), 7.92 (s, lS lH), 8.80 (d, IH, j=10 Hz). Anal calc. for C22H16FN3O6-H2O: C, 56.77; H, 6.06; N, 9.03; Found: C, 56.70; H, 5.80; N, 8.81.

Step 28 lh. 3(R)- 10-(3-amino- 1 -pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyranor2.3.4-ijlquinolizine-5-.~~rboxylic acid hydrochloride A 115.7 mg (0.259 mmol) sample of 3(R)- 10-(3-(N-BOC)amino-l -pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylic acid, from step 281g above, was dissolved in 3 mL of 4N HCI in dioxane, and the reaction was stirred for 1.5 hours at room telll~JtldLulc~ The solution was conce~ tcd to dryness, and the residue was dried in a vacuum. The residue was dissolved in water, filtered though sintered glass, and freeze-dried to give 97.3 mg of the title product as a yellow solid. MS:
348 (M-CI)+. IR (KBr): 3440, 1690, 1640, 1600 cm~l. IH NMR (DMSO-d6) a 1.27 (d, 3H, J=7 Hz)), 2.10 (m, lH), 2.22 (m, IH), 3.20 (m, lH), 3.88 (m, lH), 3.99 (m, 2H), 4.10-4.16 (m, 3H), 4.27 (m, lH), 7.82 (s, lH), 8.95 (d, lH, J-10 Hz). Anal calc.
for C17HlgFN3O4-0.5H20-2HCl: C, 47.57; H, 4.93; N, 9.79; Found: C, 47.72; H, 4.81; N, 9.58.

VVO 96/39407 PCTAJS96,'0~331 Step 281 i. 3(R)- 10-(3-amino- 1 -pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyranor2.3.~ijlquinolizine-5-carboxylic acid A 50 mg sample of the hydrochloride salt from step 281h was dissolved in 5 mL
of water, and satd. NaHCO3 was adde until the solution was pH 7. The solid (27.8 mg) s was collected by filtration, and t'ne filtrate was extracted with 10% methanol in methylene chloride and methylene chlonde. The extract was washed, dried and concentrated to afford a second crop of product. MS: 34$ (M+H)+. IR (KBr): 3440, 1650, 1640, 1600 cm~l.lH NMR (DMSO-d6) a 1.25 (d, 3H, J=7 Hz), 1.68 (m, lH), 1.95 (m, lH), 3.16 (m, lH), 3.55 (m, 2H), 3.94-4.05 (m, 4H), 4.25 (m, lH), 7.74 (s, lH), 8.89 (d, lH, J=l l Hz). Anal calc. for C17HlgFN3O4-l.5H2O: C, 54.54; H, 5.57; N, 11.23; Found: C, 54.78; H, 5.31; N, 11.05.

Fx~ >le 282 3(R)- 10-(3-aminomethyl- 1 -pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo-~yranor2.3.4-ul~luinolizine-5-carboxylic acid hvdrochloride Following the procedure of Example 281f, replacing the the 3-(BOC-amino)pyrrolidine of that step with 3-(BOC-amino)methylpyrrolidine (~ ~cd according to EP pllhli~htoA application 0106489), and carrying the product fu~ d according to steps 281g and h, 118 mg of the title compound was p~ d. MS: 362 (M-Cl)+. lR (KBr):
3440~ 1640, 1600 cm~l. lH NMR (DMSO-d6) a 1.25 (d, 3H, J=7 Hz), 1.72 (m, lH), 2.10 (m, lH), 2.53 (m, lH), 2.94 (rn, 2H), 3.16 (m, lH), 3.76 (m, lH), 3.96 (m, 2H), 4.05 ~m, 2H), 4.25 (m, lH), 7.77 (s, lH), 8.12 (br, 4H), 8.90 (d, lH, J=10 Hz), 13.92 (br, lH). Anal calc. for C18H26FN3O4O2Hcl: C, 49.78; H, 5.11; N, 9.68; Found: C,49.9û; H, 5.04; N, 9.74.

F~mple 283 3(R)- 10-((2S ,4S)-4-amino-2-methyl- 1 -pyrrolidinyl)-9-fluoro-3-methyl-2H.3H.6H-6-oxo-pyranor2.3.4-ijl~uinolizine-5-carboxvlic acid hydrochloride Following the procedure of Example 281f, replacing the the 3-(BOC-amino)pyrrolidine of that step with (2S,4S)-~BOC-amino-2-methylpyrrolidine (fromExample 171, step 5), and carrying the product forward according to steps 281g and h,57 rng of the title compound was prepared. MS: 362 (M-CI)+. IR (KBr): 3440, 1700, 1635, 3s 1610 cm~l. lH NMR (DMSO-d6) ~: 1.20 (d, 3H, J=6 Hz), 1.28 (d, 3H, J=7 Hz), 1.92 ~m, lH), 2.37 (m, lH), 3.22 (m, lH), 3.77 (m, lH), 3.91 (m, lH), 4.09 (m, lH), 4.34 ..

CA 02222322 1997-11-2~

WO 96/39407 PCT~US96/08991 (m, 2H), 4.82 (m, lH), 7.88 (s, lH), 8.28 (br, 4H), 9.00 (d, lH, J=10 Hz), 13.94 (br, lH). Anal calc. for ClgH26FN3O4~2HCl: C, 49.78; H, 5.11; N, 9.68; Found: C, 49.78; r H, 5.04; N, 9.73.

Fx~ le 284 3(R)-9-fluoro- 10-(3-hydroxy- 1 -pyrrolidinyl)-3-methyl-2H,3H,6H-6-oxo-pyranor2.3.4-ijlquinoli7ine-5-carboxylic acid Followirlg the procedure of Example 281f, replacing the the 3-(BOC-amino)pyrrolidine of that step with (3-hydroxypyrro'~idine (Aldrich Ch~mi~l Co.), and carrying the product forward according to step 281 g, 69 mg of the title compound was prepared. MS: 349 (M+H)+. 1H NMR (DMSO-d6) a 1.24, 1.26 (two d, 3H, J=6 Hz), 1.80 (m, 2H), 3.16 (m, lH), 3.69 (m, lH), 3.92 (m, lH), 4.06 (m, 3H), 4.26 (dd, lH, J=10, 4 Hz), 4.36 (m, lH), 5.09 (d, lH, J=3 Hz), 7.76 (s, lH), 8.90 (d, lH, J=10 Hz), 13.94 (br, lH). Anal calc. for C17H17FN2O5: C, 58.62; H, 4.92; N, 8.04; Found: C, 58.23; H, 4.91; N, 7.81.

P~ ?le 285 9-fluoro- 10-(4-methyl- 1-~ azinyl)-2H 3H,6H-6-oxo-pyranor2.3.4~ uinoli7ine-5-~~~rboxylic acid hydrochloride Step 285a. 9-fluoro- 10-(4-methyl- 1 -pi~ lyl)-2H,3H,6H-6-oxo-pyranor2.3.4-ijlquinolizine-5-carboxvlic acid Following the procedure of Example 281f, replacing the the 3-(BOC-amino)pyrrolidine of that step with N-methylpiperazine (Aldrich ~hernic~l Co.), and carrying the product forward according to step 281f and Example 278 step h, 69 mg of the titie compound was prepared. MS: 348 (M+H)+. lH NMR (CDC13) a 2.39 (s, 3H), 2.57 (m, 4H), 3.12 (t, 2H, J=6 Hz), 3.60 (m, 4H), 4.40 (t, 2H, J=6 Hz), 8.10 (s, lH), 8.94 (d, lH, J=9 Hz), 13.87 (s, lH). Anal calc. for C17HlgFN3O4-0.5H2O; C, 57.30;
H, 5.37; N, 11.79; Found: C, 57.71; H, 5.23; N, 11.41.

Step 285b. 9-fluoro-10-(4-methyl-1-pi~ inyl)-2H,3H,6H-6-oxo-py-ranor2~3.4-ijl~uinoli7in~-s-r~rboxylic acid hydrochloride Following the procedure of Example 278i, replacing the compound of step 278h 3s with the 9-fluoro- 10-(4-methyl- 1 -piperazinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylic acid, from step 285a above, the title compound was ~ie~al~,d.

_ WO 96/39407 PCTrUS9~la59~1 Examples 286-296 Following the procedures of Steps 253j, 253k and 2531 (if required), above, 5 replacing ~e 3-BOC-aminopyrrolidine of Step 253j with the reagent shown, the compounds of Examples 286-296 are prepared as shown in Table 11, below.

Table 11 ~NJ~cooH
R2J~

CH3~
(continued . . . ) F x. No . Reagent R2 286 1~3-dimeth~ e H3C--N N--287 3-(N-BOC-N-methyl)aminopiperidine ~N--288 2-(N-BOC-~min-~methyl)morpholine 0/--\N--289 3(S)-(N-BOC-N-methylarnino)-pyrrolidine ~N--290 3-((N-BOC-N-methylamino)methyl)-pyrrolidine ~CN~

-WO 96/39407 PCTrUS96/08991 291 3-((N-BOC-N-ethylamino)methyl)-pyrrolidine _~CN--292 2-BOC-octahydropyrrolo[3,4-c]pyrrole H NXN--293 5-BOC-octahydropyrrolo[3,4-c]pyridine ~CN--HN

294 cis-3-BOC-amino-4-methylpyrrolidine CH3 $~N--295 ~rans-3-BOC-amino-~methylpyrrolidine CH3~.~N--296 7-amino-5-azaspiro[2.4]heptane $~N

Example 297 8-(2S,4S-4-amino-2-methylpyrrolidinyl)- 1-cyclopropyl-7-fluoro-9-(fluoro)methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride s Following the procedure of FY~mrle 253c, reacting the product of Step 253b with LDA at -78~C, then adding formaldehyde and stirring until the reaction is complete, followed by reaction of the newly formed interm~ te with diethylaminosulfur trifluoride (DAST) in methylene chloride to form the intPrme~ t~ product 4-t-butoxy-2,3,6-trifluoro-10 5-(fluoro)-methylpyridine, and carrying this product through the remaining steps as in Example 253d-1, the title compound is prepared.
Example 298 8-(3-Dimethylaminopyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methvl-4-oxo-4H-quinolizine-3-carboxvlic acid~ acetic acid salt A 81 mg sample of 8-chloro- 1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in 2.5 W O 96/39407 PCTrUS96/08991 nnL of dry pyridine under a nitrogen a~nosphere. To this solu~on was added a solution of 114 g of 3-(dimethylamino)pyIrolidine in 2.5 mL of pyridine, andl the reaction mixture was heated at 60~C for 39 hours. The pyridine was removed under vacuum. and the residue was stirred with lN NaOH in THF/water for at 60~C for 6 hours. The solution was made acidic with acetic acid, and the product was extracted with chloroform. After drying over MgSO4, the solvent was removed, and the residue was purified by cl~o.l.a~ugraphy on silica gel, eluting with 100:40:20:8 chl~.lor,llll: m.othz~nol: ace~ic acid:water to give the title product. mp 165-170~C (dec.). MS 374 (M+H)+; lH NMR(D6-DMSO) a: 0.53 (m, 2H), 0.82-1.08 (m, 2H), 1.75 (s, 3H), 2.22 (s, 6H), 2.08-2.33 10 (m, 2H), 2.74 (m, 2H), 3.44-3.94 (m, 5H), 8.01 (br s, lH), 8.90 (br s, lH).

Fx~rnple 299 (3R)-8-(3-Dimethylaminopyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quino~zine-3-carboxylic acid hydrochloride Following the procedure of Example 298, replacing the 3-(dimethylamino)-pyrrol;dine with (3R)-3-(dimethylamino)pyrrolidine, the title compound was ~lG~ ,d. mp 146-148~C. MS 374 (M+H)+; lH NMR (D6-DMSO) a 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, lH)~ 9.12 20 (d, lH:, J=ll Hz), 11.14 (br s, lH), 13.83 (br s, lH).

F.xample 300 (3R,1 S)-8-(3-(1 -Aminoethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methvl-4-oxo-4H-quinolizine-3-~rboxylic acid hvdrochloride A sample of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl~-oxo-4H-quinolizine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in anhydrousace~llillile, reacted with (3R,lS)-3-(1-(t-butoxycarbonylamino)ethyl)pyrrolidine (~ al~,d as described by Schroeder et al., J. Heterocyclic Chem., 29: 1481- 1498 (1992)), and carried forward as described in Example 253k-1 to give the title product. mp 250-255~C
(dec.). MS 374 (M+H)+; IH NMR (D6-DMSO) a o.s9 (m, 2H), 1.00 (m, 2H), 1.29 (d, 3H, J=6 Hz), 1.77 (m, lH), 2.13 (m, lH), 2.29 (m, IH), 2.41 (m, IH), 2.64 (s, 3H), 3.57 (s, lH), 3.76 (m, 3H), 3.94 (m, lH), 7.91 (s, lH), 8.17 (brs, 3H), 9.07 (d, lH, J=11 Hz), 13.83 (brs, lH).

CA 02222322 1997-11-2~

W O 96/39407 PCT~US96/08991 Fxzlm~le 301 (3S,lR)-8-(3-(1-Aminoethyl)pyrrolidinyl)-l-cyclopropyl-7-fluoro-9-methyl-~oxo-4H-quinolizine-3-carboxylic acid hydrochloride A 0.44 g sample of 8-chloro- 1-cyclopropyl-7-fluoro-9-methyl~oxo-4H-quinolizine-3-carboxylic acid ethyl ester, from Example 253i above, and 1.51 g of NaHCO3 were dissolved in 40 mL of anhydrous acetonitrile, reacted with (3S,lR)-3-(1-(t-butoxycarbonylamino)ethyl)pyrrolidine (1.06 g, prepared as described by Schroeder et al., J. Heterocyclic Chem., 29: 1481-1498 (1992)), and carried forward as described in Example 253k-l to give the title product. mp 235-240~C (dec.). MS 374 (M+H)+; lHNMR (D6-DMSO) a o.ss (m, 2H), 1.00 (m, 2H), 1.29 (d, 3H, J=6 Hz), 1.76 (m, lH), 2.13 (m, lH), 2.28 (m, lH), 2.41 (m, lH), 2.63 (s, 3H), 3.30 (m, lH), 3.74 (m, 3H), 3.94 (m, lH), 7.90 (s, lH), 8.16 (br s, 3H), 9.07 (d, lH, J=l l Hz).

Fxam~l?le 302 (3R,1 R)-8-(3-(1 -Aminoethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-~oxo-4H-quinolizine-3-carboxylic acid hvd~iochloride A 0.35 g sample of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester, from Example 253i above, and 0.73 g of sodium bicarbonate were dissolved in 24 mL of alhydrous aceto,~ ;le, reacted with (3R,lR)-3-(1-(t-butoxycarbonylamino)ethyl)-pyrrolidine (0.51 g, prepared as described by Schroeder et al., ~. Heterocyclic Chem., ~: 1481-1498 (1992)), and carried forward as described in Example 253k-1 to give the title product. mp 220-222~C. MS 374 (M+H)+; IH NMR
(D6-DMSO) a 0.61 (m, 2H), 0.94 (m, lH), 1.07 (m, lH), 1.28 (d, 3H, J=6 Hz), 1.82(m, lH), 2.27 (m, 2H~, 2.46 (m, lH), 2.62 (s, 3H), 3.57 (s, lH), 3.92 (m, lH), 7.90 (s, lH), 8.17 (br s, 3H), 9.07 (d, lH, J=ll Hz), 13.84 (brs, lH).

F.Y~,nple 303 1-cyclopropyl-8-((R,S)-3-fluoropyrrolidine)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3 - carboxylic acid Step 303a. N-CBZ-~R.S)-3-hydroxypylTolidine (R,S)-3-hydroxypyrrolidine (1.0 g, 0.011 mmol) was dissolved in ethyl acetate (50 mL) and to this solution at room temperature was added N-(benzyloxycarbonyl)succi~.~imide (2.86 g, 0.011 mmol). The mixture was stirred overnight W 0 96/39407 PCTrUS96,'~31 then partitioned between dilute aqueous HCl and ethyl acetate. The aqueous phase was extracted witn ethyl acetate (2x). The organics were cnmbin~l, dried (MgSO4) andconcentldled in vacuo. The crude product was purified by flash cll,o~ ography on silica gel (e~hyl acetate-hexane) to give the desired compound as a clear oil, 2.1 g, 83%. MS
S (DCI/NH3) m/z: 222 (M+H)+, 239 (M+NH4)+ lH NMR (CDC13) d: 1.85-2.10 (m, 2H), 3.37-3.65 (m, 4H), 4.44-4.55 (m, lH), 5.15 (s,2H), 7.28-7.45 (m, SH).

Step 303b. N-CBZ-(R.S)-3-fluoropyrrolidine The compound from step 303a above (32.01gm, 9.10mmole) was dissolved in 10 aLnhydrous CH2C12 (40 mL) and cooled under nitrogen to -78 C. To the cold solution was a1dded in one portion via syringe dietnylaminosulfur trifluo~i-le (DAST) (1.32 mL, 10.0 rnrnol), and the r~s--lting solution was stilred overnight at room temperature. The product was isolated by conce..L,d~ g the reaction mixture in vacuo with flash cl~lul,la~graphy of the residue on silica gel(ethyl acetate-hexane) to give a clear oil, 1.53gm, 75%. MS
(DCVNH3) m/z: 224 (M+H)+, 241 (M+NH4)+ lH NMR (CDCl3) ~: 1.83-2.15 (m,lH), 2.16-2..35 (m, lH), 3.43-3.90 ( m, 4H), 5.21-5.24 (m, 2.5H) 5.28-5.36, (m, 0.5H), 7.28-7.5 (m,5H).

SteD 303c. (R ~)-3-fluoro~yrroli-line hydrochloride The compound from step 303b above (1.53 g, 6.85 mmol) was dissolved in methanol (50 mL) to which was added 5% Pd/BaSO4 (0.5g). The m~xture was vacuum degassed (3x) then exposed to a low ~ s~.u,e atmosphere of hydrogen (balloon) at room lel~ d~lllC for 4 hours. The reaction was l~ l by vacuum filtration to remove catalyst. The filtrate was cooled in an ice bath, then HCl gas was bubbled into the cold solution for one minute. The res-lhing solution was conce,,LIc-Lt;d in vacuo, and the residue was ~ ed with ethyl acetate-ether. The solid was collected by vacuum filtration to give 0.659 g, 76%, of the hydrochloride as an off white solid. IHNMR (CD30D) d: 2.1-2.46 (m, 2H), 3.33-3.65 (m, 4H), 5.43 (db.t., lH, JF,H=51Hz).

Step 303d. 1-cyclopropyl-8-((R,S)-3-fluoropy~rrolidine)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carbcxvlic acid The N-boc-3-aminopyrrolidine of Example 253j above was replaced by the (R,S)-3-fluoro pyrrolidine hydrochloride of step 303c above (0.66 g, 5.24 mrnol), and the reaction product was carried folwald as previously described to give 0.326 g (65%) of the CA 02222322 1997-11-2~

W 096/39407 PCT/U~.~'/AQ991 title compound as a bright yellow solid. mp 227.5-230~C (dec.). MS (DCVNH3) m/z: 349 (M+H)+. lH NMR( CDC13) d: 0.58-0.78 (cm, 2H), 0.85-0.98, (cm,lH) 1.04-1.16 (cm, lH), 2.03-2.53 (cm, 3H), 2.67 (s,3H), 3.60-3.86 (cm, 2H), 4.05-4.26 (cm, 2H), 5.43 (db.t, lH, JF,H=52Hz), 7.26 (s,lH), 8.26 (s, lH), 8.26 (s,lH), 9.08 (d, lH, J-lO.SHz), 13.8 (br.s., lH). Calc. for C1gHlgN2O3F2: %C, 62.05; H, 5.22; N, 8.04.
Found: %C, 62.06; H, 5.22; N, 7.86.

Example 304 8-(4-(1 -piperidyl)- 1 -piperidyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid A 70 mg sample of 8-chloro- 1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-qllino!i7ine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in 2 nL
of anhydrous acetonitrile, reacted with 4-(1-piperidyl)piperidine (70 mg, 0.4 mmol, 5 Aldrich Chem. Co.), and carried forward as described in Example 253j-k to give the title product. MS 428 (M+H)+; lH NMR (CDC13) a 0.69 (m, 2'~), 1.02 (m, 2H), 1.18 (m, 4H), 2.27 (n, lH), 2.78 (s, 3H), 2.72 (m, lH), 3.35 (m, 3H), 3.55 (m, lH), 3.75 (m, lH), 8.36 (s, lH), 9.20 (d, lH). Anal. Calcd for C24H30N303F-l.S H20: C, 63.42; H, 7.32; N, 9.24; Found: C, 62.99; H, 7.04; N, 8.78.
Example 305 8-(4-(1 -piperidyl)- 1 -piperidyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid trifluoroacetic acid salt 2s A 100 mg sample of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in 3 mL
of anhydrous acetonitrile, reacted with 4-(4-piperidyl)-piperidine (0.24 g, 0.93 mmol, obtained from Aldrich Chem. Co.), carried forward as described in Example 253j-k and converted to the TFA salt by the procedure of Example 162 to give the title product. MS
428 (M+H)+; IH NMR (CDC13) ~: 0.69 (m, 2H), 1.03 (m, 2H), 1.70 (m, 2H), 1.87 (m,2H), 1.98 (m, 2H), 2.14 (m, 2H), 2.27 (m, lH), 2.77 (s, 3H), 2.91 (m, 2H), 3.33 (m, 2H), 3.54 (m, 4H), 8.37 (s, lH), 9.21 (d, lH). Anal. Calcd for C24H30N3OsF4-1.5 H2O: C, 54.93; H, 6.03; N, 7.39; Found: C, 54.97; H, 5.39; N, 7.24.

W 096~9407 PCTrUS96108991 Fx~mrle 306 ~, 8-(4-(2-pyridyl)- 1 -piperazinyl)- 1 -cyclopropyl-7-fluoro-9-methyl~-oxo-4H-quinolizine-3-~rboxylic acid A 60 mg sample of 8-chloro- 1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in 2 mL
of anhydrous acetonitrile, reacted with 4-(2-pyridyl)pipera~ine (63.5 mg, 0.39 mlmol, Aldnch Chem. Co.), and canied forwald as described in Example 253j-k to give ~he title product. MS 423 (M+H)+; lH NMR (CDC13) a 0.71 (m, 2H), 1.05 (m, 2H), 2.30 (m, o lH), 2.86 (s, 3H), 3.59 (m, 4H), 3.78 (m, 4H), 6.76 (m, 2H), 7.57 (m, lH), 8.25 (m, lH), 8.40 (s, lH), 8.25 (d, lH), 13,83 (bs, lH). Anal. Calcd for C23H23N4O3F-1.5H2O: C, 61.46; H, 5.83; N, 12.46; Found: C, 61.76; H, 5.54; N, 11.64.

Fxarn,ple 307 8-((2-arnino)thioethoxy)- 1-cyclopropyl-7-fluoro-9-methyl-1 oxo-4H-quinolizine-3-carboxylic acid trifluoroacetic acid salt A 50 mg sample of 8-chloro- 1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in 2 mL
20 of anhydrous ~cetQnitril~, reacted with N-BOC-2-aminothiol (57.4 mg, 0.32 mmol, JalGd by standard procedures from the ~ ~ct~d compound obtained from Aldrich Chem. Co.), carried forward as described in Example 253j-k, dep~ute~,~ed as in step 2531, and converted to the TFA salt by the procedure of Example 162 to give the title product.
MS 337 (M+H)+; lH NMR (d6-DMSO) a 0.74 (m, 2H), 1.08 (m, 2H), 3.04 (t, 2H), 25 3.16 (s, 3H), 3.33 (t, 2H), 8.27 (s, lH), 9.32 (d, lH), 13.8 (br, lH).

F.xarn~ple 308 (3R,1 S)-8-(3-(1 -amino)propyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-~arboxylic acid hydrochloride A 147 mg sample of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in 3 mL
of anhydrous ac~ ile, reacted with (3R,lS)-3-(1-BOC-amino)propyl)pyrrolidine (326 mg, 1.13 mmol, prG~ ,d as described by Hayakawa et al., U.S. Patent 5,098,912, issued . 35 March 24, 1992, using modifications for chiral products described by Plummer, et al.
Tetr. Lett. ~L:7529-32 (19g3)), and carried forward as described in Example 253j-1 to give the title produc~ MS (high resolution) found: 388.2039; calc: 388.2036 (M+H)+; lH

CA 02222322 1997-11-2~

W O 96/39407 PCTAUS96/03~1 NMR (D6-DMSO) a 0.60 (m, 2H), 1.00 (t, 3H), 1.01 (m, 2H), 1.63 (m, 2H), 2.13 (m,lH), 2.29 (m, 2H), 3.73 (m, 3H), 3.95 (m, lH), 7.96 (s, lH), 8.00 (b m, 2H), 9.08 (d, lH), 13.83 (b s, lH). Anal. Calcd for C21H27N3O3FCl-0.5 H2O: C, 58.13; H, 6.74;
N, 9.68; Found: C, 58.24; H, 6.51; N, 9.71.
Example 309 (3R,1 S)-8-(3-(1 -(N-methyl)amino)propyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxYlic acid hydrochloride A 492.9 mg sample of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in 8 mL
of anhydrous acetonitrile, reacted with (3R,lS)-3-(1-(N-methyl)amino)propyl)pyrrolidine (501 mg, 3.53 mmol, ~.~,p~.,d as described by Hayakawa et al., U.S. Patent 5,098,912, issued March 24, 1992, using mo~lifir~tinns for chiral products described by Plummer, et al. Tetr. Lett. 34:7529-32 (1993)), and carried forward as described in Example 253 j-l, omitting the d.,~lo~ g step, to give the title product. MS 402 (M+H)+; lH NMR (D6-DMSO) a 0.61 (m, 2H), 0.98 (t, 3H), 1.00 (m, 2H), 1.75 (m, SH), 2.15 (m, lH), 2.30 (m, lH), 2.59 (s, 3H), 2.63 (s, 3H), 3.66 (m, lH), 3.77 (m, 2H), 3.95 (m, lH), 7.90 (s, lH), 8.60 (bs, 2H), 9.08 (d, lH), 13.83 (bs, lH) Anal. Calcd for C22H29N3O3FCl-H2O: C, 57.95; H, 6.85; N, 9.22; Found: C, 58.24; H, 6.58; N, 9.30.

Example 310 (3R,1 S)-8-(3-(1 -amino-3-methylpropyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride A 171 mg sample of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in 4 mL
of anhydrous acetonitrile, reacted with (3R,lS)-3-(1-amino-3-methylpropyl)pyrrolidine (400 mg, 1.32 mmol, p.~,p:~d as described by Plummer et al., Tetr. Lett. 34:7529-32 (1993), and carried forward as described in Example 253j-1, omitting the deprotection reaction, to give the title product. MS (high resolution) found: 402.2174; calc: 402.2193 (M+H)+; lH NMR (D6-DMSO) a 0.60 (m, 2H), 0.95 (d, 3H), 1.06 (d, 3H), 1.75 (m, lH), 2.13 (m, lH), 2.29 (m, 2H), 2.50 (s, 3H), 3.66 (m, 3H), 3.78 (m, lH), 3.97 (m, IH), 7.88 (s, lH), 9.08 (d, lH), 13.82 (bs, lH). Anal. Calcd for C22H29N3O3FCI-0.75 H2O: C, 58.53; H, 6.81; N, 9.31; Found: C, 58.88; H, 6.70; N, 9.26.

U10 96/39407 PCTrUS9G~9~1 F~ mple 311 8-(3-(1 -aminocyclopropyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methvl-~oxo-4H-quinolizine-3-~rboxylic acid hydrochloride .

A 98 mg sample of 8-chloro- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-qLuinolizine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in 2 mL
of anhydrous acetoni~ , reacted with l-(N-BOC-arnino)cyclopropyl)pyrrolidine (172 mg, 0.76 mmol, prepared as described by Hayakawa et al., U.s. Patent 5,098,912, issued March 24, 1992), and carried forward as described in Example 253j-1 to give the title o product. MS (high resolution) found: 386.1893; calc: 386.1880 (M+H)+; 1 H NMR (D6-DMSO) a 0.60 (m, 2H), 0.91 (m, 5H), 1.04 (m, lH), 1.67 (m, lH), 2.04 (m, lH), 2.29 (]m, 2H), 2.61 (s, 3H), 3.70 (m, 3H), 3.93 (m, lH), 7.90 (s, lH), 8.43 (bs, 2H), 9.08 (d, lH), 13.82 (s, lH). Anal. Calcd for C22H29N3O3FC1: C, 59.55; H, 6.12; N, 9.80;
Found: C, 59.78; H, 5.97; N, 9.69.
F.xample 312 (3R,1 S)-8-(3-(1 -amino-2-hydroxyethyl)pyrrolidinyl)- l-cyclopropyl-7-fluoro-9-methyl~-oxo-4H-quinolizine-3-~rboxylic acid hydrochloride 20 Step 312a. (S)-N-BOC-O-(methoxymethvl)serine methvl ester A 7 g (31.96 rnrnol) sample of ((S)-N-BOC-serine methyl ester (obtained from A~ldrich) was dissolved in CH2C12 and cooled in an ice bath. To this stirred solution was added dropwise 2.83 g (35.16 mmol) of methoxymethyl chloride, followed by dropwise addition of 4.544 g (6.12 mL, 35.16 mmol) of diisopropylethylamine. After all reagents 25 were added the reaction was stirred for 16 hours at room ~ dlUlt;. The solution was washed with 0.5 % HCl, satd. NaHCO3, H2O, and brine, dried over MgSO4 and filtered.
The solvent was removed to leave a yellow oil. The residue was purified by cl.ro,llalography on silica gel, eluting with 15-20% ethyl acetate:hexane to afford 6 g of title product after removal of the solvent. MS 264 (M+H)+; 1 H ~R (C -C!~) ~: ! .47 (s, 30 9H), 3.31 (s, 3H), 3.74 (dd, lH), 3.79 (s, 3H), 4.00 (dd, lH), 4/45 (b M, lH), 4.60 (s, 2H), 5.43 (b m, lH).

Sle~ 312b. 2-(BOC-arnino)-3-(methoxymethoxv)- 1 -propanol A solution of the compound from step 312a above (5.202 g, 19.78 mmol) in 15 35 mL of THF was added dropwise to a cooled (ice bath) suspension of 570 mg (14.84 -CA 02222322 1997-11-2~

W O 96/39407 PCTrUS~ 331 mrnol) of LAH in 15 mL of THF under N2 atmosphere. The mixture was stirred for 1.5 hours, the reaction was quenched with water and 50% NaOH, filtered, and the filtrate evaporated to obtain the crude product. A yellow oil was obtained, which was purified by chromatography on silica gel, eluting with 35-40% ethyl acet~te-h~xane to give 3.475 g of 5 the title product as a colorless oil. MS 236 (M+H)+

Step 312c. 2-(BOC-amino)-3-(methoxymethoxy)- 1 -propanal To a solution of the compound from step 312b above (3.47 g, 14.77 mmol) in 7 mL of DMSO cooled to 0~C was added dropwise 6.8 mL (48.74 mmol) of triethylamine.
Pyridine-SO3 complex (7.05 g, 44.31 mmol) was dissolved in 27 mL of DMSO and added to the first solution, and the reaction was stirred for one hour after the addition was complete. The solution was poured into 120 mL of cold brine, and the mixture waswashed 3x with ethyl acetate. The extract was washed with water, dried over MgSO4, filtered and the solvent was removed under vacuum to give 6 g of a yellow oil, which was taken directly to the next step.

Step 312d. 4-(BOC-amino)-5-(methoxymethoxy)-2-pentenoic acid ethyl ester To a solution of the compound from step 312c above (14.77 mmol) in 42 mL of CH2Cl2 and cooled in an ice bath was added dropwise 5.454 g (15.66 mmol) of (carboethoxymethylene)t~iphenylphosphorane in 56 mL of CH2Cl2. After addition was complete, the reaction was stirred for 16 hours at room temperature. The solvent was removed, and the residue purified by column cluollla~ography on silica gel, eluting with 10% ethyl ~et~t~-hexane, to give 2.763 g of a colorless oil. MS 304 (M+H)+; lH NMR
(CDC13) ~: 1.25 (t, 3H), 1.47 (s, 9H), 3.36 (s, 3H), 3.67 (dd, lH), 3.73 (dd, lH), 3.72 (m, lH), 4.20 (q, 2H), 4.62 (s, 2H), 5.99 (dd, lH), 6.93 (dd, lH).

Step 312e. 4-(BOC-amino)-5-(methoxymethoxy)-3-(niL'u~ hyl)-pentanoic acid ethyl ester To a solution of the compound from step 312d above (2.76 g, 9.71 mmol) in 8 mL of ni~lo.l-~,ll.ane cooled in an ice bath was added 7 mL (6.934 g, 45.55 mmol) of 1,8-diazabicyclo[S.4.0]undec-7-ene dropwise under N2. The mixture was warmed to room~tlllpeld~ and stirred for 16 hours. The solution was diluted with CH2C12 and extracted with water, 10% HCl, 10% NaHCO3, water and b~ine. The solution was dried over MgSO4, and the solvent was removed. The residue was chl unlalographed on silica gel, , WO 96/39407 PCT~US96/08991 eluting with 10-15% ethyl acetate:hexane, and the solvent was removed to give 2.01 g of the title product as a white solid. MS 365 (M+H)+; lH NMR (CDC13) a 1.27 (t, 3H), " 1.47 (s, 9H), 2.46 (dd, lH), 2.98 (br, lH), 3.38 (s, 3H), 3.58 (ddd, lH), 3.76 (dd, lH), 3.97 (b m, lH), 4.16 (q, lH), 4.53 (dd, lH), 4.62 (s, 2H), 4.67 (dd, lH), 4.99 (b d, lH).
sl .
Step 312f. 4-(BOC-amino)-5-(methoxymethoxy)-3-(aminomethyl)-pentanoic acid ethyl ester Two g of the compound from step 312e above was dissolved in 200 mL of 10 ethanol and hydrogenated at 4 Atm over 4 g of Raney nickel catalyst for 24 hours. The catalyst was removed by filtration and the solvent was evaporated. The residue was taken direcl:ly to the next step.

Stel~ 312~,. N-BOC-2-(methoxymethoxy)- 1 -(5-oxo-3-pvrroli-iinvl)-ethylamine The residue from step 312f above was dissolved in 150 mL of ethanol and heated at reflux for 8 hours. The solvent was removed, the residue was chromatographed on silica gel, eluting with 4% methanoVmethylene çhk)ri-le Removal of the solvent gave 1.36 g of title product. MS 289 (M+H)+; lH NMR (CDC13) a 1.47 (t, 3H), 2.17 (dd, lH),2.38 (dd, lH), 2.78 (m, lH), 3.31 (t, lH), 3.46 (s, 3H), 3.46 (t, lH), 3.59 (m, 2H), 3.81 (b t, lH), 4.62 (s, 2H), 4.94 (br d, lH), 5.43 (br, lH).

Ste~ 312h. N-BOC-2-(methoxymethoxy)- 1 -(5-thioxo-3-pyrrolidinvl)-ethylamine A 500 mg (1.74 mmol) sample of the compound from step 312g above and 387 rng (0.957 mmol) of Lawesson's reagent were dissolved in 4 mL of THF and stirred under N2 for 3 hours. The solvent was removed, and the residue was dissolved in CH~C12 and clllum~L~graphed on silica gel, eluting with 35% ethyl ~et~te htoxane. Removal of the solvent left 500 mg of product. MS 305 (M+H)+; IH NMR (CDC13) ~: 1.47 (s, 9H), 2.71 (dd, lH), 2.89 (m, lH), 3.00 (dd, lH), 3.37 (s, 3H), 3.53 (dd, 2H), 3.66 (m, 2H), 3.83 ~b m, lH), 4.61 (s, 2H), 4.98 (b d, lH).
" Step 31~i. N-BOC-2-(methoxymethoxy)-3-~yrrolidinyl)-ethylamine acetic acid salt A 250 mg (0.825 mmol) sample of the compound from step 312h above and 1.57g (6.6 mmol) of NiC12-6H20 were dissolved in 10 mL of a 1:1 mixture of methanol and THF, and the solution was cooled to -78~C and stirred under N2. A 749 mg ~19.8 CA 02222322 1997-11-2~

WO 96/39407 PCTrUS96108991 mmol) sample of NaBH4 was added in portions, and the mixture was stirred for 2 hours.
The solvents were removed under vacuum, and dissolved in 20% methanol in chluloro,.ll.
The solution was filters and the solvent removed. The residue was cl.lu,naLugraphed on silica gel, eluting with 1:1:1:1 n-butanol:ethyl acetate:H2O:acetic acid to provide 349 mg of title product. MS 275 (M+H)+; lH NMR (D2O) a 1.44 (s, 9H), 3.03 (m, lH), 3.30 (m, lH), 3.40 (s, 3H), 3.48 (m, lH), 3.60 (t, 2H), 3.75 (m, lH).

Step 312j. (3R,lS)-8-(3-(1-amino-2-hydroxyethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride A 107 mg (0.33 mmol) sample of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in 2.5 mL of anhydrous ace~unil,ile, reacted with the compound from step 312i above (0.825 mmol), and carried forward as described in Example 253j-1 to give 74 mg of the title product. lH NMR (D6-DMSO) ~: 0.60 (m, 2H), 0.94 (m, lH), 1.05 (m, lH), 1.78 (m, lH), 2.05 (m, lH), 2.19 (m, 2H), 2.60 (s, 3H), 3.57 (m, lH), 3.73 (m, 3H), 3.92 (m, lH), 5.41 (m, lH), 7.91 (s, lH), 9.09 (d, lH), 13.83 (br s, lH).

Example 313 (8-(3-(1 -amino- 1 -methylethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride A 150 mg sample of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in 2 mL
of anhydrous acetonitrile, reacted with l-amino-l-methylethyl)pyrrolidine (155 mg, 0.77 25 mmol, prepared by standard method from the free base described by Hayakawa et al., U.s.
Patent 5,098,912, issued March 24, 1992), and carried forward as described in Example 253k-1 to give the title product. MS (high resolution) found: 388.2047; calc: 388.2036 (M+H)+; lH NMR (D6-DMSO) ~: 0.60 (m, 2H), 0.94 (m, lH), 1.07 (m, lH), 1.33 (s, 3H), 1.34 (s, lH), 2.83 (m, lH), 2.07 (m, lH), 2.19 (m, 2H), 2.63 (s, 3H), 3.60 (b t, lH), 3.68 (b t, lH), 3.81 (m, lH), 3.93 (m, lH), 7.90 (s, lH), 8.11 (b s, lH), 9.08 (d, lH), 13.83 ( b s, lH). Anal. Calcd for C21H27N3O3FCl-1.5 H2O: C, 55.93; H, 6.71;N, 9.32; Found: C, 56.07; H, 6.71; N, 8.95.

W'O 96/39407 PCTrUS~6/08991 Fxample 314 8-(3-(1 -aminobutyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-~oxo-4H-quinolizine-3-carboxy~ic acid hydrochloride S Ste~ 314a. 4-(BOC-amino)-3-(niLIon.e~hyl)-heptanoic acid ethvl ester Following the procedure of Example 312 step b, sub..Li~uLil~g DL-N-BOC-norvaline methyl ester (~ aL~d from norvaline by standard methods) for the compound of step 312a thereof, and carrying the product forward via the procedures of Example 312 steps c-e, the title compound was prepared.
S~e~ 314b. 4-(E?.OC-Amino)-3-(ni~lulll~Ll~yl)-heptAnol Repeating the procedure of example 312 step b, subshtnhn~ 4-(BOC-amino)-3-(nillu~ Lhyl)-heptanoic acid ethyl ester (1.3 g, 3.91 mmol), from step 314a above, for the compound of step 312a thereof, the title compound was prepared. MS 291 (M+H)+; IH
lS NMR (CDClD3) ~: 0.93 (t, 3H), 1.45 (s, 9H), 1.48 (m, SH), 1.77 (m, lH), 2.53 (m, lH), 3.79 (m, 3H), 4.33 (m, lH), 4.38 (dd, lH), 4.49 (dd, lH).

Slev 314c. 4-(BOC-Amino)-3-~lliL ù~ ,Lhyl)-he~tanûl~ O-mesi~yl ether A 610 mg (2.03 mmol) sample of the compound from step 314c above was dissolved in 2 mL of CH2Cl2, and the solution was cooled to -10~C. To this was added dropwise 289 mg (0.195 mL, 2.52 mmol) of mrthAnçsulfonyl chloride and 319 mg (3.15 mmol) of triethylamine. The solution was sti~Ted for 2 hours at 0- 10~C. The solution was diluted with CH2C12 and washed, once with water, once with 5% NaHCO3, and once with brine. The solvent was dried over MgS04 and filtered, and the solvent was removed to give 720 mg of the title product as an oil.

Ste~ 3 l 4d. 3-(1 -(N-BOC-amino)butyl)pvrrolidine The 720 mg sample of the product from step 314c was dissolved in 50 mL of m~th~nol and hydrogenated over 360 mg of 10% Pd/C catalyst at 4 Atm and room Le~ el;lL lre for 24 hours. MS 2243 (M+H)+; lH NMR (CD30D) ~: (0.94 (t, 3H), 1.34 (m, 3H), 1.44 (s, 9H), 1.48 (m, lH), 1.70 (m, lH), 2.13 (m, lH), 2.37 (q, lH), 3.04 (m, lH), 3.22 (m, lH), 6.71 (b d, lH).

WO 96/39407 PCTrUS~ 3~1 Step 314e. 8-(3-(1-aminobutyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-~oxo-4H-quinolizine-3-carboxylic acid hydrochloride A 238 mg sample of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-qu nolizine-3-carboxylic acid ethyl ester, from F.~mpl~, 253i above, was dissolved in 5 mL
5 of anhydrous acetonitrile, reacted with 3-(1-(N-BOC-amino)butyl)pyrrolidine (620 mg, 1.83 mmol, ~ ,d in step 314d above), and carried forward as described in Example253j-1 to give the title product. MS (high resolution) found: 402.2199; calc: 402.2193 (M+H)+; lH NMR (D6-DMSO) ~: 0.60 (m, 2H), 0.89 (m, 4H), 1.05 (m, lH), 1.49 (m, SH), 1.17 (m, lH), 2.14 (m, lH), 2.27 (m, lH), 2.62 (s, 3H), 3.77 (m, 4H), 3.94 (m, lH), 7.89 (s, lH), 8.54 (b m, lH), 9.07 (d, lH), 11.47 (br, lH).

Fx~rn~les 315-323 Following the procedures of Steps 253j, 253k and 2531 above, replacing tne 3-15 BOC-aminopyrrolidine of Step 253j with the reagent shown, the compo~mds of Examples 315-323 are prepared as shown in Table 12, below.

Table 12 F~COOH

Ex.No. Reagent R2_ BOCNH_~ rN

316 rNH
BOC-NH_~ r \
_ H NH2 CH3S _ H

~ CA 02222322 1997-11-25 - ~.

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Claims (33)

CLAIMED :

1. A compound having the formula (I) , or a pharmaceutically acceptable salt, ester or amide thereof, wherein R1 in formula (I) is selected from (a) loweralkenyl, (b) loweralkenyl, (c) halo(lower-alkyl), (d) loweralkoxy, (e) cycloalkyl of from three to eight carbon atoms, (f) phenyl, (g) substituted phenyl, (h) halo, (i) cyano, (1) nitro, (k) bicycloalkyl, (1) loweralkynyl, (m) loweralkoxycarbonyl, (n) nitrogen-containing aromatic heterocycle, (o) halo-substituted nitrogen-containing aromatic heterocycle, (p) a 4-, 5- or 6-membered cyclic ether, and (q) -NR7R8 where R7 and R8 are independently selected from the group consisting of hydrogen, loweralkyl and alkanoyl of from one to eight carbon atoms or, taken together with the nitrogen atom to which they are attached, R7 and R8 form a 5-, 6- or 7-membered heterocycle;

R2 in formula (1) is selected from (a) halogen, (b) loweralkyl, (c) loweralkenyl, (d) cycloalkyl of from three to eight carbons, (e) cycloalkenyl of from four to eight carbons, (f) loweralkoxy, (g) aryloxy, (h) aryl(loweralkyl)oxy, (i) aryl(loweralkyl), (1) hydroxy-cycloalkyl-(loweralkyl), (k) amino, (l) (loweralkyl)amino, (m) aryl(loweraLkyl)-amino, (n) nitrogen-substituted (loweralkyl)amino, (o) phenyl, (p) substituted phenyl, (q) bicyclic nitrogen-containing heterocycle, (r) nitrogen-containing aromatic heterocycle, (s) nitrogen-containing heterocycle having the formula (la), and (t) non-nitrogen-containing heterocycle having the formula (Ib);
where x is zero, one, two or three;

R9 is selected from the group consisting of (i) -(CH2)m- where where m is one, two or three, and (ii) -(CH2)nR13(CH2)p- where R13 is selected from -S-, -O- and -NH-, R10 is CH2, or when R9 is selected from option (i) may be O, S or N, n is one or two, and p is one or two; and R31 is -(CH2)qR32- where R32 is selected from -S- and -O-, and q is one, two or three; and Y is independently selected at each occurrence from the group consisting of:
(i) loweralkyl, (ii) hydroxy, (iii) halogen, (iv) halo(loweralkyl), (v) hydroxy-substituted loweralkyl, (vi) loweralkenylamino, (vii) loweralkylamino, (viii) loweralkoxy, (ix) (loweralkoxy)loweralkylamino, (x) loweralkoxy(loweralkyl), (xi) loweralkoxy(loweralkoxy)(loweralkyl), (xii) hydroxy-substituted loweralkyl, (xiu) imino, (xiv) alkoxycarbonyl, (xv) carbamoyl, (xvi) aryl(loweralkyl), (xvii) aminoxy (xviii) amino(loweralkyl), (xix) halo(loweralkyl)amino, (xx) halo(loweralkyl)amino(loweralkyl), (xxi) thioloweralkoxy(loweralkyl), (xxii) aminothioloweralkoxy, (xxiii) cycloalkyl of from three to six carbon atoms, (xxiv) cycloalkyl(loweralkyl), (xxv) cycloalkylamino, (xxvi) phenyl, (xxvii) substituted phenyl, (xxviii) substituted phenyl(loweralkyl) (xxix) nitrogen-containing aromatic heterocycle, (xxx) -NR11R12 where R11 and R12 are independently selected from hydrogen and loweralkyl or, when one of R11 and R12 is hydrogen, the other is alkanoyl off from one to eight carbon atoms, an alpha-amino acid, or a polypeptide residue of from two to five amino acids, and (xxxi) -C(R21)(R22)NH2 where R21 and R22 are independently selected from among hydrogen, loweralkyl, hydroxy-substituted loweralkyl, amino(loweralkyl), loweralkoxy-(loweralkyl), thioloweralkoxy(loweralkyl), cycloalkyl of from three to six carbon atoms, and loweralkyl substituted with nitrogen-containing aromatic heterocycle (or, taken together with the carbon atom to which they are attached, R21 and R22 form a ring structure selected from cycloalkyl of from three to six carbon atoms and nitrogen-containing heterocycle);
R3 is selected from the group consisting of hydrogen, halogen and loweralkoxy;
R4 is selected from the group consisting of hydrogen, loweralkyl, a pharmaceutically acceptable cation, and a prodrug ester group;
R5 is selected from the group consisting of (a) hydrogen, (b) halogen, (c) hydroxy, (d) loweralkyl, (e) halo(loweralkyl), (f) loweralkoxy, and (g) -NR13R14 where R13 and R14 are independently selected from the group consisting of hydrogen, loweralkyl, hydroxy-substituted loweralkyl, loweralkoxy(loweralkyl), and alkanoyl of from one to eight carbon atoms; and A is =N- or =CR6-, where R6 is selected from the group consisting of (a) hydrogen, (b) halogen, (c) loweralkyl, (d) halo(loweralkyl), (e) hydroxy-substituted loweralkyl, (f) loweralkoxy(loweralkyl), (h) loweralkoxy, and (i) amino(loweralkyl); or, taken together with the atoms to which they are attached, R1 and R6 form a 6-membered saturated ring aptionally containing an oxygen or a sulfur atom and optionally substituted withloweralkyl;
provided that, when R5 is hydrogen and A is =CH-, R1 is not unsubstituted phenyl.

2. A compound according to Claim 1 wherein A is =CR6- and R6 is selected from the group consisting of halogen, loweralkyl, halo(loweralkyl), hydroxy-substituted loweralkyl, loweralkoxy(loweralkyl), loweralkoxy, and amino(loweralkyl).

3. A compound according to Claim 2 wherein R3 is halogen.

4. A compound according to Claim 3 wherein R5 is selected from the group consisting of hydrogen, loweralkyl, halo(loweralkyl), and -NR13 R14 where R13 and R14 are as previously defined.

5. A compound according to Claim 4 wherein R1 is selected from the group consisting of cycloalkyl of from three to eight carbon atoms and substituted phenyl.

6. A compound according to Claim 5 wherein R6 is selected from the group consisting of halogen, loweralkyl, and loweralkoxy.

7. A compound according to Claim 6 wherein R2 is selected from the group consisting of bicyclic nitrogen-containing heterocycle and a nitrogen-containing heterocycle having the formula (Ic), where R9, Y and x are as previously defined.

8. A compound according to Claim 7 wherein R2 is selected from the group consisting of , and where Y and x are as previously defined.

9. A compound according to Claim 8 wherein x is one or two and Y is selected from the group consisting of -NR11 R12 and -C(R21)(R22)NH2, where R11, R12, R21 and R22 are as previously defined.

10. A compound according to Claim 2 wherein R6 is methyl.

11. A compound according to Claim 10 wherein R3 is halogen.

12. A compound according to Claim 11 wherein R5 is selected from the group consisting of hydrogen, loweralkyl, halo(loweralkyl), and -NR13 R14 where R13 and R14 are as previously defined.

13. A compound according to Claim 12 wherein R1 is selected from the group consisting of cycloalkyl of from three to eight carbon atoms and substituted phenyl.

14. A compound according to Claim 13 wherein R2 is selected from the group consisting of bicyclic nitrogen-containing heterocycle and a nitrogen-containing heterocycle having the formula (Ic), where R9, Y and x are as previously defined.

15. A compound according to Claim 14 wherein R2 is selected from the group consisting of:

, , , , , , , and , where Y and x are as previously defined.

16. A compound according to Claim 15 wherein x is one or two and Y is selected from the group consisting of -NR11R12 and -C(R21)(R22)NH2, where R11, R12, R21 and R22 are as previously defined.

17. A compound according to Claim 1 having the formula (Id) or a pharmaceutically acceptable salt, ester or amide thereof, wherein R2 is selected from the group consisting of bicyclic nitrogen-containing heterocycle and a nitrogen-containing heterocycle having the formula (Ic) and where R4, R9, Y and x are as previously defined.

18. A compound according to Claim 17 wherein R2 is selected from the group consisting of:

, and where Y and x are as previously defined.

19. A compound according to Claim 18 wherein x is one or two and Y is selected from the group consisting of -NR11 R12 and -C(R21)(R22)NH2, where R11, R12, R21 and R22 are as previously defined.

20. A compound according to Claim 1 having the formula (Ie) or a pharmaceutically acceptable salt, ester or amide thereof, wherein Z is selected from the group consisting of -CH2-, -O- and -S-, R16 is loweralkyl, and R2, R3, R4 and R5 are as previously defined.

21. A compound according to Claim 20 wherein Z is -O- and R2 is a nitrogen-containing heterocycle having the formula (Ic), wherein R9, Y and x are as previously defined.

22. A compound according to Claim 1 selected from the group consisting of:
3-fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin-1-yl)-6(H)-6-oxo-pyrido [1,2-a]pyrimidine-7-carboxylic acid;
9-(2,4-difluorophenyl)-3-fluoro-2-(4-methylpiperazin-1-yl)-6(H)-6-oxo-pyrido [ 1,2-a]pyrimidine-7-carboxylic acid;
3-fluoro-9-cyclopropyl-2-(4-methylpiperazin- 1-yl)-6(H)-6-oxo-pyrido [ 1 ,2-a]pyrimidine-7-carboxylic acid;
8-(3-aminopyrrolidin- 1 -yl)- 1 -ethyl-4H-quinolizin-4-one-3-carboxylic acid;
2-(3-aminopyrrolidin- 1 -yl)-9-cyclopropyl-3-fluoro-6H-6-oxo-pyrido [ 1 ,2-a]pyrimidine-7-carboxylic acid;
2-(3-aminopyrrolidin- 1 -yl)-9-cyclopropyl-3-fluoro-6H-6-oxo-pyrido [ 1 ,2-a]pyrimidine-7-carboxylic acid;

9-(2,4-difluorophenyl)-3-fluoro-2-(4-methylpiperazin- 1 -yl)-6H-6-oxopyrido[ 1,2-a]pyrimidine-7-carboxylic acid;
2-(3-aminopyrrolidin- 1 -yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[ 1,2-a]pyrirnidine-7-carboxylic acid;
2-(3-(N-t-butoxycarbonyl)aminopyrrolidin- 1 -yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimifiine-7-carboxylic acid;
2-(3-aminopyrrolidin- 1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[ 1,2-a]pyrimidine-7-carboxylic acid;
9-cyclopropyl-3-fluoro-2-(4-methylpiperazin- 1 -yl)-6H-6-oxo-pyrido[ 1 ,2-a]pyrimidine-7-carboxylic acid;
9-cyclopropyl-3-fluoro-2-(piperazin- 1 -yl)-6H-6-oxo-pyrido[ 1 ,2-a]pyrimidine-7-carboxylic acid;
9-cyclopropyl-3-fluoro-2-(morpholin- 1 -yl)-6H-6-oxo-pyrido[ 1 ,2-a]pyrimidine-7-carboxylic acid;
9-(2,4 -difluorophenyl)-3-fluoro-2-(3-(N-(S)-norvalyl)aminopyrrolidin- 1 -yl)-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylic acid;
2-(3-(N-(S)-alanyl)aminopyrrolidin- 1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopylido[1,2-a]pyrimidine-7-carboxylic acid;
2-(3-(N-(S)-alanyl-(S)-alanyl)aminopyrrolidin- 1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylic acid;
2-((2S,4S)-4-acetamido-2-methylpyrrolidin- 1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylic acid;
9-(2,4-difluorophenyl)-3-fluoro-2-(3-hydroxypyrrolin- 1 -yl)-6H-6-oxopyrido[ 1,2-a]pyrimidine-7-carboxylic acid;
2-((2S ,4S)-4-amino-2-methylpyrrolidin- 1 -yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylic acid;
8-(3-amino- 1-pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-(arninomethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(2S,4S-4-amino-2-methylpyrrolidinyl)- 1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-aminoazetidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3(S)-aminopyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;

1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-methyl-1-piperazinyl)-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-piperazinyl-4H-quinolizine-3-carboxylic acid;
1 -cyclopropyl-7-fluoro-9-methyl-8-(2-((N-methyl)aminomethyl)-4-morpholinyl)-4-oxo-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(1,2,3,4-tetrahydro-2-isoquinolinyl)-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-amino-1-piperdinyl)-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-amino-1-piperdinyl)-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-(aminomethyl)-1-piperdinyl)-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(5-amino-1,2,3,4-tetrahydro-2-isoquinolinyl)-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-(1-pyrrolyl)-1-piperidinyl)-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-8-(cis-3.5-dimethyl-1-piperazinyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-8-(2,7-diaza-7-bicyclo[3.3.0]octyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-8-(2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3(S)-(1-pyrrolyl)-1-pyrrolidinyl)-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-8-(3-hydroxy-1-pyrrolidinyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-8-(4-methyl-1-piperazinyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-9-chloro-7-fluoro-8-(3-amino-1-pyrrolidinyl)-4-oxo-4H-quinolizine-3-carboxylic acid trifluoroacetic acid;
8-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-7,9-difluoro-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methoxy-4-oxo-4H-quinolizine-3-carboxylic acid.

1-cyclopropyl-8-(2,7-diaza-7-bicyclo[3.3.0]oct-2-yl)-7-fluoro-9-methyl-4-oxo-4H-quilinolizine-3-carboxylic acid;
1-cyclopropyl-8-(2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3(S)-(1-pyrrolyl)-1-pyrrolidinyl)-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-8-(3-hydroxy-1-pyrrolidinyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-8-(4-methyl-1-piperazinyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-9-chloro-7-fluoro-8-(3-amino-1-pyrrolidinyl)-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-7,9-difluoro-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methoxy-4-oxo-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-8-(3(S)-methylamino-1-pyrrolidinyl)-4-oxo-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-8-(3(S)-methylamino-1-pyrrolidinyl)-4-oxo-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-8-(3(R)-amino-1-pyrrolidinyl)-4-oxo-4H-quinolizine-3-carboxylic acid;
(3S)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylic acid;
3(R)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylic acid;
9-fluoro-10-(1-morpholinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylic acid;
(3S)-10-(3-amino-1-pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylic acid;
3(S)-10-(3-aminomethyl-1-pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylic acid;
3(S)-10-((2S,4S)-4-amino-2-methyl-1-pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylic acid;
3(S)-9-fluoro-10-(3-hydroxy-1-pyrrolidinyl)-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4-ij)quinolizine-5-carboxylic acid;

9-fluoro-10-(4-methyl-1-piperazinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylic acid;
8-(2,4-dimethyl-1-piperazinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-(methylamino)-1-piperazinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-(methylamino)-1-morpholinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-(S)-(methylamino)-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-(S)-(1-(methylamino)methyl)-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-(S)-(1-(ethylamino)methyl)-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-qninolizine-3-carboxylic acid;
8-(octahydropyrrolo[3,4-c]pyrrol-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(octahydropyrrolo[3,4-c]pyridin-5-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(cis-4-amino-3-methylpyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(trans-4-amino-3-methylpyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-methyl-4-spirocyclopropylpyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(2S,4S-4-amino-2-methylpyrrolidinyl)-1-cyclopropyl-7-fluoro-9-(fluoro)methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-dimethylaminopyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
(3R)-8-(3-dimethylaminopyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
(3R,1S)-8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
(3S,1R)-8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
(3R,1R)-8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;

1-cyclopropyl-8-((R,S)-3-fluoropyrrolidine)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(4-(1-piperidyl)-1-piperidyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(4-(1-piperidyl)-1-piperidyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(4-(2-pyridyl)-1-piperazinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-((2-amino)thioethoxy)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
(3R,1S)-8-(3-(1-amino)propyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
(3R,1S)-8-(3-(1-(N-methyl)amino)propyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
(3R,1S)-8-(3-(1-amino-3-methylpropyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-(1-aminocyclopropyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
(3R,1S)-8-(3-(1-amino-2-hydroxyethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
(8-(3-(1-amino-1-methylethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-(1-aminobutyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(trans-4-trifluoromethyl-3-aminopyrrolidinyl)-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(trans-4-trifluoromethyl-3-aminomethylpyrrolidinyl)-4H-quinolizine-3-carboxylic acid;
3(S)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-(N-(S)-norvalylamino)pyrrolidinyl)-4H-quinolizine-3-carboxylic acid;
3(S)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-(N-(S)-alanylamino)pyrrolidinyl)-4H-quinoline-3-carboxylic acid;
3(S)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-(N-(S)-alanyl-(S)-alanylamino)pyrrolidinyl)-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-6-methyl-4-oxo-8-(3-aminopyrrolidinyl)-4H-quinolizine-3-carboxylic acid;

1-cyclopropyl-7-fluoro-4H-8-(1-imidazolyl)-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-amino- 1 -pyrrolidinyl)- 1-ethyl-7-fluoro-4H-4-oxo-9-methyl-quinolizine-3-carboxylic acid;
8-(3-amino- 1 -pyrrolidinyl)- 1 -cyclopropyl-9-ethyl-7-fluoro-4H-4-oxo-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-8-(3-(1,2,3-triazol- 1 -yl)- 1 -pyrrolidinyl)-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-8-(cis-3-amino-4-methyl- 1 -pyrrolidinyl)-qninolizine-3-carboxylic acid;
8-(2-aminoethyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(ethylaminomethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(1-aminoethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-4H-9-methyl-8-(2-methyl-2,8-diaza-8-bicyclo[4.3.0]nonyl)-4-oxo-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-4H-8-((1S,4S)-2,5-diaza-bicyclo[2.2.1]heptan-2-yl)-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-8-(3-(2-pyridinyl)- 1 -pyrrolidinyl)-quinolizine-3-carboxylic acid;
8-((1R*,2S*,6R*)-2-amino-8-azabicyclo[4.3.0]nonan-8-yl))- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-((1R*,2R*,6R*)-2-amino-8-azabicyclo[4.3.0]nonan-8-yl))- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-((1a,5a,6a)-6-amino-3-azabicyclo[3.1.0] hexan-3-yl))- 1 -cyclopropyl-9-methyl-7-fluoro-4H4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-amino-4-fluoro- 1 -pyrrolidinyl))- 1 -cyclopropyl-9-methyl-7-fluoro-4H-4-oxo-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-4H-8-(1-homopiperazinyl))-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
7,9-difluoro-4H-8-(4-methylpiperazinyl)-4-oxo- 1 -phenyl-quinolizine-3-carboxylic acid;
8-(spiro-1,3-dioxacyclopentane[2.3]- 1 -piperidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-amino-4-methoxypyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;

8-(4-amino-4-methylpyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(4-(2-hydroxyethyl)piperidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(4-(methoxymethyl)piperidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-amino-3-methylpiperidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-pyrrolylpiperidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-aminopiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-amino-3-methylpyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-amino-4-(1',3'-dioxolanyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-amino-4-hydroxy-pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(4-(1-(N-ethylamino)methyl)piperidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
1-cyclopropyl- 7 -fluoro-8-(3-hydroxy-4-methylaminopyrrolidinyl)-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-aminomethylpiperidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(2-aminomethyl-4-morpholinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(1-(methylamino)methypiperidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(methyl(methylenedioxy)methyl)piperidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(S)-aminopiperidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(S)-(N-ethyl-N-methylamino)piperidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
1-cyclopropyl-8-(4-(2'-(N-methylamino)methyl- 1',3'-dioxolanyl)piperidinyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;

1-cyclopropyl-8-(3-aza-6-amino-6-methylbicyclo[3.3.0]octan- 1 -yl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-8-(3-fluoromethylpiperidinyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine;
1-cyclopropyl-8-(4-(N,N-dimethyl)aminopiperidinyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-8-(6-amino-3-azabicyclo[3.3.0]octyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-8-((2-aza-4-(dimethylaminomethyl)bicyclo[4.3.0]non-2-yl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine carboxylic acid;
1-cyclopropyl-8-(3-aza-6-(L-alanylamino)-6-methylbicyclo[3.3.0]octane)-7-fluoro-9-methyl-4-oxo-4H-quinolizine carboxylic acid;
(3R, 1R)-8-(3-(1-(N-methyl)amino)propyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
(3R, 1S)-8-(3-(1-amino-2-methoxyethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-(S)-(acetylamino)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-carbamoylpiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-hydroxypiperidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-hydroxymethylpiperidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(R)-hydroxypiperidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
(3R)-9-fluoro-3-methyl- 10-(piperazin- 1 -yl)-2H, 3H, 6H -6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylic acid;
1-cyclopropyl-8-(S,S-2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
1-cyclopropyl-8-(R,R-2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
1-cyclopropyl-8-(1-amino-3-aza-bicyclo[3.1.0]hexan-3-yl)-7-fluoro-4H-9-methyl-4-oxo-qninolizine-3-carboxylic acid;
8-(3-amino-3-fluoromethyl- 1 -pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;

.

8-(3-aminomethyl-3-fluoro- 1 -pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(S)-hydroxy- 1 -pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(R)-hydroxy-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(7-(S)-amino-5-aza-spiro[2.4]heptan-5-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride;
8-(7-(R)-amino-5-aza-spiro[2.4]heptan-5-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride;
8-(3-(1-amino-2,2,2-trifluoroethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(S*)-(1-(S*)-amino-2,2,2-trifluoroethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-aminoxypyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(R)-aminoxypyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(S)-aminoxypyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(octahydropyrrolo[3,2-b]pyridin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-amino-4-fluoromethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(cis-3-amino-4-fluoromethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(8-amino-6-azaspiro[3.4]oct-6-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(2-aminomethyl-4-hydroxypyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(R)-(aminomethyl)morpholin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(R)-(L-alanylamino)piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(5-aminooctahydroindol-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;

8-(3-(2-piperidyl)piperidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(5-amino-decahydroisoquinolin-2-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-qninolizine-3-carboxylic acid;
8-(2,7-diazabicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3,7-diazabicyclo[3.3.0]oct-3-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-carboxypyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(2,2,2-trifluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4 oxo-quinolizine-3-carboxylic acid;
8-(3-(2-fluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-((2-fluoroethyl)aminomethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(S)-(2-fluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(R)-(2-fluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-qninolizine-3-carboxylic acid;
8-(3a-amino-octahydroisoindol-2-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(6-amino-2-aza-spiro[3.3]non-2-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid (Isomer (I));
8-(3-amino-3-trifluoromethylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(S)-hydroxymethylazetidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-aminomethyl-3-trifluoromethyl-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(octahydropyrrolo[3.4-c]pyrid-2-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(cyclopropylamino)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(6-amino-2-aza-spiro[3.3]non-2-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid (Isomer (II));

8-(2,7-diazabicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid Isomer A;
8-(2,7-diazabicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid Isomer B;
8-(3-(R)-(hydroxymethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(S)-(hydroxymethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(2-(R)-(hydroxymethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(2-(S)-(hydroxymethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(2-(R)-aminomethyl-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(2-(S)-aminomethyl-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(R)-(1-aminocyclopropyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-(S)-(1-aminocyclopropyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-(1-amino-1-cyclopropyl-methyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-(R)-(pyrrolidin-2-(S)-yl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-(aminomethyl)azetidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
(8-(3-amino-4-methyl-piperidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid; and 8-(3-(7-amino-5-azaspiro[2.4]heptan-5-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(7-(S)-amino-5-aza-spiro[2.4]heptan-5-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(7-(R)-amino-5-aza-spiro[2.4]heptan-5-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-(S)-amino-4-(R)-cyclopropylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;

8-(trans-3-(R)-amino-4-(S)-cyclopropylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-(S)-amino-4-(R)-methylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-(R)-amino-4-(S)-methylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(cis-3-(S)-amino-4-(S)-cyclopropylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(cis-3-(R)-amino-4-(R)-cyclopropylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-amino-4-ethylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomer A;
8-(trans-3-amino-4-ethylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomer B;
8-(cis-3-amino-4-ethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomer A;
8-(cis-3-amino-4-ethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomer B;
8-(cis-3-(S)-amino-4-(S)-methylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid; and 8-(cis-3-(R)-amino-4-(R)-methylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
and the pharmaceutically acceptable salts, esters and amides thereof.

23. A compound according to Claim 22 selected from the group consisting of:
8-(3-(aminomethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3(S)-amino-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
(3R,1S)-8-(3-(1-amino)propyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-(1-aminobutyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;

(3R, 1S)-8-(3-(1-amino-2-methoxyethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-amino-1-piperdinyl)-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-(aminomethyl)-1-piperdinyl)-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-amino-1-piperdinyl)-4H-quinolizine-3-carboxylic acid;
8-(3-(S)-aminopiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
1-cyclopropyl-8-(3-aza-6-amino-6-methylbicyclo[3.3.0]octan-1-yl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-8-(6-amino-3-azabicyclo[3.3.0]octyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-((1R*,2S*,6R*)-2-amino-8-azabicyclo[4.3.0]nonan-8-yl))-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-((1R*,2R*,6R*)-2-amino-8-azabicyclo[4.3.0]nonan-8-yl))-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
(8-(3-(1-amino-1-methylethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
(3R, 1S)-8-(3-(1-(N-methyl)amino)propyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-aminopiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(1-aminocyclopropyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
(3S,1R)-8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
(3R, 1S)-8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
(3R, 1R)-8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-8-(S,S-2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;

1-cyclopropyl-8-(R,R-2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
1-cyclopropyl-8-(1-amino-3-aza-bicyclo[3.1.0]hexan-3-yl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-amino-3-fluoromethyl-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-amino-4-fluoromethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(cis-3-amino-4-fluoromethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(S)-(2-fluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(R)-(2-fluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(R)-(hydroxymethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(2-(R)-aminomethyl-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-qninolizine-3-carboxylic acid;
8-(2-(R)-aminomethyl-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-qninolizine-3-carboxylic acid;
(8-(3-amino-4-methyl-piperidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-(7-amino-5-azaspiro[2.4]heptan-5-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(7-(S)-amino-5-aza-spiro[2.4]heptan-5-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(7-(R)-amino-5-aza-spiro[2.4]heptan-5-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-(S)-amino-4-(R)-cyclopropylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-(R)-amino-4-(S)-cyclopropylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-(S)-amino-4-(R)-methylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-(R)-amino-4-(S)-methylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;

8-(cis-3-(S)-amino-4-(S)-cyclopropylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(cis-3-(R)-amino-4-(R)-cyclopropylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-amino-4-ethylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomer A;
8-(trans-3-amino-4-ethylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomer B;
8-(cis-3-amino-4-ethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomer A;
8-(cis-3-amino-4-ethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomer B;
8-(cis-3-(S)-amino-4-(S)-methylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid; and 8-(cis-3-(R)-amino-4-(R)-methylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
and the pharmaceutically acceptable salts, esters and amides thereof.

24. A compound according to Claim 22 selected from the group consisting of:
8-(3(S)-amino-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
(3R, 1S)-8-(3-(1-amino-2-methoxyethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H[-quinolizine-3-carboxylic acid;
(8-(3-(1-amino-1-methylethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-(1-aminocyclopropyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
(3R, 1S)-8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-8-(S,S-2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
1-cyclopropyl-8-(R,R-2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
1-cyclopropyl-8-(1-amino-3-aza-bicyclo[3.1.0]hexan-3-yl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;

8-(3-amino-3-fluoromethyl-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-amino-4-fluoromethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(cis-3-amino-4-fluoromethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(S)-(2-fluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(R)-(2-fluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(R)-(hydroxymethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(2-(R)-aminomethyl-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid; and (8-(3-amino-4-methyl-piperidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid; and 8-(3-(7-amino-5-azaspiro[2.4]heptan-5-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(7-(S)-amino-5-aza-spiro[2.4]heptan-5-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(7-(R)-amino-5-aza-spiro[2.4]heptan-5-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-(S)-amino-4-(R)-cyclopropylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-(R)-amino-4-(S)-cyclopropylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-(S)-amino-4-(R)-methylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-(R)-amino-4-(S)-methylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(cis-3-(S)-amino-4-(S)-cyclopropylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(cis-3-(R)-amino-4-(R)-cyclopropylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-amino-4-ethylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-qninolizine-3-carboxylic acid diastereomer A;

8-(trans-3-amino-4-ethylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomer B;
8-(cis-3-amino-4-ethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomer A;
8-(cis-3-amino-4-ethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomer B;
8-(cis-3-(S)-amino-4-(S)-methylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid; and 8-(cis-3-(R)-amino-4-(R)-methylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
and the pharmaceutically acceptable salts, esters and amides thereof.

25. A pharmaceutical composition comprising a compound according to Claim 1 in combination with a pharmaceutically acceptable carrier.

26. A pharmaceutical composition comprising a compound according to Claim 10 in combination with a pharmaceutically acceptable carrier.

27. A pharmaceutical composition comprising a compound according to Claim 22 in combination with a pharmaceutically acceptable carrier.

28. A pharmaceutical composition comprising a compound according to Claim 25 in combination with a pharmaceutically acceptable carrier.

29. A method of treating a bacterial infection in a human or veterinary patient, comprising administering to the patient a therapeutically effective amount of a compound according to Claim 1.

30. A method of treating a bacterial infection in a human or veterinary patient, comprising administering to the patient a therapeutically effective amount of a compound according to Claim 10.

31. A method of treating a bacterial infection in a human or veterinary patient, comprising administering to the patient a therapeutically effective amount of a compound according to Claim 22.

32. A method of treating a bacterial infection in a human or veterinary patient,comprising administering to the patient a therapeutically effective amount of a compound according to Claim 25.

33. A synthetic intermediate selected from the group consisting of:
4-t-butoxy-3-chloro-2,5,6-trifluoropyridine;
4-t-butoxy-2,3,6-trifluoropyridine;
4-t-butoxy-2,3,6-trifluoro-5-methylpyridine;
4-t-butoxy-2,5-difluoro-3-methylpyridine;
2-(4-t-butoxy-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetonitrile;
2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetonitrile;
2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetic acid;
ethyl 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetate;
2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetaldehyde;
2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneethanol;
2-(2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylethylidinyl)-1,3-propanedicarboxylic acid, diethyl ester; and 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4h-quinolizine-3-carboxylic acid ethyl ester.