KR19990022524A - Quinolone type compound - Google Patents

Abstract

The present invention relates to compounds of formula I and their pharmaceutically acceptable salts, esters and amides, as well as pharmaceutical compositions comprising such compounds and their use for the treatment of bacterial infections.

(I)

(A)

[Formula b]

(C)

[Chemical formula d]

In the above formulas I, a, b, c and d,

A is = CR < ⁶ > -,

R < ¹ > is cycloalkyl of 3 to 8 carbon atoms or substituted phenyl,

R ² is selected from the group consisting of formulas a, b, c and d,

R < ³ > is halogen,

R < ⁴ > is hydrogen, lower alkyl, a pharmaceutically acceptable cation or a prodrug ester group,

R ⁵ is a ¹⁴ hydrogen, lower alkyl, halo (lower alkyl) or -NR ¹³ R,

R ⁶ is a halogen, lower alkyl, halo (lower alkyl), hydroxy substituted lower alkyl, lower alkoxy (lower alkyl), lower alkoxy or amino (lower alkyl).

Description

Quinolone type compound

The present invention relates to a compound having antimicrobial activity, a pharmaceutical composition containing such a compound, a therapeutic method using such a compound, and a chemical synthesis method thereof. More particularly, the present invention relates to novel 4-oxo-4H-quinolizine-3-carboxylic acid compounds which are highly effective in treating microbial infections and especially bacterial infections, as well as compositions and therapeutic uses of such compounds.

BACKGROUND OF THE INVENTION

There is a continuing need for novel antibacterial agents. Although many compounds are known to be useful for the treatment of Gram-positive and Gram-negative bacteria as well as other microbial infections, the widespread use of such compounds has led to the development of microbial resistant strains, i.e., special antibiotics or antibiotic groups that were previously effective but no longer useful There are continuing microbial strains of resistance. Also, known antibiotics are effective only for certain microbial strains or have only limited activity against gram-positive or gram-negative, aerobic or anaerobic microorganisms.

Therapeutic uses of any quinolizine derivatives have been described above. For example, US Patent 4,650,804 (March 17, 1987, Y. Kitaura et al.) Describes quinolizine compounds having tetrazolylcarbamoyl substituents useful in the treatment of allergic and ulcerative diseases. European Patent Application No. 0308019 (March 22, 1989, J. V. Heck and E. D. Thorsett) describes any 4-oxo-4H-quinolizine-3-carboxylic acid and derivatives thereof for treating bacterial infections. However, there is a continuing need for new compounds with improved antimicrobial capacity and / or different activity spectra.

SUMMARY OF THE INVENTION

In one aspect of the invention, compounds of formula I, pharmaceutically acceptable salts, esters and amides thereof are described.

(I)

(Ia)

(Ib)

In the above formulas I, Ia and Ib,

R ¹ is selected from the group consisting of lower alkyl (a), lower alkenyl (b), halo (lower-alkyl) (c), lower alkoxy (d), cycloalkyl (I), nitro (j), bicycloalkyl (k), lower alkynyl (l), lower alkoxycarbonyl (m), nitrogen containing aromatic heterocycle (n) ), halo-substituted nitrogen-containing aromatic heterocycle, (o), cyclic 4 W, 5-or 6-ether (p) and -RN ⁷ R ⁸ (q) (where the radical R ⁷ and R ⁸ are independently hydrogen , Lower alkyl and alkanoyl of 1 to 8 carbon atoms, or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered heterocycle, preferably the remainder of which is a carbon atom, (Which can be formed)

R ² is selected from the group consisting of halogen (a), lower alkyl (b), lower alkenyl (c), cycloalkyl having 3 to 8 carbons, cycloalkenyl having 4 to 8 carbons, (K), (lower alkyl) amino (1), aryl (lower alkyl), aryl (lower alkyl) (N), phenyl (o), substituted phenyl (p), acyclic nitrogen containing heterocycle (q), nitrogen containing aromatic heteroatom (s) The cycle (r) is selected from the nitrogen-containing heterocycle (s) of formula (Ia) and the nitrogen-containing heterocycle (t)

x is 0, 1, 2 or 3,

R ⁹ is _{(i) - (CH 2)} m - ( wherein, m is 1, 2 or 3) or _{(ii) (CH 2) n} R 13 (CH 2) p - ( wherein, R ¹³ is -S -, -O-, and -NH-,

R ¹⁰ is CH ₂ ,

R ⁹ is selected from (i) O, S and N, n is 1 or 2, p is 1 or 2,

Radical Y is each independently selected from the group consisting of (i) lower alkyl, (ii) hydroxy, (iii) halogen, (iv) halo (lower alkyl), (v) hydroxy substituted lower alkyl, (lower alkyl), (xi) lower alkoxy (lower alkoxy) (lower alkyl), (xii) lower alkylamino, (viii) lower alkoxy, (Xii) imino, (xiv) alkoxycarbonyl, (xv) carbamoyl, (xvi) aryl (lower alkyl), (xvii) aminoxy, (xxii) halo (lower alkyl) amino, (xx) halo (lower alkyl) amino (lower alkyl), (xxi) thio lower alkoxy (lower alkyl), (xxii) aminothio lower alkoxy, (Xxiv) cycloalkyl, (xxv) cycloalkylamino, (xxvi) phenyl, (xxvii) substituted phenyl, contain (Xxx) -NR ¹¹ R ¹² wherein R ¹¹ and R ¹² are independently selected from hydrogen and lower alkyl, or when one of R ¹¹ and R ¹² is hydrogen, the other is selected from the group consisting of C 1-8 of alkanoyl, alpha-amino acid or amino acid number 2 to 5, the polypeptide moiety) and ^{(xxxi) -C (R 21)} (R 22) NH 2 [ where, R ²¹ and R ²² are independently hydrogen, lower alkyl (Lower alkyl), lower alkoxy (lower alkyl), thio lower alkoxy (lower alkyl), cycloalkyl of 3 to 6 carbon atoms, lower alkyl substituted by nitrogen containing aromatic heterocycle, And R < ²¹ > and R < ²² > together with the carbon atoms to which they are attached form a ring structure selected from a cycloalkyl and a nitrogen-containing heterocycle having from 3 to 6 carbon atoms,

R ³¹ is - (CH ₂ ) _q R ³² -, wherein R ³² is -S- and -O-,

q is 1, 2 or 3,

R < ³ > is selected from hydrogen, halogen and lower alkoxy,

R ⁴ is selected from hydrogen, lower alkyl, pharmaceutically acceptable cations and prodrug ester groups,

R ⁵ is hydrogen (a), a halogen (b), hydroxy (c), lower alkyl (d), halo (lower alkyl) (e), lower alkoxy (f), and -NR ¹³ R ¹⁴ (g) (wherein , R ¹³ and R ¹⁴ are independently selected from the group consisting of hydrogen, lower alkyl, hydroxy-substituted lower alkyl, lower alkoxy- (lower alkyl) and alkanoyl having 1 to 8 carbon atoms,

A is = N- or = CR ⁶ (wherein, R ⁶ is hydrogen (a), a halogen (b), lower alkyl (c), halo (lower alkyl) (d), hydroxy-substituted lower alkyl (e), Lower alkoxy- (lower alkyl) (f), lower alkoxy (h) and amino (lower alkyl) (i).

Also, when the atoms bonded to them are bonded together, R ¹ and R ⁶ form a 6-membered saturated ring optionally containing oxygen or sulfur and optionally substituted with lower alkyl to form a tricyclic compound.

The compounds of the invention and R ⁵ is hydrogen in formula I, A is = CR ^6, when R ⁶ is hydrogen, R ¹ is not substituted phenyl.

The above compounds of the present invention surprisingly exhibit antimicrobial activity against a wide spectrum of Gram-positive bacteria and Gram-negative bacteria as well as the host bacteria. Susceptible microorganisms capable of inhibiting growth generally include those belonging to the genus Stapylococcus, Lactobacillus, Micrococuus, Enterococcus, Streptococcus, The genus Escherichia, the genus Escherichia, the genus Escherichia, the genus Enterobacter, the genus Klebsiella, the genus Pseudomonas, the genus Acinobacter, the genus Proteus, A plant belonging to the genus Providencia, a genus of Citrobacter, a species of Nisseria, a genus of Bacillus, a genus of Bacteroides, a genus of Campylobacter, a genus of Peptococcus, Both aerobic and anaerobic pathogens from the genus Clostridium, Salmonella, Shigella, Legionella, Serritia, Haemophilus and Brucella have been described . Thus, the compounds of the present invention may be useful for treating and preventing susceptible bacterial infections in both humans and downstream animals. In addition, due to their in vitro activity, this compound can be used as a rinse for surface inhibition of bacterial growth.

Accordingly, a further aspect of the present invention describes pharmaceutical compositions useful for the treatment and prevention of bacterial and / or fungal infections in humans and animals, including combinations of the compounds of the present invention with pharmaceutically acceptable carriers have.

Another embodiment of the present invention is the use of a compound of the invention in a human or animal patient in need of such treatment, including administration in such patient for a period of time sufficient to exhibit a therapeutically effective amount of a compound of the invention and the desired result Methods of treating and / or preventing microbial infections are described.

Yet another aspect of the invention describes synthetic intermediates which can be used herein, as well as synthetic formulas and methods useful in the preparation of the compounds of the present invention.

This patent application is a continuation-in-part of U.S. Patent Application No. 08 / 469,159, filed June 6, 1995, which is a continuation-in-part of U.S. Patent Application Serial No. 08 / 316,319 filed September 30, 1994 Filed October 14,1993, which is a continuation-in-part of U.S. Patent Application Serial No. 08 / 137,236 (1993, 10, 14) filed October 14, 1993, This application is a continuation-in-part of U.S. Patent Application Serial No. 07 / 940,870 filed on May 2, 1990 and is a continuation-in-part of U.S. Patent Application No. 07 / 517,780.

In the compounds of the invention A is = CR ⁶ - is an R ⁶ is halogen, lower alkyl, halo (lower alkyl), hydroxy substituted lower alkyl, lower alkoxy (lower alkyl), lower alkoxy or amino (lower alkyl) ≪ / RTI > Compounds found as sub-classes of such compounds, particularly preferred and surprisingly effective anti-bacterial agents, include compounds wherein R < ⁶ > is methyl. More preferred compounds in each case are those wherein R ³ is halogen (especially fluoro) and R ⁵ is hydrogen, lower alkyl, halo- (lower alkyl) or -NR ¹³ R ¹⁴ wherein R ¹³ and R ¹⁴ are as defined above as shown), and, R ¹ is 3 to 8 carbon atoms or a cycloalkyl is a substituted phenyl, and / or R ⁶ is halogen, lower alkyl or lower alkoxy compounds.

In the preceding compounds the radical R ² is preferably a nitrogen-containing heterocycle or a non-cyclic nitrogen-containing heterocycle or the formula Ic, and more preferably R ² has the formula

≪ / RTI >

(Ic)

In this radical R ² , x is preferably 1 or 2 and Y is preferably -NR ¹¹ R ¹² or -C (R ²¹ ) (R ²² ) NH ₂ wherein R ¹¹ , R ¹² , R ²¹ And R < ²² > are as defined above.

Particularly preferred compounds of the present invention are the compounds of formula (Id) as well as the pharmaceutically acceptable salts, esters and amides thereof, wherein R ² is a nitrogen-containing heterocycle or a nitrogen-containing heterocycle of formula (Ic).

(Ic)

(Id)

Among them, particularly preferred compounds are those in which R < ^{2 &}

And particularly wherein x is 1 or 2 and Y is -NR ¹¹ R ¹² or -C (R ²¹ ) (R ²² ) NH ₂ .

Among Compound Z is -CH ₂ of the present invention is, -O- or -S-, R ¹⁶ is lower ^{alkyl, R 2, R 3, R} 4 and R ⁵ are pharmaceutically acceptable, as defined above Esters and amides thereof, as well as the compounds of formula (Ie).

(Ie)

Among these compounds, preference is given to compounds wherein Z is -O- and R < ² > is a nitrogen-containing heterocycle of formula (Ic).

(Ic)

Exemplary special compounds of the compounds of the present invention and their pharmaceutically acceptable salts, esters and amides are:

-6-Hexano-pyrido [l, 2-a] pyrimidine-l- 7-carboxylic acid;

(H) -6-oxo-pyrido [l, 2-a] pyrimidin- Pyrimidine-7-carboxylic acid;

3-Fluoro-9-cyclopropyl-2- (4-methylpiperazin-l-yl) -6 (H) -6-oxo-pyrido [l, 2-a] pyrimidine-7-carboxylic acid;

8- (3-Aminopyrrolidin-1-yl) -1-ethyl-4H-quinolizin-4-one-3-carboxylic acid;

2- (3-Aminopyrrolidin-l-yl) -9-cyclopropyl-3-fluoro-6H-6-oxo-pyrido [l, 2-a] pyrimidine-7-carboxylic acid;

2- (3-Aminopyrrolidin-l-yl) -9-cyclopropyl-3-fluoro-6H-6-oxo-pyrido [l, 2-a] pyrimidine-7-carboxylic acid;

6H-6-oxopyrido [l, 2-a] pyrimidin-7 (4-fluorophenyl) -Carboxylic acid;

6H-6-oxopyrido [l, 2-a] pyrimidine-lH- 7-carboxylic acid;

(2,4-difluorophenyl) -3-fluoro-6H-6-oxopyrido [1, 2-dihydroxypyrrolidin- , 2-a] pyrimidine-7-carboxylic acid;

6H-6-oxopyrido [l, 2-a] pyrimidine-lH- 7-carboxylic acid;

9-Cyclopropyl-3-fluoro-2- (4-methylpiperazin-l-yl) -6H-6-oxo-pyrido [l, 2-a] pyrimidine-7-carboxylic acid;

9-Cyclopropyl-3-fluoro-2- (piperazin-1-yl) -6H-6-oxo-pyrido [l, 2-a] pyrimidine-7-carboxylic acid;

9-Cyclopropyl-3-fluoro-2- (morpholin-l-yl) -6H-6-oxo-pyrido [l, 2-a] pyrimidine-7-carboxylic acid;

6-oxopyrido < / RTI > (3-fluoro-phenyl) [L, 2-a] pyrimidine-7-carboxylic acid;

(2,4-difluorophenyl) -3-fluoro-6H-6-oxopyrido < / RTI > [L, 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 [l, 2-a] pyrimidine-7-carboxylic acid;

2-methylpyrrolidin-1-yl) -9- (2,4-difluorophenyl) -3-fluoro-6H-6-oxo Pyrido [l, 2-a] pyrimidine-7-carboxylic acid;

6H-6-oxopyrido [l, 2-a] pyrimidine-lH-pyrrolo [ 7-carboxylic acid;

2-methylpyrrolidin-1-yl) -9- (2,4-difluorophenyl) -3-fluoro-6H-6-oxopyrido [L, 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- (Aminomethyl) 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- (l, 2,3,4-tetrahydro-2-isoquinolinyl) -4H-quinolizine-3-carboxylic acid;

1-Cyclopropyl-7-fluoro-9-methyl-4-oxo-8- (4-amino-1-piperidinyl) -4H-quinolizine-3-carboxylic acid;

1-Cyclopropyl-7-fluoro-9-methyl-4-oxo-8- (3-amino-1-piperidinyl) -4H-quinolizine-3-carboxylic acid;

1-Cyclopropyl-7-fluoro-9-methyl-4-oxo-8- (4- (aminomethyl) -1-piperidinyl) -4H-quinolizine-3-carboxylic acid;

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;

Yl) -7-fluoro-9-methyl-4-oxo-4H-quinolizine-l- 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;

Yl) -7-fluoro-9-methyl-4-oxo-4H-quinolizine-l- 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 (S) -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 [ 5-carboxylic acid;

(3R) -9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -2H, 3H, 6H-6-oxo-pyrano [ 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 [ 5-carboxylic acid;

3 (S) -10- (3-Aminomethyl-1-pyrrolidinyl) -9-fluoro-3-methyl-2H, 3H, 6H-6-oxo-pyrano [2.3.4] 5-carboxylic acid;

3-methyl-2H-3H, 6H-6-oxo-pyrano (2S, [2,3,4-ij] quinolizine-5-carboxylic acid;

3 (S) -9-fluoro-10- (3-hydroxy-1-pyrrolidinyl) -3-methyl-2H, 3H, 6H-6oxo-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) -l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;

8- (3- (Methylamino) -1-piperazinyl) -l-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;

7-fluoro-9-methyl-4-oxo-4H-quinolizine-3 -Carboxylic acid;

7-fluoro-9-methyl-4-oxo-4H-quinolizine-l- 3-carboxylic acid;

7-fluoro-9-methyl-4-oxo-4H-quinolizine-3 (2S) -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;

Methyl-4-oxo-4H-quinolizine-3-carboxylic acid (5-fluoro-4- ;

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, 1 R) -8- (3- (1-aminoethyl) pyrrolidinyl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;

(3R, 1 R) -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;

9- (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- ;

Pyrrolidinyl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolin- 3-carboxylic acid;

7-fluoro-9-methyl-4-oxo-4H-quinolizine-l- 3-carboxylic acid;

8- (3- (1-aminocyclopropyl) pyrrolidinyl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;

Pyrrolidinyl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine 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) -norbornylamino) pyrrolidinyl) -4H-quinolizine-2-carboxylic acid 3-carboxylic acid;

3 (S) -I-Cyclopropyl-7-fluoro-9-methyl-4-oxo-8- 3-carboxylic acid;

3 (S) -Ilanyl- (S) -alaninylamino) pyrrolidinyl) -7-fluoro- -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) -l-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;

4-oxo-8- (3- (1,2,3-triazol-1-yl) -1-pyrrolidinyl) -quinolizine 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- (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;

8-Bicyclo [4.3.0] nonyl) -4-oxo-quinolizine-l- 3-carboxylic acid;

(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)) - -4H-9- methyl-1-cyclopropyl-7-fluoro -4-oxo-quinolizine-3-carboxylic acid;

^{8 - ((1R *, 2S} *, 6R *)) - 2- amino-8-azabicyclo [4.3.0] nonan-8-yl)) - -4H-l-cyclopropyl-7-fluoro-9- Methyl-4-oxo-quinolizine-3-carboxylic acid;

3-azabicyclo [3.1.9] hexan-3-yl)) - 1- cyclopropyl-9-methyl-7-fluoro-4H-4- 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;

(Spiro-1, 3-dioxacyclopentane [2.3] -1-piperidinyl) -1-cyclopropyl-7-fluoro-4H- 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) -l-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-Pyrrolipiperidinyl) -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;

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) (methylpiperidinyl) -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;

Methyl-4-oxo-quinolizine-3-carboxamide < / RTI > Carboxylic acid;

Methyl-1 ', 3'-dioxolanyl) piperidinyl) -7-fluoro-9-methyl- 4H-quinolizine-3-carboxylic acid;

6-methylbicyclo [3.3.0] octan-1-yl) -7-fluoro-9-methyl-4-oxo-4H-quinazolin- 3-carboxylic acid;

1-Cyclopropyl-8- (3-fluoromethylpiperidinyl) -7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;

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;

Cyclopropyl-8- ((2-aza-4- (dimethylaminomethyl) bicyclo [4.3.0] non-2-yl) -7-fluoro- Anthraquinone carboxylic acid;

(3-aza-6- (L-alaninylamino) -6-methylbicyclo [3.3.0] octane) -7- Quinolizinecarboxylic acid;

Pyrrolidinyl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolyl (2R, 3-carboxylic acid;

(3R, 1S) -8- (3- (1-Amino-2-methoxyethyl) pyrrolidinyl) -1-cyclopropyl-7-fluoro-9- 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- ;

8-Bicyclo [4.3.0] nonyl) -7-fluoro-4H-9-methyl-4-oxo-quinolizine- 3-carboxylic acid;

(R, R-2,8-diaza-8-bicyclo [4.3.-] nonyl) -7-fluoro-4H-9-methyl-4-oxo-quinolizine- 3-carboxylic acid;

3-aza-bicyclo [3.1.0] hexan-3-yl) -7-fluoro-4H-9-methyl-4-oxo-quinolizine- -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;

-7-fluoro-4H-9-methyl-4-oxo-quinolizine-l- 3-carboxylic acid hydrochloride;

4-oxo-quinolizine-1-carbonitrile The title compound was prepared in analogy to the procedure described for the synthesis of 8- (7- (R) -amino-5-aza- spiro [2.4] heptan- 3-carboxylic acid hydrochloride;

Pyrrolidinyl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine- 3-carboxylic acid;

(S ^* ) - (1- (S ^* ) - amino-2,2,2-trifluoroethyl) pyrrolidinyl) -1-cyclopropyl-7-fluoro- 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- (R) -aminopiperidinyl) -l-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- (octahydropyrrolo [3,2-b] pyridin- l-yl) -l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid <;

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-hydroxypyrrolidinyl-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-l-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-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;

7-fluoro-4H-9-methyl-4-oxo-quinolizine (prepared according to the method described in < Carboxylic acid;

8- (3- (2-fluoroethyl) aminopyrrolidin-1-yl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;

Yl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3 -Carboxylic acid;

7-fluoro-4H-9-methyl-4-oxo-quinolizine-l- 3-carboxylic acid;

7-fluoro-4H-9-methyl-4-oxo-quinolizine-l- 3-carboxylic acid;

8- (3-amino-octahydroisoindol-2-yl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;

3-carboxylic acid (prepared as described for the synthesis of 8- (6-amino-2-aza- spiro [3.3] non-2-yl) -l-cyclopropyl-7-fluoro-4H- Isomer (I));

8- (3-Amino-3-trifluoromethylpyrrolidin-l-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;

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxamide was prepared from 8- (3-aminomethyl-3- trifluoromethyl- 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-quinolizine-3-carboxylic acid;

3-carboxylic acid (prepared as described for the synthesis of 8- (6-amino-2-aza- spiro [3.3] non-2-yl) -l-cyclopropyl-7-fluoro-4H- Isomer (II));

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;

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid <;

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid (2-fluoro- ;

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid <;

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid <;

8- (2- (R) -aminomethyl-pyrrolidin-l-yl) -l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;

8- (2- (S) -Aminomethyl-pyrrolidin-l-yl) -l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;

8- (3- (R) - (1-aminocyclopropyl) pyrrolidinyl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-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;

7-fluoro-9-methyl-4-oxo-4H-pyrrolo [2,3- - 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-l-yl) -l-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- Carboxylic acid;

-7-fluoro-4H-9-methyl-4-oxo-quinolizine-l- 3-carboxylic acid;

4-oxo-quinolizine-1-carbonitrile The title compound was prepared in analogy to the procedure described for the synthesis of 8- (7- (R) -amino-5-aza- spiro [2.4] heptan- 3-carboxylic acid;

7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-l- Quinolizine-3-carboxylic acid;

7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-l- Quinolizine-3-carboxylic acid;

A solution of 8- (trans-3- (S) -amino-4- (R) -methylpyrrolidin- 1 -yl) -l-cyclopropyl-7-fluoro-4H-9- 3-carboxylic acid;

7-fluoro-4H-9-methyl-4-oxo-quinazolin-3- 3-carboxylic acid;

7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-l- Quinolizine-3-carboxylic acid;

7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-1-carboxylic acid ethyl ester was prepared from 8- (cis-3- (R) -amino-4- (R) -cyclopropylpyrrolidin- Quinolizine-3-carboxylic acid;

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomeric mixture of 8- (trans-3-amino-4-ethylpyrrolidin- 1 -yl) Isomer A;

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomeric mixture of 8- (trans-3-amino-4-ethylpyrrolidin- 1 -yl) Isomer B;

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomer <A;

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomer <B;

7-fluoro-4H-9-methyl-4-oxo-quinolin-2- 3-carboxylic acid; And

7-fluoro-4H-9-methyl-4-oxo-quinolin e (1 H) Carboxylic acid.

Among the above representative compounds of the compounds of the present invention, preferred compounds are the following compounds, pharmaceutically acceptable salts, esters and amides thereof:

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- ;

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- Carboxylic acid;

1-Cyclopropyl-7-fluoro-9-methyl-4-oxo-8- (4-amino-1-piperidinyl) -4H-quinolizine-3-carboxylic acid;

1-Cyclopropyl-7-fluoro-9-methyl-4-oxo-8- (4- (aminomethyl) -1-piperidinyl) -4H-quinolizine-3-carboxylic acid;

1-Cyclopropyl-7-fluoro-9-methyl-4-oxo-8- (3-amino-1-piperidinyl) -4H-quinolizine-3-carboxylic acid;

8- (3- (S) -aminopiperidinyl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-3-carboxylic acid;

6-methylbicyclo [3.3.0] octan-1-yl) -7-fluoro-9-methyl-4-oxo-4H-quinolin- 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)) - -4H-9- methyl-1-cyclopropyl-7-fluoro -4-oxo-quinolizine-3-carboxylic acid;

8- ((1R ^* , 2R ^* , 6R ^* ) - 2-amino-8-azabicyclo [4.3.0] nonan- -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- 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, 1 R) -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, 1 R) -8- (3- (1-aminoethyl) pyrrolidinyl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;

8-Bicyclo [4.3.0] nonyl) -7-fluoro-4H-9-methyl-4-oxo-quinolizine- 3-carboxylic acid;

8-Bicyclo [4.3.0] nonyl) -7-fluoro-4H-9-methyl-4-oxo-quinolizine- 3-carboxylic acid;

3-aza-bicyclo [3.1.0] hexan-3-yl) -7-fluoro-4H-9-methyl-4-oxo-quinolizine- -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-fluoromethylpyridin-l-yl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;

8- (cis-3-Amino-4-fluoromethylpyridin-l-yl) -l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;

7-fluoro-4H-9-methyl-4-oxo-quinolizine-l- 3-carboxylic acid;

7-fluoro-4H-9-methyl-4-oxo-quinolizine-l- 3-carboxylic acid;

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid <;

8- (2- (R) -aminomethyl-pyrrolidin-l-yl) -l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;

(8- (3-Amino-4-methyl-piperidin-l-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- Carboxylic acid;

-7-fluoro-4H-9-methyl-4-oxo-quinolizine-l- 3-carboxylic acid;

4-oxo-quinolizine-1-carbonitrile The title compound was prepared in analogy to the procedure described for the synthesis of 8- (7- (R) -amino-5-aza- spiro [2.4] heptan- 3-carboxylic acid;

7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-l- Quinolizine-3-carboxylic acid;

7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-l- Quinolizine-3-carboxylic acid;

A solution of 8- (trans-3- (S) -amino-4- (R) -methylpyrrolidin- 1 -yl) -l-cyclopropyl-7-fluoro-4H-9- 3-carboxylic acid;

7-fluoro-4H-9-methyl-4-oxo-quinazolin-3- 3-carboxylic acid;

7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-l- Quinolizine-3-carboxylic acid;

7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-1-carboxylic acid ethyl ester was prepared from 8- (cis-3- (R) -amino-4- (R) -cyclopropylpyrrolidin- Quinolizine-3-carboxylic acid;

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomeric mixture of 8- (trans-3-amino-4-ethylpyrrolidin- 1 -yl) Isomer A;

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomeric mixture of 8- (trans-3-amino-4-ethylpyrrolidin- 1 -yl) Isomer B;

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomer <A;

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomer <B;

7-fluoro-4H-9-methyl-4-oxo-quinolin-2- 3-carboxylic acid; And

7-fluoro-4H-9-methyl-4-oxo-quinolin e (1 H) Carboxylic acid.

Particularly preferred compounds among the representative compounds of the present invention are the following compounds, their pharmaceutically acceptable salts, esters and amides.

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- 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;

Cyclopropyl-8- (S, S, -2,8-diaza-8-bicyclo [4.3.0] nonyl) -7-fluoro-4H-9-methyl-4-oxo-quinolizine Carboxylic acid;

8-Bicyclo [4.3.0] nonyl) -7-fluoro-4H-9-methyl-4-oxo-quinolizine Carboxylic acid;

3-aza-bicyclo [3.1.0] hexan-3-yl) -7-fluoro-4H-9-methyl-4-oxo-quinolizine- -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-fluoromethylpyridin-l-yl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;

8- (cis-3-Amino-4-fluoromethylpyridin-l-yl) -l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;

7-fluoro-4H-9-methyl-4-oxo-quinolizine-l- 3-carboxylic acid;

7-fluoro-4H-9-methyl-4-oxo-quinolizine-l- 3-carboxylic acid;

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid <;

8- (2- (R) -aminomethyl-pyrrolidin-l-yl) -l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;

(8- (3-Amino-4-methyl-piperidin-l-yl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;

7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid <;

-7-fluoro-4H-9-methyl-4-oxo-quinolizine-l- 3-carboxylic acid;

4-oxo-quinolizine-1-carbonitrile The title compound was prepared in analogy to the procedure described for the synthesis of 8- (7- (R) -amino-5-aza- spiro [2.4] heptan- 3-carboxylic acid;

7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-l- Quinolizine-3-carboxylic acid;

7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-l- Quinolizine-3-carboxylic acid;

A solution of 8- (trans-3- (S) -amino-4- (R) -methylpyrrolidin- 1 -yl) -l-cyclopropyl-7-fluoro-4H-9- 3-carboxylic acid;

7-fluoro-4H-9-methyl-4-oxo-quinazolin-3- 3-carboxylic acid;

7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-l- Quinolizine-3-carboxylic acid;

7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-1-carboxylic acid ethyl ester was prepared from 8- (cis-3- (R) -amino-4- (R) -cyclopropylpyrrolidin- Quinolizine-3-carboxylic acid;

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomeric mixture of 8- (trans-3-amino-4-ethylpyrrolidin- 1 -yl) Isomer A;

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomeric mixture of 8- (trans-3-amino-4-ethylpyrrolidin- 1 -yl) Isomer B;

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomer <A;

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomer <B;

7-fluoro-4H-9-methyl-4-oxo-quinolin-2- 3-carboxylic acid; And

7-fluoro-4H-9-methyl-4-oxo-quinolin e (1 H) Carboxylic acid.

As described above, many asymmetric centers are present in the compounds of the invention as R or S coordination. Unless otherwise indicated, the present invention encompasses many stereoisomers and mixtures thereof.

Many of the terms defined herein represent particular elements of the invention. When used, the following meanings are to be expressed.

The term alkanoyl having 1 to 8 carbon atoms refers to the formula - (CO) R ¹⁵ , wherein R ¹⁵ is hydrogen or an alkyl radical having 1 to 8 carbon atoms and includes, but is not limited to, acetyl and pivaloyl.

The term alkyl refers to straight or branched chain hydrocarbon radicals having from 1 to 10 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl and neopentyl.

The term alpha-amino acid and polypeptide residue refer to a single amino acid and two to five amino acids, respectively, linked by amide (peptide) linkage. The amino acid may be a natural amino acid such as valine, phenylalanine and glycine, or may be a synthetic alpha-amino acid such as cyclohexyl alanine, further in the L or D configuration, or a mixture of the two isomers. Preferably, the amino acid substituent is optically active and has the L configuration.

The term amino (lower alkyl) refers to lower alkyl radicals having one or more substituents attached to them, optionally substituted with one or two lower alkyl radicals or alpha-amino acids or polypeptide residues. Examples of amino (lower alkyl) groups include aminoethyl, aminomethyl and N, N-dimethylaminoethyl.

The term aminooxy refers to an amino group optionally substituted once or twice with lower alkyl or halo (lower alkyl), which binds the remaining molecule via an oxygen atom (e.g., -O-NR'R, where , R 'and R are hydrogen, lower alkyl or halo (lower alkyl)).

The term aminothio lower alkoxy refers to a thio lower alkoxy radical to which an amino group is attached, such as, for example, aminothiomethoxy and 2-aminothioethoxy.

The term aromatic group refers to aromatic C ₆ to C ₁₀ cyclic radicals according to Huckle's rule. Examples of aromatic groups include nitrogen containing aromatic heterocyclic radicals as defined below, as well as carbocyclic aromatic radicals such as phenyl and naphthyl.

The term aryl (lower alkyl) refers to lower alkyl radicals to which aromatic hydrocarbon groups are attached, such as, for example, benzyl and phenylethyl.

The term aryl (lower alkyl) amino refers to amino radicals to which an aryl (lower alkyl) group is attached. Examples of aryl (lower alkyl) amino groups are benzylamino and phenylethylamino.

The term aryl (lower alkyl) oxy refers to an aryl (lower alkyl) radical to which the remaining molecule is attached via an ether linkage (i.e., through an oxygen atom). Examples of aryl (lower alkyl) oxy radicals are benzyloxy and phenylethyloxy.

The term aryloxy refers to an aromatic hydrocarbon radical to which the rest of the molecule is attached via an ether linkage (i. E. Via an oxygen atom), such as, for example, phenoxy.

The term bicycloalkyl refers to a radical comprising a bridged, saturated or unsaturated ring system of 5 to 9 carbon atoms in which two nonadjacent carbon atoms of the first ring are further joined with an alkylene bridge having from 1 to 3 carbon atoms, (Lower alkyl), hydroxy (lower alkyl), hydroxy substituted lower alkyl, hydroxy, lower alkoxy, halogen and amino, (lower alkyl) Amino and an alkanoylamino group having 1 to 8 carbon atoms, wherein the amino group may be further substituted with an alkanoyl, alpha-amino acid or polypeptide having 1 to 8 carbon atoms. do. Examples of bicycloalkyl radicals include, but are not limited to, norbornyl, bicyclo [2.2.1] hept-2-ethyl and bicyclo [1.1.1] fentanyl.

The term non-cyclic nitrogen-containing heterocyclic group refers to a radical comprising a bicyclic ring system in which the ring is fused (a), bridged (b) or spiro (c). The fused ring cyclic nitrogen-containing heterocyclic group may be optionally substituted with one or more groups selected from the group consisting of a first nitrogen-containing heterocycle or an aromatic heterocycle having a second saturated or unsaturated carbocyclic or zero, one or two heteroatoms selected from S, O and N And is fused to three to six heterocyclic rings which are atoms. Halogen (lower alkyl), hydroxy substituted lower alkyl, hydroxy, halogen, amino (lower alkyl), alkanoylamino of 1 to 8 carbon atoms, phenyl and -NR < ¹⁷ >, wherein the first and second rings are independently selected from the group consisting of lower alkyl, R ¹⁸ (wherein, R ¹⁷ and R ¹⁸ are independently hydrogen or lower alkyl, when one is hydrogen and the other is alpha-amino acid or a polypeptide residue), optionally with one to three additional radicals a ² selected from among . Examples of fused ring cyclic nitrogen containing heterocyclic radicals include radicals having 5: 3, 5: 4, 5: 5 and 6: 5 ring systems,

≪ / RTI >

The bridged ring cyclic nitrogen-containing heterocyclic group may have the formula

A group selected from (where, j and k is 1, 2 or 3, A ¹ is a carbon selected from optionally substituted S, O and N in an arbitrary position in front of one or three additional radicals A ² of the same as defined Atoms or heteroatoms) and unsaturated derivatives thereof.

The spiro-ring-cyclic nitrogen-containing heterocyclic group may be optionally substituted with one or two groups of three to six atoms wherein zero, one, or three of the first nitrogen-containing heterocycle or aromatic heterocycle is a heteroatom selected from S, O and N, Lt; / RTI > carbocyclic or heterocyclic ring bonded by a single shared carbon atom. Both the first ring and the second ring may be substituted with one to three additional radicals A ² , wherein A ² is as defined above. Examples of spiro-ring-cyclic nitrogen-containing heterocyclic radicals include, but are not limited to,

≪ / RTI >

The term cyclic ether refers to a 4 to 6 membered monocyclic hydrocarbon radical containing an oxygen reductant and attached to the rest of the molecule via any carbon atom, including, but not limited to, oxetane.

The term cycloalkenyl having 4 to 8 carbon atoms includes, but is not limited to, monounsaturated monocyclic hydrocarbon radicals having 4 to 8 carbon atoms in the ring, including cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. Lower alkyl, hydroxy (lower alkyl), hydroxy, lower alkoxy, halogen, amino, lower alkylamino and amino (lower alkyl) , (Lower alkyl) amino, and alkanoylamino of 1 to 8 carbon atoms, wherein the amino group may be further substituted with an alkanoyl, alpha-amino acid or polypeptide of 1 to 8 carbon atoms. Lt; / RTI > are optionally substituted with additional radicals.

The term cycloalkyl having 3 to 8 carbon atoms refers to a saturated monocyclic hydrocarbon radical of 3 to 8 carbon atoms in the ring and refers to aryl (lower alkyl), alkoxycarbonyl, lower alkyl, halo (lower alkyl), amino Lower alkoxy, halogen and amino, (lower alkyl) amino and alkanoylamino of 1 to 8 carbon atoms, wherein the amino group is an alkanoyl, alpha-amino acid or polypeptide of 1 to 8 carbon atoms, , ≪ / RTI > which may optionally be further substituted with one to three additional radicals. Examples of cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-fluoro-cyclopropyl, 2-fluorocyclopropyl, and 2-aminocyclopropyl.

The term cycloalkyl (amino) refers to an amino group, typically substituted with one or more cycloalkyl groups, having from 3 to 8 carbon atoms.

The term cycloalkyl (lower alkyl) refers to a lower alkyl radical bonded to a cycloalkyl radical having from 3 to 8 carbon atoms, and the cycloalkyl radical is optionally substituted as previously described.

The term fused as used herein generally refers to two cyclic groups having two adjacent ring atoms.

The terms halo and halogen refer to monovalent radicals selected from chloro (Cl), bromo (Br), fluoro (F) and iodo (I).

The term halo (lower alkyl) refers to lower alkyl radicals to which one to three halogen atoms are attached. Examples of halo (lower alkyl) radicals include fluoromethyl, trifluoromethyl, 1-fluoromethyl, 1-fluoroethyl, 2-fluoroethyl and 1,2-difluoroethyl.

The term halo (lower alkyl) amino refers to an amino group substituted with one or more halo (lower alkyl) groups.

The term halo (lower alkyl) amino (lower alkyl) refers to amino (lower alkyl) radicals to which the halo (lower alkyl) group is attached, such as, for example, 2-fluoroethylaminomethyl.

The term halo substituted nitrogen containing aromatic heterocycle refers, without limitation, to a nitrogen containing aromatic heterocycle having one to three halogen atoms attached, including 5-fluoro-2-pyrimidyl.

The term hydroxy substituted lower alkyl refers to lower alkyl radicals to which one to three hydroxyl groups are attached, such as, for example, hydroxymethyl and 2-hydroxyethyl.

The term hydroxy-substituted (lower alkyl) amino refers to (lower alkyl) amino radicals to which one to three hydroxyl groups are attached, such as, for example, hydroxymethylamino and 2-hydroxyethylamino.

The term iminocarbose refers to the divalent radical of the formula = N-OH.

The term lower alkenyl refers to straight or branched chain hydrocarbon radicals containing from 2 to 6 carbon atoms and having at least one carbon-carbon double bond. Examples of lower alkenyl radicals include vinyl, allyl, 2- or 3-butenyl, 2-, 3- or 4-pentenyl, 2-, 3-, 4- or 5-hexenyl and isomeric forms thereof .

The term lower alkoxy means that the remainder of the molecule via an ether linkage (i. E. Via an oxygen atom), such as methoxy, ethoxy, propoxy, tert-butoxy, pentyloxy, hexyloxy, Refers to a fused lower alkyl radical.

The term lower alkoxycarbonyl refers to a radical of the formula -C (O) R ²⁵ , wherein R ²⁵ is, for example, a lower alkoxy group such as ethoxycarbonyl and methoxycarbonyl.

The term lower alkoxy (lower alkoxy) (lower alkyl) refers to lower alkoxy (lower alkyl) radicals to which lower alkoxy groups are attached, such as, for example, methoxymethoxymethyl and ethoxymethoxymethyl.

The term lower alkoxy (lower alkyl) refers to lower alkyl optionally substituted by a further amino radical, such as, for example, methoxyethyl, ethoxymethyl and 1-amino-2-methoxyethyl do.

The term lower alkyl refers, without limitation, to an alkyl radical of one to six carbon atoms, including methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl and neopentyl.

The term (lower alkyl) amino refers, without limitation, to amino radicals substituted with one to three lower alkyls, including methylamino, ethylamino, dimethylamino, propylamino and ethylmethylamino.

The term lower alkynyl refers to straight- or branched-chain hydrocarbon radicals having from 2 to 6 carbon atoms and having at least one carbon-carbon triple bond. Examples of lower alkynyl radicals include ethynyl, 2-hexyn-1-yl, 3,3-dimethyl-1-butyn-1-yl and 3-methylbutyn-3-yl.

The term nitrogen-containing aromatic heterocycle refers to monocyclic aromatic radicals of the reductors 5 to 7 wherein one of the reductors is nitrogen and 0, 1 or 2 of the reductants are independently selected from the group consisting of additional heteroatoms selected from S, O and N Atoms, the remainder of the reductant is carbon, and the radical is bound to the remaining molecule via any reductant. Nitrogen containing aromatic heterocycles include pyridine, pyrazine, pyrimidine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isoxazole, thiadiazole, oxadiazole and substituted derivatives thereof.

The term nitrogen-containing heterocycle refers to a nitrogen-containing heterocycle, wherein one nitrogen is zero, one or two are independently selected from S, O and N, the radical is bonded to the rest of the molecule via any reductant, (Lower alkyl), hydroxy substituted lower alkyl, hydroxy, lower alkoxy, halogen, amino, lower alkyl amino (lower alkyl), lower alkoxy And an additional radical selected from amino, (lower alkyl) amino and alkanoylamino wherein the amino group may also be substituted with an alkanoyl, alpha-amino acid or polypeptide of 1 to 8 carbon atoms. To 7 saturated or unsaturated monocyclic ring system radicals. Examples of nitrogen containing heterocycles include pyrrolidine, dihydropyrrole, isoxazolidine, oxazolidine, tetrahydropyridine, piperidine, piperazine, morpholine, thiomorpholine, aziridine and azetidine .

The term pharmaceutically acceptable cation generally refers to a positively charged inorganic or organic ion that is believed to be suitable for human consumption. Examples of pharmaceutically acceptable cations are hydrogen, alkali metals (lithium, sodium and potassium), magnesium, calcium, ferrous, ferric, ammonium, alkylammonium, dialkylammonium, trialkylammonium, tetraalkylammonium, Diethanolammonium, triethanolammonium, and guanidinium ions and proton forms of lysine, procaine and choline. When the compound of the present invention is prepared in a carboxylic acid form (i.e., when R ₄ is hydrogen) by adding a cationic base form (such as a hydroxyl or free amine), a suitable cation form is obtained.

Pharmaceutically acceptable salts, esters and amides, as in the compounds of formula I, may be used in contact with the tissues of humans and downstream animals without causing toxicity, irritation, allergic response, etc., within the scope of sound medical judgment Refers to carboxylate salts, amino acid addition salts, esters and amides, as well as their zwitterionic forms, which are suitable and effective to be desired / desired in a benefit / risk ratio.

Pharmaceutically acceptable salts are well known in the art. See, for example, S.M. Berge, et al. J. Pharmaceutical Sciences, 66: 1-19 (1977). Pharmaceutically acceptable non-toxic acid addition salts are 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, , ≪ / RTI > and other methods used in the art. Other pharmaceutically acceptable salts include, but are not limited to, nitrate, bisulfate, borate, formate, butyrate, valerate, 3-phenylpropionate, camphorate, adipate, benzoate, oleate, palmitate, stearate, , Lactate, fumarate, ascorbate, aspartate, nicotinate, p-toluenesulfonate, camphorsulfonate, methanesulfonate, 2-hydroxyethanesulfonate, gluconate, gluheptonate, lactobionate , Glycerophosphate, pectinate, lauryl sulfate, or metal salts such as sodium, potassium, magnesium or calcium salts or amino salts such as ammonium, triethylamine salts and the like, all of which can be prepared by conventional methods.

Examples of pharmaceutically acceptable, non-toxic esters of the present invention include C1 to C6 alkyl esters and C5 to C7 cycloalkyl esters, with C1 to C4 alkyl esters being preferred. Esters of compounds of formula (I) can be prepared according to conventional methods.

The pharmaceutically acceptable, non-toxic amides of the present invention include amides derived from ammonia, primary C1 to C6 alkyl amides, and secondary C1 to C6 dialkylamines. In the case of a secondary amine, the amine may also be in the form of a 5 or 6 membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1 to C3 alkyl primary amides and C1 to C2 dialkyl secondary amides are preferred. Amides of the compounds of formula (I) can be prepared according to conventional methods. The amides of the present invention include amino acids and peptide derivatives of the compounds of formula (I).

As used herein, the term pharmaceutically acceptable carrier means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary in any form. Examples of materials that can provide pharmaceutically acceptable carriers include sugars such as lactose, glucose, sucrose, as well as other non-toxic compatible substances used in pharmaceutical compositions; Starches such as corn starch and sweet potato starch; Cellulose and sodium carboxymethylcellulose, ethyl cellulose and derivatives thereof such as cellulose acetate; Powder tragacanth rubber; malt; gelatin; Talc; Excipients such as cocoa butter and suppository wax; Oils such as peanut oil, cottonseed oil, sunflower oil, olive oil, corn oil and kidney bean oil; Glycols such as propylene glycol; Esters such as ethyl oleate and ethyl laurate; Agar; Buffers such as magnesium hydroxide and aluminum hydroxide; Alginic acid; Pyrogen removal number; Isotonic saline; Ringer's solution; Ethyl alcohol and phosphate buffer solutions. Lubricants such as wetting agents, emulsifiers and sodium lauryl sulfate and magnesium stearate, and preservatives as well as colorants, emollients, fabric agents, sweeteners, fragrances and perfumes may be incorporated into the compositions as judged by the formulator.

The term prodrug refers to derivative compounds that are rapidly converted in vivo, e.g., by hydrolysis in blood, to the parent compound of formula I, such as the compound of formula (I). T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. Symposium Series, American Chemical Society (1975)]. Examples of esters useful as prodrugs for compounds containing carboxyl groups are described in Bioreversible Carriers in Drug Design: Theory and Application, pages 14-21, edited by E.B. Roche, Pergamon Press: New York (1987). These references and any other references cited herein are hereby incorporated by reference.

The term prodrug ester group refers to several ester forming groups that undergo hydrolysis under physiological conditions. Examples of prodrug ester groups include other groups known in the art, including (5-R-2-oxo-1,3-dioxolen-4-yl) methyl groups, as well as povyloxymethyl, Ethoxymethyl, phthalidyl, indanyl, and methoxymethyl. Other examples of prodrugs can be found in the above-cited references (T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems).

The term protection group is well known in the art and refers to a substituent in the functional group of the chemically converting compound that prevents undesired reactions and decomposition during synthesis (T. Greene, Protective Groups in Organic Synthesis, John Wiley Sons, New York (1981)].

The term substituted phenyl is each independently selected from the group consisting of halogen, hydroxy, lower alkoxy, lower alkyl, hydroxy substituted lower alkyl, amino, (lower alkyl) amino, amino (lower alkyl) To five non-hydrogen substituents. Examples of substituted phenyl include 2-fluorophenyl, 4-fluorophenyl and 2,4-difluorophenyl.

The term thio-lower-alkoxy refers to a radical of the formula -SR ³⁵ (wherein, R ³⁵ is, without limitation, tea omega lower alkyl groups include ethoxy and thio ethoxy).

The term thio lower alkoxy (lower alkyl) refers to lower alkyl radicals to which a thio lower alkoxy group is attached, including, but not limited to, thiomethoxymethyl and thiomethoxyethyl.

According to the treatment method of the present invention, the compounds of the present invention can be administered alone or in combination or in combination with other agents. When using the compounds of the present invention for antimicrobial therapy, the specific therapeutically effective dose level for any particular patient will depend upon the severity of the disorder and disorder being treated; The activity of the particular compound used; The particular composition used; Age, weight, general health, sex and patient's diet; The time of administration, the route of administration and the rate of excretion of the particular compound employed; Treatment period; Drugs used in combination or concurrent with the particular compound used; And factors well known in the medical arts.

The total daily dose of a compound of the present invention administered to a host by itself or in a bolus dose can be, for example, an amount such as from 0.1 to 200 mg / kg of body weight or more usually from 0.25 to 100 mg / kg of body weight. The sole dose composition contains such an amount or a minor amount thereof that is in a daily dose.

According to the pharmaceutical composition of the present invention, the compounds of the present invention may be administered orally, parenterally, orally in unit dose formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, diluents and / , By the inhalation unit, rectally, or topically. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, sternal injection or infusion techniques.

For example, injectable preparations such as 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 sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as, for example, a solution in 1,3-butanediol. Among the acceptable excipients and solvents that may be employed are water, Ringer's solution (U.S.P.) and isotonic sodium chloride solution. In addition, sterile, hydrogenated oils may be used as a solvent or suspending medium. In addition, fatty acids such as oleic acid are used in injectable preparations.

It is often desirable to slow the absorption of the drug by subcutaneous or intramuscular injection to maintain the effect of the drug. The most common way of doing this is to inject a suspension of poorly water-soluble crystalline or amorphous material. The rate of drug absorption depends on the drug dissolution rate, i. E., On the physical state of the drug, e. G., Crystal size and crystal form. Another approach to delay drug absorption is to administer the drug with a solution or suspension in oil. The injectable depot form may also be prepared by forming a biodegradable polymer such as a microcapsule matrix of the drug and a polylactide-polyglycolide. Depending on the drug ratio to the polymer and the polymer composition, the rate of drug release can be controlled. Depot injections can also be prepared by entrapping the drug in a liposome or microemulsion suitable for body tissue.

Suppositories for intrathecal or rectal administration of the drug can be prepared by mixing the drug with a suitable non-irritating excipient such as cocoa butter and polyethylene glycol that dissolves in the solid or rectum or vagina at room temperature and releases the drug.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, prills, and granules. In this solid dosage form, the active compound may be mixed with one or more inert diluents such as sucrose, lactose or starch. Such dosage forms may also contain additional substances other than inert diluents, such as, for example, common practice, tablet lubricants such as magnesium stearate and microcrystalline cellulose and other tablet adjuvants. In the case of capsules, tablets and pills, the dosage form may also comprise a buffer. Tablets and pills may additionally be prepared as intestinal and other controlled release preparations.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art such as water. Such compositions also include wetting agents; Emulsifiers and suspending agents; And adjuvants such as sweetening, flavoring and perfuming agents.

Optionally, the compounds of the present invention may be incorporated into a sustained or targeted delivery system, such as polymer matrices, liposomes, and microspheres. They may be sterilized, for example, by filtration through a bacterial retainer filter or by incorporating sterile water or sterilizing agents in the form of a sterile solid composition that is dissolved in the other sterile injectable medium immediately prior to use.

The active compound may also be in microencapsulated form with one or more excipients as mentioned above.

Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and, if desired, any preservatives or buffers. Ophthalmic formulations, ointments, ointments, powders and medicaments can be used within the scope of the present invention.

The ointments, pastes, creams and gels may contain, in addition to the active compounds of the present invention, animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth gum, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, ≪ / RTI >

Powders and sprays may contain, in addition to the compounds of the present invention, lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these materials. The spray agent may additionally contain conventional propellants such as chlorofluorohydrocarbons or their substituents.

Transdermal patches have the added advantage of regulating the delivery of compounds to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. The absorption enhancer can also be used to increase the flow rate of the compound through the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

A further possible way for the delivery and / or use of the compounds of the invention is to chemically incorporate the compounds with other antibacterial agents such as beta lactam. The same dual acting formulations (beta lactam and quinolone) are disclosed in published European Patent 597 303 (Dax, et al., Published May 18, 1994) and International Patent Application PCT / US92 / 08246 , et al., publication number WO93 / 07154, published April 15, 1993). Nitrogen bond or other heterocycle bond, for example, an amino substituent at the C-8 position of the compound of the present invention or an alkyl of a carboxylic acid group and beta lactam at the C-3 position, or other Can be formed between the groups.

In general, the compounds of the present invention are synthesized according to Reaction Schemes 1 to XVIII shown below, wherein R ¹ to R ¹⁶ , A, X, Y and Z correspond to the group defined in relation to Formula I, R is lower alkyl and X Is a halogen atom, P is a protecting group, and L is a suitable leaving group such as, for example, a halogen atom.

The following abbreviations are used repeatedly in this specification. BOC for t-butoxycarbonyl; (BOC) ₂ for di-t-butyl dicarbonate; CBZ for benzyloxy-carbonyl; DMF for dimethylformamide; DMSO to dimethylsulfoxide; LDA for lithium diethylamide; RaNi for Raney riche; And THF for tetrahydrofuran.

Condensation of Amano groups with amino acids and peptides in order to prepare compounds of formula (I) which are alpha-amino acids or peptide derivatives of amine groups at R ² can be carried out by azide method, mixed acid anhydride method, DCC (dicyclohexylcarbodiimide) method , The active ester method (p-nitrophenyl ester method, N-hydroxysuccinimide ester method, cyanomethyl ester method etc.), Woodward reagent K method, DCC-HOBT (1-hydroxy- Sol) method, and the like. Classic methods for amino acid condensation reactions are described in Peptide Synthesis, Second Edition, M. Bodansky, YS Klausner and MA Ondetti (1976). The amino acid coupling reaction describes that the amino containing group can be carried out before or after the introduction of the 7-fluoro atom of the appropriate intermediate into the compound.

Depending on the conventional peptide synthesis, side chain amino and carboxyl groups can optionally be protected or deprotected at the alpha and omega positions of the amino acid. Protecting groups for the available amino groups include, for example, benzyloxycarbonyl (Z), o-chloro-benzyloxycarbonyl ((2-Cl) Z), p-nitrobenzyloxycarbonyl (Z NO ₂ )), p-methoxybenzyloxy carbonyl (Z (OMe)), t-butoxycarbonyl (Boc), t-amyloxycarbonyl (Aoc), isoborneyoxycarbonyl, adamantyl (Boc), 9-fluoro-methoxycarbonyl (Fmoc), methylsulfonylethoxycarbonyl (Msc), and the like. (Nps), diphenylphosphinothiol (Ppt), and dimethylphosphino-thy oil (Mpt), which are known in the art.

Examples of the protecting group for the carboxyl group include benzyl ester (OBzl), cyclohexyl ester, 4-nitrobenzyl ester (OBzlNO ₂ ), t-butyl ester (OeBu), 4-pyridyl methyl ester (OPic) and the like.

Certain amino acids having functional groups other than amino and carboxyl groups on side chains such as arginine, cysteine, serine, etc., can optionally be protected with a suitable protecting group during any synthetic process of the compounds of the present invention. For example, the guanidino group (NG) in arginine is reacted with nitro, p-toluenesulfonyl (Tos), benzyloxycarbonyl (Z), adamantyloxycarbonyl (Adoc), p-methoxybenzenesulfonyl , 4-methoxy-2,6-dimethyl-benzenesulfonyl (Mts), and the like; The thiol group in the cysteine is protected with benzene, p-methoxybenzyl, triphenylmethyl, acetamidomethyl, ethylcarbamyl, 4-methylbenzyl (4-MeBzl), 2,4,6-trimethylbenzyl Lt; / RTI > It is preferable to protect the hydroxy group in serine with benzyl (Bzl), t-butyl, acetyl, tetrahydropyranyl (THP) or the like.

[Reaction Scheme I]

[Reaction Scheme II]

[Reaction Scheme III]

[Reaction Scheme IVA]

[Reaction Scheme IVB]

[Reaction Scheme IVC]

[Reaction Scheme VA]

[Reaction Scheme VB]

[Reaction Scheme VI]

[Reaction Scheme VII]

[Reaction Scheme VIII]

[Reaction Scheme IX]

[Scheme X]

[Reaction Scheme XI]

[Reaction Scheme XII]

[Reaction Scheme XIII]

[Reaction Scheme XIV]

[Reaction Scheme XV]

[Reaction Scheme XVI]

[Reaction Scheme XVII]

[Reaction Scheme XVIII]

According to Scheme I shown above, the alpha-haloacetate derivative of compound (I), such as ethyl 2-fluoroacetate, is reacted with compound (2) in the presence of a suitable base such as, for example, sodium ethoxide in an inert solvent such as diethyl ether ) ≪ / RTI > formate ester to give the enolate of compound (3). That is, the compound (3) is reacted with the compound (4) (wherein R ¹ is phenyl, trifluoromethyl, cyano, perfluoroalkyl, vinyl, substituted vinyl, fluorine, nitro, acetylene, substituted acetylene, Or an electron-withdrawing group such as a nitrogen-containing aromatic heterocycle, into compound (5). The compound (5) is reacted with an alkoxy of the compound (8) in the presence of a suitable strong base such as, for example, lithium diisopropylamide (LDA) or n-butyl lithium at a temperature of preferably below 0 ° C, Methylene malonate derivative to obtain compound (9A).

Compounds 9A can be prepared in the presence of a base such as, for example, DBU or piperidine, or in the presence of an acid such as sulfuric acid, in the presence of a solvent such as toluene, THF, ethanol or chlorobenzene, Compound 10C is obtained by heating in a solvent such as diglyme, triglyme, sulfolane or Dowtherm A ^R (a common mixture of biphenyl and diphenyl ether) at a temperature of 120 ° C or higher. The ester (10C) is reacted with the ester (11A) via transesterification in the presence of a suitable alcohol such as benzyl alcohol or 2- (trimethylsilyl) ethanol (TMSE) and suitable for its hydrolysis in the presence of a catalyst such as tetraethoxide ).

When one of the 2-hydroxy compounds of the compound (11A) is used, it is optionally added in an inert solvent, depending on the boiling point of the halogenating agent and the solvent, at a temperature of about 20 째 C to 145 째 C and usually at room temperature, Treatment with a halogenating agent such as phosphorus affords the corresponding halo derivative of compound (12A). The leaving group L in compound (12A) is then displaced with a nucleophile such as a nucleophilic amine (e.g. N-methylpyrrazine or 2-methylpiperazine) to give compound (13A). The reaction is carried out at a temperature of about 20 < 0 > C to 130 < 0 > C in a suitable organic solvent such as pyridine, methylene chloride, chloroform or 1-methyl-2-pyrrolidinone. It is preferred to carry out the reaction in a molar ratio of 1.0 to 2.0 moles of acid acceptor per mole of compound (6) in the presence of an acid acceptor such as triethylamine, potassium carbonate and the like. The amine can also be used as an acid acceptor when two or more equivalents of this reagent is used.

The benzyl ester group of compound (13A) is then removed by hydrogenolysis if R ^* is benzyl and, if R ^* is TMSE, removed with tetrabutylammonium fluoride to give the compound of formula (I).

According to Scheme II above, compound (4B), wherein Rl is an alkyl, cycloalkyl, halo (lower alkyl) group or (lower alkyl) amino group protected with a protecting group such as benzyloxycarbonyl, Is a group of electron-withdrawing groups as described) is reacted with diethyl carbonate and sodium hydride in an inert organic solvent such as toluene, THF or the like to give a substituted cyanoacetic acid ester of compound (5B) . The cyano group of compound (5B) is then reacted with an inorganic acid such as hydrochloric acid in the presence of 1 equivalent of anhydrous alcohol such as ethanol and then reacted with ammonia to obtain a substituted amidine ester of compound (6B), followed by reaction with a suitable base Pyrimidine ester compound (8B) was obtained by condensing an enolate compound (7B) prepared in the same manner as the compound (3) in the reaction scheme I in a polar solvent such as methanol in the presence of a base do. The ester action of compound (8B) can be carried out by treatment with diisobutyl aluminum hydride or hindered aluminum hydride such as LiAlH (Ot-butyl) 3 or N, N-dimethyl-chloromethyleneiminium chloride or diamino aluminum hydride in pyridine (9B). ≪ / RTI > This reaction is carried out in the presence of an aprotic solvent such as hexane, toluene, methylene chloride or THF at a temperature of -20 占 폚 or lower, usually -78 占 폚.

The aldehyde compound (9B) is reacted with a suitable base such as piperidine in the presence of a catalytic amount of an acid such as acetic acid or sulfuric acid in a polar solvent such as ethanol such as diethylalonate, dibenzylmalonate, t-butylmalonate, di- Is reacted with a malonic acid diester such as butyl malonate to obtain a pyridopyrimidine compound (10B). Compound (10B) is reacted with a suitable halogen ring such as phosphoryl chloride at room temperature to give compound (11B). Halo group is substituted as described in Scheme I to give compound (12B) and then converted to compound of formula (I) as described in Scheme I for the conversion of compound (10) to the compound of formula (I).

According to Scheme III, shown above, 2-picoline-N-oxide is converted to a mixture of compound (22) and compound (23) by treatment with a halogen pendant such as phosphorous oxychloride in any inert solvent. The reaction is carried out at a temperature of from about 25 [deg.] C to 125 [deg.] C depending on the selected halogen pendant. When the halogen pendant is phosphorus oxychloride, the reaction temperature is preferably 60 ° C to 120 ° C. The following compound (23) is reacted with a strong and disrupted base such as lithium diisopropylamide (LDA), suitably at 0 DEG C or lower, usually at -78 DEG C to obtain compound (24). Compound (24) is ring-closed by heating in a solvent having a boiling point of 120 占 폚 or more in a solvent such as xylene, diglyme, triglyme, sulfolane or Dotum A ^R (a common mixture of biphenyl and diphenyl ether) The leaving group at the 8-position of the quinolizone compound (25) is substituted with a protected primary amino group (e.g., t-butoxycarbonyl) using 3-aminopyrrolidine. The protecting group is removed to give compound (26).

The ester compound (26) is converted to the carboxylic acid of formula (III) as described in scheme I for converting compound (10) into compound of formula (I).

Alternatively, treatment of compound (23) with an alkyl, cycloalkyl or carbocyclic aryl (lower alkyl) halide in the presence of a suitable base such as LDA provides compound (27) wherein R ¹ is alkyl, cycloalkyl or carbocyclic aryl Lower alkyl). Wherein R ¹ is a phenyl group as defined herein or is converted to the corresponding halomethyl compound and reacted with an aryl metal compound such as phenyllithium or a compound of the formula VA Lt; RTI ID = 0.0 > methylamine < / RTI > Compound (27) is converted to compound (29) by the reaction sequence described above for converting compound (25). The leaving group at the 8-position of quinolinone compound (29) is substituted with a nucleophilic amine such as, for example, N-methylpiperazine or 2-methylpiperazine to give compound (30). The reaction is carried out in a suitable organic solvent such as pyridine, methylene chloride, chloroform or 1-methyl-2-pyrrolidinone at a temperature of about 20 캜 to 130 캜. The reaction is preferably carried out in a molar ratio of 1.0 to 2.0 moles of acid acceptor per mole of compound (29) in the presence of an acid acceptor such as triethylamine, potassium carbonate and the like. When 2 equivalents or more of the reagent is used, the amine may be used as an acid acceptor.

When R2 is a phenyl group as defined herein, compound (29) is coupled with an aryl metal compound (e.g., phenyllithium) to form compound (30) to replace the 8-leaving group with an unsubstituted phenyl group do. The coupling reaction is carried out in a reaction inert solvent, that is, a solvent which does not interfere with the coupling reaction of the aryl metal compound with the compound (29). Suitable reaction inert solvents include, for example, ethers such as diethyl ether, dimethoxyethane and tetrahydrofuran (THF). The co-solvent can optionally be used with the ether. The cosolvents are benzene, toluene, tetramethylethyleneamine (TMEDA) and hexamethylphosphoramide (HMPA). The aryl metal compound is prepared by a known method. For example, they may be prepared by direct lithium-halogen exchange of the corresponding aryl halide using n-butyl-, sec-butyl or t-butyl-lithium, 1, page 104) by a metal exchange reaction with a wide range of salts.

(31) is reacted with malonic acid ester (e.g. diethyl malonate) in a polar aprotic solvent such as ether (e.g. diethyl ester or THF) in the presence of a suitable base such as sodium hydride, (32). ≪ / RTI > The following compound (32) is decarboxylated by heating them in a strong mineral acid such as aqueous sulfuric acid to give compound (33). The nitro compound (33) is reduced to the corresponding amino compound (34). The nitro group is reduced by a number of known reducing agents, such as catalytic hydrogenation using standard techniques, or using metals such as zinc, tin or iron, generally in the presence of hydrochloric acid, when mineral oils are used. The amino compound (34) is treated with ethyl nitrite and tetrafluoroboric acid and then treated with potassium fluoride to give the corresponding fluoro compound (35). Compound (35) is then converted to the corresponding N-oxide compound (36) by oxidation, for example, using peracetic acid. The reaction is carried out at a temperature in the range of about 20 째 C to the reflux temperature of the solvent used, preferably about 50 째 C. Compound (36) is nitrated to give compound (37). The nitration reaction can be carried out using various known nitrating agents (for example, a mixture of nitric sulfuric acid or a mixture of sulfuric acid and potassium nitrate) or a nitronium salt such as nitronium trifluoromethane sulfonate. Compound (37) is then optionally treated with mineral oil at ambient or elevated temperature to convert to halo compound (38). For example, treatment of compound (37) with aqueous hydrochloric acid at about 100-120 < 0 > C at this temperature gives compound (38) wherein L is Cl. Compound (38) is then reduced in the presence of an acid such as acetic acid, for example, using a metal such as iron or zinc, to convert to compound (IVAl). The compound (IV1) is then treated with a suitable base such as LDA and then treated with a halogen pesticide such as N-chloro or N-bromosuccinimide to give compound (IV2). (IV < 1 >) is treated with an alkyl, cycloalkyl or carbocyclic aryl (lower alkyl) halide in the presence of a suitable base such as LDA to give a compound wherein Rl is alkyl, cycloalkyl or carbocyclic aryl A3). Compound (IV A3) can also be treated with a suitable base such as LDA followed by treatment with a halogenating agent such as N-chloro or N-bromosuccinimide to give compound (IV A4). The compounds (IV A1) to (IV A4) are the main intermediates used in the synthesis of quinolinone compounds.

(IV A3) and (IV A4) are respectively converted to the quinolinone compounds of compounds (IV B) and (IV C) according to the following series of reactions according to schemes IV B and IV C shown above: Is reacted with the malonate derivative compound (8) in the presence of a strongly and undoped base (for example, lithium diisopropylamide (LDA)) at a temperature of preferably not more than 0 ° C, usually -78 ° C, (2) to obtain compounds (40) and (43), respectively, as described in Scheme III, to give the leaving group (42) (IV) and (IV), respectively, by hydrolysis or hydrolysis of the carboxylic acid ester as described in Scheme III, to give compounds (41) and (44) 0.0 > (4). ≪ / RTI >

According to Scheme VA set forth above, compound (IVIl) is reacted with a compound of formula (IV) in the presence of a free radical initiator such as AIBN, for example using N-bromo- or N-chlorosuccinimide, under conditions suitable for generating a halogen radical Is treated with a halogenating agent to give compound (45). Substituting the halogen of the alpha carbon atom with a nucleophile (such as an alkoxide), the compound (51) is obtained or substituted with an amine to give the compound (46). Conversion of the amine function to the corresponding formamidine action during synthesis yields compound 47 and protection. Compound (47) is reacted with an alkoxymethylenemalonate derivative compound (8), preferably in the presence of a strong and hindered base such as lithium diisopropylamide (LDA), at a temperature preferably below 0 ° C, typically at -78 ° C, Lt; / RTI > The formamidine group is then removed by reaction with hydrazine and acetic acid to give compound (48). Compound (48) is cyclized as described in Scheme III to give compound (49). The leaving group L is then substituted as in Scheme III to give compound (50). Compound (50) is then converted to compound (IVAl) as in Scheme I.

Compound (51) is converted to compound (V A2) by the following series of reactions: The alkoxymethylene malonate derivative (8) is suitably treated with a strong and interfering base such as lithium diisopropylamide (LDA) (2) to obtain compound (53) by ring closure under the same reaction as in scheme (III) to obtain compound (52), preferably at a temperature of 0 ° C or lower, , Chelating the leaving group at the 8 position as in Scheme III to give compound (54), and converting the carboxylic acid ester to the corresponding carboxylic acid compound (V A2) (4).

(V B1) and (V B2) by the same procedure described in Scheme V for converting compound (IV A1) to compounds (V A1) and (V A2) according to Scheme V B shown above.

According to Scheme VI shown above, the perfluorinated pyridine is converted to compound (66) by the procedure described in Scheme IV A to prepare compound (33). Compound (66) is then converted to compounds (VI A) and (VI B) by a series of reactions described in Scheme III for converting compound (23) to compound of formula (III).

According to Scheme VII shown above, compound (IV A2) is reacted with protected alcohol compound (71) in the presence of a suitable base such as LDA to give compound (72). The hydroxy protecting group is preferably THP (tetrahydropyranyl) ether group. Compound (72) is then deprotected by standard methods to give compound (73). Compound (73) is cyclized in the presence of a suitable non-nucleophilic base such as sodium hydride to give compound (74). Compound (74) is then converted to compound (77) by a series of reactions described in Scheme IV B for converting compound (IV A3) to compound (IV B).

Compounds of formula (I) wherein R < ² > contains the free primary amino group are synthesized according to Scheme VIII shown above. According to Scheme VIII, an α-haloacetate derivative compound (1) such as ethyl 2-fluoroacetate is reacted with formate ester (2) in the presence of a suitable base (eg sodium ethoxide) in an inert solvent such as diethyl ether And condensed to obtain the enolate compound (3). Compound (3) is then converted to compound (5) by condensation with amidine derivative compound (4) in the presence of a suitable base (e.g. triethylamine) in a polar solvent such as methanol. If one hydroxy-substituted compound (5) is optionally used in an inert solvent, treatment with a halogenating agent (such as phosphorus oxychloride) at a temperature of about 20 ° C to 145 ° C, depending on the boiling point of the halogenating agent and the solvent, (6) is converted to a chloro derivative. When phosphorus oxychloride is a halogenating agent, the reaction temperature is preferably about 80 캜 to 100 캜. The leaving group at the 5-position of the pyrimidine ring compound (6) is substituted with a nucleophile such as a nucleophilic amine (for example, N-methylpyrazine or 2-methylpiperazine) to give compound (7). The reaction is carried out in a suitable organic solvent such as pyridine, methylene chloride, chloroform or 1-methyl-2-pyrrolidinone at a temperature of about 20 캜 to 130 캜. It is preferable to carry out the reaction at a molar ratio of 1.0 to 2.0 moles per mole of the compound (6) in the presence of an acid acceptor such as triethylamine, potassium carbonate and the like. When two or more equivalents of this reagent are used, the amine may be used as an acid acceptor.

The compound (7) is reacted with an alkoxymethylene malonate derivative compound (8) in the presence of a strong and hindered base, such as lithium diisopropylamide (LDA), preferably at a temperature of 0 DEG C or lower, (9). ≪ / RTI > Compound (9) is ring closed in an aprotic solvent such as toluene, THF or chlorobenzene in the presence of a suitably disturbed base (e.g. DBU) to give compound (10). The cyclization is carried out at a temperature of about 30 ° C to 130 ° C, preferably at the reflux temperature of the reaction mixture. Compound (10) is hydrolyzed in the presence of a suitable base such as sodium hydroxide or sodium potassium to give compound (78). Compound (78) is then reacted with a suitable chlorinating agent such as phosphorus oxychloride to give compound (10a). The leaving group at position 8 of the quinolinone compound (10a) is then reacted with a nucleophilic amine such as 3-aminopyrrolidine (protected, for example, with a primary amine such as t-butoxycarbonyl) . The protecting group is then removed to give compound (10b). The ester compound (10b) is converted to the carboxylic acid of formula (I). The conversion can be effected by transesterification with an alcohol suitable for selective hydrolysis such as benzyl alcohol or 2- (trimethylsilyl) ethanol (TMSE) in the presence of a conventional hydrolysis or catalyst such as titanium tetraethoxide 10b) is converted to the corresponding ester, followed by hydrogenolysis when R ^* is benzyl or when R ^* is TMSE, the alcohol group is removed with tetrabutylammonium fluoride to give the compound of formula (I).

Compounds of formula (I) wherein R < ³ > is lower alkyl or halo (lower alkyl) are synthesized according to scheme IX. According to formula IX shown above, an alpha-haloacetate derivative compound (1), such as ethyl 2-fluoroacetate, is reacted in the presence of a suitable base such as sodium methoxide or sodium ethoxide in a suitable solvent such as methanol, ethanol or ether Is condensed with a compound (78) wherein X is halogen or alkanoyl and R3 is lower alkyl or halo (lower alkyl) such as acetyl chloride or ethyl trifluoroacetate to give an alpha-fluorobeta-keto ester compound 79). Compound (79) can then be reacted with a compound of formula (I) in a suitable solvent, such as methanol or ethanol, in which R ¹ is alkyl, halo (lower alkyl) or cycloalkyl group or phenyl, trifluoromethyl, cyano, perfluoroalkyl, vinyl, Are reacted with an amidine compound (4) or a compound (6) which is a fluorine, nitro, acetylene, substituted acetylene, alkoxycarbonyl or nitrogen containing aromatic heterocycle to give compounds (80) and (81), respectively. Compound (80) is substituted with compound (8B) in Scheme II and converted to the compound of formula (I) via the previously described scheme. Compound (81) is converted to compound (I) by displacement of compound (5) in Scheme I and via the reaction of Scheme I described hereinabove. Alternatively, compound (81) is converted to compound of formula (I) by displacement with compound (5) in scheme III and by reaction in the previous reaction scheme.

Compounds of formula I wherein R ² is lower alkyl, cycloalkyl, carbocyclic aryl (lower alkyl), cycloalkyl (lower alkyl), phenyl, nitrogen containing aromatic heterocycle are synthesized according to Scheme X. According to Scheme X described above, an organometallic derivative 82 such as phenylmagnesium bromide, cyclopentylmagnesium bromide or N-methylpiperidin-4-magnesium bromide is reacted with ethyl (trimethylsilyl) amide in an anhydrous solvent The alpha-fluoro compound (84) is condensed with an alpha-haloacetate derivative (83) in which X is a halogen or alkoxy group such as 2-fluoroacetate or 2-fluoroacetyl chloride. Compound 84 is then reacted with formate compound 2 in an inert solvent such as diethyl ether in the presence of a suitable base such as sodium ethoxide to yield the enolate derivative 85. Compound (85) is reacted with a compound of formula (I) where R ¹ is lower alkyl, halo (lower alkyl) or cycloalkyl or phenyl, trifluoromethyl, cyano, perfluoro (4) or (6) which is an electron-withdrawing group such as carbonyl, vinyl, substituted vinyl, fluorine, nitro, acetylene, substituted acetylene, alkoxycarbonyl or nitrogen containing aromatic heterocycle, (86) or (87). Compound (87) is substituted with compound (7) in Scheme VIII and converted to the compound of Formula (I) via the previously described scheme. Compound (86) is converted to compound (I) by direct conversion to compound (12B) by displacement with compound (9B) in Scheme II and reacting with a malonic acid diester as described in Scheme II.

Compounds of formula I wherein R ² is lower alkyl, cycloalkyl, carbocyclic aryl (lower alkyl), cycloaryl (lower alkyl), phenyl, nitrogen containing aromatic heterocycle or nitrogen containing heterocycle are synthesized according to Scheme XI . (88) in the presence of a suitable base such as sodium methoxide or NaN (TMS) ₂ in an anhydrous solvent (e.g. ether, THF, anhydrous ethanol or anhydrous ethanol) (91) by condensation with a suitable base (e.g., acetyl chloride, benzoyl chloride, isonicotinoyl chloride or 2,6-dimethylisocyanuronyl chloride) to form the beta-keto ester derivative (91) and reacting it with sodium methoxide or sodium ethoxide (92) in a suitable solvent such as methanol, ethanol or ether in the presence of a suitable base such as sodium hydride to give compound (92) or (93) which is hydroxy substituted. These compounds are then converted to the corresponding halo-derivative compounds (94) and (95) under the same conditions as described for converting compound (5) to compound (6) in Scheme VIII. Compounds (86) and (87) are then prepared by reacting compounds (94) and (95) with a reducing agent such as zinc in a suitable solvent such as ethanol or methanol in the presence of a catalyst such as Ni, Pd or Pt with acetic acid or hydrogen. And converts it to a compound of formula (I) as described in Scheme X.

In addition, R ² can be prepared by using a non-fluorinated derivative (90) as described above with a reagent such as N-fluoropyridinium triflate, N-fluorosulfonylamide, cesium fluorooxysulfate or acetyl hypofluoride To the beta-keto ester derivative (91).

According to Scheme XII describes a process for preparing a compound of formula (Ic) to the desired R ¹ is cyclopropyl, pyridine (compound 88) 3-chloro-2, 4,5, 6-tetrafluoro-a commercially available THF (E.g., sodium t-butoxide or lithium t-butoxide) in a polar organic solvent such as tetrahydrofuran or dioxane for 1 to 4 hours at 10 ° C to -78 ° C and then for 2 to 72 hours at room temperature, (89) (separating the product mixture by chromatography). Compound (89) is reacted with hydrogen in sodium acetate buffer solution with a catalyst such as Pd / C to remove chlorine and obtain compound (90) (also separating the product mixture by chromatography). When R < ⁶ > is alkyl, the compound (90) is suitably treated with a suitable alkyl, such as lithium diisopropylamide (LDA), at a temperature of preferably below 0 & (For example, methyl halide or the like) to obtain compound (91). When R6 is haloalkyl (e.g., fluoroalkyl), compound 90 is first suitably treated with a strong and hindered base such as lithium diisopropylamide (LDA) at a temperature of preferably below 0 C, by reaction at a temperature of -78 ℃ and then reacted with formaldehyde to give the R ⁶ is a hydroxymethyl phosphorus compound, and reacted with diamino sulfur trifluoride (DAST) in a non-polar solvent such as methylene chloride, this compound (91) ≪ / RTI > When the R ⁶ group is a difluoromethyl (for example, compound (90)), it is first suitably used in the presence of a strong and hindered base such as lithium diisopropylamide (LDA) At -78 < 0 > C and then reacted with DMF to give an intermediate compound wherein R < ⁶ > is CHO and this intermediate is reacted with DAST to give compound (91) wherein R < ⁶ > is difluoromethyl. Compound 91 is then reacted with hydrazine at reflux temperature for 2 to 8 hours under nitrogen, excess hydrazine is removed and the residue is dissolved in an organic solvent such as methanol or benzene and air is treated for 8 to 16 hours with hydrazino product To give compound (92). Compound (92) is reacted in the presence of a strong base such as lithium diethylamide (LDA) or lithium diisopropylamide in a polar organic solvent such as THF at -78 占 폚 for 1-4 hours, at 0 占 폚 for 1-4 hours Compound 93 is prepared by condensation with propyl acetonatril or condensation with NaNH ₂ at -5 ° C to -10 ° C. Compound (93) is reacted with trifluoroacetic acid at ambient temperature under nitrogen for 1 to 4 hours to remove the protecting group t-butoxide and, in an appropriate organic solvent such as DMF or methylene chloride, at ambient temperature for 8 to 24 hours And reacted with POCl ₃ to prepare a compound (94).

Considering part of the present invention in an improved process, compound (89) is treated with a strong base such as t-butyllithium or s-butyllithium in a polar solvent such as THF for 0.5-3 hours, And reacted with methyl iodide at less than 50 < 0 > C for 4 to 20 hours. Compound 91 is treated with a hydride reducing agent such as LAH or sodium bis- (2-methoxyethoxy) aluminum hydride (Red-Al ^TM ) at 0 ° C to ambient temperature for 8-24 hours. The resulting compound (93) is reacted with POCl ₃ in an organic solvent such as DMF or methylene chloride at ambient temperature for 6 to 20 hours to prepare the direct compound (94).

The cyano compound (94) is treated with anhydrous ethanolic HCl and then treated with H ₂ O to give the ester compound (95). The ester compound (95) is reacted with lithium aluminum hydride in THF at a low temperature for 0.5 to 2 hours to reduce it to the aldehyde compound (96) and then reacted with oxalyl chloride and sodium hydride at -78 ° C for 0.25 to 1.0 hour in the presence of triethylamine. And reacted with DMSO. Compound (96) is reacted in the presence of a catalytic amount of an acid such as acetic acid or sulfuric acid in the presence of a suitable base, such as piperidine, in a polar solvent such as ethanol, with diethyl malonate, dibenzyl malonate, -Butyl malonate and then heated in a polar high boiling point solvent such as DMF or DMSO at reflux temperature or in a Dow Therm A ^{TM for} 0.5-4 hours to obtain the pyridopyrimidine compound 98 ). Substituting the chloro group of compound (98) as in Scheme I gives compound (99) and then converting compound (13A) to compound of formula (Ic) as described in Scheme I for converting compound of formula (I).

According to Scheme XIII, the trifluoropyridine ether compound (90) is reacted with a suitable strong base (e.g., LDA), preferably in an inert solvent such as THF, at a temperature of less than 0 ° C, typically -78 ° C. Then the resulting anion alkyl borate: in which (for example, trimethyl borate or triethyl borate) and the reaction then to obtain the same reaction system in the oxidation with hydrogen peroxide in the presence of a base such as sodium hydroxide, R ⁷ is lower alkyl, the compound (100). Subsequently, the compound (100) is reacted with an alkyl iodide or alkylsulfate in a polar solvent such as acetone, ethanol, DMF, THF or the like in the presence of a base such as sodium hydroxide, barium hydroxide, potassium carbonate, Alkylation with a suitable alkylating agent such as, for example, methylsulfate or ethyl iodide to give compound (101). Compound 101 may also be prepared by reacting compound 101 with a compound of formula R ⁷ OH (wherein R ⁷ is as defined above) in a solvent such as THF at a temperature ranging from 0 < 0 > C to room temperature with triphenylphosphine and diethyldiazocarboxylate Can be obtained by treating Compound (100).

According to Scheme XIV, the commercially available pentafluoropyridine compound (102) is reacted with an alkali metal salt of t-butanol (e.g., sodium t-butoxide or potassium t-butoxide) in an anhydrous organic solvent such as THF at a temperature ranging from- Butoxide) to obtain compound (103). Compound (103) is then reacted with hydrazine in a solvent such as methanol, iso-propanol, ether or the like at a temperature ranging from room temperature to reflux temperature, and then the intermediate solution is bubbled with air in the presence of a base such as sodium hydroxide in a solvent such as benzene or toluene (104). ≪ / RTI >

According to Scheme XV, the pentafluoropyridine compound 102 is dissolved in a solvent (e.g., THF or methylene chloride) and reacted in the presence of a suitable base such as a tertiary amine (e.g. triethylamine) the formula R ² H (wherein, R ² are the same as defined above, or, R, if a ^divalent substituted with a reactive group such as an amino group, a substituted cyclic amine to a suitably protected reactive substituent), a cyclic amine and is reacted, the reaction (106) (wherein, R ¹⁶ is the same as defined above TBS represents a tributyl silyl group) to the corresponding iodide by reaction with t- butyl lithium at -78 ℃ in ether from starting materials to produce And reacted with compound (105) at -78 < 0 > C in a solvent such as THF or ether to give compound (107). The protected TBS group is reacted with tetrabutylammonium fluoride in THF at room temperature to remove from compound (107) to give compound (108). The trifluoro compound 108 is converted to the difluoro compound 109 by reacting 108 with hydrazine in a solvent such as ether, propanol or methoxymethyl ether at reflux temperature, followed by the addition of methanol, ethanol or toluene , The intermediate hydrazino product is treated with CuSO ₄ or replaced with air in the presence of a base such as NaOH. The monocyclic compound (109) is then converted to the acyclic compound (100) by reaction with NaH in a solvent such as dioxane or THF at reflux temperature. Compound (110) is then treated with a strong base such as LDA at -78 < 0 > C and condensed with diethylethoxymethylenemalonate to give an intermediate product, which is reacted with DBU or In the presence of a base such as piperidine / acetic acid to obtain a tricyclic ester compound (111). The ester (111) is hydrolyzed, for example, in an aqueous THF to the acid compound (112) with an alkali metal hydroxide. Any protecting group remaining in the R 2 or R 16 group is typically removed at this stage to yield the desired compound of formula I.

According to Scheme XVI, an alternative method of making compound (112) is provided. Compound 103 (from Scheme XIV) is reacted with compound 106 (from Scheme XV) in a solvent such as THF or ether at -78 <0> C to give the TBS-protected intermediate compound, from which the TBS group is converted to the THF At room temperature to give compound (113). &Lt; / RTI &gt; The trifluoro compound (113) is reacted with hydrazine in a solvent such as ether, propanol or methoxymethyl ether at reflux temperature to convert to the difluoro compound (114), then the intermediate hydrazino product is dissolved in methanol, ethanol or toluene treated or replaced with CuSO ₄ is reacted with in the presence of a base such as NaOH in a solvent, such as air. The monocyclic compound 114 is then converted to the bicyclic compound 115 by reaction with NaH in a solvent such as dioxane or THF at reflux temperature. Compound 115 can be treated with a strong base such as LDA, for example, at -78 &lt; 0 &gt; C and condensed with diethylethoxymethylenemalonate to give an intermediate product and reacted in a solvent such as ethanol or aqueous THF In the presence of a base such as DBU or piperidine / acetic acid to give the tricyclic ester compound (116). The protected t-butoxy group is removed from compound (116) by reaction with an acid such as HCl or trifluoroacetic acid in a suitable solvent such as methylene chloride or dioxane at room temperature to give compound (117). Followed by reacting the free hydroxyl group of compound (117) in POCl ₃ / DMF at room temperature in a suitable solvent such as methylene chloride to give the chloro compound (118). Compound 118 can be reacted with a compound of formula R ² H, wherein R ² is as defined above, or a salt thereof, in the presence of a suitable base such as a tertiary amine (e.g. triethylamine) in a suitable solvent such as acetonitrile or pyridine at reflux temperature, When R &lt; ² &gt; is substituted with a reactive group such as an amino group, the cyclic amine is suitably replaced with a protected reactive substituent) to yield compound (111). The ester group is hydrolyzed and any additional protecting groups are removed as described in Scheme XV.

According to Scheme XVII, compounds of formula I wherein R &lt; ⁵ &gt; is amino are prepared. Compound (91) is reacted with RNH in the presence of a solvent, such as ethanol or toluene, at elevated temperature to afford RKH, where P is an amino protecting group such as, for example, benzyl and p-methoxybenzyl groups, . Compound (119) is treated according to procedures as described in Scheme VII, XV and XVI to give compound (120). For example, for catalytic hydrogenation such as Pd-C in ethanol or methanol at room temperature or by oxidation with ammonium cerium nitrate if R is p-methoxybenzyl, to deprotect protected amino compound (120) ) Is hydrolyzed with a base such as LiPH or NaOH to give compound (122).

To give a compound of formula I wherein R &lt; ² &gt; is a ring group bound through a carbon source according to Scheme XVIII. Compounds (123) in which X is a leaving group such as, for example, chloride, bromide, fluoride or sulfonate are suitably substituted in the presence of a strong base such as NaH in a polar solvent such as DMF, DMSO etc. at a temperature of 0-60 & (R &apos; and R &apos; are the same or different and are alkyl groups such as diethyl and di-t-butyl malonate) to give compound (124). Decarboxylation of compound (124) in a solvent such as methylene chloride, ethanol, water or the like under acidic conditions such as trifluoroacetic acid and hydrogen chloride, and then the intermediate acid is treated with diphenyldiazomethane in a solvent such as methylene chloride or THF Followed by treatment with an ester such as diphenylmethyl ester to obtain compound (125). Then, for example, at room temperature or elevated temperature in a solvent in such as DMF, DMSO of the compound 125 in the presence of a base such as NaH, Br (CH _{2) n} B (CH _{2) m} Br or I (CH _{2) n} B ( CH ₂ ) _m I wherein B is CH ₂ , N, O or S, or R _b substituted iodide or bromide, to effect cyclization to compound 126. Alternatively, the compound (125) is reacted with an aqueous formaldehyde in the presence of a base such as sodium carbonate in a solvent such as DMF to convert it to a methylene intermediate, followed by reaction with methanesulfonyl chloride and triethylamine. The methylenyl compound is then cyclized or bipolarly added to a suitable reagent such as trimethylsulfonium iodide or diazomethane in the presence of a suitable base such as NaH at a temperature of 0-60 &lt; 0 &gt; C in a solvent such as DMF, DMSO, (126). Diphenyl esters, such as using acetic acid and anisole in trifluoroacetic at room temperature for a methyl ester, an optionally deprotecting the ROCO then give compound 127 for the purpose of decomposing the other ester alkali hydrolysis, and "R ₂ is In case of NH ₂ , Curtius rearrangement is performed. In compounds (126) and (127), n and m are from 0 to 4, n + m is from 1 to 4, B is CH ₂ , N, O or S and R ^b is hydrogen, Alkyl, hydroxyl or alkoxy group or other substituents as described for substituent Y in formula IC.

Representative compounds of the chemical intermediates useful in the above synthesis and considered as further aspects 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- (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- (2- (4-Chloro-5-fluoro-3-methyl-2-pyridinyl) cyclopropaneethanol;

Methyl-2-cyclopropylethylidinyl) -1, 3-propanedicarboxylic acid diethyl ester and (2-fluoro-3-

8-Chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4h-quinolizine-3-carboxylic acid ethyl ester.

The foregoing is better understood by the following examples, which are intended to illustrate, but not to limit the scope of the invention.

Example 1

6-oxo-pyrido [l, 2-a] pyrimidine-7-carboxylic acid (6-fluoro-4-

Step 1. 5-Fluoro-2- (4-fluorobenzyl) -4-hydroxypyrimidine

Sodium hydride (4.36 g, 107.6 mmol, 60% in mineral oil) is suspended in 125 ml of anhydrous diethyl ether under a nitrogen atmosphere in a 500 ml round bottomed flask equipped with a mechanical stirrer, thermometer and condenser. 6.28 ml (107.7 mmol) of anhydrous ethyl alcohol was gradually added to the mixture with vigorous stirring. After gas evolution is complete, a mixture of ethyl 2-fluoroacetate (10 ml, 102.5 mmol) and ethyl formate (12.5 ml, 153.7 mmol) is added dropwise to the solution in ethoxide. Optionally, the reaction mixture is cooled to maintain the reaction temperature at 18-20 &lt; 0 &gt; C. The reaction mixture is stirred under a nitrogen atmosphere at 18-20 [deg.] C for 4.75 h. The solvent was removed under aspirator pressure and fresh anhydrous diethyl ether was added to the residue and the ether solution was concentrated under reduced pressure to give sodium enolate of ethyl 2-fluoro-3-oxo-2-propanecarboxylate as a solid residue (E. Elkik and M. Ibbeaux-Oudotte in Bull Soc Chim, 1165-1169, 1975). To the residue was added 20.3 g (107.6 mmol) of 4-fluorobenzylamidine hydrochloride, and then 250 ml of methanol and 28.8 ml (205 mmol) of triethylamine (TEA) were added. The reaction mixture is heated to reflux temperature for 16 hours with stirring and then concentrated in vacuo. The residue is polished with hexane and taken up with hexane. Water is added to the residue, the aqueous mixture is acidified with glacial acetic acid and extracted with 4 x 150 ml of methylene chloride. The combined organic extracts are washed with 200 ml of water and concentrated in vacuo. The residue noreo T ^R (Norite ^R) was recrystallized twice with ethyl acetate containing carbon, to give the title compound. mp 169-170 &lt; 0 &gt;C; _{MS DCI-NH 3 M / Z} : 223 (M + H) +; _{^{1 H NMR (DMSO-d 6}} ) d 3.87 (s, 2H), 7.14 (m, 2H), 7.33 (m, 2H), 7.98 (d, 1H). Anal. Calcd. C ₁₁ H ₈ F ₂ N ₂ O: C, 59.46; H, 3.63; N, 12.61. Measured value C, 59.08; H, 3.70; N, 12.57.

Step 2. 4-Chloro-5-fluoro-2- (4-fluorobenzyl) -pyrimidine

1.93 g (8.7 mmol) of 5-fluoro-2- (4-fluorobenzyl) -4-hydroxypyrimidine from Step 1 and 15 ml of phosphorus oxychloride were heated in an oil bath at 90 캜 for 1.5 hours, Concentrate. The residue is triturated with 75 ml of ice water and the aqueous mixture is adjusted to pH 8-9 by addition of solid sodium bicarbonate. The mixture is extracted with 3 x 70 ml of methylene chloride. The combined organic extracts are dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a light brown residue. Flash chromatography of the residue on a 230-300 mesh silica gel column (4.8 x 14.6 cm) eluting with hexane: methylene chloride (1: 1 v / v) gave 1.94 g (yield 90%) of the title compound; _{MS DCI-NH 3 M / Z} : 241 (M + H) +; _{^{1 H NMR (CDCl 3) d}} 4.22 (s, 2H), 7.00 (m, 2H), 7.30 (m, 2H), 8.48 (s, 1H).

Step 3. 5-Fluoro-2- (4-fluorobenzyl) -4- (4-methylpiperazin-1-yl) -pyrimidine

A mixture of 0.48 g (2 mmol) of 4-chloro-5-fluoro-2- (4-fluorobenzyl) -pyrimidine from step 2 and 1.35 ml (14 mmol) of 4-methylpiperazine in 10 ml of methylene chloride was cooled to ambient temperature Lt; / RTI &gt; for 1.5 hours. The reaction mixture is concentrated in vacuo and the residue is dissolved in methylene chloride. The resulting solution was washed with 4 x 30 ml of water, dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give 0.59 g (yield 95%) of the title compound as an oil; _{^{1 H NMR (CDCl 3) 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, 1 H). The next step is carried out without purification of the product.

Step 4. Synthesis of diethyl 2-ethoxy-3- (4-fluorophenyl) -3- [5-fluoro-4- (4- methylpiperazin- 1 -yl) pyrimidin- -1, 1-dicarboxylate

A solution of 0.35 ml (2.5 mmol) diisopropylamine in 5 ml anhydrous tetrahydrofuran (THF) was prepared under a nitrogen atmosphere and cooled in an ice / water bath. 1.0 ml of a 2.5 M solution of n-butyl lithium (2.5 mmol) in hexane is added to the solution via syringe. The solution is stirred at 0 &lt; 0 &gt; C for 15 minutes and then cooled to -78 &lt; 0 &gt; C. To a mixture at -78 [deg.] C was added 0.7 g (2.3 mmol) of 5-fluoro-2- (4- fluorobenzyl) -4- (4-methylpiperazin- l-yl) -pyrimidine from step 3 ) Is added to form a dark red solution. The solution was stirred at -78 &lt; 0 &gt; C for 1 hour and then 0.46 ml (2.3 mmol) of ethyl 2-carboxyethoxy-3-ethoxy-2-propenecarboxylate were added. Continue stirring at -78 &lt; 0 &gt; C for 3 hours to turn the reaction mixture into a pale yellow color. The reaction mixture is poured into 30 ml of water containing 6 g of solid ammonium chloride. The aqueous mixture is extracted with 4 x 50 ml of methylene chloride. The combined organic layers are dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is dissolved in 300 ml of methylene chloride. The resulting solution was washed with 50 ml of water, then with 75 ml of water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound; _{MS DCI-NH 3 M / Z} : 521 (M + H) +; _{^{1 H NMR (CDCl 3) d}} 0.84 (2 × t, 3H), 1.18 (t, 3H), 1.28 (t, 3H), 2.33 (s, 3H), 2.50 (m, 4H), 3.36-3.53 (m (M, 2H), 3.83 (s, 4H), 3.96-4.22 (m, 4H), 4.42 (t, d, 1H).

Step 5. Synthesis of ethyl 3-fluoro-9- (4-fluorophenyl) -2- (4-methylpiperazin- l-yl) -6H-6-oxo-6-pyrido [ Pyrimidine-7-carboxylate

(4-fluorophenyl) -3- [5-fluoro-4- (4-methylpyrrazin-1-ylpyrimidin- A solution of 0.57 g (1.1 mmol) of 1-methyl-2-propane-1,1-dicarboxylate and 0.2 ml of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) was stirred at reflux temperature for 20.5 hours 125 ml of toluene is removed via a Dean Stark trap and 100 ml of fresh toluene is added via a dropping funnel to the reaction mixture and the mixture is stirred for 3 hours at ambient temperature. The organic layer was combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was dissolved in ethyl alcohol: chloroform (1: 10 v / v) Eluting with a 70-230 mesh silica gel column (2.4 x 43 cm) to give 0.26 g (56% yield) of the title compound. C. mp 202-204 ℃; MS DCI-NH 3 M / Z: 429 (M + H) +; 1 H NMR (CDCl 3) d 1.40 (t, 3H), 2.33 (s, 3H), 2.51 (m 2H), 7.50 (m, 2H), 8.43 (s, 1H), 9.20 (d, 1H).

Step 6. Benzyl 3-fluoro-9- (4-fluorophenyl) -2- (4-methylpiperazin-l-yl) -6H-6-oxo-pyrido [ -7-carboxylate

(4-fluorophenyl) -2- (4-methylpiperazin-l-yl) -6H-6-oxo-6-pyrido [l, 2- ] Pyrimidine-7-carboxylate, 50 ml of anhydrous benzyl alcohol and 0.05 ml of titanium tetraethoxide is heated at 100 DEG C for 22 hours with stirring. The benzyl alcohol is removed by distillation under reduced pressure and the residue is dissolved in 75 ml of methylene chloride. To this solution was added 5 ml of saturated aqueous lithium fluoride and the resulting mixture was stirred at ambient temperature for 20 minutes. The layers are separated and the organic layer is diluted with 75 ml of methylene chloride and washed with 20 ml of water. The aqueous layer is extracted with 25 ml of methylene chloride and the methylene chloride layer thus extracted is combined with the organic layer. The combined organic layers are dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was chromatographed on a 70-230 mesh silica gel column (1.8 x 34 cm) eluting with ethanol: chloroform (1: 13 v / v) to give 87 mg (67%) of the title compound; _{^{1 H NMR (CDCl 3) 2.33}} (s, 3H), 2.52 (m, 4H), 3.94 (m, 4H), 5.40 (s, 2H), 7.08 (s, 2H), 7.27 (m, 5H), 8.44 (s, 1 H), 9.21 (d, 1 H).

The next step is carried out without further purification of the product.

Step 7. Preparation of 3-fluoro-9- (4-fluorophenyl) -2- (4-methylpiperazin- 1 -yl) -6H- 6-oxo-6-pyrido [ Methyl-7-carboxylic acid

(4-fluorophenyl) -2- (4-methylpiperazin-l-yl) -6H-6-oxo-6-pyrido [l, 2- ] Pyrimidine-7-carboxylic acid (87 mg, 0.177 mmol) is dissolved in 20 ml of ethyl acetate. To this solution is added 10% palladium on carbon / 20 mg and the resulting mixture is hydrogenated at ambient temperature under hydrogen at 4 atm for about 19 hours. The catalyst is filtered off and washed with 400 ml of ethyl acetate. The filtrate was concentrated in vacuo to give 65.2 mg of a solid. The solid is purified by chromatography on a 70 to 230 mesh silica gel column (1.8 x 18.5 cm) eluting with chloroform: methanol: acetic acid: water (100: 25: 5: 2.5 v / v / v / v). The fractions containing the desired product are combined and concentrated. Toluene was evaporated in vacuo to give the title compound as a yellow solid. mp 225-230 [deg.] C; _{MS DCI-NH 3: 401 (} M + H) +; _{^{1 H NMR (CDCl 3) 1.68}} (brs, 1H), 2.33 (s, 3H), 2.53 (brs, 4H), 3.98 (brs, 4H), 7.10 (t, 2H), 7.48 (m, 2H), 8.57 (s, 1 H), 9.08 (d, 2 H). Anal. Calcd. C ₂₀ H ₁₈ F ₂ N ₄ O ₃ + 0.75 H ₂ O: C, 58.03; H, 4.75; N, 13.54. Found: C, 57.98; H, 4.32; N, 13.22.

Example 2

6-oxo-pyrido [l, 2-a] pyrimidine-7-carboxylic acid (6-fluoro-4-

Step 1. Preparation of ethyl 3-fluoro-9- (4-fluorophenyl) -2-hydroxy-6H-6-oxo-pyrido [l, 2-a] pyrimidine-

To a stirred solution of ethyl 3-fluoro-9- (4-fluorophenyl) -2- (4-methylpiperazin-l-yl) -6H -6-oxo-pyrido [l, 2-a] pyrimidine-7-carboxylate (0.87 g, 2.05 mmol) was added 6 ml of 1 N aqueous sodium hydroxide solution. The reaction mixture is stirred at ambient temperature for 6 hours and then allowed to stand overnight at ambient temperature. The solid was filtered and dried to give the title compound; _{^{1 H NMR (d 6 -DMSO)}} 1.23 (t, 3H), 4.15 (q, 2H), 7.17 (m, 2H), 7.52 (m, 2H), 7.91 (s, 1H), 8.77 (d, 1H) .

Step 2. Ethyl 2-chloro-3-fluoro-9- (4-fluorophenyl) -6H-6-oxo-pyrido [l, 2-a] pyrimidine-

55.7 mg of ethyl 2-chloro-3-fluoro-9- (4-fluorophenyl) -6H-6-oxo-pyrido [l, 2-a] pyrimidine- A mixture of 0.5 ml of phosphorus chloride is stirred and heated at 90 &lt; 0 &gt; C for 1.25 h. The crude product is evaporated under reduced pressure to give the title compound, which can be reacted with the amine without further purification. A pure sample of the title compound was obtained by reacting the crude product with aqueous sodium bicarbonate and extracting the aqueous mixture with methylene chloride. The organic solution is concentrated, extracted with ethyl acetate and subjected to silica gel chromatography.

Step 3. Preparation of ethyl 3-fluoro-9- (4-fluorophenyl) -2- (4-methylpiperazin-l-yl) -6H-6-oxo-pyrido [ -7-carboxylate

(4-fluorophenyl) -6H-6-oxo-pyrido [l, 2-a ] Pyrimidine-7-carboxylate with 4-methylpiperazine to give the title compound.

Step 4. Benzyl 3-fluoro-9- (4-fluorophenyl) -2- (4-methylpiperazin- 1 -yl) -6H-6-oxo-pyrido [ -7-carboxylate

The title compound was prepared from ethyl 3-fluoro-9- (4-fluorophenyl) -2- (4-methylpiperazin- 1 -yl) -6H-6-oxo-pyrido [ Methyl-7-carboxylate, 50 ml of anhydrous benzyl alcohol and 0.05 ml of titanium tetraethoxide is heated at 100 &lt; 0 &gt; C for 22 hours with stirring. The benzyl alcohol is removed by distillation under reduced pressure and the residue is dissolved in 75 ml of methylene chloride. To this solution is added 5 ml of saturated aqueous lithium fluoride and the resulting mixture is stirred at ambient temperature for 20 minutes. The layers are separated and the organic layer is diluted with 75 ml of methylene chloride and washed with 20 ml of water. The aqueous layer is extracted with 25 ml of methylene chloride and the methylene chloride layer thus extracted is combined with the organic layer. The combined organic layers are dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was chromatographed on a 70-230 mesh silica gel column (1.8 x 34 cm) eluting with ethanol: chloroform (1: 13 v / v) to give 87 mg (67%) of the title compound; _{^{1 H NMR (CDCl 3) 2.33}} (s, 3H), 2.52 (m, 4H), 3.94 (m, 4H), 5.40 (s, 2H), 7.08 (s, 2H), 7.27 (m, 5H), 8.44 (s, 1 H), 9.21 (d, 1 H). The next step is carried out without further purification of the product.

Step 5. Preparation of 3-fluoro-9- (4-fluorophenyl) -2- (4-methylpiperazin-l-yl) -6H- 6 -oxo-pyrido [l, 2-a] pyrimidine- 7-carboxylic acid

The title compound was prepared from benzyl 3-fluoro-9- (4-fluorophenyl) -2- (4-methylpiperazin- 1 -yl) -6H-6-oxo-pyrido [ 7-carboxylic acid (87 mg, 0.177 mmol) is dissolved in 20 ml of ethyl acetate. To this solution is added 10% palladium on carbon / 20 mg and the resulting mixture is hydrogenated at ambient temperature under hydrogen at 4 atm for about 19 hours. The catalyst is filtered off and washed with 400 ml of ethyl acetate. The filtrate was concentrated in vacuo to give 65.2 mg of a solid. The solid was purified by chromatography on a 70 to 230 mesh silica gel column (1.8 x 18.5 cm) eluting with chloroform: methanol: acetic acid: water (100: 25: 5: 2.5 v / v / v / v). The fractions containing the desired product are combined and concentrated. Toluene was evaporated in vacuo to give the title compound as a yellow solid. mp 225-230 [deg.] C; _{MS DCI-NH 3 MZ: 401} (M + H) +; _{^{1 H NMR (CDCl 3) 1.68}} (brs, 1H), 2.33 (s, 3H), 2.53 (brs, 4H), 3.98 (brs, 4H), 7.10 (t, 2H), 7.48 (m, 2H), 8.57 (s, 1 H), 9.08 (d, 2 H). Anal. Calcd. C ₂₀ H ₁₈ F ₂ N ₄ O ₃ + 0.75 H ₂ O: C, 58.03; H, 4.75; N, 13.54. Found: c, 57.98; H, 4.32; N, 13.22.

Examples 3 to 28

By using the appropriate amines according to the procedure of Example 2, the compounds of Examples 3 to 20, as shown in Table 1,

&Lt; / RTI &gt;

Thus, using the appropriate amine and 2,4-difluorobenzylamidine in place of 4-fluoro-benzylamidine and also as shown in Table 1,

&Lt; / RTI &gt;

[Table 1]

^The amine was protected and deprotected as described in Example 58. &lt; RTI ID = 0.0 &gt;

Example 39

Yl) -6H-6-oxo-pyrido [l, 2-a] pyrimidine-7-carboxylic acid

Step 1. 2-Cyclopropyl-3-hydroxyacrylic acid

Under a positive pressure nitrogen atmosphere, a 1.1 M solution of diethylzinc (350 ml) in an oven drying system is cooled with an ice bath. Vinylacetic acid (17 ml, 200 mmol) is added dropwise with stirring, and 24 ml (300 mmol) of diiodomethane is added dropwise. The reaction mixture is stirred overnight at ambient temperature. The reaction mixture is then carefully poured into a IN 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.

Cyclopropylacetic acid (15 g, 15 mmol) in the water-free flask was cooled in an ice bath and 13.2 ml (180 mmol) of thionyl chloride was added dropwise with stirring. After completion, the reaction mixture is warmed to ambient temperature and brought to 50 占 폚. The reaction mixture is heated at 50 &lt; 0 &gt; C for 1 hour and then cooled in an ice bath. Anhydrous ethanol (26 ml, 450 mmol) was added dropwise to the reaction mixture while stirring. After addition, the reaction mixture is stirred overnight at ambient temperature. The reaction mixture is diluted with 500 ml of methylene chloride and washed with 200 ml of 5% aqueous sodium bicarbonate solution. The organic layer is dried over anhydrous sodium sulfate, filtered and distilled to give the ethyl ester of cyclopropylacetic acid.

2-Cyclopropyl-3-hydroxyacrylic acid (12.8 g, 100 mmol) from step 1 is dissolved in 150 ml of anhydrous dimethoxyethane in an oven drying system under a positive nitrogen atmosphere. The resulting solution was cooled in an ice bath and 4.4 g of sodium hydride in 60% mineral oil was added. The mixture is stirred at about 0 ° C for several hours and stirred at ambient temperature for several hours. The reaction mixture is cooled in an ice bath and 8.9 ml (110 mmol) of ethyl formate in 90 ml of anhydrous dimethoxyethane are added with stirring. After addition, the reaction mixture is stirred overnight at ambient temperature. The reaction mixture is carefully poured into 300 ml of a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound.

Step 2. Ethyl 5-cyclopropyl-2,6-dihydroxy-nicotinic acid

A solution of 11.5 (88 mmol) monoethyl malonate monoamide in 25 ml dry THF is cooled in an ice bath and treated with 10.7 g (95 mmol) potassium t-butoxide. The reaction mixture is stirred at 0 SIMILAR 5 DEG C for 1 hour. A solution of 12.5 g (80 mmol) of 2-cyclopropyl-3-hydroxyacrylic acid from step 1 in 20 ml of anhydrous THF is added dropwise with stirring. The reaction mixture is allowed to warm to ambient temperature and is heated under reflux overnight. The reaction mixture is poured into brine and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound.

Step 3. Ethyl 5-cyclopropyl-2,6-dichloro-nicotinic acid

A solution of ethyl 5-cyclopropyl-2,6-dihydroxy-nicotinic acid (15.6 g, 70 mmol), 1,2-dichloroethane (25 ml), anhydrous DMF (2 ml) and phosphoryl chloride (14.3 ml, ) Is added to the system under a positive pressure nitrogen atmosphere. The reaction mixture is stirred at ambient temperature for 24 hours and diluted with 1, 2-dichloroethane. The reaction mixture is washed with 5% aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound.

Step 4. Preparation of 2-chloro-5-cyclopropyl-6-N - ((4,5-dimethoxy-2-nitro- phenyl) methoxycarbonyl) amino-

Ethyl 5-cyclopropyl-2,6-dichloro-nicotinic acid (11.2 g, 50 mmol) from step 3 is dissolved in 15 ml of anhydrous DMF. To this solution is added 25 ml of ammonium hydroxide and the reaction mixture is heated under reflux overnight. The reaction mixture is cooled to ambient temperature, 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-dichloroethane and 200 ml of 10% aqueous sodium carbonate solution. The reaction mixture was cooled in an ice bath and 16.5 g (60 mmol) of 3, 4-dimethoxy-6-nitrobenzyl chloroformate was added. The reaction mixture is stirred at 0 SIMILAR 5 DEG 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.

Step 5. Synthesis of 2-chloro-5-cyclopropyl-6-N - ((4,5-dimethoxy-2-nitro- phenyl) methoxycarbonyl) -N- (2- fluoroacetyl) amino-

Nitro-phenyl) methoxycarbonyl) -amino-nicotinic acid (14.4 g, 30 mmol) from step 4 was dissolved in a mixture of N, N-dimethylaniline The reaction mixture is cooled in an ice bath and 1.3 g of sodium hydride in 60% mineral is added. The reaction mixture is stirred at 0 SIMILAR 5 DEG C for 1 hour and 3.2 g (33 mmol) of alpha-fluoroacetyl chloride in 5 mL dry THF are added dropwise with stirring. After addition, the reaction mixture is slowly warmed to ambient temperature and stirred overnight at ambient temperature. The reaction mixture is poured into brine and extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound.

Step 6. Preparation of 2-chloro-5-cyclopropyl-6-N - ((4,5-dimethoxy-2-nitro- phenyl) methoxy- carbonyl) -N- (2-fluoro-3- -1-oxo-1-pro-2-enyl) amino-nicotinic acid

Sodium hydride (880 mg of 60% NaH in mineral oil) is suspended in 10 ml of anhydrous THF. The suspension was cooled in an ice bath and a solution of 2-chloro-5-cyclopropyl-6-N - ((4,5- dimethoxy- 2-nitro- phenyl) methoxycarbonyl) -N - (2-fluoroacetyl) -amino-nicotinic acid (10.7 g, 20 mmol) was added dropwise with stirring. After completion, the reaction mixture is stirred at 0 SIMILAR 5 DEG C for 1 hour. Ethyl formate (1.78 ml, 22 mmol) in 25 ml of anhydrous THF is added dropwise with stirring. After addition, the reaction is stirred overnight at ambient temperature and poured into 10% aqueous ammonium chloride solution. The aqueous mixture is extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound.

Step 7. Preparation of ethyl 9-cyclopropyl-l- ((4,5-dimethoxy-2-nitro-phenyl) methoxycarbonyl) -3-fluoro-2-hydroxy-6H-6-oxo-pyrido [L, 2-a] pyrimidine-7-carboxylate

(2-chloro-5-cyclopropyl-6-N - ((4,5- dimethoxy-2-nitro- phenyl) methoxy- carbonyl) (15 mmol) of amino-nicotinic acid in 200 ml dioxane / water (1: 1). To this solution was added 4.1 g (30 mmol) of potassium carbonate. The reaction mixture is heated to reflux with stirring overnight and cooled to ambient temperature. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound.

Step 8. Preparation of ethyl 9-cyclopropyl-3-fluoro-2-chloro-6H-6-oxo-pyrido [l, 2-a] pyrimidine-

Hydroxy-6H-6-oxo-pyrimidin-2-one from step 7, using ethyl 9-cyclopropyl-l- ((4,5- dimethoxy- 2- nitro- phenyl) methoxycarbonyl) [1, 2-a] pyrimidine-7-carboxylate (5.3 g, 10 mmol) is dissolved in 75 ml of 2: 1 dioxane: water and the resulting solution is illuminated with 320 nm light for 30 min. The reaction mixture is extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is purified by silica gel chromatography to give the product of step 7 with the nitrogen protecting group removed. This product is dissolved in 1, 2-dichloroethane and treated with phosphorus oxychloride at ambient temperature for 18 hours. The reaction mixture is diluted with 1, 2-dichloroethane and washed with aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude title compound which was purified by recrystallization from ethyl alcohol.

Step 9. Preparation of ethyl 9-cyclopropyl-3-fluoro-2- (4-methylpiperazin-l-yl) -6H-6-oxo-pyrido [l, 2-a] pyrimidine-

Chloro-6H-6-oxo-pyrido [l, 2-a] pyrimidine-7 from step 8 following the procedure described in step 3 of Example 1 -Carboxylate with 4-methylpiperazine and the title compound.

Step 10. Synthesis of 9-cyclopropyl-3-fluoro-2- (4-methylpiperazin-l-yl) -6H-6-oxo-pyrido [l, 2-a] pyrimidine-

Yl) -6H-6-oxo-pyrido [l, 4-dihydro-lH-pyrazolo [ 2-a] pyrimidine-7-carboxylic acid is converted to the title compound.

Examples 40 to 57

Methylpiperazine in step 4 according to the procedure described in example 39 was converted to the appropriate amine and as shown in Table 2,

&Lt; / RTI &gt;

[Table 2]

^The amine is protected and deprotected as described in Example 58. &lt; RTI ID = 0.0 &gt;

Example 58

8- (3-Amino-1-pyrrolidinyl) -4H-quinolizine-4-one-3-carboxylic acid hydrochloride

Step 1, 4-Chloro-2-picoline

(0.25 mmol) of 2-picoline-N-oxide (commercial product: Aldrich Chemical Company) was added in small portions to 34.5 ml (0.37 mmol) of phosphorus oxychloride under a nitrogen atmosphere. The temperature is raised to 60 占 폚 while the reaction temperature is increased. The reaction mixture after the addition is a homogeneous dark red solution and the reaction temperature is 80 ° C. This solution is heated to 120 占 폚 for 1.5 hours. The reaction mixture is concentrated under reduced pressure to remove most of the phosphorus oxychloride and the concentrate is poured into ice water. The aqueous mixture is allowed to stand at ambient temperature for 2 hours and then extracted with diethyl ether. Discard the ether extract. The aqueous layer is adjusted to pH 8.0 with potassium carbonate and extracted with ethyl acetate. The organic extracts are dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The liquid concentrate was distilled to give 8.737 g of a mixture of the title compound and the isomer 6-chloro-2-picoline as a clear, colorless liquid. bpm 70 [deg.] C (25 mmHg). This product is combined with another sample of the same mixture prepared separately by the same procedure. Isomeric products can not be separated by distillation. The combined product (12.905 g) is dissolved in 750 ml of ethyl alcohol. To the resulting solution, add the nitric acid solution until a white precipitate is formed and the pH of the supernatant is 1. The precipitate is removed by filtration and dissolved in water. The resulting aqueous solution is adjusted to neutral pH with sodium bicarbonate and extracted with methylene chloride. The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 7.487 g of the title compound. _{^{1 HMR (CDCl 3) d 2.55}} (s, 3H), 7.12 (dd, 1H, J = 3Hz), 6Hz), 7.18 (d, 1H, J = 3Hz), 8.40 (d, 1H, J = 6Hz).

Step 2. Diethyl 2-ethoxy-3- (5-fluoropyridin-2-yl) -propane- 1, 1-dicarboxylate

Lithium diisopropylamide (LDA: 16 ml of a 1.5M solution in hexane) is added to 8 ml of anhydrous THF under a nitrogen atmosphere and the resulting solution is cooled to -70 DEG C in an isopropyl alcohol / dry ice bath. To the cooled LDA solution is added dropwise a solution of 2.5 g (19.6 mmol) of 4-chloro-2-picoline from step 1 in 20 ml of anhydrous THF over 30 minutes. The solution turns very dark red. The dark red solution is stirred at -70 &lt; 0 &gt; C for 0.5 h, then a solution of 4.04 ml (19.6 mmol) ethoxymethylenemalonate in 18 ml dry THF is added dropwise over 30 min. The reaction solution changes from dark red to orange. After stirring at -70 ° C for 0.5 hours, the reaction solution was warmed to -20 ° C and stirred at -20 ° C for 1 hour. The reaction is quenched 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 methylene chloride and the organic extract is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue (8.03 g) was eluted with 0.5% methanol in methylene chloride and purified by chromatography on a silica gel column (SiO ₂ to 120 g) to give 4.59 g (68% yield) of the title compound.

Step 3, Ethyl 8-chloro-4H-quinolizin-4-one-3-carboxylate

80 ml of Dow Therm A ^R in a three-necked flask equipped with a thermometer, dropping funnel and air cooling condenser is heated to 235 ° C using a heating mantle under a nitrogen atmosphere. A solution of 4.26 g (12.4 mmol) of diethyl 2-ethoxy-3- (5-fluoropyridin-2-yl) -propane- 1, 1 -dicarboxylate from step 2 in 45 ml of DOW Therm A ^R was heated Is added dropwise over 5 hours to the stirring DOW TEM A ^R through a dropping funnel. After the addition, the resulting solution is heated to ~ 200 ° C for 1 hour and then cooled to ambient temperature. A black green solution is poured into 500 ml of hexane to form a precipitate. The precipitate was collected by filtration, washed with 5 x 100 ml of hexane and dried to give 1.487 g (48% yield) of the title compound.

Step 4. Ethyl 8- (3-Nt-butoxycarbonyl) amino-1-pyrrolidine) -4H-quinolizine-

Chloro-4H-quinolizine-3-carboxylate (1.0 g, 3.97 mmol) from step 3 is dissolved in 20 ml of anhydrous pyridine under a nitrogen atmosphere. The resulting solution is added to a solution of 1.85 g (9.92 mmol) of 3- (N-t-butoxycarbonylamino) pyrrolidine in 5 ml of anhydrous pyridine and the reaction mixture is heated at 70 ° C for 4.5 hours. The reaction mixture is concentrated under vacuum to remove all pyridine. The anhydrous residue (3.124 g) was purified by silica gel chromatography eluting with 2% methanol in methylene chloride to give 0.889 g (56% yield) of the title compound.

Step 5. 8- (3-Amino-1-pyrrolidin) -4H-quinolizin-4-one-3-carboxylic acid hydrochloride

To a solution of ethyl 8- (3- (Nt-butoxycarbonyl) amino-1-pyrrolidinyl) -4H-quinolizine-4-one-3-carboxylate from step 4 in 0.8 ml of tetrahydrofuran g &lt; / RTI &gt; (2.2 mmol) in toluene is stirred at ambient temperature for 2 hours. TFA is evaporated in vacuo and the residue is dissolved in 200 ml of methanol. 4.5 g of a strong base ion exchange resin is added to the resulting solution and the mixture is stirred at ambient temperature for 1 hour. The mixture is filtered and the filtrate is concentrated under reduced pressure to give crude ethyl 8- (3-amino-1-pyrrolidin) -4H-quinolizine-4-one-3-carboxylate as a residue. The residue is dissolved in 5 ml of THF and 11 ml of a 1 M aqueous sodium hydroxide solution are added. The reaction mixture is heated at 60 ° C for 1 hour, and then the reaction temperature is raised to 85 ° C to evaporate the THF. The concentrated reaction solution is diluted with 20 ml of water and the pH of the resulting solution is adjusted to 1 to 2 with concentrated hydrochloric acid. The aqueous solution is concentrated under vacuum. The residue was crystallized from ethyl alcohol: isopropyl alcohol: water (4: 4: 1 v / v / v) and recrystallized from ethyl alcohol to yield 0.388 g (57% yield) of the title compound. mp 225-230 [deg.] C; _{MS DCI-NH 3: 274 (} M-Cl) + 90%, 230 (M-Cl) -CO 2 H) + base; IR (KBr): 3420 (OH), 1650 (C = O) cm- ¹ ; ^{1 H NMR (TFA) d 2.8-3.1} (m, 6H), 4.62 (m, 1H), 7.06 (s, 1H), 7.4 (d, 2H, J = 9Hz), 8.14 (d, 1H, J = 9Hz ), 9.06 (d, 1H, J = 9 Hz). Anal. Calcd. C ₁₄ H ₁₈ Cl ₃ N ₃ O ₃ + _1/3 H ₂ O: C, 58.21; H, 5.10; N, 13.30. Found: C, 53.58; H, 5.38; N, 13.30.

Example 59

8- (3- (N-norvalyl) amino-pyrrolidinyl) -4H-quinolizin-4-one-

3-amino-1-benzylpyrrolidine (I. Sumio and T. Matsu, JP Kobai JP 3528161, 1978, 3, 16) was reacted with Nt-butoxy Is coupled to carbonyl norvaline (Boc-nVal). The 1-benzyl group is removed by hydrogenolysis in methanol using a palladium / carbon catalyst. Subsequently, 3- (Nt-butoxycarbonylamino) pyrrolidine was converted to 3- (N-Boc-norballyl) aminopyrrolidine as described in step 4 of Example 58 to give 3- (N-Boc -Norvalyl) aminopyrrolidine was reacted with the product of step 3 of Example 58, ethyl 8-chloro-4H-quinolizine-4-one-3-carboxylate to give the 8- (3-N-norvalyl) amino-pyrrolidinyl) -4H-quinolizin-4-one-3-carboxylic acid. The Boc protecting group is removed by standard hydrolysis with trifluoroacetic acid and dilute aqueous hydrochloric acid.

Other amino acid derivatives of the compounds of the present invention having an amino group can be prepared using the procedures outlined in Example 59 or other conventional condensation methods listed above. Examples of amino acids that may be coupled alone or in combination with other amino acids include synthetic amino acids such as cyclohexyl alanine, cyclohexyl glycine, aminopenanoic acid, and the like, as well as natural amino acids such as glycine, alanine, leucine, isoleucine, methionine, phenylalanine, .

Example 60

8-Chloro-4H-quinolizin-4-one-3-carboxylic acid

Step 1. Ethyl 8-chloro-4H-quinolizine-4-one-3-carboxylate

In a three-necked flask equipped with a thermometer, dropping funnel and an air-cooled condenser, 35 ml of Dow Therm A ^R are heated to 230-235 ° C under positive pressure nitrogen using a heating mantle. A Dow term ^R in the Example 58 Step 2 product, diethyl 2-ethoxy-3- (pyridin-2-yl 5-fluoro) 45ml - propane-1, 1-dicarboxylate 2.7g (7.85mmol) The solution is added dropwise over 1.5 hours to a stirred stirring DOW TEM A ^{R, which} is heated with a dropping funnel. After the addition, the resulting solution is heated to ~ 200 ° C for 40 minutes and then cooled to ambient temperature. A black green solution is poured into 600 ml of hexane to form a precipitate. The precipitate was collected by filtration, washed with 2 x 150 ml of hexane and dried to give 1.15 g (58% yield) of the title compound. mp 153-154 [deg.] C.

Step 2. 8-Chloro-4H-quinolizin-4-one-3-carboxylic acid

Ethyl 8-chloro-4H-quinolizin-4-one-3-carboxylate (15 mg, 0.5 mmol) is suspended in 0.5 N aqueous sodium hydroxide solution. The reaction mixture is heated to 65 &lt; 0 &gt; C and 2 ml of THF are added. The reaction mixture was stirred at 65 &lt; 0 &gt; C for 1 hour and then the THF was distilled from the mixture. Lt; RTI ID = 0.0 &gt; 65 C &lt; / RTI &gt; for 2 hours and then cooled to ambient temperature. The aqueous mixture is 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, washed with 2 x 15 ml of water and dried under vacuum to give 100 mg (89% yield) of the title compound. mp 229-230 [deg.] C. The product was recrystallized from ethyl alcohol and dried under vacuum to give 50 mg (44.5% yield) of the title compound. mp 237-238 [deg.] C; _{MS DCI-NH 3 M / Z} : 224 (M + H) +, 241 (M + NH4) +; IR (KBr): 3430 (OH), 1740 (C = O) cm- ¹ ; _{^{1 H NMR (CDCl 3) d}} 6.89 (d, 1H, J = 6.9Hz), 7.30 (dd, 1H, J = 6.6Hz), 7.71 (d, 1H, J = 2.1Hz), 8.64 (d, 1H, J = 6.9 Hz), 9.25 (d, 1H, J = 6.6 Hz). Anal. Calcd. C ₁₀ H ₈ ClNO ₃ : C 53.71; H, 2.70; N, 6.26. Found: C, 54.27; H, 2.86; N, 6.23.

Example 61

8- (4-Methylpiperazin-1-yl) -4H-quinolizin-4-one-3-carboxylic acid hydrochloride

Step 1. Ethyl 8- (4-methylpiperazin-1-yl) -4H-quinolizin-4-one-3-

The product of step 3, ethyl 8-chloro-4H-quinolizine-4-one-3-carboxylate (755 mg, 3.0 mmol) is dissolved in 12 ml of anhydrous pyridine under a nitrogen atmosphere. To the resulting solution is added a solution of 6.0 ml (6.0 mmol) of N-methylpiperazine and the reaction mixture is heated at 70 &lt; 0 &gt; C for 8 h. The reaction mixture is concentrated under vacuum to remove all the pyridine. The anhydrous residue (3.124 g) is dissolved in 125 ml of methylene chloride and the methylene chloride solution is washed with 125 ml of saturated sodium chloride (brine). The aqueous layer was extracted with 125 ml of methylene chloride, and the combined methylene chloride solution was dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and dried to give 1.01 g of the title compound.

Step 2. 8- (4-Methylpiperazin-1-yl) -4H-quinolizin-4-one-3-carboxylic acid hydrochloride

A mixture of 0.865 g (2.75 mmol) of 8- (4-methylpiperazin-1-yl) -4H-quinolizin- Is heated at 75 DEG C for 88 hours with stirring. The THF is removed from the reaction mixture by distillation at the reaction temperature. The concentrated reaction mixture is cooled to ambient temperature and adjusted to pH 2.0 with 10.5 ml of a 1N aqueous hydrochloric acid solution. The aqueous solution is concentrated in vacuo to remove about 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 under vacuum to give the desired product. The product was recrystallized from ethyl alcohol / water (3: 1 v / v) to give the title compound 0.332 (37% yield). mp 257-258 [deg.] C; MS DCI-NH ₃ M / Z: 288 (M-Cl) ⁺ 90%, 241 (M-Cl) -CO ₂ H)) ⁺ base, 270 (M-Cl-H ₂ O) ⁼ ; IR (KBr): 3420 (OH), 1645 (C = O) cm- ¹ ; ^{1 H NMR (TFA) d 3.20} (m, 3H), 3.52 (dd, 2H, J = 10Hz), 4.02 (m, 4H), 4.63 (d, 2H, J = 12Hz), 7.41 (m, 2H), 7.65 (d, 1H, J = 7.5 Hz), 8.26 (s, 1H, J = 9 Hz), 9.18 (d, 1H, J = 7.5 Hz). Anal. Calcd. C ₁₅ H ₁₈ ClN ₃ O ₃ : C 54.14; H, 5.75; N, 12.62. Found: C, 54.23; H, 5.54; N, 12.64.

Example 62

8- (3-Amino-1-pyrrolidinyl) -l-ethyl-4H-quinolizin-4-one-3-carboxylic acid hydrochloride

Step 1. 4-Chloro-2-pyridine

1.5 M LDA solution in hexane (100 ml, 150 mmol) is cooled to -70 캜 in an isopropyl alcohol / dry ice bath. To the stirred LDA solution is added dropwise a solution of 17.466 g (137 mmol) of 4-chloro-2-picoline (product from example 58 step 1) in 80 ml of anhydrous THF under nitrogen over 0.5 h. The reaction mixture is stirred at -60 &lt; 0 &gt; C for 0.5 h, then a solution of 10.95 ml (137 mmol) ethyl iodide in 30 ml dry THF is added dropwise over 20 min. The reaction mixture is stirred at -60 &lt; 0 &gt; C for 0.5 h, then the cooling bath is slowly warmed to -30 &lt; 0 &gt; C (1.5 h). The reaction is terminated by silica gel TLC analysis developed with 5% methanol in methylene chloride. Half the 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 concentrated under reduced pressure. Distillate the residue to obtain 12.667 g (60% yield of the title compound, b. P. 77-80 占 폚).

Step 2. Diethyl 2-ethoxy-3- [4-chloro-2-pyridyl] -pentane-1, 1-dicarboxylate

A solution of 12.6 ml (89.9 mmol) diisopropylamine in 20 ml anhydrous tetrahydrofuran (THF) is prepared under a nitrogen atmosphere and cooled in ice / water. To this solution, 36 ml of a 2.5M solution of n-butyl lithium (90 mmol) in hexane was added dropwise over 30 minutes. The solution is stirred at 0 &lt; 0 &gt; C for 1 minute and then cooled to -60 &lt; 0 &gt; C. 12.66 g (81.9 mmol) of 4-chloro-2-propyl-pyridine from step 1 in 10 ml of anhydrous THF are added dropwise over 30 minutes to the amine solution at -60 deg. C to form a dark red solution. The solution is stirred at -60 &lt; 0 &gt; C for 0.5 h and then 16.55 ml (81.9 mmol) of ethyl 2-carboxyethoxy-3-ethoxy-2-propenecarboxylate are added dropwise over 30 min. Stir at -60 &lt; 0 &gt; C for 0.5 h and stir at -20 &lt; 0 &gt; C for 1.5 h. The reaction mixture is poured into cold brine and the aqueous mixture is extracted with methylene chloride. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 35.48 g of the title compound. The next step is carried out without further purification of the product.

Step 3. Ethyl 8-chloro-1-ethyl-4H-quinolizin-4-one-3-

A solution of 35.48 g (99.2 mmol) of diethyl 2-ethoxy-3- [4-chloro-2-pyridyl] -pentin-1, 1 -dicarboxylate from step 2 in xylene Heat for 24 h and then concentrate under vacuum. By washing of the residue with hexane and cyclohexane mixture to give the title compound 14.867g (54% yield) as a green _{solid: MS DCI-NH 3 M /} Z: 288 (M + H) +, 246 (M-Cl) ⁺ , 217 (M-Cl-Et) ^&lt; ⁺ &^gt;; _{^{1 H NMR (CDCl 3) d}} 1.31 (t, 3H, J = 7.5Hz), 1.43 (t, 3H, J = 7.2Hz), 2.78 (q, 2H, J = 7.5Hz), 4.43 (q, 2H, J = 7.2 Hz), 7.10 (dd, 3H, J = 2.4 Hz, 8.1 Hz), 7.70 (d, 1H, J = 2.4 Hz), 8.32 (s, 1H), 9.40 (d,

Step 4. Ethyl 8- (3-N-T-butoxycarbonyl) amino-1-pyrrolidinyl) -l-ethyl-4H- quinolizine-

Chloro-1-ethyl-4H-quinolizine-3-carboxylate (1.20 g, 4.3 mmol) in step 3 is dissolved in 15 ml of anhydrous pyridine under a nitrogen atmosphere. 1.04 g (5.59 mmol) of 3- (Nt-butoxycarbonylamino-pyrrolidine) and 1.8 ml (12.9 mmol) of anhydrous triethylamine are added to the resulting solution, and the reaction mixture is heated at 60 ° C for 12 hours. The reaction mixture is concentrated under vacuum to remove all pyridine. Ethyl alcohol (4 ml) is added to the dry residue. The mixture is filtered to give 0.421 g of the desired product as a solid. The filtrate was concentrated and the residue was eluted with 2% methanol in methylene chloride, then eluted with 5% methanol in methylene chloride and purified by silica gel chromatography to give 1.273 g of the desired compound. The title compound was obtained as a yellow solid in 92% yield (1.694 g) and used in the next step.

Step 5. Preparation of 8- (3-amino-1-pyrrolidinyl) -l-ethyl-4H-quinolizin-4-one-3-carboxylic acid hydrochloride

To a solution of ethyl 3- (Nt-butoxycarbonyl) -amino-1-pyrrolidinyl) -l-ethyl-4H-quinolizin-4-one-3-carboxylate from step 4 in 25 ml of trifluoroacetic acid (TFA) Rate

1.694 g (3.94 mmol) of a solution are stirred at ambient temperature for 2 hours. TFA is evaporated in vacuo and the residue is dissolved in 200 ml of methanol. To the resulting solution is added 25 g of a strong base ion exchange resin and the mixture is stirred at ambient temperature for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 1.146 g (88% yield) of ethyl 8- (3-amino-1-pyrrolidinyl) As a residue. The residue is dissolved in 6 ml of THF and 10.5 ml of a 1 M aqueous sodium hydroxide solution are added. The reaction mixture is heated at 60 &lt; 0 &gt; C for 2 hours and then the reaction temperature is raised to 90 &lt; 0 &gt; C for 2 hours to evaporate the THF. The concentrated reaction solution is poured into water and the pH of the resulting solution is adjusted to about 2 with concentrated hydrochloric acid. Filtration of the solid afforded 0.365 g (31% yield) of the title compound. mp 196-198 [deg.] C; _{MS DCI-NH 3: 302 (} M-Cl) + base, 258 ((M-Cl) -CO 2 H)) + 25%; IR (KBr): 3440 (OH), 2960, 1650 (C = O), 1500, 1360, 1280 cm- ¹ ; ^{1 H NMR (TFA) d 1.41} (t, 3H, J = 7.5Hz), 2.39 (q, 2H, J = 7.5Hz), 2.70 (m, 3H), 4.53 (m, 1H), 6.93 (d, 1H J = 1.5 Hz), 7.33 (dd, 1H, J = 9 Hz, 1.5 Hz), 7.93 (s, 1H), 9.08 (d, 1H, J = 9 Hz). Anal. Calcd. C ₁₆ H ₂₀ ClN ₃ O ₃ : C, 56.98; H, 5.97; N, 12.44. Found: C, 56.83; H, 6.00; N, 11.93.

Example 63

Amino-pyrrolidinyl) -1-ethyl-4H-quinolizine-4-one-3-carboxylic acid

3-amino-1-benzylpyrrolidine (I. Sumio and T. Matsu, JP Kokai JP 5328161, 1978, 3, 16) was reacted with Nt-butoxy Is coupled to carbonylalanine (Boc-Ala). The 1-benzyl group is removed by hydrogenolysis in methanol using a palladium / carbon catalyst. Subsequent conversion of 3- (Nt-butoxycarbonylaminopyrrolidine) to 3- (N-Boc-alanyl) aminopyrrolidine as described in step 4 of Example 62 provided 3- (N-Boc - alanyl) aminopyrrolidine was reacted with the product of step 3 of Example 62, ethyl 8-chloro-1-ethyl-4H-quinolizine-4-one-3-carboxylate to give the nitrogen of the amino acid as a Boc group Protected 8- (3- (N-alanyl) amino-pyrrolidinyl) -4H-quinolizin-4-one-3-carboxylic acid. The Boc protecting group is removed by standard hydrolysis with trifluoroacetic acid and dilute aqueous hydrochloric acid.

Other amino acid derivatives of the compounds of the present invention having an amino group can be prepared using the procedures outlined in Example 63 or other conventional condensation methods listed above. Examples of amino acids that may be coupled alone or in combination with other amino acids include synthetic amino acids such as cyclohexyl alanine, cyclohexyl glycine, aminopenanoic acid, and the like, as well as natural amino acids such as glycine, alanine, leucine, isoleucine, methionine, phenylalanine, .

Example 64

1-ethyl-8- (3-methyl-1-piperazinyl) -4H-quinolizin-4-one-3-carboxylic acid hydrochloride

Step 1. Ethyl 1-ethyl-8- * 3-methyl-1-piperazinyl) -4h-quinolizin-

Example 62 The product of step 3, ethyl 8-chloro-1-ethyl-4H-quinolizine-4-one-3-carboxylate (588 mg, 2.0 mmol) is dissolved in 10 ml of anhydrous pyridine under a nitrogen atmosphere. To the resulting solution is added 600 mg (6.0 mmol) of 2-methylpiperazine and the reaction mixture is heated at 65 &lt; 0 &gt; C for 3 hours. The reaction mixture is cooled to ambient temperature and concentrated under vacuum to remove all pyridine. The residue is dissolved in methylene chloride and the methylene chloride solution is washed with 60 ml of water. The aqueous layer was extracted with 2 x 60 ml of methylene chloride, and the combined methylene chloride solution was dried over anhydrous sodium sulfate, filtered, concentrated and dried under vacuum to give 690 mg of the title compound. The next step is carried out without further purification of the product.

Step 2. Preparation of 1-ethyl-8- (3-methyl-1-piperazinyl) -4H-quinolizin-4-one-3-carboxylic acid hydrochloride

To a suspension of 0.686 g (2 mmol) of 1-ethyl-8- (3-methyl-1-piperazinyl) -4H-quinolizin- 8.0 ml of aqueous solution are added and the mixture is heated to 65 [deg.] C with stirring for 3 hours. The THF is removed from the reaction mixture by distillation during the reaction. The concentrated reaction mixture is cooled to ambient temperature and adjusted to pH 1-2 with 16 ml of a 1N aqueous hydrochloric acid solution. The aqueous solution is concentrated in vacuo to remove water and the residue is suspended in 10 ml of water. The solid was collected by filtration and dried under vacuum to give the title compound. mp 295 [deg.] C; _{MS DCI-NH 3: 316 (} M-Cl) +; IR (KBr): 3420 (OH), 1720 (C = O) cm- ¹ ; ^{1 H NMR (TFA) d 1.50} (t, 3H, J = 7.5Hz), 1.79 (d, 3H, J = 6Hz), 3.00 (q, 2H, J = 7.5Hz), 3.70-4.10 (m, 6H) , 4.55 (m, 1H), 4.60 (m, 1H), 7.40 (d, 1H, J = 3.0 Hz), 7.68 (dd, 1H, J = 3.0 Hz, 8.4 Hz) (d, IH, 8.4 Hz). Anal. Calcd. C ₁₇ H ₂₂ ClN ₃ O ₃ + H ₂ O: C, 55.21; H, 6.54; N, 11.36. Found: C, 55.19; H, 6.07; N, 11.34.

Example 65

1-ethyl-8- (4-methylpiperazin-1-yl) -4H-quinolizine-

Step 1. Ethyl 1-ethyl-8- (4-methylpiperazin-l-yl) -4H-quinolizin-

Example 62 The product of step 3, ethyl 8-chloro-1-ethyl-4H-quinolizin-4-one-3-carboxylate (279 mg, 1.0 mmol) is dissolved in 5 ml of anhydrous pyridine under a nitrogen atmosphere. 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 cooled to ambient temperature and concentrated under vacuum to remove all pyridine. The residue is dissolved in 50 ml of methylene chloride and the methylene chloride solution is washed with 50 ml of 5% sodium bicarbonate solution. The aqueous layer was extracted with 3 x 50 ml of methylene chloride, and the combined methylene chloride solution was dried over anhydrous sodium sulfate, filtered, concentrated, and dried under vacuum to give 343 mg of the title compound. mp 94-96 [deg.] C; _{MS DCI-NH 3: 344 (} M + H) +

Step 2. Preparation of l-ethyl-8- (4-methylpiperazin-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-quinolizine- 4.0 ml of an aqueous sodium solution is added and the mixture is heated to 75 [deg.] C with stirring for 4.5 hours. The reaction mixture is cooled to ambient temperature and adjusted to pH 2 with 5 ml of 1 N aqueous hydrochloric acid solution. The aqueous solution is concentrated under vacuum to about 5 ml and the solid is collected by filtration and dried under vacuum to give 120 mg (68% yield) of the title compound. mp 293-294 [deg.] C (dry); _{MS DCI-NH 3: 316 (} M-Cl) + 90%, 272 ((M-Cl) -CO 2 H)) + base; IR (KBr): 3420 (OH), 1695 (C = O), 1640 (C = O) cm- ¹ ; ^{1 H NMR (TFA) d 1.47} (t, 3H, J = 7.5Hz), 3.00 (q, 2H, J = 7.5Hz), 3.23 (s, 3H), 3.55 (dd, 2H, J = 9Hz), 4.12 1H, J = 9 Hz), 8.16 (s, 1H), 9.20 (d, 1H, 7.5 Hz, ). Anal. Calcd. C ₁₇ H ₂₂ ClN ₃ O ₃ : C, 56.59; H, 6.42; N, 11.64. Found: C, 56.86; H, 6.19; N, 11.60.

Example 6

4-Chloro-5-fluoro-2-picoline

Step 1. Preparation of 2- (5-nitro-2-pyridyl) -1,3-propanedicarboxylate

Sodium hydride (20.2 g of suspended NaH in hexane, 0.504 mmol) is suspended in 600 ml of anhydrous THF under a nitrogen atmosphere in a 2 L round bottomed flask equipped with a dropping funnel and a mechanical stirrer. The suspension is cooled to 0 &lt; 0 &gt; C with an ice bath. A solution of 71.8 ml (0.473 mmol) diethylmalonate in 60 ml dry THF is added dropwise over 1 hour to the suspension of sodium hydride. After the gas bubbling is finished, the reaction mixture is stirred at 0 ° C for 20 minutes. A solution of 50 g (0.315 mmol) of 2-chloro-5-nitropyridine in 150 ml of dry THF is added dropwise to the mixture over 25 minutes. The ice bath is removed and the dark red solution is stirred at ambient temperature for 48 hours. Repeat this process in the same way. The two solutions containing the product are concentrated to about 500 ml and poured into a mixture of 1 L aqueous 10% sodium bicarbonate solution and 1 L brine. The aqueous mixture is extracted with 3 x 500 ml of methylene chloride. The combined organic extracts are dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a solid residue. The ethyl and the residue crystallized with alcohol and washed with hexane to give the title compound 140g (79% _{yield): MS DCI-NH 3 M} / Z: 283 (M + H) + base, 253 ((M + H ) -C ₂ H ₅₎ ^{+ _{base: 1 H NMR (CDCl 3)}} d 1.30 (t, 6H, J = 7.5Hz), 4.26 (q, 2H, J = 6.0Hz), 4.29 (q, 2H, J = 1H), 5.08 (s, 1H), 7.77 (dd, 1H, J = 9.0 Hz, 0.6 Hz), 8.19 (dd, 1H, J = 3.0 Hz, 9.0 Hz), 9.38 Hz, 9.0 Hz).

Step 2. 5-Nitro-2-picoline

A suspension of 102.0 g (0.36 mmol) of 2- (5-nitro-2-pyridyl) -1,3-propanecarboxylate from step 1 in 600 ml of a 20% aqueous sulfuric acid solution is heated at 95 [deg.] C for 24 hours. The resulting solution is poured into 1 kg of ice and the aqueous mixture is adjusted to pH 10-12 with 50% sodium hydroxide. The precipitate is filtered off and dissolved in ethyl acetate. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered, and concentrated to give a solid residue. The residue is washed with hexane. The hexane was removed by filtration and the solid was dried to give 45.86 g (92% yield) of the title compound; _{^{1 H NMR (CDCl 3) d}} 2.71 (s, 3H), 7.36 (d, 1H, J = 9.0Hz), 8.37 (dd, 1H, J = 3.0Hz, 9.0Hz), 9.33 (d, 1H, J = 3.0Hz).

Step 3. 5-Amino-2-picoline

The product of step 2, 5-nitro-2-picoline (45.86, 0.332 mol) is dissolved in 200 ml of methanol and 1.15 g of 10% palladium on carbon are added to the resulting solution. The reaction mixture is hydrogenated at ambient temperature under hydrogen 4 atm. The palladium catalyst was filtered through a 45μ Millipore ^{R (R} Millipore) filter and the filtrate was concentrated under vacuum to give the title compound 33.96g (95% yield) as a tan solid; _{^{1 H NMR (CDCl 3) d}} 2.42 (s, 3H), 3.54 (brs, 2H), 6.91 (m, 2H), 8.00 (m, 1H).

Step 4. 5-Fluoro-2-picoline

A solution of 5-amino-2-picoline (20 g, 0.185 mmol) from step 3 in 105 ml of ethyl alcohol is cooled to 0 &lt; Tetrafluoroboric acid (55 ml of a 48% solution in water) is added to a cold 5-aminopicolin solution and the flask containing the resulting solution is cooled. Ethyl nitrite is bubbled through the cold solution until 13.88 g (0.185 mol) is added. It goes over 1.25 hours. After completion of the addition, the reaction solution is allowed to stand at 0 ° C for 15 minutes, and excess ethyl nitrite evaporates from the solution during this time. Diethyl ether (120 ml) is added to the reaction mixture to ensure precipitation of the tetrafluoroborate salt. After 30 minutes at 0 &lt; 0 &gt; C, the mixture is filtered. The filter cake is washed with 200 ml of diethyl ether and 300 ml of hexane. The solid is transferred to a 1 L beaker containing approximately 300 ml of hexane and 10.75 g (0.185 mol) of potassium fluoride. The mixture is heated at 40 &lt; 0 &gt; C over 4.5 hours. The orange solid is converted to a black oily solid. The hexane is decanted and the residue is cooled to 0 &lt; 0 &gt; C. The cold residue is polished with about 200 ml of 50% sodium hydroxide. The mixture is combined with the material obtained in two runs of the preceding procedure and the combined aqueous mixture is subjected to steam distillation. The aqueous distillate collected at 92 &lt; 0 &gt; C to 100 &lt; 0 &gt; C is extracted twice with methylene chloride. The combined methylene chloride extracts are dried over anhydrous sodium sulfate, filtered and added to a concentrated (hexane) distillate at 62 ° C to 65 ° C. The product is subjected to the following steps as a solution.

Step 5. 5-Fluoro-2-picoline-N-oxide

To a solution of 5-fluoro-2-picoline from step 4 is added a cold 40% solution of peracetic acid (prepared by careful addition of 50 ml of 30% hydrogen peroxide solution to 150 ml of glacial acetic acid) with vigorous stirring at 0 ° C. The reaction mixture is heated at reflux temperature (50 ° C) for 4 days and then poured into 600 ml of ice water. The aqueous mixture is adjusted to pH 9 with potassium carbonate and stirred at ambient temperature for 4 hours. The aqueous solution was successively extracted with methylene chloride for 24 hours and the methylene chloride extract was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 30.8 g (22% yield) of the title compound; _{MS DCI-NH 3, M /} Z: 128 (M + H) + base; _{^{1 H NMR (CDCl 3) d}} 2.48 (s, 3H), 7.00 (ddd, 1H), 7.22 (dd, 1H), 8.22 (d, 1H).

Step 6. 5-Fluoro-4-nitro-2-picoline-N-oxide

The reaction mixture is run in a flask bent with a gas scrubber containing sodium hydroxide solution. The product of step 5, 5-fluoro-2-picoline-N-oxyl (1.0 g, 7.86 mmol) is cooled to 0 C and concentrated sulfuric acid (4,2 ml) is slowly added dropwise with stirring. Solid sodium nitrate (1.27 g, 12.5 mmol) is added to this mixture in small portions over 45 min at 0 &lt; 0 &gt; C. The reaction mixture is allowed to warm to ambient temperature and stirred at ambient temperature for 1 hour. The completely dissolved potassium nitrate is dissolved and the reaction mixture is heated at 50 占 폚 for 0.5 hours and 100 占 폚 for 18 hours. The homogeneous reaction solution is poured into ice and the resulting aqueous solution is adjusted to pH with solid potassium carbonate. The aqueous solution is extracted with 3 x 80 ml of methylene chloride. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 1.084 g (80% yield) of the title compound; mp 107-108 [deg.] C; _{MS DCI-NH 3 M / Z} : 190 (M + NH 4) + 10%, 173 (M + H) + 30%, 157 (MO) + 50%; ¹ H NMR (CDCl ₃ ) d 2.48 (s, 3H), 8.05 (d, 1H, J = 9.0 Hz), 8.31 (d, 1H, 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) is dissolved in 3 ml of concentrated (37.5%) aqueous hydrochloric acid. The resulting solution is heated at 110 &lt; 0 &gt; C for 48 hours with stirring and then concentrated in vacuo. Water (30 ml) is added to the residue and the resulting aqueous solution is adjusted to pH 9-10 with sodium carbonate. The aqueous solution is extracted with 3 x 50 ml of methylene chloride and the combined organic extracts are dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Crystallization of the product with hexane afforded 1.8 g (55% yield) of the title compound. mp 92-93 [deg.] C; _{MS DCI-NH 3 M / Z} : 179 (M + NH 4) + 30%, 162 (M + H) + ^{base, 146 (MO) + 60%} ; ¹ H NMR (CDCl ₃ ) d 2.46 (s, 3H), 7.30 (d, 1H, J = 9.0 Hz), 8.26 (d, 1H, J = 4.5 Hz); IR (chloroform solution) 1605 (NO), 1180 (CF) cm -1. Anal. Calcd. C ₆ H ₅ ClFNO: C, 44.61; H, 3.12; N, 8.62. Found: C, 44.89; H, 3.25; N, 9.40.

Step 8. Preparation of 4-chloro-5-fluoro-picoline

4-Chloro-5-fluoro-2-picoline-N-oxide (12.43 g, 76.93 mmol) from step 7 is dissolved in 52 ml of glacial acetic acid in a three-necked flask equipped with a mechanical stirrer, condenser and thermometer. Iron powder (6.45 g, 115.5 mmol) is added to the solution at ambient temperature and the reaction mixture is carefully heated to 35-40 [deg.] C. After 10 minutes at 30 ° C, an exothermic reaction takes place, the reaction temperature is raised to 120 ° C and the reaction mixture becomes a very dark brown solution. Transfer the flask to a cold water bath and set the solution temperature to ambient temperature. The reaction mixture is poured into ice. The resulting aqueous mixture is adjusted to pH 9 with potassium carbonate and steam distilled. The aqueous distillate collected at 92-96 &lt; 0 &gt; C is extracted into three portions of methylene chloride. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and distilled to give 15.91 g (71% yield) of the title compound. bp 138-140 C; MS GC-MS M / Z: 146 (M + H) &lt; ⁺ &gt;; _{^{1 H NMR (CDCl 3) d}} 2.53 (s, 3H), 7.23 (d, 1H, J = 6.0Hz), 8.37 (s, 1H).

Example 67

3, 4-Dichloro-5-fluoro-2-picoline

0.75 ml of t-butyl hypochlorite was added to 0.87 g (6 mmol) of the product of Example 66, 4-chloro-5-fluoro-2-picoline in 20 ml of chloroform cooled to -45 占 폚. The reaction mixture is stirred at -45 [deg.] C for 2 hours and the resulting aqueous mixture is extracted with methylene chloride. The organic solution was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and distilled to give the title compound.

Example 68

3-Bromo-4-chloro-5-fluoro-2-picoline

The product of example 66 was treated with bromine in fuming sulfuric acid containing 4-chloro-5-fluoro-2-picoline 65% trioxide termination at 80 &lt; 0 &gt; C for 7 hours to give the title compound. van der Does and H.J. Hertog in Rec Tram Chim 81: 864 (1965)].

Example 69

4-Chloro-3, 5-difluoro-2-picoline

4-Chloro-5-difluoro-2-picoline is treated with 1.1 equivalents of acetyl hypofluorite to give the title compound. Lerman, et al. J Org Chem 49: 806-813 (1984)]

Example 70

4-Chloro-5-fluoro-2-propyl-pyridine

Diisopropylamine (924 L, 6.59 mmol) is dissolved in 9 ml dry THF and the resulting solution is cooled to 0 C with an ice bath. n-Butyl lithium (3.07 ml of a 2.05 M solution in THF, 6.29 mmol) is added via syringe to the amine solution and the resulting solution is stirred at 0 &lt; 0 &gt; C for 30 minutes. The lithium diisopropylamide (LDA) solution is cooled to -50 캜 in an isopropyl alcohol / dry ice bath. The cooled LDA solution is added dropwise to the resulting solution of the product of Example 64, 4-chloro-5-fluoro-2-picoline (435 L, 3.0 mmol) in 9 ml THF dropwise over 15 minutes. The reaction solution is stirred at -50 ° C to -45 ° C for 5 hours and then cooled to -78 ° C over 30 minutes. Ethyl iodide (792 [mu] L, 9.9 mmol) was added in one portion and the reaction solution was stirred at -78 [deg.] C for 20 min. The reaction solution is quenched by pouring into 60 ml of a 10% aqueous ammonium chloride solution. The aqueous mixture is extracted with 2 x 50 ml of methylene chloride. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound. bp 80-82 DEG C (12 mmHg); _{MS DCI-NH 3 M / Z} : 174 (M + H) + 40%; _{^{1 H NMR (CDCl 3) d}} 0.96 (t, 3H, J = 7.5Hz), 1.73 (spt, 2H, J = 7.5Hz), 2.73 (t, 2H, J = 7.5Hz), 7.21 (d, 1H, J = 6.0 Hz), 8.38 (s, 1 H).

Example 71

3, 4-Dichloro-5-fluoro-2-propyl-pyridine

Chloro-5-fluoro-2-picoline (the product of Example 66) was reacted with 4-chloro-5-fluoro-2-propyl-pyridine (the product of Example 70 ), The title compound can be prepared.

Example 72

3-Bromo-4-chloro-5-fluoro-2-propyl-pyridine

Chloro-5-fluoro-2-picoline (the product of Example 66) was reacted with 4-chloro-5-fluoro-2-propyl-pyridine (the product of Example 70 ), The title compound can be prepared.

Example 73

4-Chloro-3,5-difluoro-2-propyl-pyridine

Chloro-5-fluoro-2-picoline (the product of Example 66) was reacted with 4-chloro-5-fluoro-2-propyl-pyridine (the product of Example 70 ), The title compound can be prepared.

Example 74

(4-methylpiperazin-1-yl) -4H-quinolizine-4-one-3-carboxylic acid hydrochloride

The title compound can be prepared by replacing 4-chlorophorcholine with 4-chloro-5-fluoro-picoline (the product of Example 66) according to the procedure described in step 2 of Example 62 and Example 65.

Example 75

7-fluoro-8- (3-methyl-1-piperazin) -4H-quinolizin-4-one-3-carboxylic acid hydrochloride

The title compound can be prepared by replacing 4-chloropicolin with 4-chloro-5-fluoro-picoline (the product of Example 66) following the procedure described in step 2 of Example 62 and Example 65.

Example 76

7-fluoro-4H-quinolizin-4-one-3-carboxylic acid hydrochloride

The title compound can be prepared by replacing 4-chloropicolin with 4-chloro-5-fluoro-picoline (the product of Example 66) according to the procedure described in Example 62. [

Example 77

7-fluoro-8- (4-methylpiperazin-l-yl) -4H-quinolizin-4-one-3-carboxylic acid hydrochloride

The title compound can be prepared by replacing 4-chloropicoline with 3, 4-dichloro-5-fluoro-picoline (the product of Example 67) following the procedure described in step 2 of Example 62 and Example 65 have.

Example 78

7-fluoro-8- (3-methyl-1-piperazinyl) -4H-quinolizin-4-one-3-carboxylic acid hydrochloride

4-Chloropyricoline was converted to 3, 4-dichloro-5-fluoropicoline (the product of Example 67) according to the procedure described in step 2 of Example 62 and Example 65 and N-methylpiperazine was replaced with 2 -Methylpiperazine &lt; / RTI &gt; to give the title compound.

Example 79

Chloro-l-ethyl-7-fluoro-4H-quinolizin-4-one-3-carboxylic acid hydrochloride

The title compound can be prepared by replacing 4-chloropicolin with 3, 4-dichloro-5-fluoropicoline (the product of Example 67) according to the procedure described in Example 62. [

Example 80

7-fluoro-8- (4-methylpiperazin-l-yl) -4H-quinolizin-4-one-3-carboxylic acid hydrochloride

The title compound was prepared according to the procedure described in step 2 of Example 62 and Example 65 by replacing 4-chloropicolin with 3-bromo-4-chloro-5-fluoropicoline (the product of Example 68) do.

Example 81

7-fluoro-8- (3-methyl-1-piperazinyl) -4H-quinolizin-4-one-3-carboxylic acid hydrochloride

Chloropicoline was converted to 3-bromo-4-chloro-5-fluoro-picoline (the product of Example 68) according to the procedure described in step 2 of Example 62 and Example 65, 2-methylpiperazine to give the title compound.

Example 82

8- (3-Amino-1-pyrrolidinyl) -9-bromo-1-ethyl-7-fluoro-4H- quinolizine-

Chloro-5-fluoro-picoline (the product of Example 68) according to the procedure described in Example 62 to give the title compound.

Example 83

(4-methylpiperazin-1-yl) -4H-quinolizine-4-one-3-carboxylic acid hydrochloride

Chloro-3, 5-difluoropicolin (the product of Example 69) according to the procedure described in step 2 of Example 62 and Example 65 to give the title compound.

Example 84

(3-methyl-1-piperazinyl) -4H-quinolizine-4-one-3-carboxylic acid hydrochloride

Following the procedure described in step 2 of Example 62 and Example 65, 4-chloropicolin was converted to 4-chloro-3,5-difluoropicolin (the product of Example 69) and N-methylpiperazine Methylpiperazine to give the title compound.

Example 85

8- (3-Amino-1-pyrrolidinyl) -7,9-difluoro-1-ethyl-4H-quinolizin-4-one-3-carboxylic acid hydrochloride

Chloro-3, 5-difluoropicolin (the product of Example 69) according to the procedure described in Example 62 to give the title compound.

Example 86

7-fluoro-8- (4-methylpiperazin-l-yl) -4H-quinolizin-4-one-3-carboxylic acid hydrochloride

Following the procedure described in step 2 of Example 62 and Example 65, 4-chloropicoline was converted to 4-chloro-5-fluoropicoline (the product of Example 66) and ethyl iodide was replaced with cyclopropyl iodo Id to give the title compound.

Example 87

7-fluoro-8- (3-methyl-1-piperazinyl) -4H-quinolizin-4-one-3-carboxylic acid hydrochloride

Following the procedure described in step 2 of Example 62 and Example 65, 4-chloropicoline was converted to 4-chloro-5-fluoropicoline (the product of Example 66) and ethyl iodide was replaced with cyclopropyl iodo The title compound is prepared by replacing N-methylpiperazine with 1-methylpiperazine according to the procedure described in Example 65. &lt; RTI ID = 0.0 &gt;

Example 88

8- (3-Amino-1-pyrrolidinyl) -1-cyclopropyl-7-fluoro-4H-quinolizine-

Chloro-5-fluoropicolin (the product of Example 66) and replacing ethyl iodide with cyclopropyl iodide according to the procedure described in Example 62 to give the title compound .

Example 89

7-fluoro-8- (4-methylpiperazin-l-yl) -4H-quinolizin-4-one-3-carboxylic acid hydrochloride

Following the procedure described in steps 1 and 2 of Example 62, 4-chloropicolin was converted to 3, 4-dichloro-5-fluoropicoline (the product of Example 66) Ethyl iodide into cyclopropyl iodide, the title compound is prepared.

Example 90

7-fluoro-8- (3-methyl-1-piperazinyl) -4H-quinolizin-4-one-3-carboxylic acid hydrochloride

4-Chloropyricoline was converted to 3, 4-dichloro-5-fluoropicoline (the product of Example 67) following the procedure described in Example 62 Steps 1 and 2, and ethyl iodide was treated with cyclopropyl iodide The title compound was prepared according to the procedure described in example 65 substituting N-methylpiperazine with 2-methylpiperazine.

Example 91

8- (3-Amino-1-pyrrolidinyl) -9-chloro-1-cyclopropyl-7-fluoro-4H- quinolizine-

Chloropicoline was converted to 3, 4-dichloro-5-fluoropicoline (the product of Example 67) and ethyl iodide was replaced with cyclopropyl iodide according to the procedure described in Example 62 to give the title compound .

Example 92

7-fluoro-8- (4-methylpiperazin-l-yl) -4H-quinolizin-4-one-3-carboxylic acid hydrochloride

Following the procedure described in steps 1 and 2 of Example 62, 4-chloropicolin was converted to 3-bromo-4-chloro-5-fluoropicoline (the product of Example 68) Iodide into cyclopropyl iodide, the title compound is prepared.

Example 93

7-fluoro-8- (3-methyl-1-piperazinyl) -4H-quinolizin-4-one-3-carboxylic acid hydrochloride

4-Chloropyridine was converted to 3-bromo-4-chloro-5-fluoropicoline (the product of Example 68) following the procedure described in Example 62 Steps 1 and 2 and ethyl iodide was converted to cyclopropyl Iodide and replacing N-methylpiperazine with 2-methylpiperazine according to the procedure described in Example 65 to give the title compound.

Example 94

8- (3-amino-1-pyrrolidinyl) -9-bromo-1-cyclopropyl- 7-fluoro-4H- quinolizin-

Following the procedure described in Example 62, 4-chloropicoline was converted to 3-bromo-4-chloro-5-fluoropicoline (the product of Example 68) and the ethyl iodide was converted to cyclopropyl iodide The title compound is prepared.

Example 95

7-Difluoro-8- (4-methylpiperazin-l-yl) -4H-quinolizin-4-one-3-carboxylic acid hydrochloride

According to the procedure described in steps 1 and 2 of Example 62, 4-chloropyridine was converted to 4-chloro-3,5-difluoropicoline (the product of Example 69) Iodide into cyclopropyl iodide, the title compound is prepared.

Example 96

7-Difluoro-8- (3-methyl-1-piperazinyl) -4H-quinolizin-4-one-3-carboxylic acid hydrochloride

Following the procedure described in steps 1 and 2 of Example 62, 4-chloropicoline was converted to 4-chloro-3,5-difluoropicoline (the product of Example 69) and ethyl iodide was converted to cyclopropyl Methylpiperazine according to the procedure of Example 65 to obtain the title compound.

Example 97

8- (3-Amino-1-pyrrolidinyl) -1-cyclopropyl-7,9-difluoro-4H-quinolizin-4-one-3-carboxylic acid hydrochloride

Chloropicoline was converted to 4-chloro-3,5-difluoropicoline (the product of Example 69) according to the procedure described in Example 62 and ethyl iodide was changed to cyclopropyl iodide to give the title compound .

Example 98

7-Fluoro-l-methylamino-8- (4-methylpiperazin-l-yl) -4H- quinolizin-4-one-3-carboxylic acid hydrochloride

Step 1. Preparation of 4-chloro-5-fluoro-alpha-bromo-2-picoline

The product of Example 66, 4-chloro-5-fluoro-2-picoline (2.9 g, 20 mmol) is dissolved in 50 ml of 1,2-dichloroethane in a dry flask. The resulting solution was heated to 75 캜 with stirring, 4.09 g (23 mmol) of N-bromosuccinimide was added, and then 100 mg (0.7 mmol) of 2,2-azobisisobutyronitrile (AIBN), which is a free radical initiator, do. The reaction mixture is stirred at 75 &lt; 0 &gt; C for 24 hours, then diluted with 450 ml of methylene chloride and washed with 400 ml of water. The organic layer is separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dried in vacuo to give 3.5 g (69% yield) of the title compound as a yellow oil; _{^{1 H NMR (CDCl 3) d}} 4.50 (s, 2H), 7.54 (d, 1H), 8.44 (s, 1H).

Step 2. 4-Chloro-5-fluoro-2- (N-methylaminomethyl) -pyridine

4-Chloro-5-fluoro-alpha-bromo-2-picoline (1.37 g, 6.1 mmol) from step 1 is dissolved in 15 ml of methanol in a vacuum tube. Methylamine (3 ml of 40% aqueous solution) is added to the tube and passed through a tube. The reaction mixture is stirred at ambient temperature for 26 hours and then the solvent is removed under reduced pressure. To the residue is added 50 ml of a 10% aqueous sodium carbonate solution and the resulting aqueous mixture is extracted with 3 x 50 ml of methylene chloride. The combined organic extracts are dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Dry the residue under vacuum to give 754 mg (70% yield) of the title compound; _{MS DCI-NH 3 M / Z} : 175 (M + H) + base; ¹ H NMR (CDCl ₃ )? 2.50 (s, 3H), 3.90 (s, 3H), 3.90 (s, 2H), 7.47 (d, 1H), 8.42

Step 3. N- (4-Chloro-5-fluoro-2-pyridyl) methyl-N-methyl-N- (2,2-dimethylethyl-formamidine

4-Chloro-5-fluoro-2- (N-methylaminomethyl) -pyridine (650 mg, 3.72 mmol) from step 2 is dissolved in 15 ml of toluene. 2.3 ml (15 mmol) of N, N-dimethyl-N- (2,2, -dimethylethyl) -formamide was added to the resulting solution, and 40 mg (0.3 mmol) of ammonium sulfate was added. The reaction mixture is heated to reflux temperature for 28 hours with stirring and then cooled to ambient temperature. The solvent was removed under reduced pressure and the residue was dried in vacuo to give 560 mg (59% yield) of the title compound; _{MS DCI-NH 3 M / Z} : 175 (M + H) + 73%, 203 ((M + H) -Cl-F) + base; _{^{1 H NMR (CDCl 3) d}} 1.17 (s, 3H), 1.19 (s, 9H), 2.83 (d, 2H), 4.47 (s, 1H), 7.43 (d, 1H, J = 3Hz), 8.40 (dd , 1H, J = 3 Hz, 1.5 Hz).

Step 4. Diethyl 2-ethoxy-3- (5-fluoropyridin-2-yl) -3- [N-methyl- N- (2,2- dimethylethyl) methylamino] - dicarboxylate

Lithium diisopropylamide (LDA: 16 ml of a 1.5M solution in hexane) is added to 8 ml of anhydrous THF under a nitrogen atmosphere and the resulting solution is cooled to -70 DEG C in an isopropyl alcohol / dry ice bath. To a cooled LDA solution was added a solution of N- (4-chloro-5-fluoro-2-pyridyl) methyl-N-methyl- N- (2,2- dimethylethyl) -formamidine

3.41 g (19.6 mmol) of a solution is added dropwise over 30 minutes. The solution is stirred at -70 &lt; 0 &gt; C for 0.5 h, then a solution of 4.04 ml (19.6 mmol) ethoxymethylenemalonate in 18 ml dry THF is added dropwise over 30 min. The reaction solution changes from dark red to orange. After stirring at -70 ° C for 0.5 hour, the reaction solution is warmed to -20 ° C and stirred at -20 ° C for 1 hour. The reaction is quenched 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 methylene chloride and the organic extract is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound.

Step 5. Diethyl 2-ethoxy-3- (5-fluoropyridin-2-yl) -3-methylamino-propane-1, 1 -dicarboxylate

3- (5-fluoropyridin-2-yl) -3- [N-methyl-N- (2,2-dimethylethyl) methylamino] -Dicarboxylate, 16 mmol of hydrazine and 6 ml of glacial acetic acid are heated to 50 &lt; 0 &gt; C under nitrogen in 20 ml of 95% ethyl alcohol for about 15 hours. Upon cooling, the solvent is removed in vacuo and the residue is extracted with diethyl ether. The ether solution was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound.

Step 6. Preparation of ethyl 8-chloro-7-fluoro-1-methylamino-4H-quinolizine-

80 ml of Dow Therm A ^R in a three-necked flask equipped with a thermometer, dropping funnel and air cooling condenser is heated to 235 ° C using a heating mantle under a nitrogen atmosphere. Dow term A 45ml ^R-3- (pyridin-2-yl 5-fluoro) to diethyl 2-from step 5 in the 3-dimethylamino-propane-1,1-dicarboxylate 3.9g (12.4mmol ) Solution is added dropwise over 1.5 hours to a Dautum A ^R under heating and stirring through a dropping funnel. After the addition, the resulting solution is heated to ~ 200 ° C for 1 hour and then cooled to ambient temperature. The solution is poured into 500 ml of hexane to form a precipitate. The precipitate was collected by filtration, washed with 5X100 ml of hexane and dried to give the title compound.

Step 7. Preparation of ethyl 7-fluoro-l-methylamino-8- (4-methylpiperazin-l-yl) -4H- quinolizine-

Step 6 The product, ethyl 8-chloro-7-fluoro-1-methylamino-4H-quinolizin-4-one-3-carboxylate (899 mg, 3.0 mmol) is dissolved in 12 ml of anhydrous pyridine under a nitrogen atmosphere. 6.0 ml (6.0 mmol) of N-methylpiperazine are added to the resulting solution, and the reaction mixture is heated at 70 占 폚 for 8 hours. The reaction mixture is concentrated under vacuum to remove all pyridine. The anhydrous residue is dissolved in 125 ml of methylene chloride and the methylene chloride solution is washed with 125 ml of brine. The aqueous layer was extracted with 125 ml of methylene chloride and the combined methylene chloride solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound.

Step 8. 8- (4-Methylpiperazin-l-yl) -4H-quinolizin-4-one-3-carboxylic acid hydrochloride

1-methylamino-8- (4-methylpiperazin-l-yl) -4H-quinolizin-4-one-3-carboxylate from step 7 ) And 16.5 ml of 0.5 N aqueous sodium hydroxide solution are heated at 75 占 폚 for 8 hours with stirring. The THF is removed from the reaction mixture by distillation during the reaction. The concentrated reaction mixture is cooled to ambient temperature and adjusted to pH 2.0 with 10.5 ml of a 1N aqueous hydrochloric acid solution. The aqueous solution is concentrated in vacuo to remove about 80% of the water and the concentrate is diluted with 50 ml of 95% ethyl alcohol. The solid was collected by filtration, washed with 2 x 5 ml of ethyl alcohol and dried under vacuum to give the desired product.

Examples 99 to 116

Examples 99 to 116 were carried out as described in Table 3, replacing the N-methylpiperazine of step 7 with the appropriate amine as indicated in accordance with the procedure described in example 98, &Lt; / RTI &gt;

[Table 3]

* Amines are protected and deprotected as described in Example 58. &lt; RTI ID = 0.0 &gt;

Example 117

7,9-difluoro-l-methylamino-8- (4-methylpiperazin-l-yl) -4H-quinolizine-

Chloro-5-fluoro-2-picoline (the product of Example 66) was reacted with 4-chloro-3,5-difluoro-2-picoline (example 69 Of the title compound). &Lt; / RTI &gt;

Examples 118 to 135

Chloro-5-fluoro-2-picoline (the product of Example 66) was reacted with 4-chloro-3,5-difluoro-2-picoline (example 69 And the N-methylpiperazine was replaced with the appropriate amine as shown, to give Examples 118 to 135 as described in Table 4 to give the compounds of formula &Lt; / RTI &gt;

[Table 4]

* Amines are protected and deprotected as described in Example 58. &lt; RTI ID = 0.0 &gt;

Example 136

1-ethyl-8- (4-methylpiperazin-1-yl) -6,7,9-trifluoro-4H-quinolizine-

Step 1. 3,4,5,6-Tetrafluoro-2-picoline

2,3,4,5,6-Pentafluoropyridine (Aldrich Chemical Co.) is oxidized to the corresponding N-oxide according to the procedure described in Example 66, Step 6. 2,3,4,5,6-pentafluoropyridine N-oxide is treated with one equivalent of methyl magnesium iodide in diethyl ether at ambient temperature (F. Binns and H. Suschitsky in Chemical Communications, 750-751 (1970) and J Chem Soc (C), 1223-1231 (1971)]. The reaction mixture is treated with aqueous ammonium chloride and extracted with diethyl ether. The ether solution was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the crude product was subjected to silica gel chromatography to obtain 2-methyl-3,4,5,6-tetrafluoropyridine N-oxide (3,4,5,6 -Tetrafluoro-2-picoline). &Lt; / RTI &gt; N-oxide was reduced to the procedure described in step 8 of Example 66 to give the title compound.

Step 2. Preparation of 2-propyl-3,4,5,6-tetrafluoropyridine

A solution of LDA 1.5 in hexane (100 ml, 150 mmol) is cooled to -60 캜 in an isopropyl alcohol / dry ice bath. To a stirred LDA solution under nitrogen is added dropwise a solution of 22.617 g (137 mmol) of 3,4,5,6-tetrafluoro-2-picoline from step 1 in 80 ml of anhydrous THF over a period of 0.5 hours. The reaction mixture is stirred at -70 &lt; 0 &gt; C for 0.5 h, then a solution of 10.95 ml (137 mmol) of ethyl iodide in 30 ml of anhydrous THF is added dropwise over 20 minutes. The reaction mixture is stirred at -60 &lt; 0 &gt; C for 0.5 h, then the cooling bath is slowly warmed to -30 &lt; 0 &gt; C for 1.5 h. 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 concentrated in vacuo. The residue is distilled to give the title compound.

Step 3. Diethyl 2-ethoxy-3- [3,4,5,6-tetrafluoro-2-pyridyl] -pentane-1,1-dicarboxylate

A solution of 12.6 ml (89.9 mmol) diisopropylamine in 20 ml anhydrous tetrahydrofuran (THF) is prepared under nitrogen atmosphere and cooled in an ice / water bath. To this solution was added 36 ml of a 2.5 M solution of n-butyllithium (90 mmol) in hexane through a syringe. The solution is stirred at 0 &lt; 0 &gt; C for 30 min and then cooled to -60 &lt; 0 &gt; C. To a solution of the amine at -60 占 폚, 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 is added dropwise over 30 minutes. The resulting solution was stirred at -60 &lt; 0 &gt; C for 0.5 h, and 16.55 ml (81.9 mmol) of ethyl 2-carboxyethoxy-3-ethoxy-2-propenecarboxylate was added dropwise over 30 minutes. Stirring is continued at -60 &lt; 0 &gt; C for 0.5 hour. The reaction mixture is poured into cold brine and the aqueous mixture is extracted with methylene chloride. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give 35.48 g of the title compound. The next step is carried out without further purification of the product.

Step 4. Ethyl 1-ethyl-6,7,8,9-tetrafluoro-4H-quinolizin-4-one-3-carboxylate

A solution of 40.61 g (99.2 mmol) of diethyl 2-ethoxy-3- [4-chloro-2-pyridyl] -pentane-1,1-dicarboxylate from step 3 in 1 L of xylene Lt; / RTI &gt; and concentrated in vacuo. The residue is washed with a mixture of hexane and cyclohexane to give the title compound.

Step 5. Preparation of ethyl 1-ethyl-8- (4-methylpiperazin-l-yl) -6,7,9-trifluoro-4H-quinolizine-

Ethyl-6,7,8,9-tetrafluoro-4H-quinolizine-4-one-3-carboxylate (317 mg, 1.0 mmol) from step 4 was treated with anhydrous And dissolved in 5 ml of pyridine. 2 ml (2.0 mmol) of N-methylpiperazine is added to the resulting solution, and the stirred reaction mixture is heated at 85 DEG C for 2.5 hours. The reaction mixture is cooled to ambient temperature and concentrated under vacuum to remove all pyridine. The residue is dissolved in 50 ml of methylene chloride and the methylene chloride solution is washed with 50 ml of 5% aqueous sodium bicarbonate. The aqueous layer was extracted with 3X50 ml of methylene chloride, and the combined methylene chloride solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to dryness to give the title compound.

Step 6. l-Ethyl-8- (4-methylpiperazin-l-yl) -6,7,9-trifluoro-4H-quinolizin-

To a solution of ethyl 1-ethyl-8- (4-methylpiperazin-l-yl) -6,7,9-trifluoro-4H-quinolizine-3-carboxylate from step 5 Is added 4.0 ml of 1.0 N aqueous sodium hydroxide solution and the reaction mixture is heated to 75 [deg.] C with stirring for 4.5 hours. The reaction mixture is cooled to ambient temperature and adjusted to pH 2 with 5 ml of 1 N aqueous hydrochloric acid solution. The aqueous solution is concentrated in vacuo to about 5 ml and the solid is collected by filtration and dried under vacuum to give the title compound.

Example 137

8- (3-Amino-1-pyrrolidinyl) -l-ethyl-6,7,9-trifluoro-4H- quinolizin-4-one-3-carboxylic acid hydrochloride

Step 1. Preparation of ethyl 8- (3- (Nt-butoxycarbonyl) amino-1-pyrrolidinyl) -l-ethyl-6,7,9- trifluoro-4H- quinolizine- 3-carboxylate

Ethyl 6,7,8,9-tetrafluoro-1-ethyl-4H-quinolizin-4-one-3-carboxylate from step 3 of Example 136 (1.26 g, 3.97 mmol) And dissolved in 20 ml of anhydrous pyridine. To the resulting solution is added a solution of 1.85 g (9.92 mmol) of 3- (N-t-butoxycarbonylamino) pyrrolidine in 5 ml of anhydrous pyridine and the reaction mixture is heated to 70 ° C for 4.5 hours. The reaction mixture is concentrated under vacuum to remove all pyridine. The anhydrous residue (3.124 g) was purified by silica gel chromatography to give the title compound.

Step 2. A mixture of 8- (3-amino-1-pyrrolidinyl) -l-ethyl-6,7,9-trifluoro-4H- quinolizine-

To a solution of ethyl 8- (3- (Nt-butoxycarbonyl) amino-1-pyrrolidinyl) -l-ethyl-6,7,9-trifluoro-4H -Quinolizin-4-one-3-carboxylate in 10 ml of dichloromethane is stirred at ambient temperature for 2 hours. TFA is evaporated in vacuo and the residue is dissolved in 200 ml of methanol. 4.5 g of a strong base ion exchange resin is added to the resulting solution, and the mixture is stirred at ambient temperature for 1 hour. The mixture was filtered and the filtrate was concentrated under reduced pressure to give crude ethyl 8- (3-amino-1-pyrrolidinyl) -1-ethyl-6,7,9-trifluoro-4H-quinolizin- 3-carboxylate is obtained as a residue. The residue is dissolved in 5 ml of TFH and 11 ml of a 1 M aqueous sodium hydroxide solution are added. The reaction mixture is heated at 60 ° C for 1 hour and then the reaction temperature is raised to 85 ° C to evaporate the THF. The concentrated reaction solution is diluted with 20 ml of water and the pH of the resulting solution is adjusted to 0 with concentrated hydrochloric acid. The aqueous solution is concentrated under vacuum. The residue was crystallized from ethyl alcohol: isopropyl alcohol: water (4: 4: 1 v / v / v) and recrystallized from ethyl alcohol / water to give the title compound.

Example 138

Amino-pyrrolidinyl) -4H-quinolizine-4-one-3-carboxylic acid

3-amino-1-benzylpyrrolidine (I. Sumio and T. Matsu, JP Kokai JP 5328161, 1978, 3, 16) was reacted with Nt-butoxy Is coupled to carbonyl norvaline (Boc-nVal). The 1-benzyl group is removed by hydrogenolysis in methanol using a palladium / carbon catalyst. Subsequently, 3- (Nt-butoxycarbonylamino) pyrrolidine was converted to 3- (N-Boc-norballyl) aminopyrrolidine as described in step 1 of Example 137 to give 3- (N-Boc -Norvalyl) aminopyrrolidine with ethyl 6,7,8,9-tetrafluoro-1-ethyl-4H-quinolizine-4-one-3-carboxylate to give the nitrogen of the amino acid as a Boc group Amino-pyrrolidinyl) -4H-quinolizine-4-one-3-carboxylic acid. The Boc protecting group is removed by standard hydrolysis with trifluoroacetic acid and dilute aqueous hydrochloric acid.

Other amino acid derivatives of the compounds of the invention having amino groups can be prepared using the procedures outlined in Example 138 or other conventional condensation methods listed above. Examples of amino acids that may be coupled alone or in combination with other amino acids include synthetic amino acids such as cyclohexyl alanine, cyclohexyl glycine, aminopenanoic acid, and the like, as well as natural amino acids such as glycine, alanine, leucine, isoleucine, methionine, phenylalanine, .

Examples 139 to 155

Examples 139 to 155 were prepared according to the procedures described in Example 136 or Example 137, substituting N-methylpiperazine or 3- (Nt-butoxycarbonylamino) pyrrolidine with the appropriate amine as shown in Table 5 Lt; RTI ID = 0.0 &gt;

&Lt; / RTI &gt;

[Table 5]

* Amines are protected and deprotected as described in Example 58. &lt; RTI ID = 0.0 &gt;

Example 156

Dihydro-7-fluoro-12-methyl-8- (4-methyl-1-piperazinyl) -4H-pyrano [ - carboxylic acid

Step 1. Preparation of 4-chloro-3,5-difluoro-2- (1- (2-tetrahydropyranyl) oxy-2-

A solution of 12.8 g (150 mmol) of 2-chloro-1-propanol is dissolved in 200 ml of acetone. 40 g of anhydrous iron chloride and 30 g (200 mmol) of sodium iodide are added to the resulting solution. The reaction mixture is stirred at room temperature for 24 hours and then filtered to remove sodium chloride. Evaporation of the solvent affords the corresponding 2-iodo-1-propanol. The iodoalcohol is dissolved in 200 ml of methylene chloride and treated with 20.5 ml (225 mmol) of 3,4-dihydro-2H-pyran and 50 mg of p-toluenesulfonic acid. The reaction mixture is stirred at room temperature for several hours and 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 give THP-protected 2-iodo-1-propanol.

A solution of 4-chloro-3,5-difluoro-2-methylpyridine (16.5 g, 100 mmol) in 150 ml of anhydrous THF is treated with 73 ml of 1.5 M lithium diisopropylamine (LDA) at -78 < . After stirring at -78 ° C for 30 minutes, a solution of 27.0 g (100 mmol) of THP-protected 1-iodo-2-propanol in 150 ml of THF is added dropwise with stirring. The reaction mixture is stirred at -78 &lt; 0 &gt; C for several hours and then slowly warmed to -20 &lt; 0 &gt; C. The reaction mixture is quenched by pouring into 400 ml of a saturated aqueous ammonium chloride solution. The aqueous layer is separated and extracted with methylene chloride. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound.

Step 2. Preparation of 4-chloro-3,5-difluoro-2- (1-hydroxy-2-propyl)

The product of Step 1 is dissolved in 2: 1 THF: water (200 ml) and to the solution is added 6 ml of acetic acid. The reaction mixture is heated to 45 &lt; 0 &gt; C for about 5 hours. The THF is removed under reduced pressure and the aqueous reaction mixture is adjusted to pH 8-9 with 10% sodium carbonate and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound.

Step 3. 8-Chloro-3,4-dihydro-7-fluoro-3-methyl-2H-pyrano [3,2- b]

The product of Step 2 (15.5 g, 75 mmol) is dissolved in 100 ml of anhydrous THF in an oven drying system under a positive nitrogen atmosphere. The reaction mixture is cooled with ice and 3.2 g (80 mmol) of 60% sodium hydride are added. The reaction mixture is allowed to warm to room temperature and then heated overnight with stirring at reflux temperature. The reaction mixture is cooled to room temperature and poured into brine. The aqueous mixture is extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound.

Step 4. Synthesis of diethyl 2- (8-chloro-3,4-dihydro-7-fluoro-3-methyl-2H-pyrano [3,2- b] pyridin- -1,1-ethanedicarboxylate

The product of step 3 is treated with ethyl 2-carboethoxy-3-ethoxy-2-propenecarboxylate and LDA according to the procedure described in step 2 of Example 62 to give the title compound.

Step 5. Preparation of ethyl 8-chloro-11,12-dihydro-7-fluoro-12-methyl-4H-pyrano [i, j] quinolin-

The product of step 4 is heated under reflux with Dowtherm ^R according to the procedure described in step 3 of Example 62 to give the desired percolated product.

Step 6. Preparation of ethyl 11,12-dihydro-7-fluoro-12-methyl-8- (4-methyl- 1- piperazinyl) -4H- pyrano [ 3-carboxylate

The product of Step 5 is reacted with N-piperazine according to the procedure described in Step 1 of Example 65 to give the title compound.

Dihydro-7-fluoro-12-methyl-8- (4-methyl-1-piperazinyl) -4H-pyrano [ Carboxylic acid

The title compound is prepared according to the procedure described in step 2 of Example 65.

Example 157

6-oxo-pyrido [l, 2-a] pyrimidine-7-carboxylic acid hydrochloride &lt; EMI ID =

Step 1. 2-Cyclopropyl-2-ethoxycarbonyl acetamidine hydrochloride

To a stirred solution of ethyl 2-cyano-2-cyclopropyl acetate in 17.7 ml (0.303 mmol) of anhydrous ethanol under anhydrous N ₂ atmosphere [RWJ Carney and J. Wojtkunski, Org. Prep. Proced. Int., 5, 25 (1973)], 10.0 g (0.274 mmol) of gaseous hydrogen chloride are introduced while cooling with ice. The mixture is warmed to room temperature and left for 72 hours. The reaction is diluted with 100 ml of absolute ethanol and 70 ml of ammonia in ethanol (4.17 M) is slowly added at room temperature, and the reaction is stirred for 3 hours. The reaction mixture was filtered to remove ammonium chloride and the solvent removed to give the title compound as an off-white oil which was used directly in the next step.

Step 2. A mixture of 2-cyclopropyl-2- (5-fluoro-4-hydroxypyrimidin-2-yl) acetic acid methyl ester and 2-cyclopropyl-2- (5-fluoro-4-hydroxypyrimidine Yl) acetic acid ethyl ester

0.253 mol of the compound from Step 1 in 250 ml of anhydrous methanol, the sodium salt of ethyl 2-fluoro-3-hydroxy-2-propenoate (see E. Elkik and M. Imbeaux-Oudotte, Bull. Soc. Chim. Fr., 5-6 pt 2, prepared according to 1165 (1975)] and 37.0 ml (0.256 mol) of triethylamine are heated under reflux for 17 hours under anhydrous N ₂ atmosphere. The solvent is removed, 200 ml of water are added, and the residue is acidified to pH 5 with acetic acid. The mixture is extracted with methylene chloride. The extract is washed with water, dried over anhydrous magnesium sulfate and the solvent is evaporated in vacuo to give a dark brown oil. The product was purified by silica gel chromatography eluting with 1: 1 ethyl acetate: hexanes to give methyl ester 22.8 g of the title compound as a pale yellow viscous oil and ethyl ester 6.45 g of the title compound as a pale yellow viscous oil.

Methyl ester: MS M / Z: 227 (M + H) &lt; + &gt;; _{NMR (CDCl 3) d 0.43 (} 1H, m), 0.52 (1H, m), 0.65 (1H, m), 0.77 (1H, m), 1.42 (1H, m), 2.97 (1H, d, J = 10Hz ), 3.80 (3H, s), 7.88 (1H, d, J = 3 Hz), 11.8 (1H, b). IR: (neat) 1740, 1690, 1615 cm &lt; ^-1 &gt;. Anal. Calcd. C ₁₀ H ₁₁ FN ₂ O ₃ .1 / 4H ₂ O: C, 52.06; H, 5.02; N, 12.14. Found C, 52.45; H, 4.94; N, 11.76.

Ethyl ester: MS M / Z: 258 ( M + NH 4); _{NMR (CDCl 3) d 0.47 (} 1H, m), 0.54 (1H, m), 0.66 (1H, m), 0.74 (1H, m), 1.31 (3H, t, J = 7Hz), 1.34 (1H, m ), 2.96 (1H, d, J = 10 Hz), 4.27 (2H, m), 7.83 (1H, d, J = 3 Hz), 11.0 (1H, IR: (neat) 1735, 1682, 1605 cm &lt; ^-1 &gt;. Anal. Calcd. C ₁₁ H ₁₃ FN ₂ O ₃ .0.3H ₂ O: C, 53.78; H, 5.58; N, 11.40. Found C, 54.05; H, 5.59; N, 11.11.

Step 3. 2-Cyclopropyl-2- (5-fluoro-4-hydroxypyrimidin-2-yl) acetaldehyde

Step in 40ml of toluene was stirred under a dry N ₂ atmosphere at -70 ℃ methyl ester of the compound from 2 4.960g 1N diisobutylaluminum of the (21.9mmol) aluminum solution in toluene and the hydride 46.0ml (46mmol). The reaction is stirred for 40 minutes and then quenched by the addition of 5 ml of acetic acid. The mixture is allowed to warm to room temperature and the reaction is extracted with ethyl acetate. The extract was washed with water (3X), dried over anhydrous magnesium sulfate and concentrated in vacuo to give 2.230 g of the title compound as a white solid. This compound is used immediately in the next step.

MS M / Z: 227 (M + NH 4); _{NMR (CDCl 3) d 0.48 (} m, 2H), 0.91 (m, 2H), 1.35 (m, 1H), 7.40 (d, 1H, J = 10Hz), 7.55 (d, 1H, J = 4Hz), 9.61 (br s, 1 H), 13.64 (d, 1 H, J = 10 Hz). IR: (KBr) 1695, 1660, 1635 cm ^-1 .

Step 4. Synthesis of 9-cyclopropyl-3-fluoro-2-hydroxy-6H-6-oxo-pyrido [l, 2-a] pyrimidine-7-carboxylic acid benzyl ester

2.230 g (11.37 mmol) of the compound sample from step 3 are dissolved in 100 ml of absolute ethanol. 3.5 ml (14.00 mmol) of dibenzylmalonate, 2.5 ml of piperidine and 0.25 ml of acetic acid are added. Heating for 3 hours under reflux conditions and the reaction mixture under a dry N ₂ atmosphere and stirred to room temperature overnight. The solvent is removed by evaporation and the residue is dissolved in methylene chloride, washed with water and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation in vacuo and purified by silica gel chromatography eluting with 1: 5: 100 acetic acid: methanol: methylene chloride. Removal of the solvent gave 1.800 g of the title compound as a light yellow solid. mp 225.5-226.5 [deg.] C. MS M / Z: 355 (M + H); _{NMR: (CDCl 3) d 0.64} (m, 1H), 1.08 (m, 2H), 1.62 (m, 1H), 5.37 (s, 2H), 7.35-7.48 (m, 5H), 8.28 (s, 1H) , 9.00 (d, 1H, J = 6 Hz), IR: (KBr) 1720, 1770, 1690 cm- ¹ . Anal. Calcd. C ₁₉ H ₁₅ FN ₂ O ₄ .1 / 4H ₂ O: C, 63.60; H, 4.35; N, 7.81. Found C, 63.54; H, 4.08; N, 7.78.

6-oxo-pyrido [l, 2-a] pyrimidine-7-carboxylic acid benzyl ester

In the compound 0.200g (0.564mmol), DMF 0.50ml, 0.60ml room temperature, phosphorus oxychloride and mixture of 10ml of methylene chloride under a dry N ₂ atmosphere from step 4 and stir for 4 hours. Ice is added to react with excess phosphorus oxychloride. The mixture was dissolved in methylene chloride, washed with water and the solvent was dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation in vacuo to give the title compound as an orange residue. This compound is used immediately in the next step.

Step 6. Preparation of 2- (3-Nt-butoxycarbonyl) aminopyridin- l-yl) -9-cyclopropyl-3-fluoro-6H-6-oxo-pyrido [ -7-carboxylic acid benzyl ester

0.564 mmol of the compound sample from the previous step is dissolved in 5 ml of anhydrous methylene chloride and cooled to 0 &lt; 0 &gt; C. To this solution was added 0.45 g of 3- (Nt-butoxycarbonyl) aminopyrrolidine and the reaction mixture was stirred overnight at room temperature. The solvent was removed by evaporation in vacuo and the product was purified by silica gel column chromatography, eluting with 10% methanol in methylene chloride to give 0.295 g of the title compound as a yellow solid. mp 159-160 [deg.] C. MS M / Z: 523 (M + H) +; _{NMR: (CDCl 3) d 0.60} (m, 2H), 1.46 (s, 2H), 1.46 (s, 9H), 1.90-2.40 (m, 1H), 3.70-4.45 (m, 5H), 4.94 (br s 2H), 7.99 (br s, 1H), 9.10 (d, 1H, J = 10 Hz) , IR: (KBr) 1715, 1685, 1660 cm ^-1 . Anal. Calcd. C ₂₈ H ₃₁ FN ₄ O ₅ .1 / 2H ₂ O: C, 63.44; H, 6.08; N, 10.57. Found C, 63.39; H, 6.13; N, 10.83.

6-oxo-pyrido [l, 2-a] pyridin-3-yl] Pyrimidine-7-carboxylic acid

0.135 g (0.259 mmol) of a benzyl ester sample from Step 6 in 20 ml of methanol and 2 ml of THF are added with 2.0 ml of 98% formic acid and 0.05 g of 10% Pd / C. The mixture is filtered off and the solvent is removed in vacuo. The crude product was purified by silica gel column chromatography eluting with 1: 5: 100 acetic acid: methanol: methylene chloride to remove the solvent to yield the title compound as a yellow solid. This product is used immediately in the next step.

Step 8. 2- (3-Aminopyrrolidin-l-yl) -9-cyclopropyl-3-fluoro-6H-6-oxo-pyrido [l, 2-a] pyrimidine- Chloride

D is reacted with 4H 10ml HCl in dioxane for three hours the previous step the compound sample under a dry N ₂ atmosphere at room temperature. Solvent is removed and the yellow solid is dissolved in distilled water. The yellow solution was filtered and lyophilized to afford 0.0681 g of the title compound as a yellow solid. mp 234 [deg.] C (dec.). MS &lt; / RTI &gt; M / Z 333 (M-Cl). _{NMR: (CDCl 3) d 0.64} (m, 2H), 0.96 (m, 2H), 2.20-2.65 (m, 3H), 3.85-4.35 (m, 5H), 7.80 (d, 1H, J = 10Hz), 9.05 (br s, 1 H), IR (KBr) 1665, 1620 ^-1 .

Example 158

6-oxo-pyrido [l, 2-a] pyrimidine-7-carboxylic acid

Step 1. 9-Cyclopropyl-3-fluoro-2-hydroxy-6H-6-oxo-pyrido [l, 2-a] pyrimidine-7- carboxylic acid tert- butyl ester

0.247 g (1.262 mmol) of the 2-cyclopropyl-2- (5-fluoro-4-hydroxypyrimidin-2-yl) acetaldehyde sample from step 3 was dissolved in 20 ml ethanol and ethyl t-butyl 0.290 ml of malonate, 0.5 ml of piperidine and 0.05 ml of acetic acid are added. Heat the reaction to reflux for 25 hours under a dry N ₂ atmosphere and to remove by evaporating the solvent the product was 1: 10: 100 acetic acid: methanol: eluting with methylene chloride and purified by silica gel column chromatography. Removal of the solvent gave 0.287 g of the title compound as a light yellow solid. mp 265 [deg.] C. MS &lt; / RTI &gt; M / Z 321 (M + H). _{NMR: (CDCl 3 + CD 3} OD) d 0.61 (m, 2H), 1.06 (m, 2H), 1.58 (s, 9H), 1.72 (m, 1H), 8.07 (s, 1H), 8.93 (d, 1H, J = 6 Hz). IR (KBr) 1720, 1525 cm &lt; ^-1 &gt;.

Step 2. 2-Chloro-9-cyclopropyl-3-fluoro-6H-6-oxo-pyrido [1,2- a] pyrimidine- 7- carboxylic acid tert-butyl ester

Compound from step 1 0.100g (0.312mmol), DMF 0.29ml , followed by stirring for 1 hour at room temperature, 0.33ml of phosphorus oxychloride and the mixture of 10ml of methylene chloride under a dry N ₂ atmosphere. After workup as described in example 157 step 5, the title compound is obtained as an orange solution in methylene chloride. This compound is used immediately in the next step.

Step 3. Synthesis of 2- (3- (Nt-butoxycarbonyl) aminopyrrolidin-l-yl) -9-cyclopropyl-3-fluoro-6H-6-oxo-pyrido [ ] Pyrimidine-7-carboxylic acid tert-butyl ester

Add 3- (N-t-butoxycarbonyl) aminopyrrolidine in small portions to 0.312 mmol of the sample in methylene chloride from the previous step at room temperature until the reaction solution changes from orange to light yellow. The solution is concentrated to leave a yellow residue. The product was purified by silica gel column chromatography eluting with 10: 100 methanol: methylene chloride to give 0.132 g of the title compound as a yellow solid after solvent removal. This compound is used immediately in the next step.

6-oxo-pyrido [l, 2-a] pyrimidine-7-carboxylic acid

The boc-protected t- butyl ester from step 4 is hydrogenated by reacting the sample with 4N HCl 1ml 0.132g in dioxane under a dry N ₂ atmosphere. The solvent is removed and the yellow solid is dissolved in water, the solution is adjusted to pH 7-8 and extracted with methylene chloride. Since the reaction is incomplete at this point, the solid is redissolved in 5 ml of trifluoroacetic acid and the reaction is stirred overnight at room temperature. The solvent is removed by evaporation. The residue was redissolved and extracted as before and the product purified by silica gel column chromatography with 2: 5: 20: 10 water: acetic acid: methanol: methyl chloride to yield 0.0515 g of the title compound as a yellow solid.

Example 159

6H-6-oxopyrido [l, 2-a] pyrimidin-7 (4-fluorophenyl) - carboxylic acid

Step 1. Preparation of 2- (2,4-difluorophenyl) -acetamidine hydrochloride

To a solution of 49.44 g (0.323 mol) of 2,4-difluorophenylacetonitrile (commercially available) in 20.8 ml (0.354 mol) of ethanol cooled at 0 ° C. with an ice bath and stirring under anhydrous N ₂ atmosphere was added 14.61 g 0.400 mol) is added. When the reaction mixture solidifies after 20 minutes, it is warmed to room temperature and maintained at this temperature for 72 hours. To the mixture is then added 140 ml of ethanol and then 150 ml (0.42 mol) of 4.2M ammonia in ethanol is added. The mixture is further stirred at room temperature for 3 hours and filtered. The solvent was evaporated and the filtrate was concentrated to give 65.7 g of the title compound as a white solid. mp 163-164 [deg.] C. 1H NMR (DMSO-d6) d 3.72 (s, 2H), 7.16 (m, IH), 7.33 (m, IH), 7.50 (m, This compound is used immediately in the next step.

Step 2. Preparation of 2- (2,4-difluorobenzyl) -5-fluoro-4-hydroxypyrimidine

(0.33 mol) of the compound from Step 1, sodium salt of ethyl 2-fluoro-3-hydroxy-2-propenoate (see E. Elkik and M. Imbeaux-Oudotte, Bull . Soc, made according to Chim, Fr., 5-6 pt 2, 1165 (1975)] is heated at reflux for 23 hours and the mixture of tree and 0.34mol ethylamine 50ml under a dry N ₂ atmosphere. The solvent is removed by evaporation in vacuo, 200 ml of water are added and the mixture is acidified to pH 3-4 with 10% HCl. The mixture is extracted with methylene chloride. The extract is washed with water, dried over anhydrous magnesium sulphate and the solvent is evaporated in vacuo to give a thick oil which solidifies. The solid was washed with ethyl acetate, ethyl acetate / hexane and hexane to give 29.8 g of the title compound as a white solid. mp 155-156 [deg.] C. A second crop of 10.2 g of product was obtained from the filtrate by silica gel chromatography eluting with 2.5% methanol in methylene chloride. MS M / Z: 258 (M = NH 4), 241 (M + H). _{NMR (CDCl 3) d 4.02 (} s, 2H), 6.88 (m, 2H), 7.33 (m, 1H), 7.89 (d, 1H, J = 3Hz), IR (KBr) 1690, 1605cm -1. Anal. Calcd. C ₁₀ H ₁₁ FN ₂ O: C, 55.00; H, 2.94; N, 11.67. Found C, 54.63; H, 2.98; N, 11.50.

Step 3. Preparation of 4-chloro-2- (2,4-difluorobenzyl) -5-fluoropyrimidine

Methylene chloride of the compound from Step 2 in 15ml 1.000g (4.16mmol), was stirred at ambient temperature for 2 hours a mixture of DMF 3.40ml (43.7mmol) of phosphorus oxychloride and 3.90ml (43.7mmol) under a dry N ₂ atmosphere and then Quench the reaction by adding water and ice. The mixture is extracted with methylene chloride, washed with water, dried, filtered and concentrated to give the title compound as a yellow oil. MS m / z: 259 (M + H). _{NMR (CDCl 3) d 4.27 (} s, 2H), 6.83 (m, 2H), 7.27 (m, 1H), 8.48 (s, 1H). This compound is used immediately in the next step.

Step 4. Preparation of 2- (2,4-difluorobenzyl) -5-fluoro-4- (4-methylpiperazin-1-yl) pyrimidine

And stirred for 1 hour and the mixture was added N- methyl-piperidine in 3ml 4.16mmol compound from Step 3 in methylene chloride 10ml at room temperature under a dry N ₂ atmosphere. The solvent is removed by evaporation and the product is purified by silica gel column chromatography, eluting with 5% methanol in methylene chloride. The solvent was removed by evaporation to give 1.228 g of the title compound as a pale yellow oil. MS m / z: 323 (M + H). _{NMR: (CDCl 3) d 2.32} (s, 2H), 2.46 (t, 4H, J + 7Hz), 3.75 (t, 4H, J = 7Hz), 4.05 (s, 2H), 6.80 (m, 2H), 7.25 (m, 1 H), 7.99 (d, 1 H, J = 7 Hz). Anal. Calcd. C ₁₆ H ₁₇ F ₃ N ₄ : C, 59.61; H, 5.32; N, 17.38. Found C, 59.63; H, 5.31; N, 17.31.

Step 5. Preparation of 3- (2,4-difluorophenyl) -2-ethoxy-3- (5-fluoro-4- Carboxylic acid diethyl ester

Following the procedure of example 1 step 4, the compound from the previous step 4 (0.74 g, 2.3 mmol), 1.0 ml (2.5 mmol) of a 2.5M solution of n-butyllithium in hexane and 0.35 ml of diisopropylamine were added to a solution of ethyl 2- Carbonatoethoxy-3-ethoxy-2-propenecarboxylate to give 1.22 g of the title compound as an oil after work-up. This material was purified by silica gel column chromatography eluting with 5% ethanol in ethyl acetate to give 0.774 g of oil; MS m / z: 539 (M + H). _{NMR: (CDCl 3) 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, IH), 4.99 (m, IH), 6.78 (m, 2H), 7.59 (m,

Step 6. Synthesis of 9- (2,4-difluorophenyl) -3-furooro-2- (4-methylpiperazin- 1 -yl) -6H-6-oxopyrido [ Pyrimidine-7-carboxylic acid ethyl ester

Is heated with absolute ethanol for 3 hours with a Dean-piperidin added 1.5ml and 0.05ml of acetic acid in the reaction sample compound 1.847g (3.43mmol) from step 5 was dissolved in 40ml under a dry N ₂ atmosphere under reflux conditions. Remove the solvent was evaporated and a yellow solid 0.5: 10: to afford after evaporation of the solvent was purified by silica gel chromatography eluting with methylene chloride, the title compound 1.282g as a yellow solid: 100 28% aq. NH ₄ OH: methanol.

Analytical Calculation C ₂₂ H ₂₁ F ₃ N ₄ O ₃ .0.5H ₂ O; C, 58.02; H, 4.87; N, 12.30. Found C, 58.15; H, 4.70; N, 12.15.

Step 7. Synthesis of 9- (2,4-difluorophenyl) -3-fluoro-2- (4-methylpiperazin-l-yl) -6H-6-oxopyrido [ Methyl-7-carboxylic acid benzyl ester

1.166 g (2.61 mmol) of the ethyl ester compound sample from Step 1. 150ml of anhydrous benzyl alcohol and a mixture of titanium tetra-methoxide 0.5ml to reflux conditions with stirring under a dry N ₂ atmosphere and heated for 17 hours. The solvent is removed by distillation at 100 &lt; 0 &gt; C under reduced pressure with a Cuggel apparatus. The product was 0.5: 10: 100 28% aq. NH ₄ OH: methanol: and eluted with methylene chloride to give the silica gel chromatography to give the title compound 0.895g as a yellow solid after removal of the solvent.

Step 8. Synthesis of 9- (2,4-difluorophenyl) -3-fluoro-2- (4-methylpiperazin-l-yl) -6H-6-oxopyrido [ Methyl-7-carboxylic acid

0.300 g (0.590 mmol) of the benzyl ester sample from step 7 are dissolved in 40 ml of anhydrous methanol and 0.1 g of 10% palladium on carbon are added. 98% formic acid was added to 4ml and the mixture was stirred for 20 minutes under a dry N ₂ atmosphere the mixture. The crystals are removed by filtration through diatomaceous earth and the solvent is removed under vacuum. The product was purified by silica gel column chromatography eluting with 1: 10: 100 acetic acid: methanol: methylene chloride to give a yellow solid. This material was washed with pH 7.5 sodium bicarbonate solution and washed with water to give 0.178 g of the title compound as a yellow solid.

Analytical Calculation C ₂₀ H ₁₇ F ₃ N ₄ O ₃ ; C, 57.42; H, 4.10; N, 13.39. Found C, 57.21; H, 4.08; N, 13.21.

Example 160

(2,4-difluorophenyl) -3-fluoro-6H-6-oxopyrido [l, 2-dicarboxylic acid 2-a] pyrimidine-7-carboxylic acid

Step 1. Preparation of 3- (2,4-difluorophenyl) -2-ethoxy-3- (5-fluoro-4- hydroxypyrimidin- ester

A solution of 4.804 g (20.0 mol) of the sample in 150 ml of anhydrous THF was added to a solution of 2- (2,4-difluorobenzyl) -5-fluoro-4-hydroxypyrimidine (prepared as described in example 159 step 2) and cooled to -78 ℃ under a dry N ₂ atmosphere with stirring. To this is slowly added 16.40 ml of 2.5N n-butanol in hexane and the mixture is stirred for 30 minutes. 4.85 ml (24 mmol) of diethylethoxymethylenemalonate are then added and the mixture is stirred at -78 [deg.] C for a further 30 minutes. The reaction mixture is quenched by addition of 10% HCl until the pH of the mixture is 3 and extracted with ethyl acetate. This was dried over anhydrous magnesium sulfate and the solvent was removed by evaporation in vacuo to afford the title compound as a yellow oil. This material is used in the next step.

Step 2. Synthesis of 9- (2,4-difluorophenyl) -3-fluoro-2-hydroxy-6H-6-oxopyrido [l, 2-a] pyrimidine-

Step dissolved compounds from 1 to 80ml of ethanol and heated to reflux for 16 hours with 2ml piperidine and the mixture was added to 0.2ml of acetic acid under a dry N ₂ atmosphere. (Bath temperature 90 ℃). The solvent was removed by evaporation and the residue was washed with methanol and methylene chloride to give 4.794 g of a light yellow solid. The wash water was concentrated and the residue was purified by silica gel column chromatography eluting with 2: 10: 100 acetic acid: methanol: methylene chloride to yield 2.220 g of the additional title compound as a light yellow solid.

Step 3. Synthesis of 9- (2,4-difluorophenyl) -3-fluoro-2-hydroxy-6H-6-oxopyridor [1,2- a] pyrimidine- 7-carboxylic acid benzyl ester

Was added to the titanium tetra-ethoxide 0.7ml ethyl ester 7.000g sample from Step 2 was dissolved in 200ml of benzyl alcohol with stirring and the mixture is heated for 2.5 hours at 100 ℃ under a dry N ₂ atmosphere. The reaction is diluted with methylene chloride, washed once with 1N HCl, three times with water, the solvent is dried over anhydrous magnesium sulfate and evaporated off under vacuum. This material was washed with ether and dried under vacuum to afford 6.655 g of the title compound as a yellow solid. mp 218-219 [deg.] C

Step 4. Preparation of 2- (3- (Nt-butoxycarbonyl) aminopyrrolidin- 1 -yl) -9- (2,4-difluorophenyl) -3-fluoro-6H- [1,2-a] pyrimidine-7-carboxylic acid benzyl ester

1.200 g (2.815 mmol) of the combined cool sample from step 3 are dissolved in 45 ml of methylene chloride and 2.50 ml of DMF and 2.95 ml of POCl _{3 are} added. The reaction mixture was stirred at room temperature under a dry N ₂ atmosphere for 2.5 hours and then quenched with ice water and reaction. The mixture is extracted with methylene chloride and the solvent is washed with water to ensure that the acidity of the water wash is above pH 3. The solvent is dried over magnesium sulfate and reacted with an excess of 2- (Nt-butoxycarbonylamino) pyrrolidine. The solution was concentrated and the product was subjected to silica gel column chromatography, eluting with 0.5: 5: 100 concentrated ammonium hydroxide: methanol: methylene chloride to give 1.579 g of the title compound as a light yellow crystalline solid.

Step 5. Preparation of 2- (3- (Nt-butoxycarbonyl) aminopyrrolidin- 1 -yl) -9- (2,4-difluorophenyl) -3-fluoro-6H- [1,2-a] pyrimidine-7-carboxylic acid

1.769 g of the compound sample from Step 4 of Example 4 are dissolved in 80 ml of anhydrous methanol and the benzyl ester is removed by reacting with 4.0 ml of 98% formic acid in the presence of 0.200 g of 10% Pd / C under anhydrous N ₂ atmosphere. After filtration, the solvent was evaporated and the product was purified by silica gel column chromatography eluting with 1: 10: 100 acetic acid: methanol: methylene chloride to give 1.125 g of the title compound as a yellow solid.

Example 161

6H-6-oxopyrido [l, 2-a] pyrimidine-lH- 7-carboxylic acid

Example 160 Preparation of 2- (3- (Nt-butoxycarbonyl) -aminopyrrolidin- 1 -yl) -9- (2,4-difluorophenyl) -3-fluoro-6H 6-oxo-pyrido [1,2-a] pyrimidine-7-carboxylic acid sample 0.100g (0.198mmol) was dissolved in a small amount of 4N HCl in dioxane and stirred at room temperature for 3 hours under a dry N ₂ atmosphere. The solvent is removed by evaporation in vacuo to give a yellow solid which is dissolved in water and neutralized to pH 7 with 5% sodium bicarbonate. The resulting precipitate was filtered off, washed with water and dried to give 0.075 g of the title compound as a yellow solid.

Analytical Calculation C ₁₉ H ₁₅ F ₃ N ₄ O ₃ · 1.25 H ₂ O; C, 53.46; H, 4.07; N, 13.12. Found: C, 53.64; H, 3.70; N, 12.80.

Example 162

6H-6-oxopyrido [l, 2-a] pyrimidine-lH- 7-carboxylic acid trifluoroacetic acid salt

Fluorophenyl) -3-fluoro-6H-6-oxopyrido [l, 2-d] pyrimidin- a] pyrimidine-7-carboxylic acid sample are dissolved in 10 ml of trifluoroacetic acid and the excess acid is removed by evaporation under vacuum. The yellow residue is dissolved in 600 ml of water containing 1 ml of trifluoroacetic acid and the solution is filtered through sintered glass and lyophilized to give 0.876 g of the title compound as a light yellow solid.

Anal. Calcd. C ₂₁ H ₁₆ F ₆ N ₄ O ₅ .H ₂ O: C, 47.02; H, 3.38; N, 10.45. Found: C, 47.36; H, 3.07; N, 10.36.

Example 163

6-oxo-pyrido [l, 2-a] pyrimidine-7-carboxylic acid benzyl ester

Step 1. 2-Chloro-9-cyclopropyl-3-fluoro-6H-6-oxo-pyrido [l, 2-a] pyrimidine-7-carboxylic acid benzyl ester

Prepared as described in example 157 step 4 from 9-cyclopropyl-3-fluoro-2-hydroxy-6H-6-oxo- pyrido [l, 2-a] pyrimidine- 7- carboxylic acid benzyl ester 0.100g of sample was added to 5ml of methylene chloride, DMF and 0.275ml 0.33ml of phosphorus oxychloride in the reaction (0.282mmol) at room temperature under a dry N ₂ atmosphere and stirred for 5 hours. The solution is cooled to 0 ° C and ice is added to break excess phosphorus oxychloride. The mixture is extracted with methylene chloride and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation in vacuo to afford the title compound as an orange solid. _{NMR (CDCl 3): d 4.27} (s, 1H), 6.83 (m, 2H), 7.27 (m, 2H), 8.48 (s, 1H). This material is used in the next step.

Step 2. Synthesis of 9-cyclopropyl-3-fluoro-2- (4-methylpiperazin-l-yl) -6H-6-oxo-pyrido [1,2- a] pyrimidine-

The pre-staged compound is dissolved in 2.5 ml of methylene chloride and 0.5 ml of N-methylpiperazine is added. The reaction is stirred overnight at room temperature. The solvent is removed by evaporation and the product is purified by silica gel column chromatography, eluting with 10% methanol in methylene chloride. Removal of the solvent gave 0.107 g of the title compound as a yellow solid. Recrystallization from methanol gives yellow needle crystals.

mp 194-195 [deg.] C. MS &lt; / RTI &gt; M / Z 437 (M + H).

Anal. Calcd. C ₂₄ H ₂₅ FN ₄ O ₃ .1 / 4H ₂ O: C, 65.37; H, 5.83; N, 12.70. Found: C, 65.21; H, 5.53; N, 12.59.

Step 3. Synthesis of 9-cyclopropyl-3-fluoro-2- (4-methylpiperazin-l-yl) -6H-6-oxo-pyrido [l, 2-a] pyrimidine-

To 0.050 g (0.115 mmol) of a benzyl ester compound sample from the previous step, 10 ml of methanol. 98% formic acid and 0.04 g of 10% Pd / C are added and the mixture is stirred under argon for 30 minutes at room temperature. The solution is diluted with methylene chloride, filtered through diatomaceous earth and the solvent is removed to give a yellow residue. The product is purified by silica gel chromatography eluting with 1: 10: 100 acetic acid: methanol: methylene chloride. After removal of the solvent, 0.0345 g of the title is obtained as a yellow solid.

Anal. Calcd. C ₁₇ H ₁₉ FN ₄ O ₃ .06 CH ₃ COOH: C, 57.17; H, 5.64; N, 14.65. Found: C, 57.60; H, 5.79; N, 14.13.

Example 164

6-oxo-pyrido [l, 2-a] pyrimidine-7-carboxylic acid

Step 1. 2-Chloro-9-cyclopropyl-3-fluoro-2-hydroxy-6H-6-oxo-pyrido [l, 2-a] pyrimidine-

(0.312 mmol) of 9-cyclopropyl-3-fluoro-6H-6-oxo-pyrido [l, 2-a] pyrimidine-7-carboxylic acid tert- butyl ester from step 1, DMF 0.33ml, stirred for 1 hour at room temperature, 0.33ml of phosphorus oxychloride and the mixture of 10ml of methylene chloride under a dry N ₂ atmosphere. The title compound is obtained as an orange solution in methylene chloride after work-up as described in example 157 step 5 and used directly in the next step.

Step 2. Synthesis of 9-cyclopropyl-3-fluoro-2- (piperazin-l-yl) -6H-6-oxo-pyrido [l, 2-a] pyrimidine-7-carboxylic acid tert-

Added dropwise in methylene chloride piperazine 0.289g yongek in methylene scroll fluoride 10ml stirring the sample under a dry N ₂ atmosphere from step 1 in 5ml. The resulting yellow solution was concentrated to give a yellow residue which was purified by silica gel column chromatography eluting with 0.5: 10: 100 concentrated ammonium hydroxide: methanol: methylene chloride to afford 0.068 g of the title compound as a yellow solid after solvent removal. This material is used in the next step.

Step 3. Synthesis of 9-cyclopropyl-3-fluoro-2- (piperazin-1-yl) -6H-6-oxo-pyrido [1,2- a] pyrimidine-

Then 4N HCl 10ml and react overnight at room temperature in DI samples under a dry N ₂ atmosphere dioxane Compound from the previous step. Solvent is removed and the yellow solid is dissolved in distilled water, adjusted to pH 7-8 with saturated sodium carbonate solution and the solution is extracted with methylene chloride. The extract was washed with water, dried, concentrated and subjected to silica gel chromatography to obtain 0.043 g of the title compound as a yellow solid.

mp 198-199 [deg.] C. MS &lt; / RTI &gt; M / Z 333 (M + H).

Anal. Calcd. C ₁₆ H ₁₇ FN ₄ O ₃ .0.1H ₂ O: C, 57.36; H, 5.20; N, 16.72. Found: C, 57.69; H, 5.22; N, 16.31.

Example 165

6-oxo-pyrido [l, 2-a] pyrimidine-7-carboxylic acid

Step 1. Synthesis of 9-cyclopropyl-3-fluoro-2- (morpholin-1-yl) -6H-6-oxo-pyrido [1,2- a] pyrimidine-

Example 164 prepared as in Step 1, was dissolved in dry methylene chloride was cooled to 0 ℃ in a 2-Inclusion stirred under a dry N ₂ atmosphere-9-cyclopropyl-3-fluoro--6H-6- oxo- Pyrido [l, 2-a] pyrimidine-7-carboxylic acid benzyl ester (0.0396 mmol). The color changes from orange to yellow and the reaction is terminated at 15 minutes. The solvent was removed by evaporation and the product was purified by silica gel column chromatography eluting with 2: 10: 100 acetic acid: methanol: methylene chloride. Removal of the solvent gave the title compound as a yellow solid. This is used in the next step.

Step 2. Synthesis of 9-cyclopropyl-3-fluoro-2- (morpholin-1-yl) -6H-6-oxo-pyrido [

The benzyl ester product from the previous step is dissolved in 20 ml of anhydrous methanol and stirred with 0.020 g of 10% Pd / C catalyst under 1 atm hydrogen at room temperature for 5 hours. The catalyst is removed by filtration and the solvent is removed in vacuo to afford 0.100 g of the title compound as a yellow solid.

mp 260 ° C

Anal. Calcd. C ₁₆ H ₁₆ FN ₃ O ₄ .H ₂ O: C, 54.70; H, 5.16; N, 11.96. Found: C, 55.01; H, 4.71; N, 11.62.

Example 166

Yl) -6H-6-oxo-6-oxo-6-oxo- Pyrido [l, 2-a] pyrimidine-7-carboxylic acid hydrochloride

Step 1. Synthesis of 2- (3-aminopyrrolidin-1-yl) -9- (2,4-difluorophenyl) -3-fluoro-6H-6-oxopyrido [ Pyrimidine-7-carboxylic acid benzyl ester

Example 160 Preparation of 9- (2,4-difluorophenyl) -3-fluoro-2- (3- (Nt-butoxycarbonyl) aminopyrrolidin- 6-oxo-pyrido [1,2-a] pyrimidine-7-carboxylic acid benzyl ester of 1.579g (2.655mmol) was dissolved in 5ml of trifluoroacetic acid and stirred at room temperature for 1 hour under a dry N ₂ atmosphere. The solvent is removed by evaporation in vacuo and the deprotected title compound is obtained as a yellow solid which is used directly in the next step. Mp 185-186 [deg.] C. _{NMR (CDCl 3) d 1.75-2.19 (} m, 2H), 3.33-4.07 (m, 5H), 5.38 (s, 2H), 6.87 (m, 2H), 7.32 (m, 4H), 7.48 (m, 2H ), 8.33 (s, 1H), 9.13 (apparent d, 1H, J = 9 Hz).

Step 2. Preparation of 2- (3- (N- (N-benzyloxycarbonyl) norvaline) aminopyrrolidin- 1 -yl) -9- (2,4- difluorophenyl) -3-fluoro- 6H-5-oxopyrido [l, 2-a] pyrimidine-7-carboxylic acid benzyl ester

Samples from the previous step are suspended in 50 ml of THF and diisopropylethylamine is added with stirring at room temperature until a homogeneous solution is formed. Then N- benzyloxycarbonyl protected (S) - Stir for norvaline succinimide is added and the mid 0.885g (2.66mmol) 1 hour at room temperature under a dry N ₂ atmosphere. 0.050 g of another protected norvaline is added and the solution is stirred for 0.5 hour. The reaction is diluted with methylene chloride and washed with water (4X), the organic solvent is dried over anhydrous magnesium sulfate and evaporated off under vacuum. This product was purified by silica gel column chromatography eluting with 5% methanol in methylene chloride to yield 1.678 g of the title compound as a yellow crystalline solid after solvent removal.

Mp 103-105 ° C

Anal. Calcd. C ₃₉ H ₃₆ F ₃ N ₅ O ₆ .0.25 H ₂ O: C, 63.97; H, 5.02; N, 9.56. Found: C, 64.19; H, 5.11; N, 9.50.

Step 3. Synthesis of 9- (2,4-difluorophenyl) -3-fluoro-2- (3- (N- (S-norvaline) aminopyrrolidin- Pyrido [l, 2-a] pyrimidine-7-carboxylic acid hydrochloride

1.515 g (2.0822 mmol) of the compound from the previous step is dissolved in 80 ml of methanol and 4.0 ml of 98% formic acid and 0.2 g of 10% Pd / C are added. The mixture was stirred at room temperature for 1.7 hours under a dry N ₂ atmosphere, filtered, and concentrated to give a yellow solid residue. The solid is dissolved in methanol and filtered through sintered glass and then the solvent is removed to give a yellow solid. This solid is dissolved in 50 ml of methanol and 3 ml of concentrated HCl is added to evaporate the solvent. The residue is dissolved in 200 ml of water and filtered through re-sintered glass and the solution is lyophilized to give 0.969 g of the title product as a yellow solid.

Anal. Calcd. C ₂₄ H ₂₅ F ₃ N ₅ O ₄ .2H ₂ O: C, 50.05; H, 5.07; N, 12.06. Found: C, 50.00; H, 4.56; N, 12.03.

Example 167

(2,4-difluorophenyl) -3-fluoro-6H-6-oxopyrido &lt; / RTI &gt; [L, 2-a] pyrimidine-7-carboxylic acid benzyl ester

Step 1. Preparation of 2- (3- (N-benzyloxycarbonyl) -alaninyl) aminopyrrolidin-l-yl) -9- (2,4- difluorophenyl) -3-fluoro- Oxopyrido [l, 2-a] pyrimidine-7-carboxylic acid benzyl ester

Example 166 By the reaction and treatment in the same manner as in Example 1 using 4- (2,4-difluorophenyl) -3-fluoro-2- (3-aminopyrrolidin- 0.982 g (1.986 mmol) of the pyrido [l, 2-a] pyrimidine-7-carboxylic acid benzyl ester sample are suspended in 40 ml of THF and 0.700 g (2.196 mmol) of N-benzyloxycarbonyl protected (S) Is added. At room temperature the mixture under a dry N ₂ atmosphere and stirred for 2 hours. The reaction solvent is evaporated and the residue is dissolved in methylene chloride and washed with water (3X). The organic solvent is dried over anhydrous magnesium sulfate and removed by evaporation under vacuum. The product was purified by silica gel column chromatography eluting with 5% methanol in methylene chloride to give after evaporation of the solvent 1.318 g of the title compound as a yellow crystalline exchange.

Anal. Calcd. C ₃₇ H ₃₂ F ₃ N ₅ O ₆ .1 / 2H ₂ O: C, 62.71; H, 4.69; N, 9.88. Found: C, 63.04; H, 4.49; N, 9.92%.

Step 2. Synthesis of 2- (3- (N- (S) -alaninyl) aminopyrrolidin- 1 -yl) -9- (2,4- difluorophenyl) -3-fluoro- Oxopyrido [l, 2-a] pyrimidine-7-carboxylic acid hydrochloride

1.262 g (1.804 mmol) of the compound from the previous step is suspended in 80 ml of methanol, 4.0 ml of 98% formic acid and 0.200 g of 10% Pd / C are added with stirring. The mixture was stirred for 1.7 hours at room temperature and then the mixture stirred for 0.3 hours under a dry N ₂ atmosphere a filtered, and concentrated to give a yellow solid residue. This is dissolved in 500 ml of water, 4 ml of concentrated HCl is added, the solution is filtered through sintered glass and lyophilized to give 0.877 g of the title compound as a yellow solid.

Anal. Calcd. C ₂₂ H ₂₁ ClF ₃ N ₅ O ₄ .1.5H ₂ O: 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) -alaninyl) aminopyrrolidin- 1 -yl) -9- (2,4- difluorophenyl) -3-fluoro -6H-6-oxopyrido [l, 2-a] pyrimidine-7-carboxylic acid hydrochloride

Step 1. Preparation of 2- (3- (N- (N-benzyloxycarbonyl) - (S) -alaninyl) - (S) -alaninylaminopyrrolidin- Difluorophenyl) -3-fluoro-6H-6-oxopyrido [l, 2-a] pyrimidine-7- carboxylic acid benzyl ester

Example 166 By the reaction and treatment in the same manner as in Example 1 using 4- (2,4-difluorophenyl) -3-fluoro-2- (3-aminopyrrolidin- Pyrido [1,2-a] pyrimidine-7-carboxylic acid benzyl ester (0.905 g, 1.830 mmol) were dissolved in DMF (10 ml) and N-benzyloxycarbonyl protected (S) mmol). The mixture is stirred at 0 占 폚 and 0.530 g of 1-ethyl-3- [3-dimethylaminopropyl] carbodiimide hydrochloride (EDAC) and 0.370 g of 1-hydroxybenzotriazole hydrate (HOBT) are added. The mixture is stirred at 0 &lt; 0 &gt; C for 30 minutes and then at room temperature for 2 hours. The solvent is removed with a Cugelro apparatus and the residue is dissolved in methylene chloride, washed twice with water, twice with saturated sodium bicarbonate solution, then twice with water and dried over magnesium sulfate. The solvent was removed by evaporation and the product was purified by silica gel column chromatography, eluting with 10% methanol in methylene chloride to give 1.187 g of the title compound as yellow crystalline.

Anal. Calcd. C ₄₀ H ₃₇ F ₃ N ₆ O ₇ · 1 / 2H ₂ O: C, 61.62; H, 4.91; N, 10.78. Found: C, 61.51; H, 4.71; N, 10.75.

Step 2. Preparation of 2- (3- (N- (S) -alaninyl) - (S) -alaninyl) aminopyrrolidin- 1 -yl) -9- (2,4- difluorophenyl) -3 6-oxopyrido [l, 2-a] pyrimidine-7-carboxylic acid hydrochloride

1.131 g (1.467 mmol) of the compound sample from the previous step is dissolved in 80 ml of methanol, 4.0 ml of 98% formic acid and 0.2 g of 10% Pd / C are added. Stirred at room temperature for 1 hour under a dry N ₂ atmosphere the mixture was filtered, and concentrate to give a yellow solid residue. This is dissolved in 500 ml of distilled water, 3 ml of concentrated HCl is added, the solution is filtered through sintered glass and lyophilized to give 0.729 g of the title compound as a light yellow solid.

mp 217-219 [deg.] C (dec.).

Example 169

2-methylpyrrolidin-1-yl) -9- (2,4-difluorophenyl) -3-fluoro-6H-6-oxo Pyrido [l, 2-a] pyrimidine-7-carboxylic acid

Step 1. Synthesis of 2 - ((2S, 4S) -4-acetamido-2-methylpyrrolidin- 1 -yl) -9- (2,4- difluorophenyl) -3-fluoro- Oxopyrido [l, 2-a] pyrimidine-7-carboxylic acid benzyl ester

6-oxopyrido [l, 2-a] pyrimidine-7-carboxylic acid benzyl ester from step 3 0.200 g (0.469 mmol) of the ester sample is dissolved in 5 ml of methylene chloride and 0.42 ml of DMF and 0.49 ml of POCl _{3 is} added. The reaction stirred for 3.5 hours at room temperature under a dry N ₂ atmosphere, and then quenched with water and ice. The mixture is extracted with methylene chloride and the solvent is washed with water such that the acidity of the wash water is above pH 3. The solvent was dried over magnesium sulfate and added to a solution of (2S, 4S) -4-acetamido-2-methylpyrrolidine [Rosen, T., et al., J. Med. Chem., 31, 1598-1611 (1988)] and 2 ml of triethylamine were added to react. The solution is then concentrated and the product is purified by silica gel column chromatography eluting with 1: 10: 100 acetic acid: methanol: methylene chloride. Removal of the solvent gave 0.205 g of the title compound as yellow crystals.

Anal. Calcd. C ₂₉ H ₂₅ F ₃ N ₄ O ₄ .H ₂ O: C, 61.26; H, 4.79; N, 9.85. Found: C, 61.59; H, 4.37; N, 9.72.

Step 2. Preparation of 2 - ((2S, 4S) -4-acetamido-2-methylpyrrolidin- 1 -yl) -9- (2,4- difluorophenyl) Oxopyrido [l, 2-a] pyrimidine-7-carboxylic acid

To 0.198 g (0.359 mmol) of the compound sample from Step 1 in 20 ml of methanol are added 1 ml of 98% formic acid and 0.1 g of 10% Pd / C. The mixture is stirred at room temperature for 1.25 h under a dry N ₂ atmosphere. The mixture is filtered and the filtrate is concentrated to give a yellow residue. The product was purified by silica gel column chromatography eluting with 1: 10: 100 acetic acid: methanol: methylene chloride to yield 0.126 g of the title compound as a yellow solid after solvent removal.

Anal. Calcd. C ₂₂ H ₁₉ F ₃ N ₄ O ₄ .H ₂ O: C, 55.23; H, 4.42; N, 11.71. Found: C, 55.25; H, 4.20; N, 11.21.

Example 170

6H-6-oxopyrido [l, 2-a] pyrimidine &lt; EMI ID = -7-carboxylic acid

Step 1. Synthesis of 9- (2,4-difluorophenyl) -3-fluoro-2- (3-hydroxypyrrolidin-1-yl) -6H-6-oxopyrido [ ] Pyrimidine-7-carboxylic acid benzyl ester

Example 160 Preparation of 9- (2,4-difluorophenyl) -3-fluoro-2-hydroxy-6H-6-oxopyrido [1,2- a] pyrimidine- 0.200 g (0.469 mmol) of benzyl ester is dissolved in 5 ml of methylene chloride and 0.42 ml of DMF and 0.49 ml of POCl _{3 is} added. The reaction stirred for 3.5 hours at room temperature under a dry N ₂ atmosphere, and then quenched with water and ice. The mixture is extracted with methylene chloride and the solvent is washed with water such that the acidity of the wash water is above pH 3. The solvent is dried over magnesium sulfate and 0.1 ml of 3-pyrrolidinol is added to react. The solution is then concentrated and the product is purified by silica gel column chromatography eluting with 1: 10: 100 acetic acid: methanol: methylene chloride. Removal of the solvent gave 0.183 g of the title compound as yellow crystals.

Anal. Calcd. C ₂₆ H ₂₀ F ₃ N ₃ O ₄ .3 / 4H ₂ O: C, 61.36; H, 4.26; N, 8.26. Found: C, 60.97; H, 3.67; N, 7.98.

Step 2. Synthesis of 9- (2,4-difluorophenyl) -3-fluoro-2- (3-hydroxypyrrolidin-1-yl) -6H-6-oxopyrido [ ] Pyrimidine-7-carboxylic acid

To 0.166 g (0.334 mmol) of the compound from Step 1 in 20 ml of methanol and 15 ml of DMF are added 2 ml of 98% formic acid and 0.12 g of 10% Pd / C. The mixture is stirred at room temperature for 1.33 hours under a dry N ₂ atmosphere. The mixture is filtered and the filtrate is concentrated to remove DMF with a Kugelro apparatus to give a yellow residue. The product was purified by silica gel column chromatography eluting with 1: 10: 100 acetic acid: methanol: methylene chloride to give 0.088 g of the title compound after solvent removal.

Anal Calculation C ₁₉ H ₁₄ F ₃ N ₃ O ₄ · 1 / 2H ₂ O: C, 55.08; H, 3.65; N, 10.14. Found: C, 55.10; H, 3.53; N, 10.04.

Example 171

2-methylpyrrolidin-1-yl) -9- (2,4-difluorophenyl) -3-fluoro-6H-6-oxopyrido [L, 2-a] pyrimidine-7-carboxylic acid hydrochloride

Step 1. (2S, 4S) -4-acetamido-2-methylpyrrolidine

Rosen, T., et al., J. Med. 6.000 g of (2S, 4S) -4-acetamido-1- (t-butoxy-carbonyl) -2-methylpyrrolidine sample prepared according to the method described in J. Chem., 31, 1598-1611 24.760 mmol) is dissolved in 30 ml of 4N HCl in dioxane and stirred at room temperature for 24 hours to remove the boc group. The solvent is evaporated off to give the hydrochloride of this compound as a white solid which is used directly in the next step.

Step 2. (2S, 4S) -4-Acetamido-1-benzyl-2-methylpyrrolidine

The salt from the previous step is suspended in 27 ml of methylene chloride, 8.4 ml of triethylamine are added and the mixture is stirred for 10 minutes. 3.2 ml (26.9 mmol) of benzyl bromide are then added and the mixture is heated under reflux for 5 hours. The mixture is diluted with methylene chloride, washed with water three times, dried over magnesium sulfate and evaporated to give the 1-benzyl protected compound as a white solid which is used directly in the next step.

Step 3. (2S, 4S) -4-Amino-l-benzyl-2-methylpyrrolidine hydrochloride

The acetyl group is removed from the pre-stage compound by heating under reflux in 6N HCl for 6 hours. The solvent is removed to give a solid product which is used in the next step.

Step 4. (2S, 4S) -l-Benzyl-4-t-butoxycarbonylamino-2-methylpyrrolidine

The sample from the previous step is dissolved in 10 ml of water and 35 ml of methanol. 5.2 ml of triethylamino and 4.21 g of di-t-butyl dicarbonate were added to this stirred solution at 0 占 폚. The reaction is stirred at 0 &lt; 0 &gt; C for 2 hours and then at room temperature for 19 hours. The solvent is removed by evaporation and the residue is dissolved in methylene chloride, washed with water and concentrated. The product was purified by silica gel column chromatography eluting with 0.5: 5: 100 concentrated ammonium hydroxide: methanol: methylene chloride to afford after purification of the solvent the title compound as a white solid. This material is used in the next step.

Step 5. Synthesis of (2S, 4S) -4-t-butoxycarbonylamino-2-methylpyrrolidine

The pre-step sample is dissolved in 150 ml of methanol and 0.90 g of 10% Pd / C is added and the mixture is shaken under 4 atm of hydrogen at room temperature for 13 hours. The mixture is concentrated and the catalyst is filtered off and the solvent is removed to give 3.081 g of the title compound as a white solid.

Step 6. Preparation of 2 - ((2S, 4S) -4-t-butoxycarbonylamino-2-methylpyrrolidin- 1- yl) -9- (2,4- difluorophenyl) 6H-6-oxopyrido [l, 2-a] pyrimidine-7-carboxylic acid benzyl ester

Example 160 Preparation of 9- (2,4-difluorophenyl) -3-fluoro-2-hydroxy-6H-6-oxopyrido [1,2- a] pyrimidine- 1.500 g (3.518 mmol) of benzyl ester are dissolved in 40 ml of methylene chloride and 3.20 ml of DMF and 3.70 ml of POCl _{3 are} added. At room temperature the reaction under a dry N ₂ atmosphere and stirred for 2.25 hours, then quenched with water and ice. The mixture is extracted with methylene chloride and the solvent is washed with water such that the acidity of the wash water is above pH 3. The solvent was dried over magnesium sulfate and treated with 1.06 g (0.656 mmol) of (2S, 4S) -4-t-butoxycarbonylamino-2-methylpyrrolidine from the previous step 5 in 50 ml of methylene chloride and 7 ml of triethylamine, . The solution is concentrated and the product is purified by silica gel column chromatography eluting with 0.5: 10: 100 concentrated ammonium hydroxide: methanol: methylene chloride. Removal of the solvent gave 1.856 g of the title compound as yellow crystals.

Anal. Calcd. C ₃₂ H ₃₁ F ₃ N ₄ O ₅ .1 / 2H ₂ O: C, 62.23; H, 5.22; N, 9.07. Found: C, 62.44; H, 5.20; N, 9.16.

6- (2S, 4S) -4-Amino-2-methylpyrrolidin- 1 -yl) -9- (2,4- difluorophenyl) Oxopyrido [l, 2-a] pyrimidine-7-carboxylic acid

8 ml of 98% formic acid and 1 g of 10% Pd / C are added to 1.814 g (2.981 mmol) of the compound sample from step 6 dissolved in 80 ml of methanol and 10 ml of TMF. The mixture is stirred at room temperature for 2.3 hours under a dry N ₂ atmosphere. The mixture is filtered and the filtrate is concentrated to give a yellow residue. The product was purified by silica gel column chromatography eluting with 1: 10: 100 acetic acid: methanol: methylene chloride to yield 1.513 g of the title compound as a yellow solid after solvent removal. The compound is used immediately in the next step.

Step 8. Preparation of 2 - ((2S, 4S) -4-amino-2-methylpyrrolidin- 1 -yl) -9- (2,4- difluorophenyl) Oxopyrido [l, 2-a] pyrimidine-7-carboxylic acid hydrochloride

1.518 g of the compound sample from the previous step is dissolved in 20 ml of 4N HCl in dioxane and stirred at room temperature for 3.5 hours. The solvent is removed and the residue is redissolved in 500 ml of water, 0.5 ml of concentrated HCl is added and the solution is lyophilized to give 1.147 g of the title compound as a yellow solid.

mp 204 [deg.] C (dec.).

Anal. Calcd. C ₂₀ H ₁₈ F ₃ N ₄ O ₃ .H ₂ O: 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-oxopyrido [ -a] pyrimidine-7-carboxylic acid hydrochloride

Step 1. Preparation of 2- (2,3,4,5,6-pentafluorophenyl) -acetamidine hydrochloride

Pentafluorophenyl cooled to 0 in an anhydrous ethanol 8.30ml ℃ and stirred under a dry N ₂ atmosphere until the mixture is solidified in acetonitrile (commercially available) 26.72g (0.129mol) solution is introduced into the gas phase HCl. The reaction is allowed to stand for 96 hours, then 60 ml of ethanol and 30.7 ml of 4.2N HCl (0.124M) in ethanol are added and the slurry is stirred at room temperature for 2 hours. The mixture is filtered through sintered glass and the filtrate is concentrated in vacuo to give the title compound as a brown solid which is used directly in the next step.

Step 2. Preparation of 5-fluoro-4-hydroxy-2- (2,3,4,5,6-pentafluorobenzyl) pyrimidine

The compound from step 1 (0.129 mol), sodium salt of ethyl 2-fluoro-3-hydroxy-2-propenoate (E. Elkik and M. Imbeaux-Oudotte, Bull, Soc. Chim. Fr., 5-6 pt 2, 1165 (1975)], 150 ml of anhydrous methanol and 25 ml of triethylamine is stirred for 24 hours under an anhydrous N ₂ atmosphere. The solvent was removed by evaporation in vacuo and the residue was dissolved in methylene chloride, washed once with 10% HCl, washed once with water, dried over anhydrous magnesium sulfate, and then evaporated under vacuum to leave a solid, &Lt; / RTI &gt; The solid was washed with 1: 2 ethyl acetate: hexane to give 4.843 g of the title compound as a white solid. mp 161-162 [deg.] C. The filtrate was concentrated and extracted with 1: 4 ethyl acetate: hexane to give 4.454 g of the second crop of the product. The additional product was chromatographed to give a total yield of 19.20 g of product. MS M / Z: 312 (M + NH 4); _{NMR (CDCl 3) d 4.15 (} apparent s, 2H), 7.80 (d, 1H, J = 3Hz), 13.38 (br s, 1H), IR (KBr) 3440, 1685, 1660, 1610cm -1.

Step 3. Synthesis of 2-ethoxy-3- (5-fluoro-4-hydroxy-3- (2,3,4,5,6-pentafluorophenyl) propane-1,1-dicarboxylic acid diethyl ester

The compound from step 2 above (0.294 g, 1.00 mmol) was dissolved in 10 ml THF and cooled to -78 C with stirring, followed by 0.82 ml (2.05 mmol) of a 2.5 M solution of n-butyllithium in hexane and the resulting yellow solution Is stirred for 30 minutes. To this was added 0.243 ml (1.2 mmol) of ethyl 2-carboxyethoxy-3-ethoxy-2-propenecarboxylate with stirring for 15 minutes. The reaction is quenched with 10% HCl, warmed to room temperature and extracted with ethyl acetate. The extract is washed twice with brine, the solvent is dried over magnesium sulfate and concentrated to give the title compound as an oil which is used directly in the next step.

Step 4. Synthesis of 9- (2,3,4,5,6-pentafluorophenyl) -3-fluoro-2-hydroxy-6H-6-oxopyrido [1,2- a] pyrimidin- -Carboxylic acid ethyl ester

The compound from step 3 above is dissolved in 10 ml of ethanol, 0.2 ml of concentrated sulfuric acid is added and the solution is heated at reflux for 18 hours. The solvent was removed and the residue was washed with ether to afford 0.222 g of the title compound as a yellow solid.

Step 5. Preparation of 3-fluoro-2-hydroxy-9- (2,3,4,5,6-pentafluorophenyl) -6H-6-oxopyrido [ -Carboxylic acid benzyl ester

1.000 g (2.391 mmol) of the compound sample from Step 4 is dissolved in 25 ml of benzyl alcohol, 0.09 ml of titanium tetraethoxide is added and the mixture is stirred at 90 占 폚 for 20 hours. The reaction is diluted with methylene chloride, washed with 10% HCl (1X) and concentrated on a rotary evaporator. The crude product was purified by a Cuggel apparatus to give a yellow solid, which was washed with ether and dried to give 0.457 g of the title compound which was used in the next step.

Step 6. Preparation of 2- (3- (Nt-butoxycarbonyl) aminopyrrolidin- 1 -yl) -3-fluoro-9- (2,3,4,5,6-pentafluorophenyl) - 6H-6-oxopyrido [l, 2-a] pyrimidine-7-carboxylic acid benzyl ester

0.400 g (0.833 mmol) of the compound sample from step 5 are dissolved in 10 ml of methylene chloride and 0.746 ml of DMF, 0.870 ml of POCl ₃ is added and the mixture is stirred at room temperature for 1.7 hours under N ₂ atmosphere. The reaction is quenched with ice, the mixture is extracted with methylene chloride and washed with water (2X). The organic layer is added to a solution of 0.235 g (1.2 mmol) of stirred 2- (Nt-butoxycarbonylamino) pyrrolidine in 4 ml of triethylamine. The solvent was removed by evaporation and the product was purified by silica gel column chromatography eluting with 2.5: 100 methanol: methylene chloride. Removal of the solvent gave 0.353 g of the title product as a yellow crystalline solid.

Step 7. 2- (3- (Nt-Butoxycarbonyl) aminopyrrolidin- 1 -yl) -3-fluoro-9- (2,3,4,5,6-pentafluorophenyl) - 6H-6-oxopyrido [l, 2-a] pyrimidine-7-carboxylic acid benzyl ester

Compound samples 0.335g (0.516mmol) from Step 6 were dissolved in 40ml of dry methanol was removed by reaction with benzyl ester in anhydrous N ₂ with stirring for 0.25 hours under an atmosphere of 98%, under 10% Pd / C 0.100g presence of formic acid 2.0ml . After filtration, the solvent was evaporated and the product was purified by silica gel column chromatography eluting with 1: 15: 100 acetic acid: methanol: methylene chloride to give the title compound as a yellow solid and use immediately in the next step.

Step 8. Preparation of 2- (3-aminopyrrolidin-1-yl) -3-fluoro-9- (2,3,4,5,6-pentafluorophenyl) -6H-6-oxopyrido [ 1,2-a] pyrimidine-7-carboxylic acid hydrochloride

The pre-staged compound is dissolved in 10 ml of 4N HCl in dioxane and stirred at room temperature for 0.7 hours and the solvent is removed in vacuo. The residue is dissolved in water and filtered through sintered glass and lyophilized to give 0.232 g of the title compound as a yellow solid.

Anal. Calcd. C ₁₉ H ₁₂ F ₆ N ₄ O ₃ .HCl .0.5H ₂ O: C, 45.30; H, 2.80; N, 11.12. Found: C, 45.46; H, 2.39; N, 10.57.

Example 173

2- ((2S, 4S) -4- (N- (S) -alanyl- (S) -alanyl) amino-2-methylpyrrolidin- Fluorophenyl) -3-fluoro-6H-6-oxopyrido [l, 2-a] pyrimidine-7- carboxylic acid hydrochloride

Step 1. Preparation of 2 - ((2S, 4S) -4-amino-2-methylpyrrolidin- 1 -yl) -9- (2,4- difluorophenyl) Oxopyrido [l, 2-a] pyrimidine-7-carboxylic acid benzyl ester

Following the procedure described in step 1 of Example 166, the boc protected benzyl ester compound was reacted with 2 - ((2S, 4S) -4-t-butoxycarbonylamino-2-methylpyrrolidine Fluorophenyl) -3-fluoro-6H-6-oxopyrido [l, 2-a] pyrimidine-7- carboxylic acid benzyl ester to give boc protected The group is removed to give 1.06 g of the title compound.

Step 2. Preparation of 2 - ((2S, 4S) -4- (N- (N-benzoyloxycarbonyl) - (S) -alanyl- (S) -alaninyl) -Yl) -9- (2,4-difluorophenyl) -3-fluoro-6H-6-oxopyrido [1,2- a] pyrimidine-7-carboxylic acid benzyl ester

Following the procedure of Example 168 Step 1, the benzyl ester compound of this Example was replaced with 1.06 g of the compound from Step 1 above to yield 0.98 g of the title compound.

Amino-2-methylpyrrolidin-1-yl) -9- (2, 4-dihydro- Difluorophenyl) -3-fluoro-6H-6-oxopyrido [l, 2-a] pyrimidine-7- carboxylic acid hydrochloride

According to the procedure of Example 168 Step 2, the boc protected benzyl ester compound of this Example is replaced with the compound from Step 2 above to yield 0.66 g of the title compound.

Example 174

Fluoro-2-hydroxy-4-methyl-6H-6-oxopyrido [l, 2-a] pyrimidine-7-carboxylic acid ethyl ester

Step 1. Preparation of 2- (2,4-difluorobenzyl) -5-fluoro-4-hydroxy-6-methylpyrimidine

8.6 g (0.0445 mmol) of 2- (2,4-difluorophenyl) -acetamidine hydrochloride, prepared as in Example 159 step 1, and 8.6 g . Chem. A mixture of 6.1 g (0.0405 mmol) of ethyl-2-fluoro-3-oxo-butanoate and 10.1 ml of a 2.5% solution of sodium methoxide in 30 ml of anhydrous methanol prepared according to the procedure described in Soc., 3278 ₂ under reflux for 16 hours. The solvent is removed by evaporation in vacuo and the residue is washed with water, then 200 ml of water is added to acidify the mixture and the resulting precipitate is filtered off. The aqueous solution is extracted with methylene chloride (3X). The solvent is washed with water, dried over anhydrous magnesium sulfate and the solvent is removed by evaporation in vacuo to give a thick solid. The solid was washed with ethyl ether, dried and then combined with the precipitate first and recrystallized from methanol: ether to give 4.51 g of the title compound. MS M / Z 272 (M + NH 4). _{NMR: (CDCl 3) d 2.22} (d, 3H, J = 4Hz), 3.92 (s, 2H), 6.92 (m, 2H), 7.30 (m, 1H).

Step 2. Preparation of 3- (2,4-difluorophenyl) -2-ethoxy-3- (5-fluoro-4-hydroxy-6-methylpyrimidin- Dicarboxylic acid diethyl ester

While dissolving the compound sample 0.615g (2.42mmol) from step 1 above in THF and stirred under a dry N ₂ atmosphere and cooled to -78 ℃. To this is slowly added 1.98 ml of n-butyllithium (2.5 N) in hexane and the mixture is stirred for 30 minutes. 0.586 ml (2.9 mmol) of diethylethoxymethylenemalonate are then added at -78 [deg.] C and the mixture is stirred at room temperature for a further 15 minutes. The reaction mixture is quenched with 10% HCl until the pH of the mixture is about 3 and extracted with ethyl acetate. This was dried with magnesium sulfate and the solvent was removed by evaporation in vacuo to afford 1.6 g of the title compound as a yellow solid. This material is used in the next step.

Step 3. Synthesis of 9- (2,4-difluorophenyl) -3-fluoro-2-hydroxy-4-methyl-6H-6-oxopyrido [1,2- a] pyrimidine- Ethyl ester

The compound from Step 2 is dissolved in toluene and 0.62 ml of DBU are added and the mixture is refluxed under an anhydrous N ₂ atmosphere in a flask equipped with a Dean-Stark condenser for 16 hours. Heating is discontinued and the mixture is stirred with 70 ml of water for 2 hours. After separation, the organic layer is dried with magnesium sulfate and the solvent is removed by evaporation. The residue was purified by silica gel column chromatography eluting with 1: 5: 100 acetic acid: methanol: methylene chloride to give 0.175 g of the title compound as a yellow solid.

Examples 175 to 178

Examples 175-178 are prepared as shown in Table 6, substituting the appropriate ester for ethyl 2-fluoro-3-oxobutyrate according to the procedure described in Example 174, wherein R = ethyl and R ^&lt; = 2,4-difluorophenyl)

[Table 6]

Examples 179 to 195

Following the procedure described in Example 160 Steps 3, 4 and 5 and Example 161, substituting 2- (Nt-butoxycarbonylamino) pyrrolidine for Step 4 with the appropriate N-methyl or boc protected amine Examples 179 to 195 are prepared as described in Table 7, wherein R &^lt; ¹ &gt; = 2,4-difluorophenyl.

[Table 7a]

[Table 7b]

Implementations 196-240

According to the procedure described in steps 160, 160, and 160 of Example 160, the 2- (Nt-butoxycarbonylamino) pyrrolidine in Step 4 was converted to the appropriately substituted or boc protected amine and 9- 6-oxopyrido [l, 2-a] pyrimidine-7-carboxylic acid benzyl ester was reacted with the appropriate R &lt; ^{1 &} example 2 and replacing the example 196 to 240 of a compound containing one as described) is prepared from 39 as described in Table 8.1 to 8.3 [wherein, R ¹ is 4-fluorophenyl (Table 8.1), 2 , 4-difluorophenyl (Table 8.2) or cyclopropyl (Table 8.3) and R ⁵ is hydrogen.

[Table 8.1]

[Table 8.2]

[Table 8.3]

Examples 241 to 250

Following the procedure for Example 157 steps 2-8, 2-cyclopropyl-2-ethoxycarbonyl acetamidine hydrochloride in step 2 was converted to the corresponding R ¹ group (referred to as compound 6B in Scheme II) And replacing the 3- (Nt-butoxycarbonyl) aminopyrrolidine in Step 6 with a suitably protected amine, Examples 241 to 250 are prepared as shown in Table 9, wherein R ⁵ is hydrogen ).

[Table 9]

Examples 251 and 252

2-cyclopropyl-2-ethoxycarbonyl acetamidine hydrochloride in step 2 was reacted with 2- (N-benzoyloxycarbonyl-N-methylamino) -2- Ethoxycarbonyl acetamidine hydrochloride and replacing the 3- (Nt-butoxycarbonyl) aminopyrrolidine in Step 6 with a suitably protected amine, Examples 251 to 252 are prepared as shown in Table 10 (Wherein R &lt; ⁵ &gt; is H).

[Table 10]

Example 253

8- (3-Amino-1-pyrrolidinyl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-

Step 253a. 4-t-Butoxy-2-chloro-2,5,6-trifluoropyridine

To 250 ml of a THF solution containing 4-chloro-tetrafluoropyridine and 106 g (0.571 mmol) of 3-chloro-tetrahydropyridine (approx 70:30 ratio, Aldrich Chemical Col.) Mixture at -78 & A solution of 38.3 g (0.399 mmol) of sodium t-butoxide is added and the solution is stirred at -78 &lt; 0 &gt; C for 2 hours and the mixture is filtered through celite and the filtrate is concentrated. The residue is first eluted with hexane and then eluted with ethyl acetate: hexane (1: 4) and purified by flash chromatography to isolate the desired title product from the product mixture.

Step 253b, 4-tert-Butoxy-2,3,6-trifluoropyridine

2.5 g of Pearlman's catalyst (Aldrich Chemical Co.) is added to the product from step 253a (24.92 g, 0.104 mmol) in 100 ml of methanol and the mixture is stirred under hydrogen atmosphere at room temperature for 14 hours. Further 2.5 g of catalyst are added and the mixture is stirred for a further 22 hours. The mixture is filtered and the filtrate is concentrated and the residue is extracted with hexane / ether. After filtration, the solvent was removed by evaporation and the residue was purified by flash chromatography (ethyl acetate: hexane 1:16) to give 12.05 g of the title product.

Step 253c, 4-t-Butoxy-2,3,6-trifluoro-5-methylpyridine

A solution of lithium diethylamide (LDA) (58.21 mmol) in 30 ml of freshly prepared THF at -78 ° C is 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 is stirred for 50 minutes. 4.3 ml (69.07 mmol) of methyl iodide are added to the reaction mixture and the mixture is stirred at -78 &lt; 0 &gt; C for 1 hour and at ambient temperature for 16 hours. The reaction was quenched with saturated NH ₄ Cl solution and extracted with hexane, the extract was washed with water, dried over MgSO ₄ and concentrated to give the title compound as a light yellow solid which was used in the next step.

Step 253d, 4-tert-Butoxy-2,5-difluoro-3-methylpyridine

The product sample (48.74 mmol) from step 253c above and 13.5 ml of hydrazine monohydrate are dissolved in 150 ml of n-propanol. The reaction is heated to reflux temperature under nitrogen for 4 hours. The volatiles were removed, washed the residue was dissolved in methylene chloride and water and then dried with MgSO _4. The solvent is removed to give the intermediate hydrazine product as a yellow liquid which is dissolved in 110 ml of methanol. 20 ml of 20% NaOH is added and air is passed through the solution for 16 hours. The solvent is removed in vacuo at 30 &lt; 0 &gt; C. After washing the residue was dissolved in methylene chloride and water and then dried with MgSO _4. The solvent was removed and the crude product was purified by flash chromatography eluting with ethyl acetate: hexane 1:16 to remove the solvent and give the title product as a colorless liquid.

Step 253e. 2- (4-t-Butoxy-5-fluoro-3-methyl-2-pyridinyl) cyclopropaneacetonitrile

The product sample from step 253d above (40.8 mmol) is dissolved in 50 ml of THF and cooled to -78 &lt; 0 &gt; C. To this is added LDA solution (0.103 mmol) in 50 ml of freshly prepared THF at -78 ° C and the reaction is stirred for 1 hour. The reaction was stirred at 0 ℃ for 1 hour, then quenched with saturated NH ₄ Cl solution and extracted with ether. The extract was washed with a saturated NaCl solution and dried with MgSO ₄ and concentrated. The residue was purified by flash chromatography eluting with 1: 4 ethyl acetate: hexanes to give 10.33 g of the title product after solvent removal.

Step 253f. 2- (4-Chloro-5-fluoro-3-methyl-2-pyridinyl) cyclopropaneacetonitrile

The product sample from step 253e (5.21 g, 19.86 mmol) from above is dissolved in 50 ml of trifluoroacetic acid and the reaction is stirred under nitrogen for 1 hour at ambient temperature and the material is concentrated to dryness. The residue is dissolved in a mixture of 15.6 ml of DMF and 90 ml of methylene chloride. The solution is cooled with water, 18.8 ml (19.86 mmol) of POCl ₃ are added and the reaction is stirred at ambient temperature for 16 hours. The reaction is quenched by pouring into ice water and the mixture is extracted with methylene chloride. The pH of the aqueous solution is adjusted to 7 with NaOH and re-extracted with methylene chloride. The combined extracts are washed with water, dried over MgSO ₄ and concentrated. The residue is purified by flash chromatography, eluting with 1: 4 ethyl acetate: hexane and after removal of the solvent, 3.26 g of the title product are obtained as a colorless liquid.

Step 253g. Ethyl 2- (4-chloro-5-fluoro-3-methyl-2-pyridinyl) cyclopropane acetate

The product sample from step 253f above (3.26 g, 14.51 mmol) is dissolved in 10 ml of ethanol and introduced until 4 g of gaseous HCl are dissolved. The solution is heated to reflux, 0.36 ml of water is added and the mixture is stirred for 1 hour. The reaction is cooled, poured into water and the mixture is adjusted to pH 7 with NaHCO ₃ . The mixture was extracted with methylene chloride, washed with water and dried with MgSO ₄ and concentrated. The residue is triturated with 1: 4 ethyl acetate: hexane and filtered. The filtrate was concentrated and the residue was purified by flash chromatography with 1: 4 ethyl acetate: hexane to give 2.262 g of the title product after solvent removal.

Step 253h. 2- (4-Chloro-5-fluoro-3-methyl-2-pyridinyl) cyclopropane-acetaldehyde

Dissolving a sample of the product from the above step 253g (1.73g, 6.37mmol) in 10ml THF was stirred under cooling in a water bath and is the LiAlH ₄ (LAH) 3.2mmol. The mixture is stirred at ambient temperature for 1 hour and then poured into water. The mixture was extracted with ether, the extract was washed, dried and concentrated to give 1.48 g of a colorless oil. This oil was dissolved in 10 ml of methylene chloride and 3.8 ml (7.6 mmol) of oxalyl chloride solution and 1.1 ml of DMSO (15.5 mmol) in 15 ml of methylene chloride stirred at -78 &lt; 0 &gt; C were added. The solution is stirred for 15 minutes and 4.4 ml (31.6 mmol) of triethylamine are added. Stir for 5 minutes at -78 &lt; 0 &gt; C and continue stirring at -10 &lt; 0 &gt; C for 10 minutes. The reaction is 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 used directly in the next step without further purification.

Step 253i: 8-Chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-

The product sample from step 253h above (6.37 mmol) is dissolved in 50 ml of ethanol, 1.5 ml of piperidine, 1.5 ml of acetic acid and 5 ml (32.9 mmol) of diethylmalonate are added. The reaction is heated under reflux under nitrogen for 4 hours. The solvent is removed and the residue is dissolved in ether. The ether was washed with water and brine, dried over MgSO ₄ , concentrated and purified with a Kugelro apparatus to give 2.4 g of crude condensation product. The intermediate product is dissolved in 20 ml of Dautum A ^TM and the solution is added to 100 ml of Dowtom A ^TM heated to 235 占 폚. The reaction is stirred at 220 &lt; 0 &gt; C for 45 minutes. After cooling, the product is separated from the solvent, eluted with hexane, flash chromatographed, the solvent is removed and the product is isolated by elution with 1: 4 ethyl acetate: hexane. After removal of the solvent by this method, 1.065 g of the title product is obtained.

Step 253j. Pyrrolidinyl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester

The product sample from step 253i above (0.500 g, 1.544 mmol) is dissolved in 20 ml of acetonitrile and 0.600 g of sodium carbonate and 0.600 g (3.22 mmol) of 3 (S) - (BOC-amino) pyrrolidine are added. The mixture is heated to reflux under nitrogen for 7 hours, then the solvent is removed and the residue is redissolved in methylene chloride. The solution is washed with water, 5% HCl, water and concentrated. The residue of 100: 10 methylene chloride: methanol and eluted with 100: 10: 0.5 methylene chloride: methanol and eluted with NH ₄ OH was purified by flash chromatography. After removal of the solvent, 0.778 g of the title product is obtained and used immediately in the next step.

Step 253k. 8- (3- (N-BOC-amino) pyrrolidinyl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-

A sample of the product from step 253j above (0.778 g, 1.654 mmol) is dissolved in 20 ml of THF, and 0.570 g of LiOH.H ₂ O and 10 ml of water are added and the mixture is stirred under nitrogen for 3 hours. The THF is removed under vacuum and the residue is adjusted to pH 2-4 with 1N HCl. The solid is collected and the filtrate is extracted with methylene chloride, washed and concentrated to afford further product. The combined solids were eluted with 100: 5: 1 methylene chloride: methanol: acetic acid and purified by flash chromatography to give 0.698 g of the title product after solvent removal. This material is used in the next step.

Step 253I. 8- (3-aminopyrrolidinyl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid hydrochloride

The product sample from step 153k above (0.697 g, 1.564 mmol) is dissolved in 17 ml of anhydrous methylene chloride, 5.0 ml of 4N HCl in dioxane is added and the reaction is stirred for 1.75 hours. Ether is added and the precipitate is collected by filtration and washed with ether. The solid is dissolved in water and filtered through sintered glass funnel and lyophilized to give the title product as a yellow solid.

Example 254

Pyrrolidinyl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride

The reaction product is reacted as in steps 253k and 253l, replacing the 3- (BOC-amino) pyrrolidinyl of step 253j above with 3-BOC-aminomethylpyrrolidine to yield 0.085 g of the title compound.

Example 255

7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride &lt;

The reaction product was reacted as in steps 253k and 253l by replacing the 3-BOC-aminopyrrolidine from step 253j with (2S, 4S) -4- (BOC-amino) -2-methylpyrrolidine to give the title compound 0.071 g.

Example 256

7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride

The reaction product is reacted as in steps 253k and 253l, substituting 3- (BOC-amino) azetidine for 3-BOC-aminopyrrolidine in step 253j above to give 0.094 g of the title compound.

Example 257

7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride &lt;

The reaction product is reacted as in steps 253k and 253l by replacing the 3-BOC-aminopyrrolidine of step 253j with 3 (S) - (BOC-amino) pyrrolidine to yield 0.087 g of the title compound.

Example 258

7-fluoro-9-methyl-4-oxo- (3-methyl-1-piperazinyl) -4H) -quinolizine-3-carboxylic acid hydrochloride

The reaction product is reacted as in steps 253k and 253l with the conversion of 3-BOC-aminopyrrolidine of step 253j above to 2-methylpiperazine (Aldrich Chemical Co.) to yield 225 mg of the title compound.

mp 300 ° C

Anal. Calcd. C ₁₉ H ₂₃ ClFN ₃ O _3. 1.25 H ₂ O: C, 54.55; H, 6.14; N, 10.04. Found: C, 54.78; H, 5.78; N, 10.05.

Example 259

7-fluoro-9-methyl-4-oxo-8-piperazinyl) -4H-quinolizine-3-carboxylic acid hydrochloride

The reaction product is reacted as in steps 253k and 253l with the conversion of 3-BOC-aminopyrrolidine of step 253j above to piperazine (Aldrich Chemical Co.) to yield 75 mg of the title compound.

Anal. Calcd. C ₁₈ H ₂₁ ClFN ₃ O ₃ .1.5H ₂ O: C, 55.32; H, 5.67; N, 10.75. Found: C, 55.52; H, 5.49; N, 10.59.

Example 260

7-fluoro-9-methyl-8- (2 - ((N-methyl) aminomethyl) Chloride

Step 260a. 1-N-benzyl-3- (chloromethyl) morpholine

A mixture of 1.5 g (10 mmol) of N-benzyl-ethanolamine (Aldrich Chemical Co.) and 7.8 ml of epichlorohydrin is heated to 40 &lt; 0 &gt; C for 30 minutes. Cool the reaction and remove excess epichlorohydrin with a rotary evaporator. The residue is dried under vacuum and dissolved in 30 ml of concentrated H ₂ SO ₄ and the mixture is heated to 150 ° C. for 30 minutes. The reaction is quenched by pouring on ice and the pH is adjusted to pH 13 with NaOH. The basic solution is extracted with toluene (3X), the extract is dried over Na ₂ SO ₄ , filtered and the solvent is removed in vacuo. The residue was dried under vacuum to give 193 mg of the title product.

Step 260b. 1-N-benzyl-3 - ((N-methamino) methyl) -morpholine

8.83 g of N-benzyl-3- (chloromethyl) morpholine from step 260a above is placed in a thick glass tube and dissolved in 15 ml of methanol. Cool the glass tube and contents and add 25 ml of anhydrous methylamine. The glass tube is sealed and heated at 100 ° C for 24 hours. Open the seal and remove the solvent under vacuum. The residue is diluted with 100 ml of 10% Na ₂ CO ₃ and extracted three times with methylene chloride. The extracts were dried with Na ₂ SO _4, filtered and the solvent removed by rotary evaporation to give the title product 8.6g.

Step 260c. 1-N-benzyl-3 - ((N-BOC-N-methylamino) methyl) -morpholine

It is a morpholine 8.6g (39mmol) - 1-N- benzyl from a dry flask positive pressure N ₂ in anhydrous methylene chloride 100ml of step 260b above in an atmosphere -3 - ((N- methylamino) methyl). The solution was cooled in an ice bath and 8.6 ml (64.3 mmol) of triethylamine and 12.7 g (58.5 mmol) of di-t-butyl dicarbonate were added. The reaction mixture is stirred at 0 SIMILAR 5 DEG C for 30 minutes, then warmed to room temperature and stirred for 72 hours. Diluting the reaction contents with methylene chloride and then 100ml then washed and dried with Na ₂ SO ₄ with water. The solution is filtered and the solvent is removed by rotary evaporation and the residue is dried under vacuum to give 12.4 g of the crude title product. Column chromatography of the product gave 7.4 g of the title product as a colorless oil. Anal. Calcd. C ₁₁ H ₂₂ ClN ₂ O ₃ : 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-aminomethyl) morpholine

1.10 g (3.43 mmol) of the 1-N-benzyl-3 - ((N-BOC-N-methylamino) methyl) -morpholine sample from step 260c above is dissolved in 100 ml of methanol. To this is added 500 mg of 20% Pd / C and the mixture is stirred at room temperature for 16 hours under H ₂ atm. The catalyst is filtered off and the solvent is removed by rotary evaporation and the residue is dried under vacuum to give 794 mg of the title product as a colorless oil.

Step 260e. 7-fluoro-9-methyl-8- (2 - ((N-methyl) aminomethyl) Chloride

The reaction product was reacted as in steps 253k and 253l with the conversion of 3-BOC-aminopyrrolidine from step 253j to 2- (N-BOC-N-methyl-aminomethyl) morpholine (step 260d, above) 280 mg of the compound is obtained.

Anal. Calcd. C ₂₀ H ₂₅ ClFN ₃ O ₄ .2H ₂ O: C, 52.01; H, 6.63; N, 9.10. Found: C, 51.90; H, 5.92; N, 9.09.

Example 261

7-fluoro-9-methyl-4-oxo-8- (l, 2,3,4-tetrahydro-2-isoquinolinyl) -4H- quinolizine-

The reaction product was reacted in the same manner as in Steps 253k and 253l except that 3-BOC-aminopyrrolidine of Step 253j was changed to 1,2,3,4-tetrahydroisoquinoline (Aldrich Chemical Co.) to give 315 mg of the title compound do.

mp 214-215 [deg.] C

Anal. Calcd. C ₂₃ H ₂₁ FN ₂ O ₃揃 1.25H ₂ O: C, 66.58; H, 5.71; N, 6.75. Found: C, 66.56; H, 5.26; N, 6.62.

Example 262

4-oxo-8- (4-amino-1-piperidinyl) -4H-quinolizine-3-carboxylic acid hydrochloride

Step 262a. N-benzyl-4- (N-hydroxyimino) piperidine

3.78 g (20 mmol) of N-benzyl-4-oxo-piperidine (Aldrich Chemical Co.) sample are dissolved in 50 ml of methanol. To this solution, 4.16 g (60 mmol) of hydroxylamine hydrochloride and 5.2 g (62 mmol) of NaHCO ₃ were added (dissolved in 80 ml of water and added in an amount of 5 ml). The mixture is stirred at room temperature for 18 hours. The mixture was filtered and the solvent was removed from the filtrate by rotary evaporator to give 3.05 g of the title product. mp 127-128 [deg.] C.

Step 262b. 1-N-benzyl-4-aminopiperidine

The oxime sample 2.04 (9.98 mmol) from step 262a, above, is dissolved in 200 ml of methanol and reduced with 10 g of Raney nickel under H ₂ 4 atmospheric pressure for 4 hours. The catalyst is removed by filtration and the solvent is removed with a rotary evaporator. The residue was dried under vacuum to give 1.79 g of the title product. MS M / Z: 191 (M + H) &lt; ⁺ & gt ^; .

Step 262c. 1-N-benzyl-4-BOC-aminopiperidine

1.78 g of 1-N-benzyl-4-aminopiperidine from step 262b above is dissolved in 9 ml of anhydrous methylene chloride in a dry system under N ₂ atmosphere. 1.6 ml (12 mmol) of triethylamine and 2.45 g (11.2 mmol) of di-t-butyl dicarbonate were added thereto. The reaction mixture is stirred at room temperature for 96 hours. The contents are diluted with 125 ml of methylene chloride and washed with water. Dry the organic layer with Na ₂ SO ₄ and filtered The solvent was removed by rotary evaporation. The residue was dried under vacuum to give 2.45 g of the title product as an off-white solid. The crude product is purified by silica gel column chromatography eluting with 2% methanol in methylene chloride. The solvent was removed to give 1.74 g of product which was recrystallized from ethanol and dried under vacuum. mp. 121-122 [deg.] C. Anal. Calcd. C ₁₇ H ₂₅ N ₂ O ₂ : C, 70.31; H, 9.02; N, 9.65. Found: C, 70.26; H, 9.02; N, 9.55.

Step 262d. 4-BOC-aminopiperidine

The benzyl group is removed according to the procedure of Example 260d above from the product of Step 262c to give the title product.

Step 262e. 4-oxo-8- (4-amino-1-piperidinyl) -4H-quinolizine-3-carboxylic acid hydrochloride

The reaction product is reacted as in steps 253k and 253l by replacing the 3-BOC-aminopyrrolidine from step 253j with 4- (BOC-amino) -methylpiperidine to yield 480 mg of the title compound.

mp 231-232 [deg.] C

Anal. Calcd. C ₁₉ H ₂₃ ClFN ₃ O ₃ .0.75 H ₂ O: C, 55.75; H, 6.03; N, 6.03. Found: C, 55.70; H, 6.07; N, 10.36.

Example 263

7-fluoro-9-methyl-4-oxo-8- (3-amino- 1 -piperidinyl) -4H- quinolizine-3-carboxylic acid hydrochloride

The reaction product was reacted as in steps 253k and 253l with 3-amino-piperidine hydrochloride (Aldrich Chemical Co.) in which the 3-BOC-aminopyrrolidine of step 253j was neutralized with triethylamine to give the title compound 250 mg.

Anal. Calcd. C ₁₉ H ₂₃ ClFN ₃ O ₃ .2H ₂ O: C, 52.84; H, 6.30; N, 9.73%. Found: C, 52.62; H, 6.62; N, 9.36.

Example 264

4-oxo-8- (4- (aminomethyl) -1-piperidinyl) -4H-quinolizine-3-carboxylic acid hydrochloride

The reaction product is reacted in the same manner as in Steps 253k and 253l except that 3-BOC-aminopyrrolidine of Step 253j is changed to 4- (amino-methyl) piperidine (Aldrich Chemical Co.) and 157 mg of the title compound is prepared.

mp 300 ° C

Anal. Calcd. C ₂₀ H ₂₅ ClFN ₃ O ₃揃 1.75H ₂ O: C, 54.42; H, 6.51; N, 9.52. Found: C, 53.92; H, 6.85; N, 9.73%.

Example 265

7-fluoro-9-methyl-4-oxo-8- (5-amino-1,2,3,4-tetrahydro-2-isoquinolinyl) -4H-quinolizine- 3-carboxylic acid hydrochloride

Step 265a. 5-Amino-1,2,3,4-tetrahydroisoquinoline

1.0 g (0.69 mmol) of 5-aminoisoquinoline (Aldrich Chemical Co.) sample is dissolved in 100 ml of methanol and reduced to 250 mg of PtO ₂ at 25 ° C under H ₂ 4 atmospheric pressure for 8 hours. The catalyst is removed by filtration, the solvent is removed by rotary evaporation and the residue is dried under vacuum to give 1.01 g of crude product. This material is crystallized from I-propanol and dried under vacuum to give 602 mg. mp = 153-154 [deg.] C. MS M / Z: 149 (M + H) &lt; ⁺ & gt ^; . ^{_{166 (M + NH 4) +}} .

Step 265b. 7-fluoro-9-methyl-4-oxo-8- (5-amino-1,2,3,4-tetrahydro-2-isoquinolinyl) -4H-quinolizine- 3-carboxylic acid hydrochloride

By converting the 3-BOC-aminopyrrolidine of step 253j into 5-amino-1,2,3,4-tetrahydroisoquinoline, the reaction product is reacted as in steps 253k and 253l to give the title compound 507mg.

Anal. Calcd. C ₂₃ H ₂₃ ClFN ₃ O ₃ .0.75 H ₂ O: C, 60.39; H, 5.40; N, 9.19. Found: C, 60.38; H, 5.16; N, 9.10.

Example 266

7-fluoro-9-methyl-4-oxo-8- (4- (1-pyrrolyl) -1- piperidinyl) -4H- quinolizine-

The 3-BOC-aminopyrrolidine of step 253j was reacted with 4- (1-pyrrolyl) piperidine (N-benzyl-4-hydroxypiperidine followed by mesylation of the mesyl group with pyrrole and benzyl Group), the reaction product is reacted as in steps 253k and 253l to give 386 mg of the title compound.

Anal. Calcd. C ₂₃ H ₂₄ FN ₃ O ₃揃 1.25H ₂ O: C, 63.95; H, 6.18; N, 9.73%. Found: C, 63.60; H, 6.61; N, 9.43.

Example 267

Methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride &lt; RTI ID = 0.0 &gt;

The reaction product is reacted in the same manner as in Steps 253k and 253l except that 3-BOC-aminopyrrolidine of Step 253j is changed to cis-3,5-dimethyl-piperazine (Aldrich Chemical Co.) and 0.46 g of the title compound is prepared .

Anal. Calcd. C ₂₀ H ₂₅ ClFN ₃ O ₃ .0.75 H ₂ O: C, 56.74; H, 6.31; N, 9.92%. Found: C, 56.66; H, 6.21; N, 9.74.

Example 268

Synthesis of 1-cyclopropyl-8- (2,7-diazabicyclo [3,3,0] oct-2-yl) -7-fluoro-9- Carboxylic acid hydrochloride

Boc-aminopyrrolidine of step 253j above was converted to 7-BOC-2,7-diaza [3.3.0] octane (prepared according to U.S. Patent No. 5,071,999) and the reaction product was treated with steps 253k and 253l Were reacted together to obtain 0.34 g of the title compound.

Anal. Calcd. C ₂₀ H ₂₄ Cl ₂ FN ₃ O ₃ : C, 54.06; H, 5.44; N, 9.46. Found: C, 53.86; H, 5.48; N, 9.63.

Example 269

8-Bicyclo [4,3,0] nonyl) -7-fluoro-9-methyl-4-oxo-4H-quinolizine- Carboxylic acid hydrochloride

Substituting the 3-BOC-aminopyrrolidine of step 253j above with 8-DOC-2.8-diaza [4.3.0] nonane (prepared according to US Patent No. 5,059,597), the reaction product is reacted as in steps 253k and 253l To give 0.50 g of the title compound.

Anal. Calcd. C ₂₁ H ₂₆ ClFN ₃ O ₃ : C, 55.03; H, 5.72; N, 9.17. Found: C, 54.75; H, 5.82; N, 9.38.

Example 270

1-Cyclopropyl-7-fluoro-9-methyl-4-oxo-8- (3 (S) - (1-pyrrolyl)

A solution of 8- (3 (S) -aminopyrrolidinyl) 1-cyclopropyl-7-fluoro-9- 257) and 40 mg of diethylacetate is heated to 100 &lt; 0 &gt; C. 0.009 ml of dimethoxytetrahydrofuran is added dropwise to this solution, the reaction is stirred at 110 DEG C for 5 minutes, and then the reaction is quenched with water. The mixture was extracted twice with methylene chloride, washing the extract with water and then concentrated and dried in MgSO _4. The residue was purified by preparative TLC eluting with 100: 10 chloroform: methanol to give 13.6 mg of the title compound as a yellow solid after removal of the solvent.

Example 271

7-fluoro-8- (3-hydroxy-1-pyrrolidinyl) -9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid hydrochloride

The reaction product is reacted as in steps 253k and 253l with the conversion of 3-BOC-aminopyrrolidine of step 253j above to 3-hydroxy-pyrrolidine (Aldrich Chemical Co.) to yield the title compound 0.15 g.

Anal. Calcd. C ₁₈ H ₁₉ FN ₂ O ₄ : C, 62.42; H, 5.53; N, 8.09. Found: C, 62.20; H, 5.55; N, 8.09.

Example 272

7-fluoro-8- (4-methyl-1-piperazinyl) -9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid hydrochloride

The reaction product is reacted as in steps 253k and 253l with the conversion of 3-BOC-aminopyrrolidine of step 253j above to 1-methylpiperazine (Aldrich Chemical Co.) to give the title compound 0.15 g.

mp 210-216 [deg.] C (dec.)

Example 273

7-fluoro-8- (3-amino-1-pyrrolidinyl) -4-oxo-4H-quinolizine-3-carboxylic acid trifluoroacetic acid salt

4-t-butoxy-2,3,6-trifluoro-5-methylpyridine of step 253d was reacted with 4-t-butoxy-3-chloro-2,5,6-trifluoropyridine And the reaction product is reacted as in steps 253d to 253l and the 4N HCl in dioxane is replaced with trifluoroacetic acid to give 0.13 g of the title compound.

Calcd _{C 17 H 17 ClFN 3 O 3} · CF 3 COOH · 0.5H 2 0: C, 46.69; H, 3.92; N, 8.60. Found: C, 46.62; H, 3.64; N, 8.45.

Example 274

8- (3-Amino-1-pyrrolidinyl) -1-cyclopropyl-7,9-difluoro-8-4-oxo-4H- quinolizine-3- carboxylic acid trifluoro hydrochloride

Step 274a. 4-t-butoxy-2,3,5,6-tetrafluoropyridine

158.5 g (0.938 mmol) of pentafluoropyridine (Aldrich Chemical Co.) sample are dissolved in 600 ml of THF and cooled to -78 &lt; 0 &gt; C. To this was added 88.29 g (0.919 mmol) of sodium-t-butoxide in 800 ml of THF over 30 minutes with stirring and the temperature was maintained at -78 占 폚. The mixture is further stirred at this temperature for 30 minutes, the temperature of the bath is raised to -20 &lt; 0 &gt; C and the reaction is stirred at this temperature for 64 hours. The reaction mixture is removed from the cold bath, diluted with 1.5 L of ether and filtered through a diatomaceous filter. The solvent is removed in vacuo to give a yellow oil. The oil was vacuum distilled to give 141.34 g of the title product.

Example 274b. 4-t-butoxy-2,3,5-trifluoropyridine

20.0 g (0.089 mmol) of the sample from step 274a above are dissolved in 100 ml of absolute ethanol and 26.08 ml (0.538 mmol) of hydrazine monohydrate are added. The reaction is stirred at room temperature for 1 hour and refluxed for 1 hour. The solvent is removed under vacuum. The residue is dissolved in ether and washed with water and brine. Layer was dried over MgSO ₄ and the solvent removed in vacuo to give a yellow solid. This material is dissolved in 120 ml of toluene and 60 ml of 20% sodium hydroxide is added to bubble air for 18 hours while stirring the solution. 100 ml of ether was added to the reaction, and the organic layer was separated, washed with water and brine, and dried over MgSO ₄ . The solvent was removed and the residue was purified by silica gel flash chromatography eluting with 1:16 ethyl acetate: hexane to give 14.6 g of the title product as a reddish liquid.

Step 274c. 8- (3-Amino-1-pyrrolidinyl) -1-cyclopropyl-7,9-difluoro-4-oxo-4H- quinolizine-3-carboxylic acid hydrochloride

By replacing 4-t-butoxy-2,5-difluoro-3-methylpyridine of step 253e with 4-t-butoxy-2,3,5-trifluoropyridine from step 274b above, the product The reaction is carried out according to the procedures of Steps 253e to 253l to give 76 mg of the title compound.

Example 275

7-fluoro-9-methoxy-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride

Step 275a. 4-t-butoxy-2,3,6-trifluoro-5-hydroxypyridine

Example 253 11.16 g (54.39 mmol) of 4-t-butoxy-2,3,6-trifluoropyridine sample from step b is dissolved in 50 ml of THF and the solution is cooled to -78 &lt; 0 &gt; C. LDA (65.6 mmol) is added to this solution with stirring for 30 minutes during which the solid precipitates. To this mixture was added 7.5 ml of trimethoxyborane while stirring at -78 占 폚 for 25 minutes. To this mixture is added 10 ml of acetic acid and the mixture is stirred and warmed to room temperature. While cooling with the following ice bath, 100 ml of 30% hydrogen peroxide and 100 ml of 2N sodium hydroxide are added. The mixture is then stirred at room temperature for 16 hours and the reaction quenched with saturated NH ₄ Cl solution. The mixture was extracted with ether. The extract was washed with brine and dried with MgSO _4. The solvent is removed in vacuo and the residue is purified by silica gel flash chromatography, eluting with 1: 8 ethyl acetate: hexanes. Removal of the solvent gave 9.769 g of the title compound as a colorless liquid.

Step 275b. 4-t-Butoxy-2,3,6-trifluoro-5-methoxypyridine

To a solution of 4-t-butoxy-2,3,6-trifluoro-5-hydroxypyridine in 3 ml of anhydrous THF from above step 275a was added triphenylphosphine 335 mg (1.277 mmol) and methanol 0.060 ml Is added. Add 0.200 ml (1.270 mmol) of DEAD to this solution at room temperature. The reaction was terminated in 10 min to remove the solvent in vacuo and the residue was purified by silica gel flash chromatography eluting with 1:16 ethyl acetate: hexanes to remove the solvent to afford 215.6 mg of the title compound as colorless liquid.

Step 275c. 7-fluoro-9-methoxy-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride

Example 253: 4-t-Butoxy-2,3,6-trifluoro-5-methylpyridine of step c was reacted with 4-t-butoxy-2,3,6-trifluoro- Methoxypyridine and the reaction product is reacted as in steps 253d to 253l to give the title compound 120 mg.

Anal. Calcd. C ₁₈ H ₂₀ FN ₃ O ₄ .2HCl. 0.5H ₂ O: C, 48.77; H, 5.23; N, 9.48. Found: C, 48.65; H, 5.19; N, 9.56.

Example 276

Methyl-8- (3 (S) -methylamino-1-pyrrolidinyl) -4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride

Step 276a. 1-N-benzyl-3 (S) - (BOC-amino) -pyrrolidine

4.2 g of (3S) -3-BOC-aminopyrrolidine (TCI America) and 4.7 ml of triethylamine are dissolved in 75 ml of methylene chloride at room temperature. 2.95 ml of benzyl bromide is added dropwise to this solution and the reaction is heated at reflux for 6 hours. After cooling, the solution is washed with water, the solvent is dried and evaporated to give 5.10 g of the title product as a white solid.

Step 276b. 1-N-benzyl-3 (S) - (methylamino) -pyrrolidine

1-N- benzyl-3 from the above step 276a (S) - (BOC- amino) pyrrolidine was dissolved in THF 25ml and 5.10g exerts a LiAlH ₄ (1.0M in THF) 55.6g. The mixture is stirred and heated to reflux for 4 hours. The reaction is quenched with water and the mixture is extracted with methylene chloride. The solvent was washed with water, dried with MgSO ₄ removed by rotary evaporation to give the title product 2.43g.

Step 276c. 1-N-benzyl-3 (S) - (N-BOC-N-methylamino) -pyrrolidine

2.43 g of 1-N-benzyl-3 (S) - (methylamino) -pyrrolidine from step 276b are dissolved in 100 ml of a 4: 1 methanol: water mixture and 3.34 g of di-t-butyl dicarbonate are added in small portions do. The reaction is stirred at room temperature for 6 hours. The methanol is removed in vacuo and the aqueous residue is extracted with methylene chloride. The solvent is washed with water, dried over MgSO ₄ and removed under vacuum. Residue 100: 5: 0.5 methylene chloride: methanol and eluted with NH ₄ OH filtrate was purified by silica gel chromatography to give the title product 3.23g.

Step 276d. (S) - (N-BOC-N-methylamino) -pyrrolidine

The product from Step 266c was treated according to the procedure of Example 171 to remove the benzyl protecting group and 2.24 g of the title compound as a white solid.

Step 276e. Methyl-8- (3 (S) -methylamino-1-pyrrolidinyl) -4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride

Example 253 Following the procedure for step j, the 3-BOC-aminopyrrolidine of this Example was converted to 3 (S) - (N-BOC-N-methylamino) -pyrrolidine from step 276d above to give the reaction product Are reacted according to the procedures of Examples 253k and 253l to give 452 mg of the title product.

Elemental analysis for C ₁₉ H ₂₂ FN ₃ O ₃ .HCl. H ₂ O:

Calculated: C, 55.14; H, 6.09; N, 10.15

Found: C, 55.29; H, 5.99; N, 10.18

Example 277

(3R) -amino-1-pyrrolidinyl) -4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride

Step 277a. 1-N-benzyl-3- (R) - (BOC-amino) -pyrrolidine

The title compound is prepared according to Example 276 step a replacing (3S) -3-BOC-aminopyrrolidine of step 276a with (3R) -3-BOC-aminopyrrolidine (TCI America).

Step 277b. 3 (R) - (BOC-amino) pyrrolidine

The benzyl group is removed from the product of step 277a by the procedure of step 276d above to give the title product.

Step 277c. (3R) -amino-1-pyrrolidinyl) -4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride

The title compound was prepared according to the procedure of Example 253 step j, but replacing the 3- (BOC-amino) pyrrolidine of this Example by 3 (R) - (BOC-amino) -pyrrolidine from step 277b, k and l to give 452 mg of the title product.

Elemental analysis for C ₁₈ H ₂₀ FN ₃ O ₃ .HCl. H ₂ O:

Calculated: C, 54.07; H, 5.80; N, 10.51

Found: C, 54.19; H, 5.65; N, 10.37

Example 278

(3R) -9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -2H, 3H, 6H-6-oxo-pyrano [ 5-carboxylic acid hydrochloride

Step 278a. (S) -1-bromo-2-methyl-3- (t-butyldimethylsilyloxy) propane

4.27 g (67.720 mmol) of imidazole was added to 9.59 g (62.67 mmol) of a sample of (S) - (+) - 3-bromo-2-methyl-1-propanol (Aldrich Chemical Co.) in 40 ml of DMF, &Lt; / RTI &gt; 9.45 g (62.69 mmol) of t-butyldimethylsilyl chloride are added to the cooled solution, and the solution is stirred at room temperature for 16 hours. The reaction solution is poured into water and extracted with hexane. The organic layer is concentrated to water, washed with saturated brine, dried over MgSO _4. The residue is distilled (0.2 mmHg, 50 [deg.] C) in a Cuggel apparatus to give 15.00 g of the title product as a colorless liquid.

Step 278b. (S) -1-Iodo-2-methyl-3- (t-butyldimethylsilyloxy) propane

15.00 g of the pre-stage product sample is dissolved in 100 ml of acetone and 42.00 g (5 eq) of NaI is added. This mixture is heated under reflux for 9 hours under N _2. The mixture is cooled, filtered and the filtrate is concentrated. The residue is dissolved in hexane and the solution is again filtered and concentrated to give 16.62 g of a colorless liquid. This material was distilled (0.2 mm Hg, 60 &lt; 0 &gt; C) in a Kugelro apparatus to give 16.479 g of the title product as a colorless liquid.

Step 278c. 1- (2,3,5,6-tetrafluoro-4-pyridyl) -4-methylpiperazine

25.10 g (0.148 mmol) of pentafluoropyridine (Aldrich Chemical Co.) sample and 23.0 ml (0.165 mmol) of triethylamine are dissolved in 150 ml of HPLC grade methylene chloride. To this solution, 17.3 ml (0.156 mmol) of N-methylpiperazine is slowly added dropwise at 0 占 폚. The solution was stirred at 0 ℃ for 16 hours and then washed with water to give a colorless oil which is dried with MgSO ₄ and concentrated to solidify when allowed to stand hyoje product was 36.95g.

Step 278d. (R) -2-methyl-3- (4- (4-methylpiperazinyl) -3,5,6-trifluoro-2-pyridinyl)

5.03 g (16.00 mmol) of the (S) -1-iodo-2-methyl-3- (t-butyldimethylsilyloxy) propane from step 278b above is dissolved in 32 ml of ether and cooled to -78 &lt; 0 &gt; C. To this solution was added 19.8 ml (33.36 mmol) of t-butyllithium (1.7M in pentane) and the temperature was maintained at -78 ° C with stirring for 40 minutes. The temperature is raised to 0 &lt; 0 &gt; C and stirring is continued for 30 minutes. This solution is labeled as lithium compound and used below. In another flask, 3.99 g (16.01 mmol) of 1- (2,3,5,6-tetrafluoro-4-pyridyl) -4-methylpiperazine from step 278c are dissolved in 50 ml of THF. The lithium compound solution is added via cannula to the latter solution at -78 ° C. The reaction is stirred for 5 minutes at -78 &lt; 0 &gt; C and 30 minutes at room temperature. The reaction is quenched by addition of saturated NH ₄ Cl and extracted with ether. The extract was washed with saturated brine and dried with MgSO ₄ and concentrated. The residue is dissolved in 30 ml of THF and 16.5 ml of tetrabutylammonium fluoride (IN in THF) is added. The mixture is stirred for 16 hours and concentrated. The residue is slurried with water and extracted with methylene chloride. The concentrated organic layer was washed with water, dried over MgSO _4. Residue 100: 5: 0.5 methylene chloride: methanol and eluted with NH ₄ OH purified by flash chromatography to give 4.307g of the title product as a viscous oil colorless.

Elemental analysis for C ₁₄ H ₂₀ FN ₃ O:

Calculated: C, 55.44; H, 6.65; N, 13.72

Found: C, 55.10; H, 6.24; N, 13.72

Step 278e. (R) -2-methyl-3- (4- (4-methylpiperazinyl) -3,5-difluoro-2-pyridyl)

4.349 g (14.337 mmol) of a sample of 2-methyl-3- (4- (4-methylpiperazinyl) -3,5,6-trifluoro-2-pyridinyl )- 1 -propanol from step 278d, a heated under reflux for 17 hours the reaction was added to hydrazine hydrate 3.50ml (72.15mmol) was dissolved in n- propanol 20ml under N _2. The solution is concentrated on a rotary evaporator and the residue is slurried with water and extracted with methylene chloride. The solvent was washed with water, dried over MgSO ₄ and concentrate to obtain 4.60g of the title product as a viscous oil. This intermediate hydrazino compound is dissolved in 300 ml of water and a solution of 29.78 g of CuSO _{4 in} 400 ml of water is pipetted over 15 minutes. Then heated to reflux for 50 minutes the reaction under N _2. Cool the reaction to ambient temperature and to make the solution made basic with NH ₄ OH. The solution was extracted with methylene chloride and washed with water and concentrated and dried with MgSO _4. Residue 100: 5: 0.5 methylene chloride: methanol and eluted with NH ₄ OH purified by flash chromatography to give 3.605g of the title product.

Elemental analysis for C ₁₄ H ₂₁ F ₂ N ₃ O:

Calculated: C, 58.93; H, 7.42; N, 14.73

Found: C, 58.93; H, 7.42; N, 14.73

Step 278f. 3R-7-fluoro-3-methyl-8- (4-methyl-1-piperazinyl) -2,3-dihydro-4H-pyrano [3,2- b]

3.557 g (12.465 mmol) of a sample of 2-methyl-2- (4- (4-methylpiperazinyl) -3,5-difluoro-2-pyridinyl) Is dissolved in 30 ml of oxalic acid and a dispersion of 1.12 g (37.33 mmol) of NaH (50% dispersion) in 100 ml of dioxane is added. The mixture is heated to reflux for 19 hours and then concentrated to dryness. The residue is slurried with water and extracted with ether. Concentrate the extract was washed with saturated brine, dried over MgSO _4. Residue 100: 5: 0.5 methylene chloride: methanol and eluted with NH ₄ OH purified by flash chromatography to give 2.299g of the title product.

Elemental analysis for C ₁₄ H ₂₀ FN ₃ O:

Calculated: 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- 5-carboxylic acid ethyl ester

3.2-b) &lt; RTI ID = 0.0 &gt; (R) -7-Fluoro-3-methyl- 132.7 mg (0.500 mmol) of the pyridine sample are dissolved in 5 ml of THF and cooled to -78 &lt; 0 &gt; C. To the solution was added 0.22 ml of n-butyllithium (0.55 mmol, 2.5 M in hexane) and the reaction was stirred at -78 캜 for 30 minutes. 0.120 ml (0.594 mmol) of diethoxyethoxymethylenemalonate was added to the reaction vessel, and the reaction was stirred at -78 ° C for 5 minutes and at room temperature for 15 minutes. The solvent is removed and the residue is dissolved in ethanol. 1.0 ml of piperidine and 0.2 ml of acetic acid were added thereto, and the solution was heated under reflux for 16 hours. The solution is removed and the residue is dissolved in methylene chloride. This solution was washed with water, concentrated and dried with MgSO _4. 50:50 and the residue ether: methylene chloride 0.5: grinding with hexane and the filtrate to separate the solid from 100: 5 methanol: by eluting with NH ₄ OH was purified by chromatography to give the title product 88.9mg.

Elemental analysis for C ₂₀ H ₂₄ FN ₃ O ₄ :

Calculated: C, 61.69; H, 6.21; N, 10.79

Found: C, 61.42; H, 5.89; N, 10.65

Step 278h. 3 (R) -9-fluoro-3-methyl-10- (4-methyl- 5-carboxylic acid

3H, 6H-6-oxo-pyrano [2.3.4 (2H) -dione &lt; / RTI &gt; -ij] quinolizine-5-carboxylic acid ethyl ester A solution of 657 mg (1.687 mmol) of the sample is dissolved in 6 ml of THF and 142 mg of LiOH.H ₂ O and 3 ml of water are added. The mixture was heated under N ₂ for 80 minutes. The solvent is removed under reduced pressure and the aqueous residue is diluted with additional water and extracted with methylene chloride. The aqueous solution is neutralized with 10% HCl and extracted with methylene chloride. Concentrate the extract was washed with water, dried over MgSO _4. The residue is dissolved in methylene chloride and filtered through a sintered glass funnel. The filtrate is concentrated to dryness and the residue is triturated with 1: 1 ether: hexane and dried to give 494.2 mg of the title product as a yellow solid.

Elemental analysis for C ₁₈ H ₂₀ FN ₃ O ₄ .HCl. H ₂ O:

Calculated: C, 51.91; H, 5.33; N, 10.03

Found: C, 51.91; H, 5.33; N, 10.03

Step 278I. 3, 6H-6-oxo-pyrano [2,3,4-ij] quinolizine -5-carboxylic acid hydrochloride

200 mg of the free base sample of the previous step is dissolved in 15 ml of methylene chloride and 0.75 ml of 1 M HCl in ether is added. Additional ether is added to precipitate the product, which is collected by filtration. The solids are dissolved in water and the solution is filtered through sintered glass. The filtrate was lyophilized to yield 213.1 mg of the title product as a yellow solid.

Elemental analysis for C ₁₈ H ₂₀ FN ₃ O ₄ .HCl 1.5 H ₂ O:

Calculated: C, 50.89; H, 5.69; N, 9.89

Found: C, 50.50; H, 5.46; N, 9.72

Example 279

3 (S) -9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -2H, 3H, 6H- -5-carboxylic acid hydrochloride

Step 279a. 2 (R) -3- (t-butyldimethylsilyl) oxy-2-methyl-

(265 mmol) of (R) - (-) - methyl 3-hydroxy-2-methylpropionate (Aldrich Chemical Co.) and 15.46 g (227 mmol) of imidazole are dissolved in 120 ml of DMF. The solution is stirred under N ₂ at 0 ° C and 34.23 g (227 mmol) of t-dimethylsilyl chloride are added in small portions. The reaction is stirred at 0 &lt; 0 &gt; C for 1 hour, at room temperature for 22 hours and then poured into water. And the mixture is extracted with hexane. The extract was washed with water and obtain a dried MgSO ₄ and concentrated to give 52.21g protected intermediate. The intermediate is dissolved in 100 ml THF and added via cannula to a flask containing 475 ml of DIBAL in 200 ml THF at -78 &lt; 0 &gt; C and stirred for 15 minutes. The reaction is quickly ramped to 0 &lt; 0 &gt; C and stirred for 2 hours. The reaction is quenched by slowly pouring into 1 L of saturated Na ₂ SO ₄ . The mixture is filtered through a filter. Separate and prepare the organic layer. The aqueous layer is extracted with ether. The organic layers were combined washed with brine, dried over MgSO ₄ and concentrated to to to give a yellow liquid. This material was distilled at 0.2 mmHg and 70 DEG C in a Cogelro apparatus to give 19.50 g of the title product.

Step 279b. 2 (R) -3- (t-butyldimethylsilyl) oxy-1-iodo-2-

19.50 g (95.41 mmol) of a sample of 2 (R) -3- (tert-butyldimethylsilyl) oxy-2-methyl-1-propanol from step 279a was dissolved in 100 ml of methylene chloride and 26.6 ml Is added. The solution is cooled to 0 C and 11.0 ml (142 mmol) of methanesulfonyl chloride are added and the reaction is stirred for 1 hour. Stirring is stopped and the reaction is maintained at -20 &lt; 0 &gt; C for 16 hours. The reaction is quenched with 5% NaHCO ₃ and extracted with methylene chloride. The extract was washed with water and then dried over MgSO ₄ and concentrated. The residue was chromatographed, eluting with methylene chloride, and the solvent removed to afford 25.59 g of mesylated intermediate. This intermediate is dissolved in 100 ml of acetone and 55 g of NaI is added. The mixture is heated to reflux for 10 hours, diluted with hexane and filtered. The filtrate is concentrated and the residue is redissolved, filtered and concentrated again. The residue is distilled at 0.2 mm Hg and a Cogelro apparatus at 60 ° C to give 18.22 g of the title product.

Step 279c. 3 (S) -9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -2H, 3H, 6H-6-oxo-pyrano [2,3,4- 5-carboxylic &lt; / RTI &gt; acid hydrochloride

(R) -3- (tert-butyldimethylsilyl) oxy-1-iodo-2-methylpropanol 2 (S) -3- (tert- butyldimethylsilyl) oxy -1-iodo-2-methylpropane and the product is reacted according to Example 278 steps f to i to give the title product.

Example 280

6H-6-oxo-pyrano- [2,3,4-ij] quinolizine-5-carboxylic acid (9-fluoro-10-

Step 280a. 3- (t-butyldimethylsilyloxy) -1-iodopropane

The reaction was carried out in 200 ml of acetone (Wilson and Zucker, J. Org. A mixture of 44.28 g (175 mmol) of 1-bromo-3- (t-butyldimethylsilyloxy) -propane and 100 g of NaI prepared according to the method of Chem., 33: 2571 (1988) was heated at reflux for 20 hours, . The residue is dissolved in hexane, re-filtered and concentrated. The residue is distilled with a Kugelro apparatus (0.2-0.3 mm Hg, 60 &lt; 0 &gt; C) and the pure product spilled at 53-57 [deg.] C and 0.3 mm Hg is collected.

Step 280b. 6H-6-oxo-pyrano [2,3,4-ij] quinolizine-5-carboxylic acid (9-fluoro-10-

(2S) -3- (tert-butylmethylsilyloxy) -1-iodo-2-methylpropane was reacted with 3- (tert-butyldimethylsilyloxy) - Iodo-propane and the product is reacted according to Example 278 steps d to h to give 20 mg of the title product.

Elemental analysis for C ₁₆ H ₁₅ FN ₂ O ₄ .1 / 8H ₂ O:

Calculated: C, 57.10; H, 14.57; N, 8.32

Found: C, 57.07; H, 14.32; N, 8.23

Example 281

(3R) -10- (3-Amino-1-pyrrolidinyl) -9-fluoro-3-methyl-2H, 3H, 6H-6-oxo-pyrano [ 5-carboxylic acid

Step 281a. (2R) -3- (4-t-butoxy-3,5,6-trifluoro-2-pyridinyl)

9.38 g (29.85 mmol) of (S) -1-iodo-2-methyl-3- (t- butyldimethylsilyloxy) -propane from step 278b above was dissolved in 50 ml of ether and t-butyllithium 36.9 ml (1.7 M in pentane, 62.73 mmol) is reacted for 40 minutes and 0 ° C for 30 minutes. This solution was cooled again to -78 ° C and a solution of 6.70 g (30.03 mmol) of 4-t-butoxy-2,3,5,6-tetrafluoropyridine from Example 274a in 40 ml of stirred ether was added dropwise at -78 ° C . The reaction is stirred for 5 minutes, the dry ice bath is removed and the reaction is stirred at room temperature for 64 hours. The reaction is quenched with saturated NH ₄ Cl and the mixture is extracted with ether. Concentrate the extract was washed with saturated brine, dried over MgSO _4. The residue is dissolved in 20 ml of THF and 30 ml of a 1N solution of tetrabutylammonium fluoride is added. The reaction is stirred for 5 hours and concentrated. The residue was dissolved in ether and washed with water, brine and dried over MgSO ₄ and concentrated to dryness. The residue was chromatographed on silica gel eluting with 1: 3 acetone: hexane and solvent removed to give 5.21 g of the title product as a colorless liquid.

Elemental analysis for C ₁₃ H ₁₈ F ₃ NO ₂ .1 / 4H ₂ O:

Calculated: C, 55.41; H, 6.62; N, 4.97

Found: C, 55.17; H, 6.30; N, 4.61

Step 281b. (2R) -3- (4-t-butoxy-3,5-difluoro-2-pyridinyl)

Following the procedure of Example 274b, the reaction of Step 278a was treated with (2S) -3- (4-t-butoxy-3,5,6-trifluoro-2-pyridinyl) -Propanol to give 3.44 g of the title product.

Elemental analysis for C ₁₃ H ₁₉ F ₂ NO ₂ :

Calculated: 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-dihydro-4H-pyrano [3,2- b]

3.29 g (12.69 mmol) of (2R) -3- (4-t-butoxy-3,5-difluoro-2-pyridinyl) -2-methyl-1-propanol in the previous step 281b was dissolved in 100 ml of dioxane And a dispersion of 0.570 g (19.00 mmol) of NaH (80% dispersion) in 100 ml of dioxane is added. The mixture is heated to reflux for 4 hours and concentrated to dryness. The residue is slurried with water and extracted with ether. The extract was washed with saturated brine and dried with MgSO ₄ and concentrated. The residue was purified by silica gel flash chromatography, eluting with 1: 2 ethyl acetate: hexane to give 2.722 g of the title product.

Elemental analysis for C ₁₃ H ₁₈ FNO ₂ :

Calculated: 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-pyrano [2,3,4-ij] quinolizine-5-carboxylic acid ethyl ester

(1.671 mmol) of 3 (R) -7-fluoro-3-methyl-8-t-butyloxy) -2,3-dihydro-4H-pyrano [ RTI ID = 0.0 &gt; -78 C. &lt; / RTI &gt; To this solution was added a solution of 0.80 ml of n-butyllithium (2.0 mmol, 2.5 M in hexane) and 0.28 ml (2.00 mmol) of LDA (prepared at -78 [deg.] C and warmed at 0 C for 15 min) Lt; / RTI &gt; for 30 minutes. 0.400 ml of diethoxyethoxymethylenemalonate was added to the reaction vessel, and the reaction was stirred at -78 ° C for 5 minutes and at room temperature for 15 minutes. 1.7 ml of NNTMS ₂ (1N in THF) was added and the reaction was allowed to warm to room temperature and then quenched with saturated NH ₄ Cl. The mixture was extracted with ether, washed and concentrated and dried in MgSO _4. The solvent is removed and the residue is dissolved in 10 ml of ethanol. 0.5 ml of DBU is added to this solution, the reaction is refluxed for 2 hours and then concentrated to dryness. The residue was dissolved in methylene chloride and 10% citric acid, washed, dried and concentrated by MgSO ₄ with water. The residue is purified by silica gel chromatography eluting with 100: 10 methylene chloride. To the residue of the desired fraction is added 3 ml of trifluoroacetic acid and the mixture is immediately concentrated. The residue was washed with ether to give 307.4 mg of the title product as a yellow solid.

Step 281e. 3H-6-oxo-pyrano] 2,3,4-ij] quinolizine-5-carboxylic acid, ethyl ester

3R, 6H-6-oxo-pyrano [2.3.4-ij] quinolizine-5-carboxylic acid, ethyl (3R) 276.1 mg (0.899 mmol) of the ester sample is dissolved in 5 ml of methylene chloride and 0.71 ml (9.17 mmol) of DMF and 0.85 ml (9.12 mmol) of POCl ₃ are added. The reaction is stirred for 15 minutes and quenched with water and ice. The mixture was extracted with methylene chloride and concentrated to give the extract washed with water, dried over MgSO _4. The residue was purified by silica gel flash chromatography eluting with 10: 1 methylene chloride: methanol and solvent removed to give 180.6 mg of the title product as a yellow solid.

Step 281f. 3-methyl-2H-3H, 6H-6-oxo-pyrano [2.3.4- ij] quinolizine-5-carboxylic acid, ethyl ester

3H, 6H-6-oxo-pyrano [2.3.4-ij] quinolizine-5-carboxylic acid, ethyl ester of 281e (R) -10-chloro-9- 130.9 mg (0.402 mmol) of the sample is 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 America, Inc.) and the reaction was refluxed for 8 hours. The solvent is removed and the residue is dissolved in methylene chloride and washed with water. The solvent was removed and the residue was 100: 10: 0.5 methylene chloride: methanol: by eluting with NH ₄ OH filtrate was purified by silica gel flash chromatography to give 187.6mg of the title product as a yellow solid.

Step 281g. 3-methyl-2H, 3H, 6H-6-oxo-pyrano [2, 3-dihydroxy- , 4-ij] quinolizine-5-carboxylic acid

(R) -10- (3- (N-BOC) amino-1-pyrrolidinyl) -9-fluoro-3-methyl- 2H, 3H, 6H-6-oxo-pyrano [2.3 4-ij] quinolizine-5-carboxylic acid, ethyl ester 187.6 mg (0.394 mmol) of the sample are dissolved in 4 ml of THF and 70 mg of LiOH.H ₂ O in ₂ ml of water are added. Stir the reaction under N ₂ at 60 ℃ for 8 hours. The pH is adjusted to 6.5 with 1N HCl and the mixture is extracted with methylene chloride. Concentrate the extract was washed with water, dried over MgSO _4. The residue was purified by silica gel flash chromatography, eluting with 100: 10: 1 methylene chloride: methanol: acetic acid to give 144 mg of the title product as a yellow solid.

Elemental analysis for C ₂₂ H ₁₆ FN ₃ O ₆ .H ₂ O:

Calculated: C, 56.77; H, 6.06; N, 9.03

Found: C, 56.70; H, 5.80; N, 8.81

Step 281h. 3H-6H-6-oxo-pyrano [2,3,4-ij] quinolizine -5-carboxylic acid hydrochloride

A sample of 281 g of 3 (R) -10- (3- (N-BOC) amino-1-pyrrolidinyl) -9-fluoro-3-methyl- 2H, 3H, 6H-6-oxo-pyrano [ 2,3,4-ij] quinolizine-5-carboxylic acid

115.7 mg (0.259 mmol) of the sample are dissolved in 3 ml of 4N HCl in dioxane and the reaction is stirred at room temperature for 1.5 hours. The solution is concentrated to dryness and the residue is dried under vacuum. The residue is dissolved in water and filtered through sintered glass and lyophilized to give 97.3 mg of the title product as a yellow solid.

Elemental analysis for C ₁₇ H ₁₈ FN ₃ O ₄ .0.5H ₂ O. 2HCl:

Calculated: C, 47.57; H, 4.39; N, 9.79

Found: C, 47.72; H, 4.81; N, 9.58

Step 281i. 3 (R) -10- (3-Amino-1- (pyrrolidinyl) -9-fluoro-3-methyl- 2H, 3H, 6H-6-oxo-pyrano [ 5-carboxylic acid

50 mg of the hydrochloride sample of the previous step 281h is dissolved in 5 ml of water and NaHCO ₃ is added until the pH of the solution is 7. The solid (27.8 mg) is collected by filtration and the filtrate is extracted with 10% methanol in methylene chloride and methylene chloride. The extract is washed, dried and concentrated to give the product a second crop.

Elemental analysis for C ₁₇ H ₁₈ FN ₃ O ₄ .1.5H ₂ O:

Calculated: C, 54.54; H, 5.57; N, 11.23

Found: C, 54.78; H, 5.31; N, 11.05

Example 282

3, 6H-6-oxo-pyrano [2.3.4-ij] quinolin-2- 5-carboxylic acid hydrochloride

(BOC-amino) methylpyrrolidine (prepared according to European Patent Publication No. 0106489) in accordance with the procedure of Example 281f and substituting the product in Step 281g and h To obtain 118 mg of the title compound.

Elemental analysis for C ₁₈ H ₂₆ FN ₃ O ₄ .2HCl:

Calculated: C, 49.78; H, 5.11; N, 9.68

Found: C, 49.90; H, 5.04; N, 9.74

Example 283

3-methyl-2H-3H, 6H-6-oxo-pyrano (2S, 4S) [2,3,4-ij] quinolizine-5-carboxylic acid hydrochloride

(BOC-amino) pyrrolidine was converted to (2S, 4S) -4-BOC-amino-2-methylpyrrolidine (from Example 171 step 5) according to the procedure for Example 281f and the product obtained in Step 281g To give the title compound (57 mg).

Elemental analysis for C ₁₈ H ₂₆ FN ₃ O ₄ .2HCl:

Calculated: C, 49.78; H, 5.11; N, 9.68

Found: C, 49.78; H, 5.04; N, 9.73

Example 284

3-methyl-2H, 3H, 6H-6-oxo-pyrano [2.3.4-ij] quinolin- 5-carboxylic acid

According to the procedure of Example 281f, 3- (BOC-amino) pyrrolidine is replaced with 3-hydroxymethylpyrrolidine (Aldrich Chemical Co.) and the product is reacted according to Step 281g to yield 69 mg of the title compound.

Elemental analysis for C ₁₇ H ₁₇ FN ₂ O ₅ :

Calculated: C, 58.62; H, 4.92; N, 9.04

Found: C, 58.23; H, 4.91; N, 7.81

Example 285

3H, 6H-6-oxo-pyrano [2,3,4-ij] quinolizine-5-carboxylic acid hydrochloride

Step 285a. 3H, 6H-6-oxo-pyrano [2.3.4-ij] quinolizine-5-carboxylic acid (9-fluoro-

(BOC-amino) pyrrolidine was converted to N-methylpiperazine (Aldrich Chemcal Co.) according to the procedure of Example 281f and the product was reacted according to Step 281f and Example 278 step h to give 69 mg of the title compound do.

Elemental analysis for C ₁₇ H ₁₈ FN ₃ O ₄ .0.5H ₂ O:

Calculated: C, 57.30; H, 5.37; N, 11.79

Found: C, 57.71; H, 5.23; N, 11.41

Step 285b. 3H, 6H-6-oxo-pyrano [2,3,4-ij] quinolizine-5-carboxylic acid hydrochloride

According to the procedure of Example 281i, the compound of Step 278h was reacted with 9-fluoro-10- (4-methyl-1-piperazinyl) -2H, 3H, 6H-6-oxo-pyrano [ -yl] quinolizine-5-carboxylic acid, the title compound is prepared.

Examples 286 to 296

The compounds of Examples 286 to 296 are prepared as shown in Table 11, replacing the 3-BOC-aminopyrrolidine of Step 253j with the indicated reagents according to the procedures of Steps 253j, 253k and 253l (as the case may be).

[Table 11a]

[Table 11b]

Example 297

(2S, 4S) -4-amino-2-methylpyrrolidinyl) -1-cyclopropyl-7-fluoro-9- Carboxylic acid hydrochloride

Following the procedure of Example 253c, the product of Step 253b was treated with LDA at -78 &lt; 0 &gt; C, then formaldehyde was added and stirred until the reaction was complete, then the newly formed intermediate was dissolved in diethylaminosulfur trifluoride (DAST ) To form the intermediate product 4-t-butoxy-2,3,6-trifluoro-5- (fluoro) -methylpyridine and the product was reacted according to the remaining steps of Examples 253d-1 The title compound is prepared.

Example 298

8- (3-dimethylaminopyrrolidinyl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid,

8-Chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester 81 mg from the preceeding 253i is dissolved in 2.5 ml of anhydrous pyridine under a nitrogen atmosphere. To this solution is added a solution of 114 g of 3- (dimethylamino) pyrrolidine in 2.5 ml of pyridine and the reaction mixture is heated at 60 DEG C for 39 hours. The pyridine is removed in vacuo and the residue is stirred with IN NaOH in THF / water at 6O &lt; 0 &gt; C for 6 hours. The solution is acidified with acetic acid and the product is extracted with chloroform. After drying over MgSO ₄ , the solvent was removed and the residue was purified by silica gel chromatography eluting with 100: 40: 20: 8 chloroform: methanol: acetic acid: water to give the title product.

Example 299

(3R) -8- (3-Dimethylaminopyrilidinyl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid hydrochloride

The title compound is prepared according to Example 298 substituting 3- (dimethylamino) -pyrrolidine with (3R) -3- (dimethylamino) pyrrolidine.

Example 300

(3R, 1S) -8- (3- (1-aminoethyl) pyrrolidinyl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine- Chloride

Step B Example 8 253i 8-Chloro-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine- 3-carboxylic acid ethyl ester was dissolved in anhydrous acetonitrile, (1-t-butoxycarbonylamino) ethyl) pyrrolidine, which is prepared according to the method described in K. et al., J. Heterocyclic Chem., 29: 1481-1498 And reacted as described in Examples 253k-1 to give the title product.

Example 301

(3S, 1R) -8- (3- (1-aminoethyl) pyrrolidinyl) -1-cyclopropyl-7-fluoro-9- methyl-4-oxo-4H- quinolizine- Chloride

8-chloro in the previous step in Example 253i -1- cyclopropyl-7-fluoro-9-methyl-4-oxo-quinolinyl -4H- Jean-3-carboxylic acid ethyl ester 0.44g and 1.51g of NaHCO ₃ in anhydrous acetonitrile 40ml (3S, 1 R) -3- (1- (t-butoxycarbonylamino) pyridin-2-ylamino) propionate prepared according to Schroeder et al., J. Heterocyclic Chem., 29: 1481-1498 ) Ethyl) pyrrolidine and reacting as described in Examples 253k-1 to give the title product.

Example 302

(3R, 1R) -8- (3- (1-aminoethyl) pyrrolidinyl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine- Chloride

Step 3 0.35 g of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester of Example 253i and 0.73 g of sodium bicarbonate were added to 24 ml of anhydrous acetonitrile (3R, 1 R) -3- (1- (t-butoxycarbonylamino) pyridin-2-ylamino) propionic acid prepared according to Schroeder et al., J. Heterocyclic Chem., 29: 1481-1498 ) Ethyl) pyrrolidine and reacting as described in Examples 253k-l to give the title product.

Example 303

((R, S) -3-fluoropyrrolidine) -7-fluoro-9-methyl-4-oxo-4H-quinolizine-

Step 303a. N-CBZ- (R, S) -3-hydroxypyrrolidine

(R, S) -3-hydroxypyrrolidine (1.0 g, 0.011 mmol) was dissolved in ethyl acetate (50 ml) and to this solution was added N- (benzyloxycarbonyl) succinimide (2.86 g, 0.011 mmol). The mixture is stirred overnight and then partitioned between dilute aqueous HCl and ethyl acetate. The aqueous layer is extracted with ethyl acetate (2X). The organic layers were combined dried (MgSO ₄₎ and concentrated in vacuo. The crude product is purified by silica gel flash chromatography (ethyl acetate-hexane) to give the desired product as a clear oil. 2.1 g, 83%.

Step 303b. N-CBZ- (R, S) -3-fluoropyrrolidine

The compound (32.01 g, 9.10 mmol) from the pre-stage 303a is dissolved in anhydrous CH ₂ Cl ₂ (40 ml) and cooled to -78 ° C under nitrogen. Diethylaminosulfurtrifluoride (DAST) (1.32 ml, 10.0 mmol) is added in one portion through the syringe to the cooled solution, and the resulting solution is stirred at room temperature overnight. The product is concentrated in vacuo and the residue is separated by silica gel flash chromatography (ethyl acetate-hexane) to give a clear oil. 1.53 g, 75%.

Step 303c. (R, S) -3-fluoropyrrolidine hydrochloride

The compound of the previous step 303b (1.53 g, 6.85 mmol) was dissolved in methanol (50 ml) and 5% Pd / BaSO ₄ (0.5 g) was added. The mixture is degassed under vacuum (3X) and exposed to a low pressure hydrogen atmosphere (balloon) at room temperature for 4 hours. The reaction is terminated by vacuum filtration and the catalyst is removed. The filtrate is cooled in an ice bath and the HCl gas is bubbled through the cold solution for 1 minute. The resulting solution is concentrated in vacuo and the residue is triturated 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. ¹ H NMR (CD ₃ OD) d 2.1-2.46 (m, 2H), 3.33-3.65 (m, 4H), 5.43 (db.t., 1H, J _FH -51 Hz).

Step 303d. ((R, S) -3-fluoropyrrolidine) -7-fluoro-9-methyl-4-oxo-4H-quinolizine-

Example 253j of N-boc-3-aminopyrrolidine was converted to (R, S) -3-fluoropyrrolidine hydrochloride (0.66 g, 5.24 mmol) in the previous step 303c and the reaction product was treated as described previously To give 0.326 g (65%) of the title compound as a light yellow solid.

Elemental analysis for C ₁₈ H ₁₈ N ₂ O ₃ F ₂ :

Calculated: C, 62.05; H, 5.22; N, 8.04

Found: C, 62.06; H, 5.22; N, 7.86

Example 304

7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid

70 mg of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester was dissolved in 2 ml of anhydrous acetonitrile and 4- -Piperidyl) piperidine (70 mg, 0.4 mmol, Aldrich Chemical Co.) and treated as described in Examples 253j-k to give the title product.

Elemental analysis for C ₂₄ H ₃₀ N ₃ O ₃ F 1.5 H ₂ O:

Calculated: C, 63.42; H, 7.32; N, 9.24

Found: C, 62.99; H, 7.04; N, 8.78

Example 305

7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid trifluoroacetate was prepared in accordance with the general method of example 1 from 8- (4- (1-piperidyl) Acetic acid salt

Example 253i 8-Chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester 100 mg was dissolved in 3 ml of anhydrous acetonitrile and 4- (4 -Piperidyl) -piperidine (0.24 g, 0.93 mmol, Aldrich Chemical Co.) and converted to the TFA salt according to the procedure of Example 162, as described for Examples 253j-k to give the title product &Lt; / RTI &gt;

Elemental analysis for C ₂₄ H ₃₀ N ₃ O ₅ F ₄ .1.5H ₂ O:

Calculated: C, 54.93; H, 6.03; N, 7.39

Found: C, 54.97; H, 5.39; N, 7.24

Example 306

7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid (2-pyridyl)

Example 253i 8-Chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester 60 mg is dissolved in 2 ml of anhydrous acetonitrile and 4- (2 -Pyridyl) piperazine (63.5 mg, 0.39 mmol, Aldrich Chemical Co.) and treated as described in Examples 253j-k to give the title product.

Elemental analysis for C ₂₃ H ₂₃ N ₄ O ₃ F 1.5 H ₂ O:

Calculated: C, 61.46; H, 5.83; N, 12.46

Found: C, 61.76; H, 5.54; N, 11.64

Example 307

7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid trifluoroacetic acid salt &lt; EMI ID =

Example 253i 8-Chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester 50 mg was dissolved in 2 ml of anhydrous acetonitrile and N- Was reacted with 2-aminothiol (57.4 mg, 0.32 mmol, prepared by standard procedure from the unprotected compound purchased from Aldrich Chemical Co.) and treated as described in examples 253j-k and deprotected And converted to the TFA salt by the procedure of Example 162 to give the title product.

Example 308

(3R, 1S) -8- (3- (1-Amino) propyl) pyrrolidinyl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine- Hydrochloride

147 mg of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester of 3i is dissolved in 3 ml of anhydrous acetonitrile, ) Of the chiral product described in the literature (see Plummer, et al., Ter. Lett. 34: 7529-32 (1993)) with 3- (1-BOC- amino) propyl) pyrrolidine [326 mg, 1.13 mmol, (Prepared as described in Hayakawa et al., U. S. Patent No. 5,098, 912 (1992, 3, 24)), using a modification to &lt; RTI ID = 0.0 & To give the title product.

MS (high resolution) Found: 388.2039; Calculated: 388.2036 (M + H) &lt; ⁺ & gt ^;

Elemental analysis for C ₂₁ H ₂₇ N ₃ O ₃ FCl 揃 0.5H ₂ O:

Calculated: C, 58.13; H, 6.74; N, 9.68

Found: C, 58.24; H, 6.51; N, 9.71

Example 309

(3R, 1S) -8- (3- (1- (N-methyl) amino) propyl) pyrrolidinyl) Chloro-3-carboxylic acid hydrochloride

492.9 mg of the 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester of 3i is dissolved in 8 ml of anhydrous acetonitrile, (Plummer, et al., Ter. Lett. 34: 7529-32 (1993)) was added to a solution of 1-methyl- (Prepared as described in Hayakawa et al., U. S. Patent No. 5,098, 912 (1992, 3, 24)), using a modification to the described chiral product, to give the compound of Example 253j The defatting step is omitted and processed as described to obtain the title product.

Elemental analysis for C ₂₂ H ₂₉ N ₃ O ₃ FCl 0 .5H ₂ O:

Calculated: C, 57.95; H, 6.85; N, 9.22

Found: C, 58.24; H, 6.58; N, 9.30

Example 310

7-fluoro-9-methyl-4-oxo-4H-quinolizine-l- 3-carboxylic acid hydrochloride

171 mg of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester was dissolved in 4 ml of anhydrous acetonitrile and treated with (3R, (400 mg, 1.32 mmol, Plummer, et al., Ter. Lett. 34: 7529-32 (1993)) was added dropwise to a solution of Prepared as described] and processed as described in Examples 253j-l to give the title product.

MS (high resolution) Found: 402.2174; Calculated: 402.2193 (M + H) &lt; ⁺ & gt ^;

Elemental analysis for C ₂₂ H ₂₉ N ₃ O ₃ FCl 0.75 H ₂ O:

Calculated: C, 58.53; H, 6.81; N, 9.31

Found: C, 58.88; H, 6.70; N, 9.26

Example 311

Pyrrolidinyl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride

98 mg of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester of 3i is dissolved in 2 ml of anhydrous acetonitrile and 1- (N (Boc-amino) cyclopropyl) pyrrolidine [172 mg, 0.76 mmol, prepared as described in the literature (Hayakawa et al., U.S. Patent No. 5,098,912 (1992, 3, 24)) The title product is obtained by treatment as described in Examples 253j-l.

MS (high resolution) Found: 386.1893; Calculated: 386.1880 (M + H) &lt; ⁺ & gt ^;

Elemental analysis for C ₂₂ H ₂₉ N ₃ O ₃ FCl:

Calculated: C, 59.55; H, 6.12; N, 9.80

Found: C, 59.78; H, 5.97; N, 9.69

Example 312

Pyrrolidinyl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine Carboxylic acid hydrochloride

Step 312a. (S) -N-BOC-O- (methoxymethyl) serine methyl ester

(31.96 mmol) of (S) -N-BOC-serine methyl ester (Aldrich) was dissolved in CH ₂ Cl ₂ and cooled in an ice bath. To this stirred solution was added 2.83 g (35.16 mmol) of methoxymethyl chloride was added dropwise and the dropwise addition of diisopropylethylamine 4.544g (6.12ml, 35.16mmol). the reaction is stirred for 16 h after adding all reagents at room temperature. the solution is 0.5% HCl, saturated NaHCO _3, h ₂ O and brine , Dried over MgSO ₄ , filtered and the solvent removed to give a yellow oil. The residue was purified by silica gel chromatography eluting with 15-20% ethyl acetate: hexanes to give 6 g of the title product after solvent removal .

Step 312b. 2- (BOC-amino) -3- (methoxymethoxy) -1-propanol

Was added dropwise LAH 570mg (14.84mmol) suspension in THF 15ml previous stage compound (5.202g, 19.78mmol) (ice bath) THF 15ml was cooled from 312a of the under N ₂ atmosphere. The mixture is stirred for 1.5 hours and the reaction quenched with water and 50% NaOH, filtered and the filtrate evaporated to give the crude product. A yellow oil was obtained which was purified by silica gel chromatography eluting with 35-40% ethyl acetate: hexane to give 3.475 g of the title product as a colorless oil. MS 236 (M + H) &lt; ⁺ & gt ^;

Example 312c. 2- (BOC-amino) -3- (methoxymethoxy) -1-propane

6.8 ml (48.74 mmol) of triethylamine are added dropwise to a solution of the compound from the previous step 312b (3.47 g, 14.77 mmol) in 7 ml of DMSO cooled to 0 占 폚. The pyridine-SO ₃ complex (7.05 g, 44.31 mmol) is dissolved in 27 ml of DMSO and added to the first solution, the reaction is quenched and the mixture is stirred for 1 hour. The solution is poured into 120 ml of cold brine and the mixture is washed three times with ethyl acetate. The extract was washed with water and dried with MgSO ₄ and filtered to remove the yongbae in vacuo to give a yellow oil 6g and uses it directly in the next step.

Step 312d. 4- (BOC-amino) -5- (methoxymethoxy) -2-pentenoic acid ethyl ester

CH ₂ Cl ₂ in the compound from the previous step 312c was cooled in an ice bath (14.77ml) in CH ₂ Cl ₂ solution in 56ml 42ml (ethoxy-methylene carboxy) was added dropwise triphenyl phosphorane 5.454g (15.66mmol). After completion, the reaction is stirred at room temperature for 16 hours. The solvent was removed and the residue was purified by column chromatography eluting with 10% ethyl acetate: hexane to give 2.763 g of a colorless oil.

Step 312e. 4- (BOC-amino) -5- (methoxymethoxy) -3- (nitromethyl) -pentanoic acid ethyl ester

In the previous stage 312d of nitromethane was cooled in an ice bath 8ml compound (2.76g, 9.71mmol) under N ₂ atmosphere a solution of 1,8-dia Arba bicyclo [5.4.0] undec-7-ene 7ml (6.934g, 45.55 mmol). The mixture is warmed to room temperature and stirred for 16 hours. The solution is diluted with CH ₂ Cl ₂ and extracted with water, 10% HCl, 10% NaHCO ₃ , water and brine. Dry the solution with MgSO ₄ and the solvent removed. The residue is chromatographed on silica gel eluting with 10-15% ethyl acetate: hexanes and the solvent is removed to give 2.01 g of the title product as a white solid.

Example 312f. 4- (BOC-amino) -5- (methoxymethoxy) -3- (aminomethyl) -pentanoic acid ethyl ester

2 g of the compound of pre-stage 312e are dissolved in 200 ml of ethanol and hydrogenated at 4Atm with 4 g of Raney nickel catalyst for 24 hours. The catalyst is filtered off and the solvent is evaporated. The residue is used immediately in the next step.

Step 312g. N-BOC-2- (methoxymethoxy) -1- (5-oxo-3-pyrrolidinyl)

The residue of the previous step 312f is dissolved in 150 ml of ethanol and heated under reflux for 8 hours. The solvent is removed and the residue is chromatographed on silica gel eluting with 4% methanol / methylene chloride. Solvent was removed to give 1.36 g of the title product.

Step 312h. N-BOC-2- (methoxymethoxy) -1- (5-thioxo-3-pyrrolidinyl) -ethylamine

500 mg (1.74 mmol) of 312 g of the compound sample and 387 mg (0.957 mmol) of Lawesson's reagent are dissolved in 4 ml of THF and stirred under N ₂ for 3 hours. The solvent is removed and the residue is dissolved in CH ₂ Cl ₂ and chromatographed on silica gel, eluting with 35% ethyl acetate: hexane. The solvent is removed to leave 500 mg of product.

Step 312i. N-BOC-2- (methoxymethoxy) 3-pyrrolidinyl) -ethylamine acetic acid salt

250 mg (0.825 mmol) of a compound sample of the previous step 312h and 1.57 g (6.6 mmol) of NiCl ₂ .6H ₂ O are dissolved in 10 ml of a 1: 1 mixture of methanol and THF, the solution is cooled to -78 ° C and stirred under N ₂ . 749 mg (19.8 mmol) of NaBH _{4 are} added in small portions and the mixture is stirred for 2 hours. The solvent is removed in vacuo and dissolved in 20% methanol in chloroform. Filter with solution and remove solvent. The residue is 1: 1: 1: 1 n- butanol: ethyl acetate: H ₂ O: by elution with acetic acid and purified by silica gel chromatography to give 349mg of the title product.

Step 312j. Pyrrolidinyl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine Carboxylic acid hydrochloride

107 mg (0.33 mmol) of the 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid ethyl ester obtained in Example 253j was dissolved in 2.5 ml of anhydrous acetonitrile And reacted with the compound of step 312i (0.825 mmol) as described in example 253j-l to give 74 mg of the title product.

Example 313

Pyrrolidinyl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride

Example 253i 8-Chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester 150 mg was dissolved in 2 ml anhydrous acetonitrile, Amino-1-methylethylpyrrolidine (155 mg, 0.77 mmol) prepared by the standard method from the free base described in Hayakawa et al., US Pat. No. 5,098,912 (1992, 3, In the same manner as in Example 253k to give the title product.

Elemental analysis for C ₂₁ H ₂₇ N ₃ O ₃ FCl · 1.5H ₂ O:

Calculated: C, 55.93; H, 6.71; N, 9.32

Found: C, 56.07; H, 6.71; N, 8.95

Example 314

Pyrrolidinyl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride

Step 314a. 4- (BOC-amino) -3- (Nitromethyl) -heptanoic acid ethyl ester

Following the procedure of Example 312b, replacing the compound of Step 312a with DL-N-BOC-norvaline methyl ester (prepared from norvaline by standard method), the product was obtained via the procedure of Example 312 Steps c to e To give the title compound.

Step 314b. 4- (BOC-amino) -3- (Nitromethyl) -heptanol

The procedure of Example 312 Step b was repeated to replace the compound of Step 312a thereof with 4- (BOC-amino) -3- (Nitromethyl) -heptanoate ethyl ester from Step 314a (1.3 g, 3.91 mmol) &Lt; / RTI &gt;

Step 314c. 4- (BOC-amino) -3- (nitromethyl) -heptanol, O-mesityl ether

610 mg (2.30 mmol) of the compound from pre-stage 314b are dissolved in ₂ ml of CH ₂ Cl ₂ and the solution is cooled to -10 ° C. 289 mg (0.195 ml, 2.52 mmol) of methanesulfonyl chloride and 319 mg (3.15 mmol) of triethylamine are added dropwise. The solution is stirred at 0-10 &lt; 0 &gt; C for 2 hours. The solution is diluted with CH ₂ Cl ₂ , washed once with water, once with 5% NaHCO ₃ and once with brine. The solvent was dried with MgSO _4, filtered and the solvent removed to give the title product as an oil 720mg.

Step 314d. 3- (1- (N-BOC-amino) butyl) pyrrolidine

720 mg of the product from Step 314c is dissolved in 50 ml of methanol and hydrogenated at 4 atm with 360 mg of 10% Pd / C catalyst at room temperature for 24 hours.

Step e. Pyrrolidinyl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride

238 mg of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester from Example 253i was dissolved in 5 ml of anhydrous acetonitrile and 3- Pyrrolidine (620 mg, 1.83 mmol, prepared from 314d) and treated as described in Examples 253j-l to give the title product. MS (high resolution) Found: 402.2199; Calculated: 402.2193 (M + H) &lt; ⁺ & gt ^;

Examples 315 to 323

The compounds of Examples 315 to 323 are prepared as shown in Table 12 by replacing the 3-BOC-aminopyrrolidine of Step 253j with the indicated reagents according to the procedures of Steps 253j, 253k and 253l above.

[Table 12a]

[Table 12b]

Example 324

4-oxo-8- (trans-4-trifluoromethyl-3-aminopyrrolidinyl) -4H-quinolizine-3-carboxylic acid hydrochloride

Step 324a. Trans-N-benzyl-4-trifluoromethyl-3-pyrrolidinecarboxylic acid ethyl ester

Trifluoroacetic acid (3ml, CH ₂ Cl ₂ of 1N) in the 0 ℃ trans of CH ₂ Cl ₂ 30ml - ethyl trifluoroacetate lock Roto carbonate (4.969g) as described in Reference: Chem. Pharm. Is added to a solution of (N-benzyl-N-methoxymethyl) trimethylsilylamine (7.00 g) prepared according to Bull., 33: 2762 (1985) and the mixture is stirred for 2 hours. After dilution with CH ₂ Cl ₂ , the solution was washed with saturated NaHCO ₃ solution and water, dried over MgSO ₄ and concentrated in vacuo to give a light yellow liquid (8.75 g).

Step 324b. Trans-N-benzyl-4-trifluoromethyl-3-pyrrolidinecarboxylic acid

The liquid sample (4.739g) in 60 ℃ THF: is hydrogenated: (1 25ml, 1.5) in LiOH · H ₂ O 1.98g 3.64g in and to give the intermediate as a post-treatment after solid H ₂ O.

Step 324c. Trans-1-benzyl-3- (BOC-amino) -4-trifluoromethylpyrrolidine

Mixture of intermediate (3.64g) sample, diphenylphosphoryl azide (3.50ml), t- butanol (40ml), triethylamine (2.3ml) and dioxane 40ml of 324b, and then heated for 17 hours under N _2. The solvent is removed under vacuum. The residue is dissolved in CH ₂ Cl ₂ , washed with saturated NaHCO ₃ solution and water, dried over MgSO ₄ and concentrated in vacuo. The product was purified by silica gel chromatography eluting with 100: 5: 5 CH ₂ Cl ₂ : methanol: NH ₄ OH to give 1.77 g of the title compound.

Step 324d. Trans-3- (BOC-amino-4-trifluoromethylpyrrolidine

The compound of the previous step 324c (1.55 g) is hydrogenated under H _{2 4} Atm in 50 ml of methanol with 0.45 g of 10% Pd / C for 3.5 days. The catalyst is removed by filtration and the solvent removed to give the title compound as a white solid (1.09 g).

Step 324e. 4-oxo-8- (trans-4-trifluoromethyl-3-aminopyrrolidinyl) -4H-quinolizine-3-carboxylic acid hydrochloride

The title compound was prepared (97mg) by replacing 3-BOC-aminopyrrolidine of Example 253j with the compound of Step 325d according to the procedure of Example 253 Steps k-1.

Elemental analysis for C ₁₉ H ₁₉ N ₃ O ₃ F ₄ .HCl ₁ .25H ₂ O:

Calculated: C, 48.31; H, 4.80; N, 8.90

Found: C, 48.45; H, 4.63; N, 8.53

Example 325

4-oxo-8- (trans-4-trifluoromethyl-3-aminomethylpyrrolidinyl) -4H-quinolizine-3-carboxylic acid hydrochloride

Step 325a. Trans-1-benzyl-3- (hydroxymethyl) -4-trifluoromethylpyrrolidine

A compound sample from step 324 above (4.02 g) is dissolved in 10 ml THF, then LAH (8.0 ml, 1.0 N in THF) is added and the solution is stirred at room temperature for 30 minutes. The reaction was quenched and the product extracted and the solvent removed to give 3.36 g of the title product.

Example 325b. Trans-1-benzyl-3- (aminomethyl) -4-trifluoromethylpyrrolidine

The compound (3.36 g) of the pre-stage 325a, triphenylphosphine and phthalimide are dissolved in 50 ml of THF and DEAD (2.05 ml) is added dropwise to this solution at room temperature. The reaction is terminated almost immediately and the solvent is removed. The residue was dissolved in 50ml of ethanol was heated under reflux for 3 hours the reaction was added _{NH 2 NH 2 · H 2 O} 0.65ml under N _2. The solution is cooled to room temperature and 5 ml of concentrated HCl is added and the mixture is filtered. The filtrate is concentrated and the residue is dissolved in 10% HCl and extracted with CH ₂ Cl ₂ (6X). The aqueous layer is adjusted to pH 11 with NaOH, extracted with CH ₂ Cl ₂ , washed with H ₂ O, dried over MgSO ₄ and concentrated. The residue is dissolved in 7:25 H ₂ O: methanol (BOC) ₂ O is added and the reaction is stirred at room temperature for 30 minutes. The methanol is removed in vacuo and the aqueous residue is extracted with CH ₂ Cl ₂ . The extract is washed with H ₂ O, dried over MgSO ₄ and concentrated. The residue was chromatographed on silica gel eluting with 1: 4 ethyl acetate: hexane to give the title compound as a white solid.

Step 325c. Trans-3- (BOC-aminomethyl) -4-trifluoromethylpyrrolidine

The compound of Step 325b is hydrogenated according to the procedure of Example 324 step d to yield the title compound as a white solid.

Step 325d. 4-oxo-8- (trans-4-trifluoromethyl-3-aminomethylpyrrolidinyl) -4H-quinolizine-3-carboxylic acid hydrochloride

Example 253 Treatment of the reaction product according to example 253 steps k-1, substituting the compound of step 325c for 3-BOC-aminopyrrolidine following the procedure for step j, affords 77 mg of the title product.

Elemental analysis for C ₂₀ H ₂₁ N ₃ O ₃ F ₄ .HCl · H ₂ O:

Calculated: C, 49.85; H, 5.02; N, 8.72

Found: C, 49.86; H, 5.10; N, 8.93

Example 326

3 (S) -norbornylamino) pyrrolidinyl) -4H-quinolizine-2-carboxylic acid 3-carboxylic acid hydrochloride

The title product is prepared according to the procedure of Example 166 substituting the starting material pyrido-pyrimidine for the product of Example 253 step j.

MS: 445 (M + 1) ^&lt; + &^gt;;

Elemental analysis for C ₂₃ H ₂₉ N ₄ O ₄ F 1.5 HCl 0.75 H ₂ O:

Calculated: C, 53.88; H, 6.29; N, 10.93

Found: C, 53.87; H, 6.10; N, 11.10

Example 327

3 (S) -I-Cyclopropyl-7-fluoro-9-methyl-4-oxo-8- 3-carboxylic acid hydrochloride

According to the procedure of Example 167, the starting material pyrido-pyrimidine was converted to the product of Example 253 step j, to give 97 mg of the title compound.

Elemental analysis for C ₂₁ H ₂₅ N ₄ O ₄ F 2 HCl:

Calculated: C, 51.54; H, 5.56

Found: C, 51.50; H, 5.48

Example 328

3 (S) -Ilanyl- (S) -alaninylamino) pyrrolidinyl) -7-fluoro- -4H-quinolizine-3-carboxylic &lt; / RTI &gt; acid hydrochloride

Following the procedure of Example 168, substituting the starting material pyrido-pyrimidine for the product of Example 253 step j, 680 mg of the title compound is prepared.

Elemental analysis for C ₂₄ H ₃₀ N ₅ O ₅ F 3 HCl 0.5 H ₂ O:

Calculated: C, 46.18; H, 5.57; N, 11.22

Found: C, 46.34; H, 5.77; N, 11.52

Example 329

7-fluoro-6-methyl-4-oxo-8- (3-aminopyrrolidinyl) -4H-quinolizine-3-carboxylic acid hydrochloride

Step 329a: 4-t-Butoxy-3-chloro-2,5-difluoro-6- (trimethylsilylmethyl)

To a solution of 4-t-butoxy-3-chloro-trifluoropyridine (7.55 g, prepared according to Example 253 step a) in 200 mL of THF stirred at -78 &lt; 0 &gt; C was added trimethylsilylmethyllithium (1.0 M in pentane, 66 ml) is added dropwise and the resulting solution is stirred for 1 hour. The reaction is quenched with saturated NaCl solution and the mixture is extracted with ether. The extract was then washed with brine, dried over MgSO ₄ and concentrated. The residue was purified by silica gel chromatography eluting with 1: 32 ethyl acetate: hexane to give 6.26 g of the title compound.

Step 329b. 4-t-2, 5-difluoro-6- (trimethylsilylmethyl) pyridine

The compound of pre-stage 329a is dissolved in 100 ml of ethyl acetate and 15 ml of triethylamine and 1.3 g of 10% Pd / C are added. The mixture is shaken with H _{2 4 At} mgk for 24 hours. The catalyst is removed and the filtrate is concentrated. The residue was purified by silica gel column chromatography eluting with 1: 32 ethyl acetate: hexane to give 4.38 g of a colorless liquid.

Step 329c. 2, 5-difluoro-4-t-butoxy-6-methylpyridine

1.00 g of the compound sample of 329c is dissolved in 10 ml of THF, BH ₄ NF (1.0 M in THF, 3.7 ml) is added, and the reaction is stirred at room temperature for 2.5 hours. The solvent was removed, washed the residue was dissolved in ether and then with water and brine, dried with MgSO _4. The solvent was removed and the residue was purified by silica gel chromatography eluting with 1: 32 ethyl acetate: hexane to give 0.68 g of the title compound as colorless liquid.

Step 329d. 7-fluoro-6-methyl-4-oxo-8- (3-aminopyrrolidinyl) -4H-quinolizine-3-carboxylic acid hydrochloride

According to the procedure of Example 253 Step e, the product is treated according to Step 253e-1, replacing the 3-methylpyridine compound with the 6-methyl compound of the previous step 329c to yield 31 mg of the title compound.

Elemental analysis for C ₁₈ H ₂₀ N ₃ O ₃ F · HCl · 1.5H ₂ O:

Calculated: C, 52.888; H, 5.92; N, 10.28

Found: C, 52.60; H, 5.98; N, 10.18

Example 330

7-fluoro-4H-quinolizine-8- (1-imidazolyl) -9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride

The title compound is prepared according to the procedure of Example 253 step j, substituting 3-t-BOC-aminopyrrolidine for imidazole and treating the product according to Example 253 step k.

Example 331

7-fluoro-4H-4-oxo-9-methyl-quinolizine-3-carboxylic acid hydrochloride

The title compound is prepared according to the procedure of Example 253 step e, by treating the product according to Example 253 Steps e - 1, substituting cyclopropylacetonitrile compound for propionitrile.

Elemental analysis for C ₁₇ H ₂₀ N ₃ O ₃ FCl HCl 1.5 H ₂ O:

Calculated: C, 51.45; H, 6.10; N, 8.93; Cl, 8.93

Found: C, 51.51; H, 5.90; N, 10.78; Cl, 8.91

Example 332

8- (3-Amino-1-pyrrolidinyl) -1-cyclopropyl-9-ethyl-7-fluoro-4H-4-quinolizine-3-carboxylic acid hydrochloride

The title compound is prepared according to the procedure of Example 253 step c, substituting ethyl iodide for methyl iodide and treating the product according to example 253 steps 253d-1.

Elemental analysis for C ₁₉ H ₂₂ N ₃ O ₃ F · 1.25 HCl · 1.5 H ₂ O:

Calculated: C, 53.95; H, 6.01; N, 9.93

Found: C, 53.82; H, 5.87; N, 10.18

Example 333

1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-8- (3- (1,2,3-triazol- Carboxylic acid

Step 333a. 1-benzyl-3- (1,2,3-triazol-1-yl) pyrrolidine

A solution of 3-azido-1-benzylpyrrolidine (2.30 g) and trimethylsilylacetylene (8.0 ml) in 15 ml of toluene is heated under reflux for 18 hours. The solvent is removed to give an oil phase residue. The residue is dissolved in 20% HCl and heated to reflux for 18 hours. The solution was cooled and made basic with NaHCO ₃ and extracted with methylene chloride. The organic layer is washed with water, dried over MgSO ₄ and concentrated. The crude product was purified by silica gel chromatography eluting with CH ₂ Cl ₂ : methanol: NH ₄ OH 100: 10: 1.

Step 333b. 3- (1,2,4-triazol-1-yl) pyrrolidine

The compound of Step 333a is dissolved in methanol and hydrogenated by hydrogenation over a 10% Pd / C catalyst for 16 hours. The mixture is filtered and the solvent is removed to give 1.00 g of product.

Stage 333c. 1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-8- (3- (1,2,3-triazol- Carboxylic acid

According to the procedure of Example 253 step j, replacing 3-BOC-aminopyrrolidine with the compound of Step 333b and treating the product according to Example 253 Steps j and k, the title compound is prepared.

Elemental analysis for C ₂₀ H ₂₀ N ₅ O ₃ F:

Calculated: C, 60.45; H, 5.07; N, 17.62

Found: C, 60.46; H, 5.20; N, 17.63

Example 334

7-fluoro-4H-quinolizine-9-methyl-4-oxo-8- (cis- Carboxylic acid hydrochloride

The title compound was prepared according to the procedure of Example 253 step j, substituting 3-BOC-aminopyrrolidine with cis-3-BOC-amino-4-methylpyrrolidine and treating the product according to Example 253 steps j- .

Elemental analysis for C ₁₉ H ₂₂ N ₃ O ₃ F · HCl · 1.25H ₂ O:

Calculated: C, 54.55; H, 6.14; N, 10.04

Found: C, 54.62; H, 6.10; N, 10.08

Example 335

8- (2-aminoethyl) - 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride

The title compound is prepared according to the procedure of Example 253 step j, substituting 3-BOC-aminopyrrolidine with 2-aminoethylamine and treating the product according to Example 253 Steps j-1.

Elemental analysis for C ₁₆ H ₁₈ N ₃ O ₃ F · HCl · 0.85 H ₂ O:

Calculated: C, 51.78; H, 5.62; N, 11.32

Found: C, 51.79; H, 5.31; N, 11.15

Example 336

Pyrrolidinyl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride

Following the procedure for example 253 step j, replacing 3-BOC-aminopyrrolidine with 3 - ((N-BOC-N-ethyl) amino) methylpyrrolidine, the product is obtained according to example 253 steps j- To give the title compound.

Elemental analysis for C ₂₁ H ₂₈ N ₃ O ₃ F · 1.25 HCl · H ₂ O:

Calculated: C, 55.92; H, 6.54; N, 9.32

Found: C, 56.18; H, 6.32; N, 9.27

Example 337

Pyrrolidinyl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride

The title compound was prepared according to the procedure of Example 253 step j, by replacing 3-BOC-aminopyrrolidine with 3- (N-BOC-aminoethyl) pyrrolidine and treating the product according to Example 253 steps j-1 to give .

MS: 374 (M-Cl) ^&lt; ⁺ &^gt;;

Elemental analysis for C ₂₀ H ₂₄ N ₃ O ₃ F · HCl · H ₂ O:

Calculated: C, 56.14; H, 6.36;

Found: C, 56.27; H, 6.14

Example 338

8-Bicyclo [4.3.0] nonyl) -4-oxo-quinolizine-l- 3-carboxylic acid hydrochloride

Following the procedure for example 253 step j, replacing 3-BOC-aminopyrrolidine with 2-methyl-2,8-diaza-bicyclo [4.3.0] nonane the product is obtained in analogy to example 253 steps j- To yield the title compound.

Elemental analysis for C ₂₂ H ₂₆ N ₃ O ₃ F · 1.25HCl · 0.5H ₂ O:

Calculated: C, 58.20; H, 6.27; N, 9.25

Found: C, 58.09; H, 6.27; N, 9.25

Example 339

Cyclopropyl-7-fluoro-4H-8- ((lS, 4S) -2,5-diaza- bicyclo [2.2.1] heptan- Quinolizine-3-carboxylic acid hydrochloride

Following the procedure for example 253 step j, replacing 3-BOC-aminopyrrolidine with (1S, 4S) -2,5-diaza-5-BOC-bicyclo [2.2.1] heptane, 253 &lt; / RTI &gt; to give the title compound.

Elemental analysis for C ₁₉ H ₂₀ N ₃ O ₃ F 1.5 HCl 1.0 H ₂ O:

Calculated: C, 53.06; H, 5.51; N, 9.77

Found: C, 53.19; H, 5.37; N, 9.58

Example 340

4-oxo-8- (3- (2-pyridinyl) -1-pyrrolidinyl) -quinolizine-3-carboxylic acid hydrochloride

The title compound is prepared according to the procedure of Example 253 step j, substituting 3- (2-pyridinyl) pyrrolidine for 3-BOC-aminopyrrolidine and treating the product according to Example 253 Steps j-1 .

Elemental analysis for C ₂₃ H ₂₃ N ₃ O ₃ F · HCl · H ₂ O:

Calculated: C, 55.43; H, 5.26; N, 8.43

Found: C, 55.69; H, 4.97; N, 8.52

Example 341

^{8 - ((1R *, 2S} *, 6R *) -2- amino-8-azabicyclo [4.3.0] nonan-8-yl)) - -4H-9- methyl-1-cyclopropyl-7-fluoro -4-oxo-quinolizine-3-carboxylic acid hydrochloride

Step 341a, 1R ^* , 2S ^* , 6R ^* -2-BOC-amino-8-azabicyclo [4.3.0] nonane

1. 2 ml of ON trifluoroacetic acid are added to a solution of 2.0 ml of cyclohexane in 20 ml of methylene chloride stirred at 0 ° C and 4.29 g of N-benzyl-N- (methoxymethyl) -trimethylsilylmethylamine. The mixture is stirred at 0 &lt; 0 &gt; C for 16 hours and then diluted with methylene chloride. The solution is washed with NaHCO ₃ and water and dried over MgSO ₄ . After solvent removal, it remains an oily residue. The residue is dissolved in 65 ml of methanol, then 2.2 g of NH ₂ OH-HCl, 10 ml of 10% NaOH and 6.5 ml of methylene chloride are added and the reaction is heated to 60 ° C for 3 hours. The solvent was removed and residue was dissolved in methylene chloride and washed with water, dried over MgSO ₄ and concentrated to give an oil. The oil is dissolved in 30 ml of THF and 1.57 g of LAH are added and the mixture is heated under reflux for 2 hours. The reaction is quenched with water, the solid is removed and the filtrate is concentrated. The concentrate is dissolved in 10 ml of methanol and 10 ml of water. To this solution is added 5.0 g of (BOC) ₂ O and the reaction is stirred for 16 hours. The methanol is removed in vacuo and the residue is extracted with methylene chloride. The oil of 100: 5: 0.5 methylene chloride: methanol and eluted with NH ₄ OH filtrate was purified by silica gel chromatography to give the title compound 1R ^*, 2S ^*, 6R ^* 0.36g isomers and 1R ^*, 2S ^*, 6R ^* isomer 2.22g &Lt; / RTI &gt; 1R ^* , 2S ^* , 6R ^* isomers are stirred under H _{2 4} Atm in 25 mL of methanol for 48 hours with 0.12 g of 10% Pd / C. The catalyst is filtered off and the solvent is removed to give the title compound.

Step 341b. ^{8 - ((1R *, 2S} *, 6R *) -2- amino-8-azabicyclo [4.3.0] nonan-8-yl)) - -4H-9- methyl-1-cyclopropyl-7-fluoro -4-oxo-quinolizine-3-carboxylic acid hydrochloride

Example 253 Following the procedure of step j, the product was prepared in a manner similar to Example 1 by replacing 3-BOC-aminopyrrolidine with 1R ^* , 2S ^* , 6R ^* -2-BOC- amino-8-azabicyclo [4.3.0] 253 &lt; / RTI &gt; to give the title compound.

Elemental analysis for C ₂₂ H ₂₆ N ₃ O ₃ F · 1.25 HCl · 1.5 H ₂ O:

Calculated: C, 55.55; H, 6.43; N, 8.83

Found: C, 55.40; H, 6.38; N, 8.72

Example 342

^{8 - ((1R *, 2S} *, 6R *) -2- amino-8-azabicyclo [4.3.0] nonan-8-yl)) - -4H-9- methyl-1-cyclopropyl-7-fluoro -4-oxo-quinolizine-3-carboxylic acid hydrochloride

342a. The N-benzyl group is removed from the 1R ^* , 2S ^* , 6R ^* -isomers to give the title compound.

Step 341b. ^{8 - ((1R *, 2S} *, 6R *) -2- amino-8-azabicyclo [4.3.0] nonan-8-yl)) - -4H-9- methyl-1-cyclopropyl-7-fluoro -4-oxo-quinolizine-3-carboxylic acid hydrochloride

Example 253 Following the procedure for step j, 3-BOC-aminopyrrolidine was reacted with 1R ^* , 2S ^* , 6R ^* -2-BOC-amino-8-azabicyclo [4.3.0] nonane prepared in step 342a The product is treated in accordance with steps 251 to 251 of Example 253 to give the title compound.

Elemental analysis for C ₂₂ H ₂₆ N ₃ O ₃ F 1.0 HCl 1.25 H ₂ O:

Calculated: C, 57.64; H, 6.49; N, 9.17

Found: C, 57.70; H, 6.80; N, 9.18

Example 343

6-amino-3-azabicyclo [3.1.0] hexan-3-yl)) - 1- cyclopropyl- Oxo-quinolizine-3-carboxylic acid hydrochloride

According to the procedure of Example 253 step j, 3-BOC-aminopyrrolidine was reacted with 1a, 2a, 6a-2-BOC-amino-8-azabicyclo [4.3.0] hexane prepared according to U.S. Patent No. 5,298,629 , The product is treated according to Example 253 steps j-1 to yield the title compound.

Elemental analysis for C ₁₉ H ₂₀ N ₃ O ₃ F 1.5 HCl 0.5 H ₂ O:

Calculated: C, 54.19; H, 5.39; N, 9.98

Found: C, 54.43; H, 5.28; N, 9.87

Example 344

4-fluoro-4H-4-oxo-quinolizine-3-carboxylic acid hydro- Chloride

Step 344a. 1-CBZ-3, 4-epoxy-pyrrolidine

1-CBZ-3-pyrroline (20 g) is dissolved in 200 ml of CH ₂ Cl ₂ . MCPBA (50-60% purity, 61.5 g) in 300 mL of CH ₂ Cl ₂ is added to the above solution at 0 ° C and the reaction is stirred at 45 ° C for 18 hours. And the reaction mixture was filtered and the filtrate was treated with NaHSO ₃ (ca. 5g). The solution was poured in 1L 1N NaOH and the mixture shaken to separate the organic layer is washed with water, dried and concentrated by MgSO _4. The residue is used immediately in the next step.

Step 344b. Trans-3-azido-1-benzyloxycarboxy-4-hydroxypyrrolidine

The compound of step 344a is dissolved in 250 ml of acetone. NaN ₃ (20.16 g) in 200 ml of water is added and the reaction is stirred at 60 캜 for 18 hours. The reaction mixture is poured into saturated NaCl solution and the mixture is extracted with CH ₂ Cl ₂ (3X). The residue was purified by silica gel column chromatography eluting with 3% methanol in CH ₂ Cl ₂ to give 5.92 g of product.

Step 344c. Trans-azido-1-benzyloxycarboxy-4-fluoropyrrolidine

The compound of step 344b is dissolved in 15 mL of CH ₂ Cl ₂ and cooled to -78 ° C. DAST (0.82 ml) is added and the reaction is stirred at room temperature for 16 hours. The solvent is removed and the residue is dissolved in ethyl acetate and the solution is washed with saturated NaHCO ₃ and dried over MgSO ₄ . The solvent was removed and the residue was purified by silica gel column chromatography eluting with 1% methanol in CH ₂ Cl ₂ to give 0.88 g of the title compound.

Step 344d. Trans-3- (BOC-amino) -4-fluoropyrrolidine

The compound of Step 344c is stirred with Rani Ni for 9 hours under H ₂ atm in methanol. The catalyst is removed by filtration. The filtrate is concentrated and the residue is treated with (BOC) ₂ O and the reaction is stirred for 16 h. The methanol is removed in vacuo and the residue is extracted with methylene chloride. Wash the extract with water, dried over MgSO ₄ and concentrated. The residue of 100: 5: 0.5 methylene chloride: methanol and eluted with NH ₄ OH filtrate was purified by silica gel chromatography to obtain 1-benzyloxy-carboxy compound. This protecting group is removed by hydrogenation under H ₂ to Pd / C for 30 min. The catalyst was removed and the filtrate was concentrated to give the title compound (331 mg).

Stage 344e. 4-fluoro-4H-4-oxo-quinolizine-3-carboxylic acid hydro- Chloride

The title compound (44 mg) is prepared according to the procedure of Example 253 step j, by treating the product according to example 253 steps j-1, substituting 3-BOC-amino-pyrrolidine for the compound of step 344d.

Elemental analysis for C ₁₈ H ₁₉ N ₃ O ₃ F ₂揃 1.3HCl 揃 2.0H ₂ O:

Calculated: C, 48.39; H, 5.48; N, 9.40

Found: C, 48.12; H, 5.58; N, 9.63

Example 345

7-fluoro-4H-8- (1-homopiperazinyl) -9-methyl-4-oxo-quinolizine-3-carboxylic acid, acetic acid salt

Following the procedure for 298, replacing 3- (dimethylamino) -pyrrolidine with homopiperazine, the title compound is prepared.

Example 346

7, 9-difluoro-4H-8- (4-methylpiperazinyl) -4-oxo-1-phenylquinolizine-3-carboxylic acid hydrochloride

Step 346a. 1- (2,3,5,6-tetrafluoro-4-pyridinyl) -4-methylpyrrazine

Pentafluorophenyl in CH ₂ Cl ₂ solution 150㎖ pyridine (16.1g, 95.2mmol) and triethylamine Pierre N- methyl piperazine in a cold solution of _{(11.1g, 110mmol) CH 2 Cl} 2 50㎖ (10.0g, 100mmol ). The solution is stirred for 2 hours and then at room temperature for 16 hours. The solution was extracted with water and the organic layer was washed with brine dried over MgSO ₄ and concentrate to obtain the product was 23.25g. MS: 250 (M + H) &lt; ⁺ &gt;; _{^{1 H NMR (CDCl 3) δ}} : 2.35 (s, 3H), 2.55 (m, 4H), 3.5 (m, 4H)

Step 346b. 1- (2-hydrazino-3,5,6-trifluoro-4-pyridinyl) -4-methylpyrellane

37.34 g (746 mmol) of hydrazine hydrate was added to a solution of the compound of the previous step 346b (23.34 g, 93.2 mmol) in 500 ml of ethanol and the reaction was refluxed for 16 hours. The solvent is removed and the residue is dissolved in CH ₂ Cl ₂ . Washing with water the solution is dried over MgSO ₄ and filtered The solvent was removed under vacuum. The residue was triturated with ether and collected by filtration to give 17.42 g of a light yellow solid.

Elemental analysis for C ₁₀ H ₁₄ N ₅ O ₃ F ₃ :

Calculated: C, 45.97; H, 5.40; N, 26.81

Found: C, 45.99; H, 5.34; N, 26.65

Step 346c. 1- (2, 3, 5-Trifluoro-4-pyridinyl) -4-methylpiperazine

A suspension of 17.36 g (66.4 mmol) of the compound of Step 346b in 200 ml of ethanol and 20 ml of 20% NaOH is stirred and bubbled with air for 16 hours. The mixture is poured into brine and the mixture is extracted with CH ₂ Cl ₂ . The extracts were dried with MgSO ₄ and filtered to remove the solvent, and the solvent removed to give a solid 13.40g. The residue was chromatographed on silica gel eluting with ethyl acetate to give 11.54 g of pure title product.

Elemental analysis for C ₁₀ H ₁₂ N ₃ F ₃ :

Calculated: C, 51.94; H, 5.23; N, 18.18

Found: C, 51.63; H, 4.92; N, 17.73

Step 346d. 2- (3,5-Difluoro-4-) 4-methylpiperazinyl) -2-pyridinyl) -phenylacetonitrile

LDA solution (99.4 mmol, 66.3 mL, 1M in hexane) in 50 mL of THF is prepared and cooled to -78 [deg.] C for 15 min. To this solution, a solution of 8.87 g (75.7 mmol) of phenylacetonitrile in 35 ml of THF is added dropwise. The reaction is stirred at -78 &lt; 0 &gt; C for 15 minutes and then at 0 &lt; 0 &gt; C for 30 minutes. The solution is cooled to-60 C and the solution of the mixture from step 346c in 35 ml THF is added dropwise. The reaction mixture is stirred at -60 &lt; 0 &gt; C for 1 h and at 0 &lt; 0 &gt; C for 3 h. The reaction contents are poured into excess NH ₄ Cl solution and the mixture is extracted with CH ₂ Cl ₂ . Wash the extract with brine, dried over MgSO ₄ and filtered to remove the solvent. The residue was purified by silica gel chromatography eluting with 1: 20 methanol: chloroform to give 10.24 g of the title compound.

Elemental analysis for C ₁₈ H ₁₈ N ₄ F ₂ .0.5H ₂ O:

Calculated: C, 64.95; H, 5.57; N, 16.83

Found: C, 62.51; H, 5.50; N, 16.96

Step 346e. 1- (2-Benzyl-3,5-difluoro-4-pyridinyl) -4-methylpyrrazine

13.6 ml of concentrated H ₂ SO ₄ is quickly added to a solution of the compound of the previous step 346d (8.55 g, 26 mmol) in 50 ml of ethanol. After the initial temperature is raised, the solution is stirred at room temperature for 2 hours and then refluxed for 48 hours. The reaction solution is cooled, poured into H ₂ O, adjusted to a basic pH with solid K ₂ CO ₃ and extracted with CH ₂ Cl ₂ . The extract is dried with MgSO ₄ and filtered to remove the solvent. The residue was purified by silica gel chromatography eluting with ethyl acetate to give 3.57 g of the title compound.

Step 346f. Ethyl-2-ethoxycarbonyl-4-phenyl-2-butanoic acid ethyl ester

To 30 ml of THF cooled to -60 占 폚, 5.8 ml of butyllithium (14.5 mmol, 2.5M in hexane) is slowly added and the solution is stirred for 10 minutes. To this first solution is added dropwise a solution of 3.52 g (116 mmol) of the compound from step 346e in 15 ml of THF. The reaction mixture is stirred for 10 minutes and then a solution of 3.4 ml (16.8 mmol) of diethyl ethoxymethylenemalonate in 15 ml of THF is added dropwise. The reaction is stirred at -60 &lt; 0 &gt; C for 0.5 h and at room temperature for 2 h. The reaction solution is poured into a 15% aqueous NH ₄ Cl solution and the mixture is extracted with CHCl ₃ . The extract is dried with MgSO ₄ and filtered to remove the solvent. The residue was purified by silica gel chromatography eluting with ethyl acetate to give 4.09 g of the title compound.

MS: 520 (M + H) &lt; ⁺ &gt;;

Elemental analysis for C ₂₇ H ₃₅ F ₂ N ₃ O ₅ :

Calculated: C, 62.41; H, 6.79; N, 8.09

Found: C, 62.58; H, 6.63; N, 8.07

Step 346g. 4-oxo-1-phenyl-quinolizine-3-carboxylic acid, ethyl ester &lt; RTI ID =

3.16 g (6.08 mmol) of the compound sample of the previous step 346f are dissolved in 20 ml of DMSO and the solution is heated under reflux for 1 hour. The solution was poured in aqueous 5% NaHCO ₃ solution and the mixture is extracted with CHCl _3. Wash the extract with brine, dried over MgSO ₄ and filtered to remove the solvent. The residue was purified by silica gel chromatography eluting with 4: 1: 0.1 ethyl acetate: ethanol: TFA to give 681 mg of the title compound.

Step 346h. 7-fluoro-4H-8- (4-methylpiperazinyl) -4-oxo-1-phenyl- quinolizine- 3-carboxylic acid hydrochloride

A solution of the compound (623 mg, 1.46 mmol) from 346 g of the previous step in 30 ml of THF is diluted with 15 ml of water. The suspension is cooled in an ice bath for 15 minutes, LiOH.H ₂ O (183 mg, 4.37 mmol) is added and the reaction is stirred for 1 hour with cooling and then at room temperature for 16 hours. On the TLC, the reaction was confirmed to be not terminated, and 123 mg of LiOH.H ₂ O was further added and the reaction was stirred for 24 hours. The reaction contents are poured into H ₂ O and 1.3 ml of acetic acid is added. Solid NaHCO ₃ was added to the solution to be a basic and the mixture was extracted with CHCl ₃ containing a small amount of DMF. The extract is dried with MgSO ₄ , filtered and the solvent is removed. Excess DMF is removed by flowing with toluene. The residue is suspended in water and carefully acidified with 0.5 M HCl. The solution is frozen and the water is freeze-dried. The substitution is polished with ether, collected by filtration and dried under vacuum at 50 &lt; 0 &gt; C for 48 hours to give 171 mg of the title compound.

Elemental analysis for C ₂₁ H ₂₀ N ₃ O ₃ F ₂ .H ₂ O:

Calculated: C, 55.57; H, 4.89; N, 9.26

Found: C, 55.89; H, 4.62; N, 8.99

Example 347

The scale-up of the preparation of 8- (3 (S) -aminopyrrolidinyl) -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-

Step 347a. 4-t-butoxy-3-chloro-2,5,6-trifluoropyridine

927.55 g (5.0 mol) of 3-chloro-2,4,5,6-tetrafluoropyridine (Fluorochem Ltd.) sample are dissolved in 4 L of anhydrous THF and the solution is cooled to -10 ° C. To this solution, 429 g (5.36 mol) of lithium t-butoxide is added in small portions over 1 hour, and the temperature is maintained at -5 캜 to -10 캜. The reaction is stirred at -10 [deg.] C for 2 hours, the cooling bath is removed and the solution is allowed to warm to room temperature over 3 hours. THF is removed under reduced pressure. The residue is dissolved in 6 L of ether and the solution is washed with 4 x 1 L of water. Dry the ether solution over MgSO _4, and remove the ether under reduced pressure to give the crude product 1123.44g. The crude product is purified by chromatography eluting with hexane. bp 43-47 DEG C / 0.6 mmHg

Step 347. 4-t-Butoxy-3-methyl-2,5,6-trifluoropyridine

499 g (2.08 mol) of the compound sample from the pre-stage 347a are dissolved in 4 L of THF and cooled to -70 占 폚. 1.6 L of sec-butyllithium (2.08 mol, 1.3 M) is quickly added dropwise while maintaining the N ₂ atmosphere and the temperature is kept below -50 ° C. The mixture is stirred while raising the temperature and stirring is continued for 16 hours. The reaction was quenched with 1 L of water while cooling with an ice bath, 2 L of hexane was added and the layers were well mixed to separate the layers. The organic layer is concentrated on a rotary evaporator. The residue was dissolved in hexane and dried over MgSO _4, filtered, and concentrated to give the title compound, 496g, and uses it directly in the next step.

Example 347c 4-t-Butoxy-2,5-difluoro-3-methylpyridine

Lithium aluminum hydride (56.7g, 1.24mmol) was added to a 6L THF and stir the suspension under N _2. The temperature was adjusted to 0-5 &lt; 0 &gt; C and 476.5 g (2.27 mol) of the compound from pre-stage 347b (dissolved in 750 ml THF) was added via steam over 15 minutes. The mixture is stirred at room temperature for 16 hours and then 500 ml of hexane are added. The reaction is quenched by adding 57 ml of H ₂ O and 15% NaOH solution in succession while maintaining the internal temperature at 10-20 ° C. The mixture is filtered and the filter cake is washed with THF and hexane. The filtrate is concentrated on a rotary evaporator at a bath temperature of 35 &lt; 0 &gt; C. The residue was purified by silica gel column chromatography eluting with hexane and 5% ethyl acetate in hexane to give 141 g of the title compound. Distillation to 1 mm Hg at 80 to 90 ° C yields 103.4 g of pure product.

Step 347d. Another preparation method of 4-t-butoxy-2,5-difluoro-3-methylpyridine

Dissolving a sample compound 476.5g (2.27mmol) from the previous stage 347b to 6L THF and stirred under N _2. The solution temperature is adjusted to 0-5 &lt; 0 &gt; C and sodium bis- (2-methoxyethoxy) aluminum hydride solution in toluene (750 mL, 3.4M, 2.5 mol) is added dropwise rapidly for 1 hour. The reaction mixture is stirred at room temperature for 16 hours and 500 ml of hexane are added. The reaction is quenched by careful addition of 500 mL of H ₂ O while maintaining the internal temperature at 25 ° C. The organic layer is decanted and the solid is washed thoroughly with hexane. The solvents are combined and concentrated to bath temperature 55 ° C using a rotary evaporator. 440 g of crude product was eluted with 3% ethyl acetate in hexanes and hexanes and twice by silica gel chromatography to give 137.5 g of the pure title compound.

Step 347e. 2- (4-t-butoxy-5-fluoro-3-methyl-2-pyridinyl) -2-cyclopropylethylacetonitrile

Diisopropylamine (445 mL, 3.18 mol) is dissolved in 1.5 L of anhydrous THF and stirred under N ₂ . The solution is cooled to-40 C and n-butyllithium (1.274 L, 3.18 mole, 2.5M in hexane) is added at such a rate that the internal temperature is maintained at -40 to -20 占 폚. The solution is warmed to -10 &lt; 0 &gt; C and then cooled to -70 &lt; 0 &gt; C. Cyclopropylacetonitrile (257 g, 3.17 mmol) was added dropwise while maintaining the temperature at -68 &lt; 0 &gt; C and the solution was stirred for 35 minutes. A sample of 4-t-butoxy-2,5-difluoro-3-methylpyridine in step 347c or step 347d is dissolved in 1.2 L of anhydrous THF. To this solution, the first solution containing the lithium salt of cyclopropyl acetonitrile is added at a rate such that the internal temperature is maintained below -70 占 폚. The solution is stirred at -78 &lt; 0 &gt; C for 1 hour and then warmed to 0 &lt; 0 &gt; C. The reaction was quenched by the addition of 1 L of saturated aqueous NH ₄ Cl solution and 1 L of H ₂ O. The organic layer is separated. The aqueous layer is extracted with ethyl acetate. The organic layers were combined, washed with brine and dried over MgSO ₄ and concentrated by rotary evaporation to give an oil and the residue. The oil is distilled at 25 SIMILAR 35 DEG C to 0.2 mmHg to remove low boiling impurities and to remove residual cyclopropyl acetonitrile. The residue was eluted with 7% ethyl acetate in hexanes to give 646 g of pure compound 2 by silica gel chromatography.

Step 347f. 2- (4-Chloro-5-fluoro-3-methyl-2-pyridinyl) -2-cyclopropylacetonitrile

300 ml (3.2 mol) of POCl _{3 was} added to a cooled (0 ° C) solution of the compound (189.78 g, 0.72 mmol) of the previous step 347e in 1.6 L of CH ₂ Cl ₂ and 270 ml of DMF and the reaction was stirred for 12 hours. 25 ml (0.27 mol) of POCl ₃ is further added and the reaction is stirred for 12 hours. The reaction mixture is poured into H ₂ O and the mixture is stirred for 1 hour. The organic was extracted with CH ₂ Cl ₂ , washed with H ₂ O, saturated aqueous NaHCO ₃ solution, H ₂ O, dried over MgSO ₄ , filtered and evaporated in vacuo to afford 129.3 g of the title compound as an oil.

Step 347g. 2- (4-Chloro-5-fluoro-3-methyl-2-pyridinyl) -2- cyclopropylacetic acid, ethyl ester

To 1 L of ethanol saturated with about 400 g of HCl gas stirred under N ₂ and cooled to 0 ° C is added a solution of 135.8 g (0.6 mol) of the compound from step 347f in 90 ml of ethanol and the reaction is stirred at 0 ° C for 3 hours. 90 ml of H ₂ O is added to this solution and the reaction mixture is heated at 80 ° C for 2 hours. The mixture is poured into ice to bring the total volume to 4L. The solution is neutralized to pH 8 with 50% NaOH while maintaining the temperature below 0 &lt; 0 &gt; C. The solid is filtered and dissolved in CH ₂ Cl ₂ to remove the remaining aqueous layer. The organic layer was dried with MgSO ₄ and evaporated to give a tan solid (134.4g).

Step 347h. 2- (4-Chloro-5-fluoro-3-methyl-2-pyridinyl) -2-cyclopropylethanol

The compound of the previous step 347g in anhydrous THF 530㎖ (130.72g, 0.48㎖) solution at -78 ℃ and stirred under N _2. The solution of LiAlH ₄ (480 mL, 1M in THF, 0.48 mol) was added dropwise while maintaining the temperature at -60 ° C. The mixture is stirred at -78 ° C for 2 hours. The reaction is quenched by addition of H ₂ O (16 mL), 15% NaOH (16 mL) and H ₂ O (46 mL) and the mixture is stirred at room temperature for 1 hour. The solid is filtered off and washed with ether. The combined organic layers were washed with brine, dried with MgSO ₄ filtered and evaporated under vacuum to give the title compound (108.6g) as a white solid.

Step 347i. 2- (4-Chloro-5-fluoro-3-methyl-2-pyridinyl) -2-cyclopropylacetaldehyde

Anhydrous DMSO (80 mL, 1.14 mol) is dissolved in 900 mL of anhydrous CH ₂ Cl ₂ and stirred under N ₂ . The solution is cooled to-78 C and an oxalyl chloride solution (2.0 M, 284 mL, 0.569 mol) in CH ₂ Cl ₂ is added over 20 minutes maintaining the internal temperature below -60 ° C and stirring is continued for a further 35 minutes. The compound of step 346h (109 g, 0.457 mol) is dissolved in 400 mL of anhydrous CH ₂ Cl ₂ and added dropwise to the first solution while keeping the internal temperature below -60 ° C. The reaction mixture is stirred for 30 minutes and triethylamine (327 mL, 2.34 mol) is added dropwise over 10 minutes. The reaction is stirred while raising the internal temperature to -10 ° C. The reaction was quenched with 500 ml H ₂ O and the organic layer was separated, washed with H ₂ O, dried over MgSO ₄ and evaporated to give 109.04 g of the title compound.

Step 347j. Methyl-2-pyridinyl) -4-cyclopropyl-2-ethoxycarbonyl-2-butenoic acid ethyl ester

The compound of the previous step 347i (109.68 g, 0.48 mol) was dissolved in 1.3 L of absolute ethanol and stirred under N ₂ . To this solution was added diethyl malonate (351 mL, 2.31 mol), piperidine (45.5 mL, 0.46 mol) and acetic acid (45.5 mol, 0.79 mol). The solution is heated to reflux for 8 hours and cooled to room temperature. The solvent is removed on a rotary evaporator and the residue is dissolved in ethyl acetate. This solution was washed with water, salts, hydrogen, and dried over MgSO ₄ and concentrated to give an oily residue. The residue is distilled at 0.2 mm Hg and a short-length distillation apparatus at 25-56 ° C to remove excess diethyl malonate and volatile impurities. The residual oil is used immediately in the next step.

Short 347k. 8-chloro-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-

The compound of the previous step 347j is dissolved in 400 ml of anhydrous DMSO and heated under reflux for 1 hour. The hot reaction mixture is poured slowly into a stirred water bath (3 L). The product was filtered and washed with water (3 L) and hexane (1.5 L). The product was dried in a vacuum oven for 16 hours to give 105 g of the title compound as a yellow crystalline solid.

Step 347l. 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid, ethyl ester &lt; RTI ID =

93.1 g (0.29 mmol) of the compound sample of the previous step 347 k was dissolved in 1.24 L of acetonitrile, 137 g (0.72 mol) of 3 (S) - (BOC-amino) pyrrolidine and 133 g (1.45 mol) of NaHCO ₃ were added. Heat the mixture to reflux for 1 hour under N _2. The reaction mixture was cooled to 25 ℃ and that the H ₂ O 700㎖. The mixture is extracted with ethyl acetate and the solvent is washed with water 1N HCl, water and brine. To give a thick tar by drying the solvent with MgSO ₄ and concentrated.

Step 347m. 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid (4-fluoro-

The material from the previous step 347 l is dissolved in 900 ml of THF and 550 ml of water and 107.5 g (2.56 mol) of LiOH.H ₂ O are added. Heat the mixture to reflux for 1 hour under N _2. The mixture is diluted by pouring into 1 L of THF and 0.5 L of water with the aid of cooling with ice. Allow the pH to become 4 by adding concentrated HCl while vigorously mixing while maintaining the temperature below 15 ° C. The yellow precipitate is filtered off and dissolved in CH ₂ Cl ₂ . The solution is washed with water until the wash water becomes neutral, then dried over MgSO ₄ and concentrated.

Step 347n. Pyrrolidinyl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride

140 g of the compound sample of 347 m before is dissolved in 1.2 L of CH ₂ Cl ₂ and 1.0 L of 1.0 M HCl in acetic acid is added over 5 minutes. The product is collected by filtration and washed with CH ₂ Cl ₂ until colorless. The solids are dried in a vacuum oven (50 캜, 10 mm Hg) for 48 hours. This material (307.45 g) is added to 3.8 L of anhydrous ethanol previously warmed to 70 占 폚. To the mixture is added 1.23 L of H ₂ O and the mixture is boiling heated and stirred until all solids are dissolved. Stirring is stopped, seed crystals are added and the solution is allowed to cool to room temperature. The mixture is cooled to 0 &lt; 0 &gt; C for 12 hours and stirred at -25 [deg.] C for 2 hours. The product is filtered and washed with cold anhydrous ethanol. The solid was dried under vacuum for 48 hours to give the title compound (261 g) as a yellow solid.

Example 348

7-fluoro-4H-9-methyl-4-oxo-quinolizine-l- 3-carboxylic acid

Step 348a. N-CBZ-3-hydroxypiperidine

A 3-hydroxypiperidine HCl sample (50.0 g) is dissolved in a small amount of water and the solution is cooled to 0 캜 in an ice bath. HCl is slowly neutralized by adding 363 mL of 1 M NaOH. 1.2 eq of additional 1M NaOH is added quickly and 52 ml of benzyl chloroformate in 20 ml of ether is added dropwise and the solution is then stirred at 0 &lt; 0 &gt; C for 4 hours. The solution is diluted with 600 ml of water and extracted with methylene chloride. The organic extract was dried with Ns ₂ SO ₄ , filtered and dried to give 89.2 g of the title compound.

Step 348b. N-CBZ-3-oxo-piperidine

30.3 g of N-CBZ-3-hydroxypiperidine sample from pre-stage 348a are dissolved in 250 ml of DMSO and the solution is cooled to 0 &lt; 0 &gt; C. To this solution cooled to 0 ° C is added 142 ml of triethylamine and then a solution of 60.88 g of pyridine · SO ₃ complex dissolved in 250 ml of DMSO is added dropwise. The cooling bath is removed and the reaction mixture is stirred at room temperature for 20 hours. The reaction mixture is diluted with water and the mixture is extracted with methylene chloride. Dry the extract is dried with Na ₂ SO ₄ and filtered. The DMSO was distilled off under reduced pressure and the residue was purified by distillation with a Cugelo apparatus to give 26.53 g of the title compound.

Step 348c. Spiro-1, 3-dioxacyclopentane [2.3] piperidine

10.0 g of N-CBZ-3-oxo-piperidine sample from pre-stage 348b is dissolved in 10 ml of toluene, and 5.98 ml of ethylene glycol and 0.408 g of p-toluenesulfonic acid are added. The solution was stirred at 130 ℃ for 96 hours and then poured into a 5% NaHCO ₃ solution. The mixture was extracted with methylene scroll fluoride and drying the extract with Na ₂ SO ₄ and the solvent removed under vacuum distillation of the residue by kugel to the device to obtain the title compound 7.30g.

Step 348d. (Spiro-1, 3-dioxacyclopentane [2.3] -1-piperidinyl) -1-cyclopropyl-7-fluoro-4H- Carboxylic acid

Following the procedure for Example 253 step j, replacing 3-BOC-aminopyrrolidinyl with spiro-1, 3-dioxacyclopentane [2.3] piperidine from pre-stage 348c gave the product as a white solid, To give the title compound (245 mg).

Elemental analysis for C ₂₁ H ₂₃ N ₂ O ₅ F 0.5H ₂ O:

Calculated: C, 61.31; H, 5.88; N, 6.81

Found: C, 61.41; H, 5.91; N, 6.62

Example 349

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride

Step 349a. N-CBZ-pyrrolidine

50.0 g of pyrrolidine (Aldrich) sample are dissolved in 868 ml of 1 M NaOH and the solution is cooled to 0 &lt; 0 &gt; C. Benzyl chloroformate (103.29 ml) is dissolved in 100 ml of ether and added dropwise to the pyrrolidine solution over 1 hour. The solution is stirred at 0 &lt; 0 &gt; C for 4 hours, then diluted with 500 ml of water and extracted with methylene chloride. The combined extracts were dried over Na ₂ SO ₄ , filtered and concentrated by evaporation to give 144.6 g of the title compound.

Step 349b. N-CBZ-3, 4-epoxy-pyrrolidine

Under N ₂ in a water-free system, 15.0 g of N-CBZ-pyrroline sample from pre-stage 349a are dissolved in 200 ml of methylene chloride and the solution is cooled to 0 &lt; 0 &gt; C. 46.3 g of m-chloroperbenzoic acid dissolved in 500 ml of methylene chloride is added dropwise to this solution over 1 hour. The reaction mixture is heated at 45 &lt; 0 &gt; C for 18 h and then cooled to 0 &lt; 0 &gt; C. To the cold solution is added 3 g of sodium bisulfite and the mixture is stirred for 1 hour and poured into 1 L of 1 N NaOH. The organic layer was washed with water and dried with Na ₂ SO _4, filtered and evaporated to give the title compound 14.5g.

Step 349c. N-CBZ-3-azido-4-hydroxy-pyrrolidine

16.18 g of N-CBZ-3, 4-epoxy-pyrrolidine sample are dissolved in 145 ml of acetone. 14.39 g of sodium azide is dissolved in 130 ml of water and an acetone solution is added. The reaction mixture is stirred at 60 &lt; 0 &gt; C for 16 hours and then 400 ml of saturated NaCl solution is added. Extract the reaction mixture was quenched with methylene chloride and evaporated and dried by Na ₂ SO ₄ and filtered. The residue was purified by silica gel flash chromatography to give 21.40 g of the title compound.

Step 349d. N-CBZ-3-azido-4-methoxy-pyrrolidine

3.36 g of NaH sample are suspended in 60 ml of THF under N ₂ in a dry flask and cooled to 0 ° C. 20.0 g of the N-CBZ-3-azido-4-hydroxy-pyrrolidinyl sample from pre-stage 349c is dissolved in 200 ml of THF and the solution is added dropwise to the NaH suspension. The reaction mixture is stirred at 0 &lt; 0 &gt; C for 30 min, at room temperature for 30 min and cooled again to 0 &lt; 0 &gt; C. To this solution is added dropwise a solution of 5.70 ml of methyl iodide in 60 ml of THF. The reaction mixture is stirred at 0 &lt; 0 &gt; C for 30 minutes and at room temperature for 23.5 hours. The reaction mixture is poured into 500 ml of a 5% NH ₄ Cl solution and the mixture is extracted with methylene chloride. And evaporated to dry the extract with Na ₂ SO ₄ and filtered. The residue was purified by silica gel flash chromatography to give 8.99 g of the title compound.

Step 349e. N-CBZ-3-amino-4-methoxy-pyrrolidine

8.98 g of N-CBZ-3-azido-4-methoxy-pyrrolidine of the previous step 349d are dissolved in 100 ml of methanol and hydrogenated for 4 days in a sealed spring in the presence of 6.8 g of RaNi at room temperature under H _{2 4} Atm. The catalyst is filtered off and the methanol is evaporated. The residue was dissolved in methylene scroll fluoride was dried with Na ₂ SO ₄ and filtered. The solvent was removed to give 5.60 g of the title compound.

Step 349f. N-CBZ-3- (BOC-amino) -4-methoxy-pyrrolidine

5.60 g of N-CBZ-3- (BOC-amino) -4-methoxy-pyrrolidine are dissolved in 120 ml of methylene chloride under N ₂ in a dry flask and cooled to 0 ° C. 6.61 ml of triethylamine and 7.76 g of di-t-butyl dicarbonate dissolved in 50 ml of methylene chloride are added dropwise. The reaction mixture is stirred at 0 &lt; 0 &gt; C for 1 hour and at room temperature for 24 hours. Water is added to quench the reaction. The mixture is extracted with methylene chloride. The extract is dried over Na ₂ SO ₄ , filtered and evaporated to give 6.88 g of crude product. The residue was purified by silica gel flash chromatography to give 1.97 g of the pure title compound.

Step 349g. 3- (BOC-amino) -4-methoxy-pyrrolidine

1.97 g of N-CBZ-3- (BOC-amino) -4-methoxy-pyrrolidine from pre-stage 349f is hydrogenated in 100 ml of methanol under H _{2 4} Atm in the presence of 0.2 g of 10% Pd / C for 24 hours . The catalyst was removed by filtration and the solvent removed to give 1.28 g of the title compound.

Step 349h. 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride

Example 253 Following the procedure for step j, the 3-BOC-aminopyrrolidine of this Example was converted to 3- (BOC-amino) -4-methoxypyrrolidine from step 349g above to give the reaction product as an oil in Example 253k 253 l to give the title product (369 mg).

Elemental analysis for C ₁₉ H ₂₃ N ₃ O ₄ ClF 4H ₂ O:

Calculated: C, 46.16; H, 6.46; N, 8.68

Found: C, 47.53; H, 6.06; N, 9.36

Example 350

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride

Step 350a. N-CBZ-4-hydroxypiperidine

35.43 g of 4-hydroxypiperidine are dissolved in 420 ml of 1 M NaOH and cooled to 0 &lt; 0 &gt; C. 50.0 ml of benzyl chloroformate dissolved in 100 ml of ether was added dropwise to this stirred solution for 1 hour. The reaction mixture is stirred for 3 hours, diluted with 200 ml of water and extracted with methylene chloride. Dry the extract with Na ₂ SO _4, filtered and evaporated to give the title compound.

Step 350b. N-CBZ-4-oxopiperidine

Previous stage then N-CBZ-4- hydroxypiperidine from 350a was dissolved in DMSO 370㎖ under N ₂ with piperidine in 43.1g anhydrous peulreu disk is cooled to 0 ℃. 204 ml of triethylamine is added to this solution, and 87.5 g of a pyridine · SO ₃ solution in 370 ml of DMSO is added dropwise for 1 hour. The reaction is stirred at room temperature for 24 hours and quenched by the addition of 1 L of NaCl solution. The mixture is extracted with methylene chloride. Evaporated by drying the extract was Na ₂ SO ₄ and filtered. The residue was purified by silica gel flash chromatography to give 11.49 g of the title compound.

Step 350c. N-CBZ-4-hydroxy-4-methylpiperidine

Placed in dry flask containing a cooled dry ether 450㎖ methylmagnesium bromide 58㎖ to -20 ℃ under N _2. 25.00 g of N-CBZ-4-oxopiperidine from pre-stage 350b is dissolved in 100 ml of anhydrous ether and added dropwise to the reaction vessel over 1 hour. The reaction mixture is stirred for 1 hour and then warmed to room temperature over 2.5 hours. The reaction is quenched by dropwise addition of an excess of NH ₄ Cl solution. The layers are separated and the aqueous layer is extracted with ether. Layer was dried over Na ₂ SO _4, filtered and evaporated. The residue was distilled in a Cuggel apparatus to give 44.3 g of the title compound.

Step 350d. N-CBZ-4- (acetylamino) -4-methylpiperidine

270 ml of 90% sulfuric acid and 34 ml of acetonitrile are prepared and cooled to 0 占 폚. 44.3 g of N-CBZ-4-hydroxy-4-methylpiperidine in the previous step 350 dissolved in acetonitrile is added dropwise to the stirred solution in the reaction vessel over 2 hours. The reaction mixture is stirred at 0 &lt; 0 &gt; C for 45 minutes and without cooling for 2.5 hours. The reaction mixture is poured into 1 kg of ice and the mixture is adjusted to pH 12-13 with 50% NaOH. The mixture is extracted with ethyl acetate. The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound (101.5 g) as a white solid.

Step 350e. N-CBZ-4-amino-4-methylpiperidine

53 g of N-CBZ-4- (acetylamino) -4-methylpiperidine from pre-stage 350e are dissolved in 202 ml of 12M HCl and heated at 115 [deg.] C for 90 hours. The reaction mixture is poured into 800 g of ice. The mixture is extracted with methylene chloride. The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to give 37.6 g of the title compound.

Step 350f. N-CBZ-4- (BOC-amino) -4-methylpiperidine

In a dry flask, 37.6 g of N-CBZ-4-amino-4-methylpiperidine from the previous step 350e was dissolved in 220 ml of CCl ₄ under N ₂ , 51.3 ml of triethylamine was added, and di-t-butyl dicarbonate 52.2 g in small amounts. The solution is stirred at 38 &lt; 0 &gt; C for 20 hours and then washed with water. The organic layer was dried with Na ₂ SO _4, filtered and evaporated to give the title compound 23.71g.

Step 350g 4- (BOC-amino) -4-methylpiperidine

23.71 g of N-CBZ-4- (BOC-amino) -4-methylpiperidine from pre-stage 350f is hydrogenated as described in Example 349g to give 15.7 g of the title compound

Step 350h. 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride

According to the procedure of Example 253 step j, the reaction product was converted to 4- (BOC-amino) -4-methylpyrrolidine (Aldrich) by reaction of 3-BOC-aminopyrrolidine and following the procedure of Examples 253k and 253l To give the title product (513 mg).

Elemental analysis for C ₂₀ H ₂₅ N ₃ O ₃ ClF ₃ H ₂ O:

Calculated: C, 51.78; H, 6.73; N, 9.06

Found: C, 51.64; H, 6.39; N, 9.01

Example 351

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid &lt;

Example 253 According to the procedure of step j, the reaction product was reacted according to the procedures of Examples 253j to 253k, except that 3-BOC-aminopyrrolidine was changed to 1-pyriridine ethanol (Aldrich) to obtain the title compound do.

Elemental analysis for C ₂₀ H ₂₄ N ₃ O ₄ F · 2.5H ₂ O:

Calculated: C, 55.29; H, 6.73; N, 9.67

Found: C, 55.08; H, 6.02; N, 9.56

Example 352

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid

Step 352a. N-CBZ-4-methoxymethoxypiperidine

4.00 g of N-CBZ-4-hydroxypiperidine prepared in the above Example 351a was dissolved in 45 ml of methylene chloride, and 11.85 ml of diisopropylethylamine was added thereto. To this solution, 3.87 ml of chloromethyl methyl ether is added dropwise over 10 minutes. The reaction mixture was stirred at room temperature for 17 hours, diluted with methylene chloride and washed 50㎖ 0.5M phosphoric acid, 5% NaHCO ₃ and water. The solvent was dried with Na ₂ SO _4, filtered and evaporated to give the title compound 4.43g.

Step 352b. 4-Methoxymethoxypiperidine

4.43 g of N-CBZ-4-methoxymethoxypiperidine from pre-stage 352a was hydrogenated as described in Example 349g to give 2.15 g of the title compound.

Step 352c. 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid

Example 253 Following the procedure for step j, the reaction product was reacted according to the procedures of Examples 253j to 253k, substituting 3-BOC-aminopyrrolidine for 4-methoxymethylpiperidine from pre-stage 352b to give the title compound ).

Elemental analysis for C ₂₁ H ₂₅ N ₂ O ₅ F 0.5H ₂ O:

Calculated: C, 61.02; H, 6.11; N, 6.87

Found: C, 61.01; H, 6.34; N, 6.78

Example 353

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt;

Step 353a. N-benzyl-3-hydroxy-3-methylpiperidine

To the dried system under N ₂ , 400 ml of anhydrous ether and 32.3 ml of methylmagnesium bromide are added and the solution is cooled to -30 ° C. To this solution is added dropwise a solution of 16.626 g of N-benzyl-3-piperidine (Aldrich) in 50 ml of anhydrous ether. The reaction mixture is stirred at room temperature for 4 hours. The reaction is quenched with cooling saturated NH ₄ Cl solution until the suspended solids are separated. 300 ml of additional 10% NH ₄ Cl solution is added and the layers are separated. The aqueous layer was washed with ether and the combined organic solution was evaporated and the extract was dried with Na ₂ SO ₄ and filtered. The residue was distilled in a Cugelro apparatus to give 17.942 g of the title compound.

Step 353b. N-Mento-3- (acetylamino) -3-methylpiperidine

21.961 g of N-benzyl-3-hydroxy-3-methylpiperidine prepared in the previous step 353a is dissolved in 16.8 ml of acetonitrile and added dropwise to 134 ml of vigorously stirred 90% sulfuric acid cooled to 0 캜 for 1.5 hours . The reaction mixture is stirred at 0 &lt; 0 &gt; C for 15 minutes and at room temperature for 6 hours. The reaction mixture is poured into ice to quench the reaction. The solution is adjusted to pH 12 with 50% NaOH and extracted with methylene chloride. Dry the extract with Na ₂ SO _4, filtered and evaporated to give the title compound 19.2g.

Step 353c. Benzyl-3-amino-3-methylpiperidine

3- (acetylamino) -3-methylpiperidine from the previous step is stirred with 100 ml of HCl at 110 &lt; 0 &gt; C for 36 h. The reaction mixture is poured into 800 g of ice. The mixture is extracted with methylene chloride. The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound.

Step 353d. N-Benzyl-3- (BOC-amino) -3-methylpiperidine

Benzyl-3-amino-methylpiperidine in the previous step is reacted with di-t-butyl dicarbonate according to the procedure of Example 350f to isolate the title compound.

Step 353e. 3- (BOC-amino) -3-methylpiperidine

3.32 g of N-benzyl-3- (BOC-amino) -3-methylpiperidine are hydrogenated according to the procedure of Example 350f to give 2.50 g of the title compound.

Step 353f. 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt;

Aminopyrrolidine was converted to 3-BOC-aminopyrrolidine from the previous step 253e according to the procedure of Example 253 Step j and the reaction product was reacted as in Example 253 Steps j-1 to give the title compound 255 Mg).

Elemental analysis for C ₂₀ H ₂₅ N ₃ O ₃ ClF H ₂ O:

Calculated: C, 56.14; H, 6.36; N, 9.82

Found: C, 55.73; H, 6.43; N, 9.48

Example 354

8- (3-pyrrolylpyridinyl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-

Step 354a. N-CBZ-3- (methanesulfonyloxy) piperidine

4.0 g of N-CBZ-3-hydroxypiperidine (prepared from 3-hydroxypiperidine by standard method) are dissolved in 25 ml of methylene chloride and cooled to 0 &lt; 0 &gt; C. To this is added 3.55 ml of triethylamine and then 1.77 ml of a methanesulfonyl chloride solution in 4 ml of methylene chloride is added dropwise. The reaction mixture is stirred at 0 &lt; 0 &gt; C for 15 minutes and at room temperature for 1.5 hours. The quenched reaction was diluted with methylene chloride and extracted with 15% NaHCO ₃ solution. To separate the layers, dry the organic layer with Na ₂ SO _4, filtered and evaporated to give the title compound 5.02g.

Step 354b. N-CBZ-3-pyrrolylpiperidine

5.02 g of N-CBZ-3- (methanesulfonyloxy) piperidine from pre-stage 354a are dissolved in 8.89 g of pyrrole and heated at 100 占 폚 for 20 hours. Thereby remove excess pyrrole under vacuum and dried by washing of the residue 5% NaHCO ₃ solution, water, dried over Na ₂ SO ₄ and filtered. The residue was purified by silica gel flash chromatography, eluting with 0-1% methanol in methylene chloride to give 0.500 g of the title compound.

Step 354c. 3-pyrrolipyridine

612 mg of N-CBZ-3-pyrrolipiperidine from pre-stage 354b is hydrogenated according to the procedure of Example 350f to give 500 mg of the title compound.

Step 354d. 8- (3-pyrrolylpiperidinyl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-

Example 253 Following the procedure of step j, the reaction product was reacted as in Example 253 steps j and k, but replacing the 3-BOC-aminopyrrolidine with 3-pyrrolipiperidine from the previous step 354c to give the title compound (157 mg) &Lt; / RTI &gt;

Elemental analysis for C ₂₃ H ₂₄ N ₃ O ₃ F · 2.25H ₂ O:

Calculated: C, 61.39; H, 5.83; N, 9.34

Found: C, 61.40; H, 5.63; N, 8.94

Example 355

8- (3-Aminopiperidinyl) - 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride

Step 355a. (R) -3-amino-2-piperidone

D-ornithine methyl ester hydrochloride A sample is dissolved in 240 ml of methanol and stirred with 75 g of an OH ^- form anion exchange resin at room temperature for 4 hours. The suspension is filtered and the filtrate is dried. The residue was distilled with a Cuggel apparatus to give 7.59 g of the title compound.

Step 355b. (R) -3-aminopiperidine

7.49 g of sample (R) -3-amino-2-piperidone from pre-stage 355a are dissolved in 140 ml of THF and the solution is cooled to 0 &lt; 0 &gt; C. 3.00 g of lithium aluminum hydride is carefully added to this solution. The reaction mixture is stirred at room temperature for 2 hours. The reaction is quenched with water and NaOH and the filter cake is extracted with THF. The solution was dried dried with Na ₂ SO _4, filtered and evaporated. The residue is purified by distillation.

Step 355c. 8- (3-Aminopiperidinyl) - 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride

Example 253 Following the procedure for step j, the reaction product was reacted as in Example 253 steps j-1 to replace 3-BOC-aminopyrrolidine with 3-aminopiperidine from pre-stage 355b to give the title compound (376 mg) &Lt; / RTI &gt;

Elemental analysis for C ₁₉ H ₂₃ N ₃ O ₃ ClF H ₂ O:

Calculated: C, 55.14; H, 6.09; N, 10.15

Found: C, 55.50; H, 6.37; N, 9.26

Example 356

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride

Example 253 By following step j, the product was converted to 3- (BOC-amino) -3-methylpyrrolidine by reaction of 3-BOC-aminopyrrolidine and the product was reacted as in Example 253 steps j-1 to afford the title compound 255 mg).

Elemental analysis for C ₁₉ H ₂₃ N ₃ O ₃ ClF H ₂ O:

Calculated: C, 55.14; H, 6.09; N, 10.15

Found: C, 55.08; H, 6.01; N, 9.77

Example 357

Pyrrolidinyl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine- 3-carboxylic acid hydrochloride

Step 357a. N-CBZ-3-amino-4-hydroxy-pyrrolidine

27.1 g of N-CBZ-3-azido-4-hydroxy-pyrrolidine prepared in pre-stage 349c is hydrogenated under the conditions of Example 349e for 24 hours to give 25.4 g of the title compound.

Step 357b. N-CBZ-3- (CBZ-amino) -4-hydroxy-pyrrolidine

25.4 g of N-CBZ-3-azido-4-hydroxy-pyrrolidine from pre-stage 357a are dissolved in 129 ml of 1M NaOH and the solution is cooled to 0 &lt; 0 &gt; C. 15.35 ml of benzyl chloroformate are dissolved in 20 ml of ethanol and the solution is added dropwise over 40 minutes to the vigorously stirred pyrrolidine solution. The reaction mixture is stirred at 0 &lt; 0 &gt; C for 4 hours and then quenched by pouring the reaction into 200 ml of water. And extracted the mixture with methylene chloride, dried and filtered as Na ₂ SO ₄ and evaporated to dryness. The residue was purified by silica gel column chromatography eluting with methanol in 0.5-3.5% methylene chloride to give 18.77 g of the title compound.

Step 357c. N-CBZ-3- (CBZ) -4-pyrrolidone

With methylene chloride in a dry vessel under N ₂ and the solids cooled to 0 ° C. 17.32 ml of DMSO is added thereto, and 21.89 ml of phenyl diclophosphate is added dropwise for 30 minutes. Then, 34.03 ml of triethylamine is added over 30 minutes. To this solution is added dropwise a solution of N-CBZ-3- (CBZ-amino) -4-hydroxy-pyrrolidine in 100 ml of methylene chloride from pre-stage 357b over 45 minutes. The reaction mixture is stirred at 0 &lt; 0 &gt; C for 1 hour and at room temperature for 20 hours. The reaction is quenched by pouring into a 20% NaCl solution. The mixture was extracted with methylene chloride, dried over Na ₂ SO _4, filtered and then evaporated to dryness. Excess DMSO was removed by heating in vacuo and the residue was purified by silica gel column chromatography, eluting with 0-1% methanol in methylene chloride to give 9.2 g of the title compound.

Step 357d. N-CBZ-3- (CBZ-amino) -4- (1'-3-dioxolanyl) pyrrolidine

0.932 g of a sample N-CBZ-3- (CBZ-amino) -4-pyrrolidinone in the previous step 357c was dissolved in 17 ml of toluene and 0.353 ml of ethylene glycol, and 24 mg of p-toluenesulfonic acid was added. The reaction mixture was stirred at 110 ℃ for 20 hours then quenched by addition of the reaction with 5% NaHCO _3. The mixture was extracted with methylene chloride, dried over Na ₂ SO _4, filtered and then evaporated to dryness. The residue was purified by silica gel column chromatography eluting with methanol in 2% methylene chloride to give 578 mg of the title compound.

Implementation to 357e. 3-Amino-4- (1'-3-dioxolanyl) pyrrolidine

2.68 g of N-CBZ-3- (CBZ-amino) -3-methylpyrrolidine are hydrogenated for 7 days according to the procedure of Example 350f to isolate 937 mg of the title compound.

Step 357f. Pyrrolidinyl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3 -Carboxylic acid hydrochloride

The product is obtained according to the procedure for Example 253 step j, replacing 3-BOC-aminopyrrolidine with 3-amino-4- (1 ', 3'-dioxoranyl) pyrrolidine, The reaction was carried out to obtain the title compound (324 mg).

Elemental analysis for C ₂₀ H ₂₃ N ₃ O ₅ ClF · H ₂ O · HCl:

Calculated: C, 48.59; H, 5.30; N, 8.50

Found: C, 48.80; H, 4.87; N, 8.52

Example 358

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt;

Step 358a. N-CBZ-3-azido-4- (methoxymethoxy) pyrrolidine

A sample of N-CBZ-3-aniso-4-hydroxypyrrolidine prepared in Example 349c was dissolved in 20 mL of methylene chloride, 5.02 mL of diisopropylethylamine was added, and 1.64 mL of methoxymethyl chloride was added dropwise to ambient temperature Dropwise over 15 minutes while cooling to maintain the temperature. The reaction mixture was stirred at room temperature for 18 hours, then 0.5M phosphate, washed with 5% NaHCO _3, dried over Na ₂ SO _4, filtered and then evaporated to dryness. The residue was eluted with methanol in 0.5% methylene chloride and purified by silica gel flash column chromatography to give 1.58 g of the title compound.

Step 358b. N-CBZ-3-amino-4- (methoxymethoxy) pyrrolidine

2.23 g of N-CBZ-3-Amino-4- (methoxymethoxy) pyrrolidine prepared in Step 358a was dissolved in 200 ml of ethyl acetate and washed with H _{2 4} Atm at room temperature for 24 hours in the presence of RaNi Lt; / RTI &gt; The catalyst is removed by filtration and the solvent is removed in vacuo to afford the title product.

Step 358c. N-CBZ-3- (BOC-amino) -4- (methoxymethoxy) pyrrolidine

2.04 g of the sample N-CBZ-3-amino-4- (methoxymethoxy) pyrrolidine of step 358b are dissolved in 20 ml of methylene chloride and the solution is cooled to 0 &lt; 0 &gt; C. To this solution is added 2 ml of triethylamine and 2.38 ml of di-t-butyl-dicarbonate dissolved in 5 ml of methylene chloride are added. The reaction mixture is stirred at 0 &lt; 0 &gt; C for 30 minutes, at room temperature for 24 hours, at 40 &lt; 0 &gt; C for 8 hours and then poured into 10% NaCl solution and quenched. The mixture is quenched by addition of 5% NaHCO _3. The mixture was extracted with methylene chloride, dried over Na ₂ SO _4, filtered and then evaporated to dryness. The residue was purified by silica gel column chromatography eluting with methanol in 1% methylene chloride to give 1.35 g of the title compound.

Step 358d. 3- (BOC-amino) -4- (methoxymethoxy) pyrrolidine

1.35 g of N-CBZ-3- (BOC-amino) -4- (methoxymethoxy) pyrrolidine are hydrogenated for 12 days according to the procedure of Example 350f from the previous step 358c to give 874 mg of the title compound.

Step 358e. 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt;

Following the procedures of Examples 253 to j, the product was treated as in Example 253 Steps j-1 to replace 3-BOC-amino-pyrrolidine with the 3-amino-4-hydroxypyrrolidine of the previous step 358d to give the title The compound is prepared (125 mg).

Elemental analysis for C ₁₈ H ₂₁ N ₃ O ₄ ClF 1.5 H ₂ O:

Calculated: C, 50.89; H, 5.69; N, 9.89

Found: C, 51.38; H, 5.65; N, 9.73

Example 359

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt; RTI ID = 0.0 &

Step 359a. 4- (N-BOC-N-ethylaminomethyl) pyridine

4.00 g of 4- (N-ethylaminomethyl) pyridine are dissolved in 50 ml of methylene chloride and the solution is cooled to 0 &lt; 0 &gt; C. 8.19 ml of triethylamine was added to this solution, and 8.01 g of di-t-butyl dicarbonate dissolved in 10 ml of methylene chloride was added dropwise. The reaction mixture is stirred at 0 &lt; 0 &gt; C for 1 hour, at room temperature for 30 minutes, then poured into 10% NaCl and quenched. The mixture was extracted with methylene chloride, dried over Na ₂ SO _4, filtered and then evaporated to dryness. The residue was purified by silica gel column chromatography eluting with methanol in 1% methylene chloride to give 5.52 g of the title compound.

Step 359b. 4- (BOC-N-ethylaminomethyl) piperidine

5.50 g of 4- (N-BOC-N-ethylaminomethyl) pyridine prepared in the previous step 359a are dissolved in 200 ml of ethyl acetate and hydrogenated in a spring sealed under H ₂ 4 Atm for 24 hours in the presence of RaNi. The catalyst is removed by filtration and the solvent is removed in vacuo to give 1.80 g of the title product.

Step 359c. Pyrrolidinyl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizin-3- Carboxylic acid hydrochloride

Example 253 Following the procedure for step j, replacing 3-BOC-amino-pyrrolidine with 4- (N-BOC-ethylaminomethyl) piperidine of the previous step 359b gave the product as in example 253 steps j- To give the title compound (488 mg).

Elemental analysis for C ₂₂ H ₂₉ N ₃ O ₃ ClF 0.5H ₂ O:

Calculated: C, 59.12; H, 6.77; N, 9.40

Found: C, 58.74; H, 6.63; N, 9.28

Example 360

Methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt; RTI ID = 0.0 &gt;

Step 360a. N-CBZ-3-cyano-4-hydroxypyrrolidine

A sample of N-CBZ-3-, 4-epoxypyrrolidine prepared in Example 349b is dissolved in 100 ml of ethanol and added to 9.88 g of MgSO _{4 and} 13.41 g of NaCN in 195 ml of water. The reaction mixture was stirred at 65 ℃ for 20 hours, it cooled sikimyeo filtered and extracted with methylene chloride, dried over Na ₂ SO _4, filtered and evaporated to dryness to give the title compound 9.0g.

Step 360b. N-CBZ-3-aminomethyl-4-hydroxypyrrolidine

13.97 g of N-CBZ-3-cyano-4-hydroxypyrrolidine prepared in Step 360a was dissolved in 210 ml of methanol containing 40 ml of triethylamine and reacted under H _{2 4} Atm at room temperature for 24 hours Hydrogenated in a sealed spring. The catalyst is removed by filtration and the solvent is removed in vacuo to give 14.38 g of the title product.

Step 360c. N-CBZ-3- (BOC-aminomethyl) -4-hydroxypyrrolidine

2.73 g of N-CBZ-3-aminomethyl-4-hydroxypyrrolidine from pre-stage 360b are dissolved in 20 ml of methylene chloride and the solution is cooled to 0 &lt; 0 &gt; C. To this solution, 2.86 g of di-t-butyl dicarbonate dissolved in 3 ml of methylene chloride is added dropwise. The reaction mixture is stirred at 0 &lt; 0 &gt; C for 1 hour and at room temperature for 18 hours. Quenching by pouring the reaction mixture into water 250㎖ and the mixture was extracted with methylene chloride, dried over Na ₂ SO _4, filtered and then evaporated to dryness. The residue was purified by silica gel flash chromatography to give the title compound.

Step 360d. 3-hydroxy-4-methylaminopyrrolidine

The N-CBZ-3- (BOC-aminomethyl) -4-hydroxypyrrolidine of the previous step 360c is hydrogenated in 100 ml methanol at 10% Pd / C under H _{2 4} Atm at room temperature for 24 hours. The catalyst was removed by filtration and the solvent removed to give 610 mg of the title compound.

Step 360e. Methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt; RTI ID = 0.0 &gt;

The title compound was prepared according to the procedure of Example 253 step j, by replacing 3-BOC-amino-pyrrolidine with 3-hydroxy-4-methylaminopyrrolidine in 360 d before treating the product as in Example 253 Steps j- The title compound is prepared (540 mg).

Elemental analysis for C ₁₉ H ₂₃ N ₃ O ₄ ClF ₂ H ₂ O:

Calculated: C, 50.95; H, 6.08; N, 9.38

Found: C, 50.88; H, 5.77; N, 9.01

Example 361

8- (3- (Aminomethylpiperidinyl) -1-cyclopropyl-7-fluoro-4-N-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride

Step 361a. 3- (N-BOC-aminomethyl) pyridine

To under a dry N _2-di -t- butyl dicarbonate 15.69g it is dissolved in CH ₂ Cl ₂ 100㎖. The flask and the contents are cooled in an ice bath, and a solution of 6.12 g of 3- (aminomethyl) pyridine in CH ₂ Cl _{2 is} added dropwise with stirring. The solution is stirred at 0-5 &lt; 0 &gt; C for 30 minutes and then at room temperature for 72 hours. The reaction is diluted with CH ₂ Cl ₂ (100 mL) and then washed with 250 mL of water. The water is re-extracted with CH ₂ Cl ₂ and the combined organic layers are dried over Na ₂ SO ₄ . The solution was filtered and the solvent was removed on a rotary evaporator to give 13 g of the title compound.

Step 361b. 3- (N-BOC-aminomethyl) piperidine

10.13 g of the sample from the previous step 361a is dissolved in 250 ml of methanol and reduced with 5 g of 5% Rh / C catalyst under H _{2 4} Atm at room temperature for 18 hours. The catalyst is filtered off and the solvent is removed in vacuo. The product was recrystallized from ethyl acetate and dried under high vacuum to give 3.8 g of product. mp. 64-65 ° C

Step 361c. 8- (3-Aminomethylpiperidinyl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride

Example 253 Following the procedure for step j, replacing 3-BOC-amino-pyrrolidine with 3- (N-BOC-aminomethyl) piperidine prepared in step 361b, To give the title compound (301 mg).

Elemental analysis for C ₂₀ H ₂₅ N ₃ O ₃ ClF 1.5 H ₂ O:

Calculated: C, 50.75; H, 6.18; N, 8.88

Found: C, 50.53; H, 6.20; N, 9.03

Example 362

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride

Step 362a. N-benzyl-2-chloromethylmorpholine

The flask is charged with 1.5 g (10 mmol) of N-benzyl-ethanolamine and 7.8 ml (71 mmol) of epichlorohydrin. The reaction mixture is heated at 40 &lt; 0 &gt; C for 30 minutes and then cooled to room temperature. Excess epichlorohydrin is removed in vacuo and the residue is dissolved in 30 mL of concentrated H ₂ SO ₄ . The solution is heated at 150 &lt; 0 &gt; C for 30 minutes and poured into 50 g of ice. The solution is adjusted to pH 13 with NaOH and the mixture is extracted with toluene. The solution was dried over Na ₂ SO ₄ and filtered to remove the solvent and the residue was dried under vacuum to give 193 mg of the title compound. MS m / z: 226,228 (M + H) &lt; ⁺ & gt ^;

Step 362b. 2- (N-Benzyl-morpholinyl) -N-methylphthalimide

The oven-dried system under positive pressure N ₂ is filled with 900 mg (4 mmol) of N-benzyl-3-chloromethylmorpholine dissolved in 20 ml of DMSO. To this was added 1.4 g (8 mmol) of potassium phthalimide. The reaction mixture is stirred at 100 &lt; 0 &gt; C for 96 h, then cooled to room temperature and poured into 50 ml of water. The mixture was extracted with methylene chloride The extract was washed with water and dried with Na ₂ SO _4. The solution was filtered, the solvent was removed in vacuo and the product was dried in vacuo to give 1.18 g of the title compound. The material was recrystallized from ethanol, filtered off and dried in vacuo to give 884 mg of the pure title compound.

Step 362d. 4-benzyl-2-aminomethylmorpholine

(N-benzyl-morpholinyl) -N-methyltolemide of the previous step 362b in which the system is suspended in 4 ml of ethanol under N ₂ pressure. To this was added 50 [mu] l of hydrazine hydrate and the reaction mixture was stirred at room temperature for 3 hours and at 70 [deg.] C for 24 hours. The reaction mixture is cooled to room temperature and diluted with 10 ml of water. The mixture is filtered and the aqueous layer is adjusted to pH 12 with NaOH and extracted with methylene chloride. The organic extracts were dried with Na ₂ SO ₄ , filtered and the solvent was removed and the solvent was dried in vacuo to give 72 mg of the title compound.

Step 362d. 4-Benzyl-32- (BOC-aminomethyl) morpholine

The oven-dried system protected from moisture is filled with 198 mg of 1-benzyl-3-aminomethylmorpholine of 362c, which is a preliminary step in which 2 ml of methylene chloride is dissolved. To this solution was added 250 mg of di-t-butyl-dicarbonate. Stirred for 24 hours at room temperature the reaction mixture was diluted with methylene chloride and dried to 30㎖ Na ₂ SO _4. The mixture is filtered and the solvent is removed in vacuo. The residue was eluted with methanol in 9% methylene chloride, purified by silica gel purification TLC, and the band with R _f = 0.48 was collected. The product is removed from the silica gel with 300 ml of methanol in 10% methylene chloride and the solvent is removed in vacuo to give 173 mg of the title compound. MS: 307 (M + 1) &lt; ⁺ & gt ^;

Step 362e. 2- (BOC-aminomethyl) morpholine

4-benzyl previous stage -2- (BOC- aminomethyl) 362d of the formate is dissolved in methanol morpholin 50㎎ 5㎖ and removing the benzyl group by hydrogenation at room temperature with Pd / C25㎎ under H ₂ for 48 hours 4Atm. Filter the catalyst and remove the solvent to give 33 mg of the title compound.

Step 362f. 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride

Example 253 Following the procedure for step j, replacing 3-BOC-aminopyrrolidine with 2- (BOC-aminomethyl) morpholine prepared in the previous step 362e, the product was reacted as in Example 253 steps j-1 to give the title The compound is prepared (287 mg).

Elemental analysis for C ₁₉ H ₂₃ N ₃ O ₄ ClF ₂ .25H ₂ O:

Calculated: C, 50.45; H, 6.13; N, 9.29

Found: C, 50.63; H, 6.17; N, 9.11

Example 363

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt;

Step 363a. 3- (N-BOC-N-methylamino) methyl) pyridine

To the anhydrous flask was added 84.7 mg (2.2 mmol) of NaH (mineral oil washed with anhydrous hexane) and 2 ml of anhydrous THF under N ₂ . The mixture is cooled in an ice bath and 416 mg of 3- (N-BOC-aminomethyl) piperidine from pre-stage 361b is added dropwise. After completion of the addition, the mixture is stirred at 0 SIMILAR 5 DEG C for 1 hour and 0.125 mL of methyl iodide is added. The mixture is stirred at 0-5 &lt; 0 &gt; C for 30 minutes, then warmed to room temperature and stirred for 24 hours. The reaction is quenched by pouring into 30 mL of saturated NaCl and the mixture is extracted with 3 x 30 mL of methylene chloride. The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated on a rotary evaporator to give 430 mg of the title compound.

Step 363b. 2- (N-BOC-N-methylamino) methyl) piperidine

1.16 g of the compound from the previous step 361a is dissolved in 50 ml of methanol and hydrogenated with 1.16 g of 5% Rh / C catalyst under H _{2 4} Atm at room temperature for 18 hours. The catalyst is filtered off and the solvent is removed in vacuo. The product was recrystallized from ethyl acetate and concentrated under high vacuum to give 1.18 g of product. MS m / z: 229 (M + H) &lt; ⁺ & gt ^;

Step 363c. Methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt; RTI ID = 0.0 &gt;

According to the procedure of Example 253 step j, 3-BOC-aminopyrrolidine was converted to 3 (N-BOC-N-methylamino) methyl) piperidine prepared according to previous step 363a to give the product as a white solid, To give the title compound (535 mg).

Elemental analysis for C ₂₁ H ₂₇ N ₃ O ₃ ClF H ₂ O:

Calculated: C, 57.08; H, 6.61; N, 9.51

Found: C, 56.93; H, 6.68; N, 10.23

Example 364

Methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt; RTI ID = 0.0 &gt;

Following the procedure for Example 253 step j, replacing 3-BOC-aminopyrrolidine with 3-BOC-amino-pyrrolidine prepared according to European Patent Application No. 342,675, the product was obtained as a white solid from Example 253 Steps j- k to give the title compound (443 mg).

Elemental analysis for C ₂₂ H ₂₇ N ₃ O ₅ F:

Calculated: C, 63.15; H, 6.50; N, 6.69

Found: C, 63.02; H, 6.42; N, 6.64

Example 365

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt;

Following the procedure for example 253 step j, the product was converted to 3- (S) - (N-BOC-amino) piperidine by reaction of 3-BOC- aminopyrrolidine and the product was reacted as in Example 253 steps j- The title compound is prepared (500 mg),

Elemental analysis for C ₁₉ H ₂₃ N ₂ O ₅ ClF _1.5 H ₂ O:

Calculated: C, 53.97; H, 6.20; N, 9.94

Found: C, 54.28; H, 6.61; N, 8.85

Example 366

Methyl-4-oxo-quinolizine-3-carboxamide &lt; / RTI &gt; Carboxylic acid

Step 366a. (S) -3-acetylamino-1-benzylpyrrolidine

(12 mmol) of acetic anhydride was added to 1.30 g (7.38 mmol) of 3-amino-1-benzylpyrrolidine and 1.7 ml (12 mmol) of triethylamine in 25 ml of ethyl acetate and the reaction was stirred for 1 hour. The solvent is removed and the residue is treated with 1: 1 20% K ₂ CO ₃ : brine and extracted with methylene chloride. The organic extracts were dried over Na ₂ SO ₄ and filtered to remove the solvent in vacuo and the residue dried under high vacuum to give 1.71 g of the title compound.

MS: 219 (M + 1) ^&lt; + &^gt;;

Elemental analysis for C ₁₃ H ₁₈ N ₂ O:

Calculated: C, 68.69; H, 8.42; N, 12.32

Found: C, 68.75; H, 8.00; N, 12.27

Step 366b. (S) -3-ethylamino-1-benzylpyrrolidine

To 1.70 g of the compound from the previous step 366a in 20 ml of THF is added 850 mg of lithium aluminum hydride and the mixture is stirred at room temperature for 72 hours. The reaction is quenched with water and NaOH, stirred for 1 hour, filtered and the filter cake is extracted with methylene chloride. The aqueous layer is extracted with methylene chloride and the organic extracts are combined. Drying the solution with Na ₂ SO _4, filtered and the solvent removed in vacuo to give the title compound 1.71g.

Step 366c. (S) -3- (N-BOC-N-ethylamino) -1-benzylpyrrolidine

1.94 g (8.9 mmol) of butoxycarbonyl anhydride was added to 1.7 g of the compound from the previous step 366b dissolved in 3 ml of methylene chloride, and the reaction was stirred for 16 hours. The solvent was removed in vacuo and the residue was chromatographed on silica gel eluting with 1: 1 hexane: ethyl acetate to give 1.8 g of the title compound.

Elemental analysis for C ₁₈ H ₂₈ N ₂ O ₂ :

Calculated: C, 68.00; H, 9.35; N, 8.81

Found: C, 68.05; H, 8.73; N, 8.85

Step 366d. (S) -3- (N-ethyl-N-methylamino) -1-benzylpyrrolidine

800 mg of LAH was added to 1.8 g (5.9 mmol) of the compound from the previous step 366c in 20 ml of THF and the mixture was stirred under reflux conditions for 48 hours. The reaction is cooled to room temperature, 0.8 ml of water is added dropwise with stirring, 0.8 ml of 15% NaOH are added simultaneously and finally 2.4 ml of water are added and the mixture is stirred at room temperature for 2 hours. The mixture is filtered and the filter cake is washed with methylene chloride and the filtrate is concentrated in vacuo to give the crude title product. This material is dissolved in acetic acid, filtered, methanol is added, the solvent is removed and the residue is dissolved again in methanol and removed. The residue is dissolved in water, adjusted to pH 10-11 with K ₂ CO ₃ and saturated with NaCl, and the solution is extracted with 10% methanol in CHCl ₃ . The extracts were dried with Na ₂ SO _4, filtered and the solvent removed to give the title product 603㎎.

Step 366e. (S) -3- (N-ethyl-N-methylamino) pyrrolidine

Step 1.3 36 g of the compound of 366d are dissolved in 50 ml of acetic acid and 0.5 ml of HCl, 0.13 g of 10% Pd / C is added and the sample is hydrogenated under H _{2 4} Atm. Additional catalyst and HCl are added before the reaction is complete. The solution is filtered, then the solvent is removed and methanol is added and removed repeatedly. The residue is dissolved in water and adjusted to pH 10 sowl 11 with K ₂ CO ₃ and repeatedly extracted with methanol in 10% CHCl ₃ . Dry the extract with Na ₂ SO _4, filtered and dried to give the title compound 603㎎. HRMS (M + 1) &lt; + & gt ^; : Calculated: 129.1936; Found: 129.1392

Step 366f. Methyl-4-oxo-quinolizin-3-ylmethyl) -3- (3- (S) - (N-ethyl-N-methylamino) piperidinyl) Carboxylic acid

Following the procedure for Example 253 step j, replacing 3-BOC-aminopyrrolidine with (S) -3- (N-ethyl-N-methylamino) -pyrrolidine in the previous step 366e, j to k to produce the title compound.

Example 367

(4-2 '- (N-methylamino) methyl-1', 3'-dioxoranyl) piperidinyl-7-fluoro- Quinolizine-3-carboxylic acid hydrochloride

Step 367a. N-CBZ-4- (4'-bromomethyl-1 ', 3'-dioxoranyl) piperidine

17.48 g of N-CBZ-4-oxopiperidine prepared as in Example 350b was dissolved in 325 ml of toluene, and 16.40 ml of 3-bromo-1,2-propanediol and 713 mg of p-toluenesulfonic acid were added . The reaction mixture is heated under reflux (120-125 &lt; 0 &gt; C) for 24 hours while collecting the reaction water with a Dean-Stark trap. The reaction mixture was cooled to room temperature and washed with 5% NaHCO ₃ and water, dried over Na ₂ SO ₄ is filtered and dried. The residue was purified by silica gel flash chromatography, eluting with 0-1.5% methanol in methylene chloride to give 26.5 g of the title compound.

Step 367b. N-CBZ-4- (4 '- (methylaminomethyl) -1', 3'-dioxoranyl) piperidine

7.29 g of N-CBZ-4- (4'-bromomethyl-1 ', 3'-dioxanyl) piperidine of the previous step 367a is heated with excess methylamine to isolate 3.427 g of the title compound and purify.

Step 367c. N-CBZ-4- (4 '- (4-BON-N-methylaminomethyl) -1', 3'-dioxoranyl) piperidine

3.43 g of N-CBZ-4- (4 '- (methylaminomethyl) -1', 3'-dioxoranyl (piperidine) of 367b was dissolved in 30 ml of methylene chloride, and 2.98 ml of triethylamine And then 3.50 g of di-t-butyl dicarbonate in 20 ml of methylene chloride is added dropwise The reaction mixture is stirred for 5 hours at 35 DEG C and for 15 hours at room temperature The mixture is diluted with methylene chloride and washed with water The extract is washed with Na ₂ and dried with a SO ₄ and filtered and dried to give the title compound 4.29g.

Step 367d. 4- (4 '- (N-BOC-N-methylaminomethyl) -1', 3'-dioxoranyl) piperidine

(4'- (N-BOC-N-methylaminomethyl) -1 ', 3'-dioxoranyl) -piperidine of step 367c was dissolved in 200 mL of methanol in 10% Pd / C to then hydrogenated for 24 hours at room temperature in the H4 ₂ 4Atm. The catalyst is filtered off and the solvent is removed to give the title compound.

Step 367e. Methyl-1 ', 3'-dioxoranyl) piperidinyl) -7-fluoro-9-methyl- 4H-quinolizine-3-carboxylic acid hydrochloride

Example 253 Following the procedure for step j, 3-BOC-amino-pyrrolidine was reacted with 4- (4'- (N-BOC-N-methylaminomethyl) -1 ', 3'-dioxolane Yl) -piperidine and the product is reacted as in Example 253 steps j-k to give 199 mg of the title compound.

Elemental analysis for C ₂₃ H ₂₉ ClFN ₃ O ₅ .2H ₂ O:

Calculated: C, 53.33; H, 6.42; N, 8.11

Found: C, 53.62; H, 6.38; N, 8.32

Example 368

6-methylbicyclo [3.3.0] octan-1-yl) -7-fluoro-9-methyl-4-oxo-4H-quinolin- Chloro-3-carboxylic acid hydrochloride

Step 368a. N-benzyl-3-aza-6-oxocyclo [3.3.0] octane

32.69 g of N-methoxymethyl-N- (trimethylsilylmethyl) -benzylamine are dissolved in 30 ml of methylene chloride and the solution is cooled to 0 &lt; 0 &gt; C. 9.5 ml of 2-cyclopenten-1-one and 1.75 ml of trifluoroacetic acid are added to this solution, and the reaction mixture is stirred at 0 ° C for 0.5 hours and at room temperature for 24 hours. The reaction was quenched with water and the mixture was extracted with methylene chloride, filtered and dried with Na ₂ SO ₄ and dried to give the title compound, 28.27g.

Step 368b. N-Benzyl-3-aza-6-hydroxy-6-methylbicyclo [3.3.0]

The mixture of step 368a under N ₂ in anhydrous ether is reacted with methylmagnesium bromide at -30 ° C. After standard work-up, the title compound is isolated.

Step 368c. N-Benzyl-3-aza-6- (acetylamino) -6-methylbicyclo [3.3.0]

The compound of step 368b is reacted with acetonitrile in the presence of concentrated sulfuric acid. The reaction was quenched with water and the product extracted with methylene chloride, filtered and dried with Na ₂ SO ₄ and dried to give the title compound.

Step 368d. N-Benzyl-3-aza-6-amino-6-methylbicyclo [3.3.0]

Gt; HCl &lt; / RTI &gt; to remove the acetyl group from the compound of step 368c. By making the reaction mixture basic with NaOH and the product extracted with methylene chloride, filtered and dried with Na ₂ SO ₄ and dried to give the title compound.

Step 368e. N-Benzyl-3-aza-6- (BOC-amino) -6-methylbicyclo [3.3.0]

The compound of Step 368d is reacted with di-t-butyl dicarbonate in the presence of triethylamine. The reaction was quenched with water and the product extracted with methylene chloride, filtered and dried with Na ₂ SO ₄ and dried to give the title compound.

Step 368f. 3-aza-6- (BOC-amino) -6-methylbicyclo [3.3.0] octane

Hydrogenation in the presence of Pd / C removes the benzyl group from the compound of Dane &lt; RTI ID = 0.0 &gt; 368f. &Lt; / RTI &gt; The catalyst is removed by filtration and the solvent is evaporated to give the product.

Step 368g. 6-methylbicyclo [3.3.0] octan-1-yl) -7-fluoro-9-methyl-4-oxo-4H-quinolin- Chloro-3-carboxylic acid hydrochloride

According to the procedure of Example 253 step j, the product was obtained by replacing 3-BOC-amino-pyrrolidine with 369 g of 3-aza-6- (BOC-amino) -6-methylbicyclo [3.3.0] The reaction is carried out as in Example 253 Steps j to k to give the title compound (418 mg).

Calculated: C, 57.62; H, 6.37; N, 9.06

Found: C, 58.02; H, 6.64; N, 9.23

Example 369

1-Cyclopropyl-8- (3-fluoromethylpiperidinyl) -7-fluoro-9-methyI-4-oxo-4H-quinolizine

Step 369a, N-BOC-3-hydroxymethylpiperidine

3-Hydroxymethylpiperidine (2.0 g, 17.4 mmol) is suspended in 60 ml of water and cooled to 0 &lt; 0 &gt; C. Sodium bicarbonate (2.63 g, 31 mmol) is added in one portion and then benzyl chloroformate (2.60 ml, 18.3 mmol) is added dropwise in 10 ml of diethyl ether. After stirring at 0 ° C for 4 hours, the reaction is poured into 150 ml of water and extracted with methylene chloride (3 x 100 ml). The combined organic layers were dried over sodium sulfate, filtered and the filtrate was evaporated to dryness to give 3.74 g (86%).

Step 369b. N-BOC-3-fluoromethylpiperidine

The compound from step 369a (3.74 g, 15 mmol) is dissolved in 10 ml of methylene chloride and is added at -78 [deg.] C to a solution of diethylaminosulfur trifluoride (2.59 ml, 19.5 mmol) in 10 ml of methylene chloride. And the reaction is stirred at room temperature for 16 hours. 10 ml of water and 1 M sodium hydroxide are added dropwise to the reaction, and the product is extracted with methylene chloride (3 x 75 ml). The combined organic layers are dried over sodium sulfate, filtered and the filtrate is evaporated to dryness. The product was purified by flash chromatography (100% methylene chloride) to give 2.42 (64%).

Step 369c. 3-Fluoromethylpiperidine

The amine is deprotected under hydrogenation conditions using palladium on carbon (2 g) in methanol. After 16 hours at room temperature and 4 atm the catalyst was filtered off and the filtrate was concentrated to afford 808 mg (68%) of the desired amine.

Step 369d. 1-Cyclopropyl-8- (3-fluoromethylpiperidinyl) -7-fluoro-9-methyl-4-oxo-4H-quinolizine

The title compound was prepared according to the procedure of Example 253 step j, substituting 3-BOC-amino-pyrrolidine with 3-fluoromethylpiperidine in the previous step 369d and reacting the product as in Example 253 Steps j-k to give 198 mg .

Elemental analysis for C ₂₀ H ₂₂ F ₂ N ₂ O ₃ :

Calculated: C, 63.82; H, 5.89; N, 7.44

Found: C, 63.35; H, 5.83; N, 6.85

Example 370

9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride &lt; RTI ID = 0.0 &gt;

Step 370a. 4- (N, N-dimethyl) aminopiperidine

4- (N, N-dimethyl) aminopyridine (1.0 g, 8.2 mmol) was hydrogenated in 100 ml of methanol using rhodium (50 mg) at room temperature under 4 atm for 72 hours. The catalyst is filtered off and the filtrate is evaporated to give the desired amine 100%.

Step 370b. 9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride &lt; RTI ID = 0.0 &gt;

Example 253 Following the procedure for step j, the product was converted to 4- (N, N-dimethyl) aminopiperidine by the previous step 370a and the product was reacted as in Example 253 steps j to k 345 mg of the title compound are obtained.

Elemental analysis for C ₂₁ H ₂₇ N ₃ ClFN ₃ O ₃ :

Calculated: C, 59.50; H, 6.42; N, 9.91

Found: C, 59.72; H, 6.69; N, 9.33

Example 371

6-Amino-3-azabicyclo [3.3.0] octyl) -7-fluoro-9-methyl-4-oxo-4H- quinolizine-

Step 371a. 3-benzyl-6- (hydroxylamino) bicyclo [3.3.0] octane

3.24 g of 3-aza-6-oxocyclo [3.3.0] octane prepared in Example 368a are dissolved in 40 ml of THF. Hydroxylamine hydrochloride (3.14g) is dissolved in water and neutralized 60㎖ the salt was added to 4.05g NaHCO _3. A neutral hydroxylamine solution is added to the THF solution and the reaction mixture is vigorously stirred at room temperature for 18 hours. THF is removed from the mixture under vacuum and the aqueous solution is extracted with methylene chloride, dried over sodium sulfate, filtered and evaporated to dryness to yield 2.80 g of the title compound.

Step 317b. 3-aza-3-benzyl-6-aminobicyclo [3.3.0] octane

29.37 g of 3-aza-6- (hydroxylamino) bicyclo [3.3.0] octane prepared in Step 371a is dissolved in 1 L of methanol and hydrogenated for 24 hours with RaNi catalyst at H ₂ IAtm to 58.74 g of RaNi catalyst. The catalyst is filtered and the solvent is evaporated to give the title compound.

Step 371c. 3-Benzyl-6- (BOC-amino) bicyclo [3.3.0] octane

3.63 g of 3-aza-3-benzyl-6-aminobicyclo [3.3.0] octane from step 371b are dissolved in 25 ml of methylene chloride, and 3.39 ml of triethylamine are added and the solution is cooled to 0 &lt; 0 &gt; C. 3.98 g of di-t-butyl dicarbonate are dissolved in 6 ml of methylene chloride and added dropwise to the first solution. The reaction mixture is stirred at 0 &lt; 0 &gt; C for 30 minutes, stirred at room temperature for 18 hours, and quenched rapidly by adding water. The mixture is extracted with methylene chloride, dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by column flash chromatography eluting with 2% methanol in methylene chloride to give the title compound.

Step 371d. 3-aza-6- (BOC-amino) bicyclo [3.3.0] octane

The compound from step 371c is dissolved in 150 ml of methanol and hydrogenated at 10% Pd / C catalyst 1.5 under H _{2 4} Atm at room temperature for 23 hours. The catalyst is filtered and the solvent is evaporated to give the title compound.

Step 371e. 6-Amino-3-azabicyclo [3.3.0] octyl) -7-fluoro-9-methyl-4-oxo-4H- quinolizine-

Amino-3-azabicyclo [3.3.0] octane of the previous step, 371d, according to the procedure of Example 253 step j and the product is obtained by reaction of the product of Example 253 Steps j- k to give the title compound (298 mg).

Elemental analysis for C ₂₁ H ₂₅ ClFN ₃ O ₃ .1.5H ₂ O:

Calculated: C, 51.97; H, 6.02; N, 8.66

Found: C, 52.07; H, 5.81; N, 8.48

Example 372

Cyclopropyl-8- ((2-aza-4- (dimethylaminomethyl) bicyclo [4.3.0] non-2-yl) -7-fluoro- N-Carboxylic Acid Hydrochloride

Step 372a. 2-aza-4-dimethylaminomethylbicyclo [3.3.0] nonane

1 g of 3-dimethylaminomethylindole is hydrogenated with Pd / C in acetic acid / HCl, the catalyst is filtered off and the solvent is diluted with water to pH 11 and extracted with ethyl acetate. The solvent was evaporated to dryness to give the title compound.

Step 372b. Cyclopropyl-8- ((2-aza-4- (dimethylaminomethyl) bicyclo [4.3.0] non-2-yl) -7-fluoro- 3-carboxylic acid &lt; / RTI &gt; hydrochloride

Amino-pyrrolidine was converted to 2-aza-4-dimethylaminomethyl) bicyclo [4.3.0] -nonane according to the procedure of Example 253 step j and the product was obtained in analogy to example 253 step j To yield 354 mg of the title compound.

Elemental analysis for C ₂₅ H ₃₃ ClFN ₃ O ₃揃 1.25H ₂ O:

Calculated: C, 60.59; H, 7.73; N, 8.48

Found: C, 60.07; H, 7.71; N, 8.15

Example 373

(3-aza-6- (L-alaninylamino) -6-methylbicyclo [3.3.0] octane) -7- Quinolizinecarboxylic acid hydrochloride

A solution of 1-cyclopropyl-8- (3-aza-6- (L-alaninylamino) -6-methylbicyclo [3.3.0] octane) -7- Oxo-4H-quinolizinecarboxylic acid hydrochloride are dissolved in 3 ml of DMF and the solution is cooled to 0 &lt; 0 &gt; C. After adding 0.44 ml of diisopropylethylamine, 35 mg of N-BOC-L-alanyl-N-hydroxysuccinimide was added and the mixture was stirred at 0 占 폚 for 20 minutes and at room temperature for 48 hours. The solution is poured into a large volume of water, the product is filtered and dried.

Elemental analysis for C ₂₅ H ₃₂ ClFN ₄ O ₄ .H ₂ O:

Calculated: C, 57.19; H, 6.14; N, 10.67

Found: C, 57.16; H, 6.48; N, 9.90

Example 374

(3R, 1R) -8- (3- (1-N-methyl) amino) propyl) pyrrolidinyl) -1-cyclopropyl-7-fluoro-9- Carboxylic acid hydrochloride

8-Chloro-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester from Example 253i was dissolved in 8 ml of anhydrous acetonitrile and (3R, 1R ) -3- (1- (N-methyl) amino) propyl) pyrrolidine (Plummer, et al., Ter. Lett. (Prepared according to Hayakawa et al., U. S. Patent No. 5,098, 912 (1992. 3, 24)), using a modification to the chiral product described in &lt; RTI ID = 0.0 & And carried out as described in example 253j-l to give the title product.

Examples 375 to 408

Following the procedures of Steps 253j, 253k, and 253l, the compounds of Examples 375-412 are prepared as shown in Table 13, replacing the 3-BOC-aminopyrrolidine of Step 253j with the appropriate unprotected or BOC-protected reagent .

[Table 13a]

[Table 13b]

[Table 13c]

[Table 13d]

Example 413

(3R, 1S) -8- (3- (1-Amino-2-methoxyethyl) pyrrolidinyl) -1-cyclopropyl-7-fluoro-9- Carboxylic acid hydrochloride

Step 413a. (S) -N-BOC-O- (t-butyldimethylsilyl) serine methyl ester

7 g of (S) -N-BOC-serine methyl ester (Aldrich) are dissolved in pyridine and cooled in an ice bath. To this stirred solution was added dropwise 5.54 g (36.76 mmol) of t-butyldimethylsilyl chloride (TBDMSC) dissolved in 40 ml of pyridine. After all the reagents have been added, the reaction is stirred at room temperature for 4 hours. 0.5 g of TBDMSC are further added and the reaction is stirred for an additional 2 hours. To the mixture is added 2.5 equivalents of imidazole in 14 ml of DMF and the reaction is stirred for 2 hours. The solvent is removed under reduced pressure and the residue is dissolved in ethyl acetate and washed with water and brine. Removal of the solvent gave the title compound as a yellow oil.

Step 413b. (S) -2- (BOC-amino) -3- (t-butyldimethylsilyloxy) -1-propanol

A cooled (ice bath) solution of the compound from step 413a (9.6 g, 28.83 mmol) in 4 ml of THF is added dropwise to a suspension of 570 mg (14.84 mmol) of LAH in 15 ml of THF under a N ₂ atmosphere. The mixture is stirred for 1.5 hours and the reaction is quenched with 50% NaOH, filtered and the filtrate evaporated to give the crude product. An oil was obtained and purified by silica gel chromatography eluting with 15-20% ethyl acetate: hexanes to give 3.456 g of the title product as a colorless oil.

Step 413c. (S) -2- (BOC-amino) -3-t-butyldimethylsilyloxy) -1-propanol

5.2 ml (37.49 mmol) of triethylamine are added dropwise to a solution of the compound of step 413b (3.47 g, 11.36 mmol) in 6 ml of DMSO cooled to 0 ° C. The pyridine-SO ₃ complex (5.424 g, 34.08 mmol) is dissolved in 21 ml of DMSO, added to the first solution, and the reaction is stirred for 1.5 hours. The solution is poured into 120 ml of cold brine and the mixture is washed three times with ethyl acetate. The extract was washed with water and dried with MgSO ₄ and filtered The solvent was removed under vacuum to give a yellow oil, 3.9g, and immediately used in the next step.

Step 413d. (S) -4- (BOC-amino) -5- (t-butyldimethylsilyloxy) -2-pentenoic acid ethyl ester

(11.36 mmol) of (carboethoxymethylene) triphenylphosphorane in 13 ml of CH ₂ Cl ₂ is added dropwise to a solution of the compound of Step 413c (11.36 mmol) in ₂₄ ml of CH ₂ Cl ₂ cooled in an ice bath. After completion, the reaction is stirred at room temperature for 16 hours. The solvent was removed and the residue was purified by silica gel column chromatography eluting with 3-10% ethyl acetate: hexane to give 3.93 g of a colorless oil.

Step 413e. (S) -4- (BOC-amino) -5- (t-butyldimethylsilyloxy) -3- (nitromethyl) -pentanoic acid ethyl ester

1,8 in the step of nitromethane was cooled in an ice bath 6ml 413d compound (3.9g, 10.46mmol) solution of diazabicyclo [5.4.0] undec-7-ene to 1.56ml (10.46mmol) under N ₂ Drop it. The mixture is warmed to room temperature and stirred for 16 hours. The solution is diluted with CH ₂ Cl ₂ and extracted with water, 10% HCl, 10% NaHCO ₃ , water and brine. The solution was dried with MgSO ₄ and the solvent removed. The residue is chromatographed on silica gel eluting with 5-10% ethyl acetate: hexanes to remove the solvent to give 3.6 g of the title product as a white solid.

Step 413f. (S) -4- (BOC-amino) -5- (t-butyldimethylsilyloxy) -3- (aminomethyl) -pentanoic acid ethyl ester

4.74 g of the compound of Step 413e are dissolved in 250 ml of ethanol and hydrogenated at 14 atm at 14.2 g of Raney nickel catalyst for 24 hours. The catalyst is filtered off and the solvent is evaporated. The residue (mp 152-154 [deg.] C) is used in the next step.

Example 413g. (S) -t- (1-BOC-amino) -2- (t-butyldimethylsilyloxy) ethyl) -2-oxo-4- pyrrolidine

The residue of step 413f is dissolved in 150 ml of ethanol and heated to reflux for 8 hours. The solvent is removed and the residue is chromatographed on silica gel eluting with 4% methanol / methylene chloride. Removal of the solvent affords the title product.

Step 413h. (S) -4- (1-BOC-amino) -2- (t-butyldimethylsilyloxy) ethyl) -1- benzyl-2-oxopyrrolidine

Step 413g 200 mg (0.558 mmol) of the compound are dissolved in 1 ml of THF and the solution is added dropwise to a suspension of NaH (47 mg, 1.172 mmol) in 2 ml of THF at 0 ° C and the reaction mixture is stirred for 1 hour. To this mixture was added 124 mg of benzyl bromide and the reaction was stirred at room temperature for 3 hours. The organic layer is acidified with citric acid solution and the mixture is extracted with ethyl acetate. The solvent was washed with brine, dried over MgSO ₄ filtered and evaporated. The residue was purified by column chromatography eluting with 30-35% ethyl acetate: hexane to give 168 mg of the title compound.

Step 413i. (S) -4- (1- (BOC-amino) -2-hydroxyethyl) -1- benzyl-2-oxopyrrolidine

143 mg of the compound from step 413h are dissolved in 1 ml of THF and reacted with 1 equivalent of tetra-n-butylammonium at room temperature for 1.5 hours. The solvent was removed and the residue was dissolved in methylene chloride, eluting with methanol in 5% methylene chloride and purification by silica gel column chromatography to give 110 mg of the title compound.

Step 413j. (S) -4- (1- (BOC-amino) -2-methoxyethyl) -1-benzyl-2-oxopyrrolidine

The compound of step 413i (7.34 mmol) is dissolved in 22 ml of THF, a suspension of 8.72 mg (16.148 mmol) of sodium methoxide in 40 ml of THF is added and the reaction mixture is stirred at room temperature for 1 hour under nitrogen. This solution is added to 3.958 g of methyl iodide in 5 ml of THF and the reaction mixture is stirred for 16 hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate then washed with sodium thiosulfate and brine, dried with MgSO _4, filtered and evaporated. The residue was purified by silica gel column chromatography eluting with methanol in 5% methylene chloride to give the title compound.

Step 413k. (S) -4- (1- (BOC-amino) -2-methoxyethyl) -1-benzyl-2-thioxopyrrolidine

50 mg of the compound of Step 413j and 29 mg (0.07 mmol) of Lewesson's reagent are dissolved in 0.3 ml of THF and stirred under N ₂ for 3 hours. The solvent is removed and the residue is dissolved in CH ₂ Cl ₂ and chromatographed on silica gel, eluting with 30% ethyl acetate: hexane. Solvent is removed to leave 51 mg of product.

Step 413I. (S) -3- (1- (BOC-amino) -2-methoxyethyl) -1-benzylpyrrolidine

45.7 mg (0.125 mmol) of the compound of step 413k and 239 mg (1.0 mmol) of NiCl ₂ .6H ₂ O are dissolved in 2 ml of a 1: 1 mixture of methanol and THF, the solution is cooled to -78 ° C and stirred under N ₂ . 114 mg (3.0 mmol) of NaBH _{4 are} added in small portions and the mixture is stirred for 2 hours. The solvent is removed in vacuo and dissolved in methanol in 20% chloroform. The solution is filtered and the solvent is removed. The residue is chromatographed on silica gel eluting with methanol in 5% chloroform to give 23 mg of the title product.

Step 413m. (S) -3- (1- (BOC-amino) -2-methoxyethyl) -pyrrolidine

203 mg of the compound of Step 413I are dissolved in 25 ml of methanol and hydrogenated for 22 hours at 50 ml of 10% Pd / C catalyst at 4 Atm. The catalyst was removed by filtration and the solvent was evaporated, yielding 160 mg of the title compound as viscous oil.

Step 413n. (3R, 1S) -8- (3- (1-Amino-2-methoxyethyl) pyridinyl) -1-cyclopropyl-7-fluoro-9- 3-carboxylic acid hydrochloride

77 mg (0.238 mmol) of ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine- - (1- (BOC-amino) -2-methoxyethyl) -pyrrolidine and carry out as described in example 253 steps j-l to give 62 mg of the title product.

Example 414

8- (3- (S) - (acetylamino) pyrrolidinyl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-

To a solution of 8- (3- (S) -aminopyrrolidinyl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4-N -Quinolizine-3-carboxylic acid, 0.342 ml of acetic anhydride is added dropwise with stirring. The reaction mixture was stirred for 3.5 hours and the precipitate was isolated by filtration and dried in vacuo to give 196 mg of the title compound.

Elemental analysis for C ₂₀ H ₂₂ FN ₃ O ₄ .1.5H ₂ O:

Calculated: C, 58.60; H, 6.02; N, 10.25

Found: C, 58.89; H, 5.85; N, 10.02

Example 415

8- (3-Carbamoylpiperidinyl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-

Step 415a. 8- (3-Carbamoylpiperidinyl) -l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-

Prepared as in Example 253i 8- chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-quinolinyl -4H- binary dissolved 3-carboxylic acid ethyl ester 971mg in 10ml DMF and N ₂ positive pressure Put it in an oven-dried system under atmospheric conditions. To this was added 1.15 g of nicotinamide (Aldrich) and 0.900 ml of triethylamine. The reaction mixture is heated at 55 &lt; 0 &gt; C with stirring for 24 hours. The reaction is quenched with water and the mixture is extracted with methylene chloride. After washing with water, the organic solution is dried over Na ₂ SO ₄ and filtered. The solvent was removed in vacuo to afford the title compound as a yellow solid (1.138 g).

Step 415b. 8- (3-Carbamoylpiperidinyl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-

Hydrolyzed with LiOH 442mg of the compound of step 415a in THF / H ₂ O and separated, as the titled product described in Example 253k.

Elemental analysis for C ₂₀ H ₂₂ FN ₂ O ₄ .0.75 H ₂ O:

Calculated: C, 59.92; H, 5.91; N, 10.48

Found: C, 60.18; H, 5.89; N, 10.62

Example 416

8- (3-Hydroxypiperidinyl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-

Example 253i manufactured by 8-chloro-1-cyclopropyl-9-methyl-7-fluoro-4-oxo-quinolinyl -4H- Jean-3-carboxylic acid ethyl ester 2.0g was dissolved in 25ml DMF and N ₂ positive pressure Put it in an oven-dried system under atmospheric conditions. To this was added 1.1 g of 3-hydroxypiperidine (Aldrich) and 1.8 ml of triethylamine. The reaction mixture is heated at 55 &lt; 0 &gt; C with stirring for 144 hours. The reaction is quenched with water and the mixture is extracted with methylene chloride. After washing with water, the organic solution is dried over Na ₂ SO ₄ and filtered. The solvent is removed in vacuo to give the intermediate ester compound as an oil (3 g).

Elemental Analysis for _{C 19 H 21 FN 2 O 4} · H 2 O:

Calculated: C, 60.13; H, 6.13; N, 7.40

Found: C, 59.92; H, 5.79; N, 7.14

Example 417

8- (3-Hydroxymethylpiperidinyl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-

Example 253i as one 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-manufactured -4H- quinone dissolved fun Jean-3-carboxylic acid ethyl ester in DMF 10ml and 0.971g positive pressure N ₂ Put it in an oven-dried system under atmospheric conditions. 1.04 g of 3-piperidinemethanol (Aldrich) and 0.900 ml of triethylamine are added thereto. The reaction mixture is heated at 55 &lt; 0 &gt; C with stirring for 72 hours. The reaction is quenched with water and the mixture is extracted with methylene chloride. After washing with water, the organic solution is dried over Na ₂ SO ₄ and filtered. The raffinate is removed in vacuo to give the intermediate ester compound as an oil (1.25 g).

Elemental analysis for C ₂₀ H ₂₃ FN ₂ O ₄ .0.25 H ₂ O:

Calculated: C, 63.40; H, 7.39; N, 6.24

Found: C, 63.25; H, 7.29; N, 6.25

Example 418

8- (3- (R) -hydroxypiperidinyl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-

Example 253i as one 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-manufactured -4H- quinone dissolved fun Jean-3-carboxylic acid ethyl ester in DMF 10ml and 0.971g positive pressure N ₂ Put it in an oven-dried system under atmospheric conditions. To this was added 1.23 g of 3- (R) - (+) - hydroxypiperidine (Aldrich) and 0.900 ml of triethylamine. The reaction mixture is heated at 55 &lt; 0 &gt; C with stirring for 72 hours. The reaction is quenched with water and the mixture is extracted with methylene chloride. After washing with water, the organic solution is dried over Na ₂ SO ₄ and filtered. The solvent is removed in vacuo to give the intermediate ester compound as an oil (1.56 g). This ester was purified by silica gel chromatography and the intermediate was hydrolyzed and the product isolated as described in Example 415 (785 mg).

Elemental analysis for C ₁₉ H ₂₁ FN ₂ O ₄ · 1.25H ₂ O:

Calculated: C, 59.60; H, 6.19; N, 7.32

Found: C, 59.30; H, 5.94; N, 7.29

Example 419

(3R) -9-fluoro-3-methyl-10- (piperazin-1-yl) -2H, 3H, 6H- 6 -oxo-pyrano [2.3.4-ij] quinolizine- Hydrochloride

According to the procedure of Example 281f, the product is treated according to steps 281g and h, substituting 3- (BOC-amino) pyrrolidine for N-BOC-piperazine to produce the title compound.

Elemental analysis for C ₁₇ H ₁₈ FN ₃ O ₄ · 2.0H ₂ O:

Calculated: C, 48.63; H, 5.52; N, 10.01

Found: C, 48.92; H, 5.57; N, 9.80

Example 420

8-Bicyclo [4.3.0] nonyl) -7-fluoro-4H-9-methyl-4-oxo-quinolizine- 3-carboxylic acid hydrochloride

Step 420a. 6H-pyrrolo [3,4-b] pyridin-5,7-dione &lt;

10 g of 2,3-pyridine dicarboxylic acid anhydride (Aldrich) are dissolved in 100 ml of anhydrous THF and cooled to 0 &lt; 0 &gt; C. To this solution is added 8.70 ml of (S) - (-) - alpha-methylbenzylamine. The solution is warmed to room temperature and stirred for 30 minutes, then 11.96 g of 1,1'-carbonyldiimidazole are added. And stirred for 20 hours under N ₂ and the reaction at room temperature. The solvent is removed and the residue is dissolved in methylene chloride. The solvent is washed with water, dried over MgSO _4. The solvent was removed in vacuo to give 15.344 g of the title compound.

Step 420b. 8- (1- (S) -phenylethyl-2,8-diazabicyclo [4.3.0] nonane-7,9-dione

15.344 g of the compound of Step 420a are hydrogenated at 100 &lt; 0 &gt; C for 22 hours in Pd / C in H ₂ 4atm in 2-methoxyethanol. The catalyst and solvent were removed to give 10.12 g of the title compound.

Step 420c. 8 - ((1- (S) -phenylethyl) -2,8-diazobicyclo [4.3.0] nonane

Dissolving 10.12g of the compound of step 420b in 30ml THF was added dropwise to the solution to 3.13g LAH suspension in a 50ml dry THF was stirred under N ₂ eseo 0 ℃. After completion, the mixture is heated under reflux for 9 hours. Then the reaction at 0 ℃ H ₂ O 25ml, then quenched by addition of 15% KOH and 25ml H ₂ O 25ml. The solid is filtered off and the filtrate is extracted with ether. The extract was dried with MgSO ₄ and the solvent removed to give 7.98 g of the title compound.

Step 420d. 2-BOC-8 - ((1- (S) -phenylethyl) -2,8- diazabicyclo [4.3.0] nonane

Is dissolved in H ₂ O 75ml: 7.98g of the compound of step 40c 2: 1 methanol. The solution is cooled to 0 C and 7.94 g of di-t-butyl dicarbonate are added. The mixture is warmed to room temperature and stirred for 1 hour. The organic solvent is removed in vacuo and the residue is slurried with methylene chloride. The organic layer is separated, washed and dried. The solvent was removed and the residue was purified by silica gel chromatography eluting with 100: 5: 0.5 methylene chloride: methanol: ammonium hydroxide to give 4.6 g of the title compound as an oil. This material is separated into 1,6- (R, R) - and 1,6- (S, S) -isomers by HPLC using a chiral support. R, R- isomer is [a] _D a + 31.9 ℃ (23 °, c = 1.01, methanol) and the S, S- isomer is [a] _D is -84.6 ℃ (23 °, c = 1.04, methanol) [For additional information on isomer identification, see Poster # 642, ICAAC 32nd Annual Meeting, 1994].

Step 420e. (S, S) -2-BOC-2,8-diazabicyclo [4.3.0] nonane

1.328 g of the S, S-isomer of step 420d and 1.27 g of ammonium formate are dissolved in 40 ml of methanol. The flask is flushed with N ₂ , 130 mg of 10% Pd / C are added and the reaction mixture is heated to reflux for 1.5 hours. The solution is cooled, filtered and the solvent is removed. The residue is dissolved in methylene chloride and filtered again. The solvent was removed in vacuo to give the title compound (858 mg). [?] _D -70.8 ° C (23 °, c = 1.30, methanol)

Step 420f. 8-Bicyclo [4.3.0] nonyl) -7-fluoro-4H-9-methyl-4-oxo-quinolizine- 3-carboxylic acid hydrochloride

Following the procedure of Example 253j, substituting BOC-aminopyrrolidine with 1,6- (S, S) -2BOC-2,8-diazobicyclo [4.3.0] nonane in step 420e gave the product as a white solid, And l to yield the title compound.

Elemental analysis for C ₂₁ H ₂₄ FN ₃ O ₃ .HCl ₁ .25H ₂ O:

Calculated: C, 56.76; H, 6.24; N, 9.45

Found: C, 56.73; H, 6.05; N, 9.44

Example 421

8-Bicyclo [4.3.0] nonyl) -7-fluoro-4H-9-methyl-4-oxo-quinolizine- 3-carboxylic acid hydrochloride

Step 421a. (R, R) -2-BOC-2,8-diazabicyclo [4.3.0] nonane

According to the procedure of Example 420e, 1.864 g of the R, R-isomer of step 420d is deprotected to give 1.219 g of the title product. [a] _D + 73.6 [deg.] C (23 [deg.], c = 1.15, methanol). Spectral data is identical to the compound of Example 420E.

Step 421b. 8-Bicyclo [4.3.0] nonyl) -7-fluoro-4H-9-methyl-4-oxo-quinolizine- 3-carboxylic acid hydrochloride

Following the procedure of Example 253j, substituting the BOC-aminopyrrolidine with 1,6- (R, R) -2-BOC-2,8-diazobicyclo [4.3.0] Steps 253k and l were reacted to yield the title compound.

Elemental analysis for C ₂₁ H ₂₄ FN ₃ O ₃ .HCl. 1.5 H ₂ O:

Calculated: C, 56.19; H, 6.29; N, 9.36

Found: C, 56.19; H, 6.15; N, 9.44

Example 422

3-aza-bicyclo [3.1.0] hexan-3-yl) -7-fluoro-4H-9-methyl-4-oxo-quinolizine- -Carboxylic acid hydrochloride

Step 422a. Boc-amino-3-aza-bicyclo [3.1.0] hexan-3-yl) -7-fluoro-4H-9-methyl-4-oxo-quinolizine -3-carboxylic acid, ethyl ester

660 mg of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester of 231 i was placed in a flask and treated according to U.S. Patent No. 5,164,402 400 mg of 1- (BOC-amino) -3-azabicyclo [b] cyclo [3.1.0] hexane are dissolved in 15 ml of anhydrous THF and added to the flask. Finally, 2.2 ml of triethylamine are added and the solution is stirred at 5 [deg.] C for 26 hours. The reaction is cooled, quenched with 15 ml of H ₂ O and the mixture is extracted with ethyl acetate. Dry the organic extracts with MgSO ₄ and the solvent removed in vacuo. The residue was purified by silica gel chromatography eluting with 3-5% methanol in methylene chloride to give 350 mg of the title compound.

Step 422b. Boc-amino-3-aza-bicyclo [3.1.0] hexan-3-yl) -7-fluoro-4H-9-methyl-4-oxo-quinolizine Carboxylic acid

Following the procedure for Example 253k, starting materials are prepared substituting the compound of Step 422a to give the title compound.

Step 422c. 3-aza-bicyclo [3.1.0] hexan-3-yl) -7-fluoro-4H-9-methyl-4-oxo-quinolizine- -Carboxylic acid hydrochloride

According to the procedure of Example 251, the starting material is substituted with the compound of Step 422b to give the title compound.

Elemental analysis for C ₁₉ H ₂₁ FN ₃ O ₃ .HCl. 1.5 H ₂ O:

Calculated: C, 54.22; H, 5.75; N, 9.98

Found: C, 54.10; H, 5.61; N, 9.86

Example 423

Fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride

Step 423a. 2-fluoromethylpropanoic acid ethyl ester

2.632 g (20 mmol) of 2-hydroxymethylpropanoic acid ethyl ester (Villieras and Rambaud, Synthesis, 1982, 924) are dissolved in 35 ml of methylene chloride and the solution is cooled to -78 &lt; 0 &gt; C. 2.94 ml (22 mmol) of DAST is added to the solution and the reaction mixture is stirred at -78 占 for 30 minutes and at room temperature for 1 hour. The reaction is quenched with H ₂ O (35 ml) and the layers are separated. The organic solution was washed with brine, dried with MgSO ₄ and the solvent removed to give the title compound 2.343g.

Step 423b. 1-Benzyl-3-fluoromethyl-3-pyrrolidinecarboxylic acid ethyl ester

733 mg (6 mmol) of the compound of 423 g and 1.327 g (6 mmol) of N-benzyl-N- (methoxymethyl) trimethylsilylmethylamine are dissolved in 4 ml of methylene chloride. The solution is cooled to 0 &lt; 0 &gt; C and stirred at 0-2 &lt; 0 &gt; C for 75 minutes. The solution was diluted with methylene chloride and washed saturated NaHCO ₃ solution and water and dried with MgSO _4. The solvent was removed and the residue was purified by silica gel chromatography, eluting with 4: 1 hexane: ethyl acetate to give 875 mg of the title compound.

Step 423c. 3-Fluoromethyl-3-pyrrolidinecarboxylic acid ethyl ester

875 mg of the compound of Step 423b and 1.04 g of ammonium formate are dissolved in 30 ml of ethanol. The flask is flushed with N ₂ and 200 mg of Pd / C are added and the mixture is heated to reflux for 15 minutes. The mixture was cooled, filtered and the solvent removed to give 454 mg of the title compound.

Step 423d. 1-CBZ-3-fluoromethyl-3-pyrrolidinecarboxylic acid ethyl ester

1 to 450mg of the compound Tange 423c: 1 dioxane: water, was dissolved in 4ml was added Na ₂ CO ₃ 324mg to cool the solution to 0 ℃. 0.44 ml of benzyloxycarbonyl chloride was added dropwise to the solution, and the reaction mixture was stirred at 0 占 폚 for 45 minutes and at room temperature for 3 hours. The solution is diluted with ether and the mixture is washed with water, saturated NaHCO ₃ , water and saturated brine in this order. The ether layer is separated and the solvent is removed. The residue was purified by silica gel chromatography eluting with 1: 3 ethyl acetate: hexane to give 666 mg of the title compound.

Step 423e. 1-CBZ-3-fluoromethyl-3-pyrrolidinecarboxylic acid

550 mg of the compound of step 423d are dissolved in 4 ml of THF and cooled to 0 &lt; 0 &gt; C. To this solution, 173 mg of LiOH and 1 ml of H ₂ O are added. The reaction mixture is stirred at room temperature for 3 hours and then acidified by addition of 1N HCl. The organic solution is washed with water and saturated brine and the layers are separated. The residue was purified by silica gel chromatography eluting with methanol in 10% methylene chloride to give 251 mg of the title compound.

Step 423f. N-BOC-1-CBZ-3-fluoromethyl-3-pyrrolidineamine

715 mg of the compound of step 423e are dried under vacuum and dissolved in 8 ml of distilled t-butanol. Was added 0.71ml of triethylamine and 0.81ml dppa mixture to the solution is refluxed for 16 hours under N ₂ atmosphere. The cooled reaction mixture was diluted with ether, washing the mixture with water, saturated NaHCO ₃ and saturated brine. The solvent was removed and the residue was purified by silica gel chromatography eluting with 1: 4 ethyl acetate: hexane to give 587 mg of the title compound.

Step 423g. 3- (BOC-amino) -3-fluoromethylpyrrolidine

183 mg of the compound of Step 423f and 164 mg of ammonium formate are dissolved in 8 ml of ethanol. The flask is flushed with N ₂ and 50 mg of Pd / C are added and the mixture is heated to reflux for 20 minutes. The mixture was cooled, filtered and the solvent removed to give 101 mg of the title compound.

Step 423h. 4-yl-methyl-4-oxo-quinolizine-3-carboxamide &lt; / RTI & Carboxylic acid ethyl ester

120 mg (0.37 mmol) of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester of step 253i are placed in a flask. To this flask was added a solution of 953 mg of 3- (BOC-amino) -3-fluoromethylpyrrolidine in 423 g of the step dissolved in 3 ml of DMF and 0.30 ml of triethylamine. The reaction mixture is heated to reflux for 16 hours and the reaction quenched with 4 ml of water. The mixture is cooled and extracted with ethyl acetate. Dry the extract over MgSO ₄ and the solvent removed. The residue was purified by silica gel chromatography eluting with 2-5% methanol in methylene chloride to give 143 mg of the title compound.

Step 423i. 4-yl-methyl-4-oxo-quinolizine-3-carboxamide &lt; / RTI & Carboxylic acid

The procedure is carried out according to the method of Example 253k except that the starting material is replaced by 143 mg of the compound of Step 423h to give 115 mg of the title compound.

Step 423j. Fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride

The title compound is prepared in analogy to Example 253, starting from 95 mg of the title compound by replacing the starting material with 115 mg of the compound of step 423i.

Elemental analysis for C ₁₉ H ₂₁ F ₂ N ₃ O ₃ .2HCl .0.5H ₂ O:

Calculated: C 49.68, H 5.27, N 9.15

Found: C 49.66, H 5.23, N 8.91

Example 424

Fluoro-1-pyrrolidinyl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-

Following the procedure of Example 245j, BOC-aminopyrrolidine was replaced with 68 mg of 3-amino-3-fluoromethylpyrrolidine as prepared in PCT patent WO9414794 and the product obtained was purified by analogy to step 253k To give the title compound (note: rearrangement of the F and amino group positions on the pyrrolidine ring).

Example 425

8- (3- (S) -hydroxy-1-pyrrolidinyl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-

Step 425a. (S) -1-BOC-3-pyrrolidinol

(S) -1-benzyl-3-pyrrolidone and stirred dinol samples 0.8g (55.2mmol) and the mixture exerts a dissolved, 20% Pd / C 1.96g in 200ml of ethanol under N _2. 17.4 g of ammonium formate are added to the mixture and the reaction mixture is stirred for 10 minutes at an internal temperature of 70 &lt; 0 &gt; C. The reaction mixture is removed from the bath and allowed to cool until the gas evolution is terminated. The mixture is cooled and then diluted with methylene chloride. The solid is filtered off and the filtrate is concentrated. The residue is suspended in 200 ml of methylene chloride and 2.07 g of di-t-butyl dicarbonate is maintained at a temperature of 19 to 23 [deg.] C with stirring. The mixture is stirred at room temperature for 16 hours. The organic solvent is removed in vacuo and the residue is slurried with methylene chloride. The organic phase is separated, washed and then dried. The solvent was evaporated and the residue was purified by chromatography on silica gel to give 8.94 g of the title compound as colorless oil.

Step 425a. 8- (3- (S) -hydroxy-1-pyrrolidinyl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-

Following the procedure of Example 253j, the BOC-aminopyrrolidine was replaced by (S) -1-BOC-3-pyrrolidinol obtained from step 425a and the obtained product was treated as in step 253k The title compound is prepared. Melting point 240 ° C

Elemental analysis for C ₁₈ H ₁₉ FN ₂ O ₄ :

Calculated: C 62.42, H 5.53, N 8.09

Found: C 62.34, H 5.38, N 7.99

Example 426

8- (3- (R) -hydroxy-1-pyrrolidinyl) -1-cyclopropyl-7-fluoro-4H-9-

(S) -1-benzyl-3-pyrrolidinol was replaced by (R) -1-benzyl-3-pyrrolidinole to produce the title compound.

Elemental analysis for C ₁₈ H ₁₉ FN ₂ O ₄ :

Calculated: C 62.42, H 5.53, N 8.09

Found: C 62.54, H 5.56, N 7.96

Example 427

-7-fluoro-4H-9-methyl-4-oxo-quinolizine-l- 3-carboxylic acid hydrochloride

See Kimura et al., J. Med. Chem., 37: 3344-3352 (1994), the title compound is prepared. When the diastereomeric product is purified by chromatography on silica gel, the compound is separated into the 7- (S) - and 7- (R) -diastereoisomers. The 7- (S) -compound And the 7- (R) -compound is used in Example 428.

Step 427b. 7- (S) -amino-5- (1- (R) -phenylethyl) -5- azaspiro [2.4] heptane

To a solution of 7- (S) -amino-5- (1- (R) -phenylethyl) -4-oxo-5-azaspiro [2.4] heptane obtained from step 427a in 15 ml of freshly distilled THF , 66.5 mmol] The sample is added dropwise to a cooled (ice bath) suspension of LAH (7.42 g) in anhydrous THF (300 ml). The reaction was stirred and allowed to warm to room temperature and was added to the starting material and then heated under reflux for 4 hours under N _2. The mixture is cooled to 0 C and H ₂ O (7.5 ml), 20% NaOH (7.5 ml) and H ₂ O (22 ml) are added successively with stirring, and the mixture is stirred at room temperature for 1 hour. The mixture is filtered and the filter cake is washed repeatedly. The combined filtrate is concentrated to give 14.75 g of the title compound as an oil. MS m / z 217 (M + H) &lt; ⁺ & gt ^; .

Step 427c. (S) - (BOC-amino-5- (1- (R) -phenylethyl) -5- azaspiro [2.4] heptane

The compound obtained from step 427b (14.75 g, 79.8 mmol) is dissolved in methylene chloride (90 ml), cooled, and (BOC) ₂ O is added portionwise and the mixture is stirred at room temperature for 2 hours. The mixture was washed with water and brine, dried (MgSO _4), filtered and concentrated. The residue was purified by chromatography on silica gel eluting with 25% ethyl acetate in hexanes to give 18.1 g (86% yield) of a white solid from the lactam. X-ray crystallography confirms that the product is an S-isomer at the pyrrolidine ring junction.

Step 427d. 7- (S) - (BOC-amino) -5-azaspiro [2.4] heptane

The 7- (S) - compound obtained from step 427c is dissolved in ethanol and hydrogenated at Pd / C for 24 hours at room temperature and H2 at 4 atm. The mixture is filtered and the filtrate is concentrated. The residue was purified by chromatography on silica gel eluting with ethyl acetate: hexane (15:85) to give the title compound. MS m / z 213 (M + H) &lt; ⁺ & gt ^;

Step 427e. -7-fluoro-4H-9-methyl-4-oxo-pyrrolidine The title compound was prepared from 8- (7- (S) - (BOC- Quinolizine-3-carboxylic acid

The title compound is prepared according to the method of Example 253j, substituting BOC-aminopyrrolidine with the compound obtained from step 427d above and treating the obtained product as described in step 253k.

Step 427f. -7-fluoro-4H-9-methyl-4-oxo-quinolizine-l- 3-carboxylic acid hydrochloride

120 ml of 1 M HCl in acetic acid are added to a solution of the acid (18.57 g, 39.43 mmol) in methylene chloride (80 ml). The slightly red solution is stirred at room temperature for 1.5 hours. A yellow precipitate is observed. Check with TLC (4% MeOH / CH ₂ Cl ₂ ), starting material is not observed. The solid was filtered, washed several times with water, and then dried at room temperature and 15 mm Hg overnight to give 10 g of a yellow solid. The filtrate is concentrated and dried under high vacuum (0.5 mm Hg) for 2 hours and polished with ether. The solid so obtained is stirred vigorously in ether, filtered and washed with ether to give 4.6 g of a slightly brown solid. The two solid samples are combined and analyzed.

Elemental analysis for C ₂₀ H ₂₃ N ₃ O ₃ FC ₁ .H ₂ O:

Calculated: C 56.17, H 5.31, N 9.64

Found: C 56.40, H 5.91, N 9.86

Example 428

4-oxo-quinolizine-1-carbonitrile The title compound was prepared in analogy to the procedure described for the synthesis of 8- (7- (R) -amino-5-aza- spiro [2.4] heptan- 3-carboxylic acid hydrochloride

(R) - (BOC-Imino) -4-oxo-5-azaspiro [2.4] heptane obtained from step 427a instead of the 7- (S) And the obtained product is treated as in step 427b to give the title compound. Melting point 200 ° C

Elemental analysis for C ₂₀ H ₂₂ FN ₃ O ₃ .HCl. 2H ₂ O:

Calculated: C 54.12, H 6.13, N 9.47

Found: C 54.21, H 5.85, N 9.38

Example 429

^{8- (3-R *) -} (1- (S *) - amino-2,2,2-trifluoroethyl) pyrrolidinyl) -1-cyclopropyl-7-fluoro--4H-9- methyl -4-oxo-quinolizine-3-carboxylic acid hydrochloride

Step 429a. Benzyl-3- (1-hydroxy-2,2,2-trifluoroethylidene) -2-pyrrolidone

1.2 g of NaH sample are suspended in 30 ml of anhydrous THF and the suspension is stirred at room temperature. 3.5 g of 1-benzyl-2-pyrrolidone (Aldrich) was added to the suspension and the mixture was stirred at 65 占 폚. To this mixture is added 3.6 ml of ethyl trifluoroacetate in 10 ml of THF over 25 minutes and the reaction is then heated to reflux for 3 hours. The reaction mixture is cooled, diluted with ether and neutralized with 1N HCl. The ether layer is separated, washed with brine and dried in anhydrous condition. The residual oil was chromatographed on silica gel eluting with ethyl acetate: hexane (1: 1) to give 2.06 g of the title compound. MS 289 (M + H) &lt; ⁺ & gt ^;

Step 429b. Benzyl-3- (1 -hydroxyamino-2,2,2-trifluoroethyl) -2-pyrrolidone

2.0 g of the compound sample obtained from step 429a, 7.6 g of hydroxyamine HCl, 20 ml of pyridine and 40 ml of ethanol are heated under reflux for 4 hours. The solvent is removed in vacuo and the residue is dissolved in methylene chloride. The solution is washed with water and brine, dried and the solvent is evaporated. The residue was azeotropically distilled with toluene to remove pyridine and then dried to give 1.30 g of the title compound. MS 287 (M + H) &lt; ⁺ & gt ^;

Step 429c. 1-benzyl-3- (1-amino-2,2,2-trifluoroethyl) -2-pyrrolidine

1.3 g of the compound sample obtained from step 429c are dissolved in 20 ml of THF and 10 ml of 1 M LAH in THF are added. The mixture is heated to reflux for 4 hours. The reaction is quenched with 0.4 ml of H ₂ O, 0.4 ml of 15% NaOH and 1.2 ml of H ₂ O successively with stirring under N ₂ atmosphere. The suspension is filtered, the filtrate is washed with brine, dried and evaporated. The residue was purified by chromatography on silica gel eluting with methanol: methylene chloride (5:95) to give 943 mg of the title compound. MS 259 (M + H) &lt; ⁺ & gt ^;

Step 429d. Benzyl-3- (1- (BOC-amino) -2,2,2-trifluoroethyl) -2-pyrrolidine

0.94 g of the compound sample obtained from step 429c was dissolved in 5 ml of methylene chloride and 0.8 g of di-t-butyl dicarbonate in 1 ml of methylene chloride was added. The mixture is stirred at room temperature for 16 hours. 0.4 g of butyl dicarbonate is added again and the reaction is stirred for 24 hours. The solvent is removed and the residue is chromatographed on silica gel eluting with ethyl acetate: hexane (25:75). The product is separated by chromatography into two diastereomers (which are abbreviated as relative stereochemistry 1S ^* , 3R ^* and 1S ^* , 3S ^* ). 1S ^* , 3R ^* compound is treated as above to give the title compound.

Step 429e. 3- (1- (BOC-amino) -2,2,2-trifluoroethyl) -2-pyrrolidine

1.49 g of the compound sample obtained from step 429d is dissolved in 100 ml of methanol, 0.9 g of 10% Pd / C is added, and the mixture is hydrogenated under 4atm of H ₂ for 44 hours. The mixture is filtered and the filtrate is concentrated. The residue is polished with acetonitrile and then filtered. The filtrate was concentrated to give 1.035 g of the title compound. MS 269 (M + H) &lt; ⁺ & gt ^;

Step 429f. ^{8- (3- (R *) -} (1- (S *) - amino-2,2,2-trifluoroethyl) pyrrolidinyl) -4H-9- to 1-cyclopropyl-7-fluoro Methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride

Was carried out according to the method of Example 253j except that BOC-aminopyrrolidine was replaced with the compound obtained from step 429e and the obtained product was treated as in step 253k, followed by 1N HCl in acetic acid To remove the BOC-group. Melting point 160 to 163 占 폚, decomposition 180 to 183 占 폚.

Elemental analysis for C ₂₀ H ₂₁ F ₄ N ₃ O ₃ .HCl. 2H ₂ O:

Calculated: C 48.05, H 5.24, N 8.41

Found: C 48.45, H 5.20, N 8.50

Example 430

(S ^* ) - (1- (S ^* ) - amino-2,2,2-trifluoroethyl) pyrrolidinyl) -1-cyclopropyl-7-fluoro- Methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride

The 1S ^* , 3R ^* compounds obtained from example 429d are treated as in examples 429e and 253j, k and l to give the title compound. Melting point: 205 占 폚, decomposition: 213 占

Elemental analysis for C ₂₀ H ₂₁ F ₄ N ₃ O ₃ .HCl · 2.5H ₂ O:

Calculated: C 47.20, H 5.34, N 8.26

Found: C 47.14, H 4.91, N 8.55

Example 431

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride

Step 431a. 1-BOC-3-pyrrolidinol

A solution of 3.25 g of 3-pyrrolidinol in 25 ml of methylene chloride is added with cooling with 5 ml of methylene chloride containing 8.2 g of di-t-butyl dicarbonate and the mixture is stirred for 4 hours. The volatiles were removed in vacuo and the residue was chromatographed on silica gel eluting with 7% methanol in methylene chloride to give 7.64 g of the title compound.

Step 341b. N- (1-BOC-3-pyrrolidinoxy) phthalimide

5.17 g of the compound obtained from the step 431a, 9.7 g of triphenylphosphine and 5.41 g of N-hydroxyphthalimide are added to 50 ml of anhydrous THF. 5.83 ml of DEAD are added to the suspension which is stirred and cooled to -20 DEG C and the mixture is stirred at -20 DEG C for 1 hour. The solution is quenched with water and extracted with methylene chloride. The organic layer is dried and concentrated. The residue was chromatographed on silica gel eluting with ethyl acetate: hexane (40:60) to give 7.60 g of the title compound.

Step 431c. (1-BOC-3-pyrrolidinoxy) amine

2.6 ml of hydrazine hydrate is added to a solution of 7.4 g of the compound obtained from step 431b in 100 ml of methylene chloride. The mixture is stirred at room temperature for 1 hour. The precipitate is filtered off and the filtrate is washed with water, then dried and evaporated to give 4.325 g of the title compound as an oil.

Step 431d. 3-pyrrolidinoxyamine

4.318 g of the compound sample obtained from step 431c are dissolved in 70 ml of anhydrous methylene chloride and 70 ml of 1M HCl acetic acid are added. The mixture is stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed and then dried to give 3.41 g of the title compound.

Step 431e. 8- (3-Aminoxypyrrolidinyl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid ethyl ester

0.25 g of the 3-pyrrolidineoxyamine sample obtained from step 431d and 1.06 ml of triethylamine are dissolved in 5 ml of anhydrous THF and the mixture is stirred at 55 ° C for 7 hours. The reaction is quenched with water and the mixture is extracted with ethyl acetate. The organic layer is washed with water, dried and evaporated. The residue in methylene chloride: _{methanol: NH 4 OH (100: 7} : 0.7) by chromatography on silica gel, eluting using to give the title compound 224mg.

Step 431f. Pyrrolidinyl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid ethyl ester (8-

A mixture of 224 mg of the compound obtained from step 431e and 0.25 g of di-t-butyl dicarbonate is dissolved in 3 ml of methylene chloride and the mixture is stirred for 4 days. The volatiles are removed and the residue is used directly in the next step.

Step 431g. 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid &lt;

The material obtained in the preceding step, 4 ml of THF, 3 ml of water and 0.216 g of LiOH are combined and the mixture is heated at 83 DEG C for 3 hours. The mixture is acidified with 1N HCl and the precipitate is filtered off. The filtrate was washed with water and brine, then evaporated to give 245 mg of the title compound.

Step 431h. 8- (3-Aminooxypyrrolidinyl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride

200 mg of the compound sample obtained from step 431g are dissolved in 23 ml of anhydrous methylene chloride and treated with 1N HCl in acetic acid for 16 hours at room temperature. The title compound was collected by filtration, washed with methylene chloride and then dried.

Elemental analysis for C ₁₈ H ₂₀ FN ₃ O ₃ .HCl. H ₂ O:

Calculated: C 51.99, H 5.57, N 10.10

Found: C 51.84, H 5.33, N 9.95

Example 432

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt;

Following the procedure of Example 432 replacing the racemate starting material with (S) -1-BOC-3-pyrrolidinol, the title compound is prepared. Melting point 160 to 168 占 폚 (decomposition)

Elemental analysis for C ₁₈ H ₂₀ FN ₃ O ₃ .HCl 0.75 H ₂ O:

Calculated: C 52.56, H 5.51, N 10.22

Found: C 52.91, H 5.57, N 10.14

Example 433

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt;

Following the procedure of Example 432 replacing the racemic starting material with (R) -1-BOC-3-pyrrolidinol, the title compound is prepared. Melting point 160 to 168 占 폚 (decomposition)

Elemental analysis for C ₁₈ H ₂₀ FN ₃ O ₃ .HCl 0.75 H ₂ O:

Calculated: C 52.56, H 5.51, N 10.22

Found: C 52.98, H 5.51, N 10.16

Example 434

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt; RTI ID =

Step 434a. 3-Nitro-2-pyridine acetic acid ethyl ester

A mixture of 25 g of diethyl malonate sample and 3 g of sodium is stirred at room temperature until the reaction is terminated and then at 120 DEG C for 30 minutes. When the mixture becomes a viscous suspension, 50 ml of toluene is added and 17.17 g of 2-chloro-3-nitropyridine is added. The mixture is heated to reflux for 16 hours. The solvent is removed in vacuo and the residue is dissolved in 50 ml of DMSO. 19.5 g of NaCl and 7.2 g of water are added to the solution and the mixture is stirred at 160 to 170 DEG C for 3 hours. The mixture is cooled and diluted with ethyl acetate. The layers are separated and the organic layer is washed with water and brine and dried over magnesium sulfate. The solvent was removed and the residue was chromatographed on silica gel to give 11.3 g of the title compound.

Step 434b. 1,3-Dihydropyrrolo [3,2-b] pyridin-2-one

6 g of the compound sample obtained from step 434a are dissolved in ethanol and hydrogenated at 4 atm with Pd / C for 2 hours. The mixture is filtered and the filtrate is evaporated to give the 3-amino compound. The intermediate is dissolved in 60 ml of 2N HCl and the solution is heated to reflux for 30 minutes. The mixture of K ₂ CO ₃ the mixture is used to neutralize to pH 7 to 8, and methylene chloride: extracts using: i- propanol (4: 1). The extract is dried and the solvent is removed to give the title compound.

¹ H NMR (CDCl ₃ )?: 8.05 (m, 1H), 7.12 (m, 2H), 3.55 (s, 2H).

Step 434c. 4- (BOC-amino) -octahydro-pyrrolo [3,2-b] pyridin-

2.8 g of the compound sample obtained from step 434b is dissolved in 150 ml of acetic acid and ₁ g of PtO2 is added. The mixture is hydrogenated at 60 psi for 24 hours and 2000 psi for 2 hours. The mixture is filtered and the solvent is removed. The residue is dissolved in 10 ml of methanol, ₃ g of NaHCO3, 5 ml of water and 6 g of di-t-butyl dicarbonate are added successively. The mixture is stirred at room temperature for 4 hours. The mixture is diluted with methylene chloride and the mixture is washed with water and brine. The solvent was dried and evaporated and the residue purified by chromatography on silica gel eluting with methanol: methylene chloride (7: 100) to give 3.1 g of the title compound.

Step 434d. 4- (BOC-amino) -octahydro-pyrrolo [3,2-b] pyridine

3.1 g of the compound sample obtained from step 434c are dissolved in 20 ml of THF and heated with 2.6 g of the Rawson reagent for 2.4 hours. The solvent is removed and the residue is chromatographed on silica gel. The intermediate product thus obtained is dissolved in 40 ml of methanol and 30 g of Raney nickel in water is added. The mixture is stirred at room temperature for 30 minutes and then filtered. The solvent was removed to give 2.5 g of the title compound.

Step 434e. 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt; EMI ID =

Amino-pyrrolidine was replaced by 4- (BOC-amino) -octahydro pyrrolo [3,2-b] pyridine obtained from step 434d and the product obtained was subjected to the same procedure as step 253 kL to give the title compound.

Example 435

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydro- Chloride

Step 435a. 4-fluoro-2-butenoic acid ethyl ester

1.6 g of ethyl fluoroacetate sample are dissolved in methylene chloride and the mixture is cooled to -78 &lt; 0 &gt; C. To this solution is added 1 equivalent of DIBAL (1.0 M in methylene chloride) over 30 minutes. The reaction mixture is stirred for another 30 minutes, then the reaction mixture is warmed to room temperature and 1.1 equivalents of (triphenylphosphorane) ylidenyl ethyl acetate are added. The reaction mixture is stirred for 16 hours. The reaction was quenched by the addition of methanol and 5% citric acid solution. The mixture is extracted with methylene chloride and the extract is dried and evaporated. The residue is distilled to give a 3: 1 mixture of the cis: trans isomers of the title compound.

Step 435b. 1-Benzyl-3-fluoromethyl-2-pyrrolidine acetic acid ethyl ester

2.6 g (20 mmol) of the compound obtained from Step 435a and 5 g of N-benzyl-N- (methoxymethyl) trimethylsilylamine are dissolved in 30 ml of anhydrous methylene chloride. The solution is stirred at 0 &lt; 0 &gt; C and 1% trifluoroacetic acid is added dropwise. The mixture is stirred at room temperature for 1.5 hours. The solvent is removed and the residue is chromatographed on silica gel to give the cis and trans isomers of the title compound.

Step 435c. Trans-1-CBZ-3-fluoromethyl-2-pyrrolidine acetic acid ethyl ester

The trans compound obtained from step 435b is dissolved in 20 ml of ethanol and 10 equivalents of ammonium formate and 170 mg of 10% Pd / C are added. The reaction mixture is heated to reflux and stirred for 30 minutes. The mixture is filtered and the filtrate is evaporated. The residue was dissolved in dioxane 10ml and 2.5ml water and exerts a 20% Na ₂ CO _3. The mixture is cooled to 0 &lt; 0 &gt; C and benzoyloxycarbonyl chloride is added slowly. The reaction is stirred for 30 minutes and diluted with 100 ml of ether. The organic layer was separated, washed with brine and dried with MgSO _4. The solvent was removed and the residue was chromatographed on silica gel to give 1.5 g of the title compound.

Step 435d. Trans-2- (BOC-amino) -1-CBZ-3-fluoromethyl-pyrrolidine

1.5 g of the compound sample obtained from step 435c is dissolved in 12 ml of THF. The solution is cooled to 0 &lt; 0 &gt; C and 4 equivalents of LiOH in 3 ml of water are added. The mixture is stirred at 0 &lt; 0 &gt; C for 2 hours, diluted with water and acidified to pH 2 using 2N HCl. The mixture is extracted with ether and the extract is washed with brine and then dried. The solvent is removed and the residue is chromatographed on silica gel to give the mesylic acid. The compound is dissolved in 10 ml of anhydrous THF and 1.1 equivalents of DPPA and 4 equivalents of triethylamine are added. The mixture is heated to reflux for 24 hours and then cooled. The solvent is removed and the residue is chromatographed on silica gel.

Step 435e. Trans-2- (BOC-amino) -3-fluoromethyl-pyrrolidine

The compound obtained from step 435d is hydrogenated using Pd / C and ethanol in NMF as in step 435c to give the title compound.

Step 435f. 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydro- Chloride

Amino-pyrrolidine was replaced by trans-2- (BOC-amino) -3-fluoromethyl-pyrrolidine and the product obtained was treated as in step 253k l To give the title compound.

Example 436

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydro- Chloride

The title compound is prepared according to the method of Example 435c, substituting the trans isomer with the cis isomer obtained from step 435b and treating the obtained product as in step 435d-f.

Example 437

6-azaspiro [3.4] oct-6-yl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride

Step 437a. Cyclobutylideneacetic acid ethyl ester

5 g of cyclobutanone are mixed with 1.1 equivalents of (carboethoxymethyl) triphenylphosphorane in 20 ml of toluene. The mixture is heated to reflux for 16 hours, filtered and the filtrate is distilled, the title compound is distilled at 186-188 占 폚.

Step 437b. 6-azaspiro [3.4] oct-6-yl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride

The title compound is prepared according to the method of Example 435b, substituting the compound of Step 435a with the ethyl cyclobutylideneacetate obtained from Step 437a and treating the obtained product according to Step 435c-f.

Example 438

A solution of 8- (2- (R) -aminomethyl-4- (R) -hydroxypyrrolidin- 1 -yl) -l-cyclopropyl-7-fluoro-4H- 3-carboxylic acid &lt; / RTI &gt; hydrochloride

Step 438a. N - ((1-BOC-4- (R) - (tributylsilyloxy) pyrrolidinyl) methyl) phthalimide

4.5 g of a sample of 1-BOC-2- (R) -hydroxymethyl-4- (R) - (tributylsilyloxy) pyrrolidine, 2.50 g (17 mmol) of phthalimide and 4.46 g ) Is dissolved in 30 ml of THF at room temperature. 2.94 g (17 mmol) of DEAD in THF are added to the solution and the mixture is stirred for 3 hours. The solvent is removed in vacuo and the residue is dissolved in ether: ethyl acetate (1: 1). The solution is washed with water and brine and dried over magnesium sulfate. The solvent was removed and the residue was chromatographed on silica gel to give the title compound.

Step 438b. N - ((1-BOC-4- (R) -hydroxypyrrolidinyl) methyl) phthalimide

4.60 g of the compound sample obtained from step 438a are dissolved in 20 ml of THF. Tetrabutylammonium fluoride (1M in THF) is added dropwise while maintaining the solution at 0 &lt; 0 &gt; C and the reaction is stirred at room temperature for 30 minutes. The mixture is diluted with ethyl acetate, washed with water and brine, and then dried. Removal of the solvent gave the title compound.

Step 438c. N - ((4- (R) -hydroxypyrrolidinyl) methyl) phthalimide

2 g of the compound sample obtained from step 438b is dissolved in 10 ml of methylene chloride and 4N HCl in dioxane is added. The mixture is stirred for 4 hours and the product is collected by filtration.

Step 438d. N - ((1-CBZ-4- (R) -hydroxypyrrolidinyl) methyl) phthalimide

Dissolving the compound obtained from Step 438c in dioxane 10ml and exerts a Na ₂ CO ₃ 3g. The mixture is stirred at 0 &lt; 0 &gt; C for 30 minutes and then 1.1 equivalents of benzyl chloroformate is added dropwise. The reaction is stirred for 1 h and ethyl acetate is added. The aqueous layer is separated and the organic layer is washed and then dried. Removal of the solvent gave the title compound.

Step 438e. 2- (R) -aminomethyl-1-CBZ-4- (R) -hydroxypyrrolidine

The compound obtained from step 438d is dissolved in 20 ml of ethanol and 1.2 equivalent of hydrazine hydrate is added. The mixture is heated to reflux for 2 hours, 6N HCl is added and the mixture is filtered. Concentrate the filtrate to give the title compound.

Step 438f. 2- (R) - (BOC-amino) methyl-1-CBZ-4- (R) -hydroxypyrrolidine

By treating the compound obtained from step 438e to di -t- butyl dicarbonate and methanol / NaHCO ₃ in water of as described above to give the title compound.

Step 438g. 2- (R) - (BOC-amino) methyl-4- (R) -hydroxypyrrolidine

The compound obtained from step 438f is treated with ammonium formate and Pd / C using methods as described above to give the title compound.

Step 438h. A solution of 8- (2- (R) -aminomethyl-4- (R) -hydroxypyrrolidin- 1 -yl) -l-cyclopropyl-7-fluoro-4H- 3-carboxylic acid &lt; / RTI &gt; hydrochloride

Following the procedure of Example 435b, the compound of Step 435a was replaced by 2- (BOC-amino) methyl-4-hydroxypyrrolidine obtained from Step 438g and the obtained product was purified according to Step 435c-f To give the title compound.

Example 439

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt;

Step 439a. L-Benzyl-3- (R) - (chloromethyl) morpholine

A mixture of 1.53 ml (10.8 mmol) of N-benzylethanolamine sample and 5.0 g (54 mmol) of (R) - (-) - epichlorohydrin was heated and heated at 40 &lt; 0 &gt; C for 40 minutes, then excess epichlorohydrin It is removed by distillation. The residue is dissolved in 2 ml of concentrated sulfuric acid and the mixture is heated at 140 &lt; 0 &gt; C for 35 minutes. The reaction is quenched by pouring on ice and adjusted to pH 10-12 using 20% sodium hydroxide. The mixture was extracted with methylene chloride, the solvent was dried, filtered and concentrated to give 0.971 g of the title compound. MS 226 (M + H) &lt; ⁺ & gt ^;

Step 439b. (R) -N- ((1-benzylmorpholin-3-yl) methyl) phthalimide

971 mg of the compound obtained from step 439a are dissolved in 20 ml of DMSO and 1.59 g of phthalimide are added. The reaction mixture is heated at 100 &lt; 0 &gt; C for 72 hours. The reaction is poured into 250 ml of water and quenched. The mixture was extracted with methylene chloride, washed and then dried and concentrated to give 1.65 g of the title compound.

Step 439c. (R) -1-benzyl-3- (aminomethyl) morpholine

1.45 g of the compound sample obtained from step 439b is dissolved in 30 ml of ethanol, 0.627 ml of hydrazine hydrate is added and the mixture is stirred at room temperature for 18 hours. 13.2 ml of 1N HCl are added to the solution and the mixture is heated at 70 占 폚 for 6 hours. The reaction is quenched by addition of water and filtered. The filtrate is adjusted to pH 12 with 20% NaOH and extracted with methylene chloride. The extract was dried, filtered and then concentrated to give 667 mg of the title compound. MS 207 (M + H) &lt; ⁺ & gt ^;

Step 439d. (R) -1-benzyl-3- (BOC-aminomethyl) morpholine

The compound (667 g) obtained from step 439c is dissolved in 10 ml of methylene chloride and the solution is cooled to 0 &lt; 0 &gt; C. 0.901 ml of triethylamine was added to the solution, and 0.812 g of di-t-butyl dicarbonate in 4 ml of methylene chloride was added. The reaction mixture is stirred at room temperature for 20 hours. The solvent was removed and the residue was purified by chromatography on silica gel to give 691 g of the title compound.

Step 439e. (R) -3- (BOC-aminomethyl) morpholine

The compound obtained from step 439d is hydrogenated at 4 atm and Pd / C at room temperature in methanol for 24 hours. The mixture was filtered and the solvent was evaporated, yielding 435 mg of the title compound.

Step 439f. 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt;

Following the procedure of Example 435b, the compound of Step 435a was replaced by (R) -3- (BOC-aminomethyl) morpholine obtained from Step 439e and the obtained product was treated according to Step 435c-f The title compound is prepared.

Example 440

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt; RTI ID = 0.0 &gt;

Step 440a. 4-yl-methyl-4-oxo-quinolizine-3-carboxylic acid &lt; RTI ID = 0.0 &gt; Hydrochloride

4-oxo-quinolizine-3-carboxylic acid hydroxycarboxylic acid monohydrochloride obtained from Example 355, (4-fluorophenyl) 0.50 g of the chloride sample is dissolved in 15 ml of DMF and the solution is cooled to 0 &lt; 0 &gt; C. 0.484 ml of diisopropylethylamine is added dropwise to the solution and the mixture is stirred for 10 minutes. To this solution was added 0.380 g of BOC-L-alanyl-N-hydroxysuccinimide and the reaction was stirred for 20 minutes and then left at 4 占 폚 for 16 hours without stirring. The solution is poured into 150 ml of 1N HCl and the precipitate is collected and dried to give 0.755 g of the title compound.

Step 440b. 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt; RTI ID = 0.0 &gt;

The compound obtained from step 440a is stirred at room temperature in 12 ml of 4N HCl in dioxane for 70 minutes. The solvent is removed and the residue is triturated with ether. The solid was collected and dried, redissolved in ethanol, re-filtered and then dried to give 0.353 g of the title compound.

Elemental analysis for C ₁₈ H ₂₀ FN ₃ O ₃ .HCl. 1.5 H ₂ O:

Calculated: C 53.49, H 6.12, N 11.34

Found: C 53.25, H 6.15, N 11.34

Example 441

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt;

Step 441a. 5-amino octahydroindole

1.0 g of 5-aminoindole sample is hydrogenated with ₄ g of H ₂ and ₂ g of Pt ₂ O in 50 ml of acetic acid at room temperature. The solution is filtered and the solvent is removed.

Step 441b. 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid ethyl ester

The title compound is prepared according to the method of Example 253j, substituting BOC-amino-pyrrolidine with 5-amino octahydroindole obtained from step 441a.

Step 441c. 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt;

The compound obtained from step 441b is treated with di-t-butyl dicarbonate in the presence of triethylamine. The resulting intermediate is treated with LiOH to hydrolyze the ester. The carboxylic acid compound is deprotected with hydrochloric acid in dioxane and 0.136 g of the title compound is isolated.

Elemental analysis for C ₂₂ H ₂₇ ClFN ₃ O ₃ .2H ₂ O:

Calculated: C 55.99, H 6.41, N 8.90

Found: C 56.08, H 6.45, N 8.40

Example 442

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt;

Step 442a. 1-BOC-2- (3-pyridyl) piperidine

Anabasin (0.300 g, Aldrich) is treated with di-t-butyl dicarbonate in methylene chloride and triethylamine for 5 hours. The reaction is quenched with water and the mixture is extracted with methylene chloride. The extract is washed, dried and concentrated. The residue was purified by chromatography on silica gel to give 0.36 g of the title compound.

Step 442b. 1-BOC-2- (3-piperidyl) piperidine

The compound of Step 442a is dissolved in 25 ml of acetic acid and hydrogenated with Pt ₂ O under H ₂ 4atm for 17 h. The mixture is filtered, the solvent is removed and the title compound is then dried under vacuum.

Step 442c. 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt;

Boc-amino-pyrrolidine was replaced by 1-BOC-2- (3-piperidyl) piperidine obtained from step 442b and the resulting product was obtained in step 253k l To give the title compound.

Elemental analysis for C ₂₄ H ₃₂ ClFN ₃ O ₃ :

Calculated: C 62.13, H 6.73, N 9.06

Found: C 61.49, H 6.68, N 8.91

Example 443

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt;

Step 443a. 5-Amino-decahydroisoquinoline

2 g of 5-aminoisoquinoline (Aldrich) sample is dissolved in 100 ml of methanol and hydrogenated to 4 g of H ₂ and 0.9 g of 5% Rh / C at room temperature. The mixture is filtered and the solvent is removed to give the title compound.

Step 443b. 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt;

Amino-pyrrolidine was replaced by 5-amino-decahydroisoquinoline obtained from step 442b to give the condensed ester. The compound is treated with di-t-butyl dicarbonate in the presence of triethylamine. The resulting intermediate is treated with LiOH to hydrolyze the ester. The carboxylic acid compound is deprotected with HCl in dioxane and the title compound is isolated.

Elemental analysis for C ₂₃ H ₂₈ FN ₃ O ₃ .HCl. H ₂ O:

Calculated: C 59.03, H 6.46, N 8.98

Found: C 58.91, H 6.77, N 9.37

Example 444

7-yl) - 1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine- Chloride

Step 444a. 7-BOC-2-CBZ-2,7-diazabicyclo [3.3.0] octane

7-BOC-2,7-diazabicyclo [3.3.0] octane (prepared in example 268) 1.06 g of the sample is dissolved in 12 ml of 1N sodium hydroxide and the solution is cooled to 0 &lt; 0 &gt; C. To this solution 1.43 ml of benzyl chloroformate in 10 ml of ether is added over 10 minutes and the mixture is stirred under nitrogen for 4 hours. The mixture is extracted with methylene chloride and the extract is washed, dried and concentrated to give the title compound (0.40 g).

Step 444b. 2-CBZ-2,7-diazabicyclo [3.3.0] octane

The compound obtained from step 444a is dissolved in ethyl acetate and treated with 4N hydrochloric acid in dioxane to remove the BOC group. Solvent is removed and the residue is dissolved in 5% NaHCO ₃ . The mixture is washed with ethyl acetate and the aqueous phase is extracted with i-propyl alcohol: methylene chloride (1: 3). The extract is washed with brine, dried and concentrated to give 0.600 g of the title compound.

Step 444c. 7-yl) - 1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine- Chloride

The condensed ester is prepared according to the method of Example 253j, substituting BOC-amino-pyrrolidine with 2-CBZ-2,7-diazabicyclo [3.3.0] octane obtained from step 444b. The ester is hydrolyzed according to the method of Example 253k, then the CBZ group is hydrogenated with Pd / C and then salt is formed and separated according to the method of step 253 l.

Elemental analysis for C ₂₀ H ₂₂ FN ₃ O ₃ .HCl. H ₂ O:

Calculated: C 56.04, H 5.92, N 9.87

Found: C 56.57, H 6.00, N 9.69

Example 445

3-yl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine- Chloride

Step 445a. 3,7-dibenzyl-2,4-dioxo-3,7-diazabicyclo [3.3.0] octane

1.80 g (10 mmol) of the N-benzyl maleimide sample and 2.38 g (10 mmol) of N-methoxymethyl-N-trimethylsilylmethyl-benzylamine are dissolved in methylene chloride and the solution is cooled to 0 &lt; 0 &gt; C. To this solution was added 1.00 ml (1.0 mmol) of 1.0 N TFA in methylene chloride over 5 minutes. The reaction is stirred for 3 hours, 238 g of amine reagent are added additionally and the mixture is stirred at room temperature for 1 hour. The mixture was diluted with 50ml of methylene chloride and the solution was washed with 5% NaHCO ₃ and brine. The solution was dried and concentrated to give the title compound as a white solid.

Step 445b. 3-benzyl-2,4-dioxo-3,7-diazabicyclo [3.3.0] octane

3.00 g (9.38 mmol) of the compound obtained from step 445a are dissolved in 50 ml of methanol, 500 mg of 10% Pd / C are added and the mixture is flushed with nitrogen. 2.96 g (46.87 mmol) of ammonium formate is added to the mixture and the reaction is stirred at 70 &lt; 0 &gt; C for 1.25 h under nitrogen. The mixture is diluted with methylene chloride and filtered. The filtrate is washed with water and concentrated. The residue was dissolved in methylene chloride and rewashed, then filtered and the solvent removed to give 2.37 g of the title compound.

Step 445c. 3-benzyl-3,7-diazabicyclo [3.3.0] octane

1.2 g (30.0 mmol) of the LAH sample are suspended in ether at room temperature under nitrogen. A solution of the compound (2.3 g, 10 mmol) obtained from step 445b in methylene chloride was added dropwise over 10 minutes while cooling the vessel in a -10 DEG C bath and the mixture was stirred for 2 hours. The reaction is quenched by dropwise addition of 1.2 ml of water, 1.2 ml of 15% NaOH and 3.6 ml of water. The mixture was filtered and the filtrate was concentrated to give 1.77 g of the title compound.

Step 445d. 3-Benzyl-7-BOC-3,7-diazabicyclo [3.3.0] octane

1.77 g of the compound obtained from Step 445c is dissolved in a mixture of methanol: water (4: 1) and 2.29 g of di-t-butyl dicarbonate is added. The mixture is stirred at room temperature for 1.5 hours and the solvent is removed. The residue was dissolved in methylene chloride and the solution was washed with 5% NaHCCO ₃ and brine, dried and concentrated. The residue was chromatographed on silica gel to give 1.68 g of the title compound.

Step 445e. 3-BOC-3,7-diazabicyclo [3.3.0] octane

The compound obtained from step 445d is treated with ammonium formate and 10% Pd / C as in step 445b and the title compound is isolated in a similar manner.

Step 445f. 3-yl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine- Chloride

Amino-pyrrolidine was replaced with 3-BOC-3,7-diazabicyclo [3.3.0] octane obtained from step 445e, and the obtained product was subjected to the step 253k to give 552 mg of the title compound.

Elemental analysis for C ₂₀ H ₂₂ FN ₃ O ₃ .HCl. H ₂ O:

Calculated: C 56.40, H 5.92, N 9.87

Found: C 56.59, H 5.80, N 9.81

Example 446

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt;

Step 446a. 1-Benzylpyrrolidine-3-carboxylic acid methyl ester

4.3 g of methyl acrylate and 13.09 g of N-methoxymethyl-N-trimethylsilylmethyl-benzylamine are dissolved in 100 ml of methylene chloride and the solution is cooled to 0 &lt; 0 &gt; C. 5.00 ml of 1.0 N TFA in methylene chloride is added to the solution over 10 minutes and the reaction is stirred at room temperature for 16 hours. The mixture is washed with 5% NaHCO3 and brine and then concentrated. The residue was chromatographed on silica gel to give 7.20 g of the title compound.

Step 446b. 1-Benzylpyrrolidine-3-carboxamide

2.02g of the compound obtained from step 446a was dissolved in methanol 50ml, and the NH ₃ bubbled until the solution is saturated and stir the solution for 4 days under balloon pressure. NH ₃ was added further and the mixture was stirred for more than two days. Removal of the solvent gave 1.60 g of the title compound.

Step 446c. 3-Carbamoyl-pyrrolidine

1.6 g of the compound obtained from step 446b are treated with ammonium formate and 10% Pd / C according to the method of step 445b and 200 mg of the title compound are isolated in a similar manner.

Step 446d. 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid

Following the procedure of Example 253j replacing BOC-amino-pyrrolidine with 1.90 g of 3-carbamoyl-pyrrolidine obtained from step 446c and treating the obtained product as in step 253k, 44 mg .

Elemental analysis for C ₁₉ H ₁₈ FN ₂ O ₅ · HCl · 0.5H ₂ O:

Calculated: C 59.53, H 5.26, N 7.31

Found: C 59.35, H 5.06, N 7.19

Example 447

7-fluoro-4H-9-methyl-4-oxo-quinolizine (prepared according to the method described in &lt; Carboxylic acid hydrochloride

Step 447a. 1-benzyl-3- (2,2,2-trifluoroacetyl) aminopyrrolidine

See J. Med. Benzyl-3-aminopyrrolidine sample described in Chem., 33: 2521, 1990 is dissolved in 300 ml of methylene chloride, the solution is cooled to 0 占 폚 and flushed with nitrogen. 4.85 ml of pyridine is added to the solution, and then 8.45 ml of trifluoroacetic anhydride is added dropwise over 10 minutes. The mixture is stirred at 0 &lt; 0 &gt; C for 10 minutes and then at room temperature for 20 minutes. The reaction mixture was washed with 5% NaHCO ₃ and brine, filtered and concentrated to give 5.76 g of the title compound.

Step 447b. Benzyl-3- (2,2,2-trifluoroethyl) aminopyrrolidine

2.64 g of the compound sample obtained from step 447a are added dropwise to a suspension of 1.11 g of LAH in ether stirred at 0 &lt; 0 &gt; C under nitrogen. After 1 hour, the reaction is stirred at room temperature for 6 hours. The reaction is quenched by successive addition of 1.2 ml of water, 1.2 ml of 15% NaOH and 2.4 ml of water. The mixture was filtered and the filtrate was concentrated to give 2.39 g of the title compound.

Step 447c. Benzyl-3- (N-BOC-N- (2,2,2-trifluoroethyl) aminopyrrolidine

2.36 g of the compound sample obtained from step 447b are treated with di-t-butyl dicarbonate in THF / water and the compound is isolated as in Example 445e above. 1.81 g of the title compound is obtained.

Step 447d. 3- (N-BOC-N- (2,2,2-trifluoroethyl) aminopyrrolidine

2.80 g of the compound sample obtained from step 447c is treated with ammonium formate and 10% Pd / C for 1.75 hours according to the method of step 445b to isolate 1.09 g of the title compound.

Step 447e. Yl) -l-cyclopropyl-7-fluoro-4H-9-methyl-lH-pyrrolo [2,3-d] pyrimidin- -4-oxo-quinolizine-3-carboxylic acid hydrochloride

BOC-amino-pyrrolidine was reacted according to the method of Example 253j, except that 0.646 g of 3- (N-BOC-N- (2,2,2-trifluoroethyl) aminopyrrolidine obtained from Step 447b And the obtained product is treated as in step 253k l to give 493 mg of the title compound.

Elemental analysis for C ₂₀ H ₂₀ F ₄ N ₃ O ₃ .HCl 0.25 H ₂ O:

Calculated: C 55.62, H 5.02, N 9.73

Found: C 55.72, H 4.83, N 9.62

Example 448

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydroxide was prepared in accordance with the general method of example 1 from 8- (3- (2- fluoroethyl) aminopyrrolidin- Chloride

Step 448a. Benzyl-3- (N-BOC-N- (2-fluoroethyl) amino) pyrrolidine

J. Med. 3.5 mg (2.00 mmol) of the N-benzyl-3-aminopyrrolidine sample prepared by the method described in Chem., 33: 2521, 1990 is dissolved in 5 ml of acetonitrile. The solution is flushed with nitrogen and 0.140 ml of 1-bromo-2-fluoroethane (Aldrich) is added. The reaction is stirred under nitrogen at 50 &lt; 0 &gt; C for 48 h and at 70 &lt; 0 &gt; C for 1.5 h. After cooling the mixture, 5 ml of water, 5 ml of methanol and 873 mg of di-t-butyl dicarbonate are added. The reaction mixture is stirred for 7 hours and then diluted with methylene chloride. Wash the mixture with 5% NaHCO ₃ and brine. The organic layer was dried and concentrated to give the title compound.

Step 448b. 3- (N-BOC-N- (2-fluoroethyl) amino) pyrrolidine

225 mg of the compound sample obtained from step 448a is treated with ammonium formate and 10% Pd / C according to the method of step 445b to isolate 190 mg of the title compound.

Step 448c. 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydroxide was prepared in accordance with the general method of example 1 from 8- (3- (2- fluoroethyl) aminopyrrolidin- Chloride

Amino-pyrrolidine was replaced by 0.245 g of 3- (N-BOC-N- (2-fluoroethyl) amino) pyrrolidine and the product obtained was purified by analogy to the procedure described in step 253k l to give 76 mg of the title compound.

Elemental analysis for C ₂₀ H ₂₃ F ₂ N ₃ O ₃ .HCl. H ₂ O:

Calculated: C 53.87, H 5.88, N 9.42

Found: C 53.75, H 5.61, N 9.45

Example 449

Yl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3 -Carboxylic acid hydrochloride

The title compound was prepared following the procedure of Example 448a-b, see J. Med. Benzyl-3- (BOC-amino) methylpyrrolidine prepared by the method described in J. Org. Chem., 1981: 1320 and then BOC-amino-pyrrolidine was prepared by the method of Example 352j and Example 253j , And the obtained product is treated as in step 253k l to give 85 mg of the title compound.

Elemental analysis for C ₂₀ H ₂₅ F ₂ N ₃ O ₃ .HCl. H ₂ O:

Calculated: C 54.84, H 6.14, N 9.14

Found: C 54.23, H 5.87, N 8.95

Example 450

7-fluoro-4H-9-methyl-4-oxo-quinolizine-l- 3-carboxylic acid hydrochloride

(S) -N-benzyl-3-aminopyrrolidine, 553 mg of the title compound is prepared.

Elemental analysis for C ₂₀ H ₂₃ F ₂ N ₃ O ₃ .HCl. H ₂ O:

Calculated: C 53.87, H 5.88, N 9.42

Found: C 53.88, H 5.75, N 9.30

Example 451

7-fluoro-4H-9-methyl-4-oxo-quinolizine-l- 3-carboxylic acid hydrochloride

Carbaldehyde is carried out according to the method of Example 448 starting with (R) -N-benzyl-3-aminopyrrolidine, to give 601 mg of the title compound.

Elemental analysis for C ₂₀ H ₂₃ F ₂ N ₃ O ₃ .HCl. H ₂ O:

Calculated: C 53.87, H 5.88, N 9.42

Found: C 53.75, H 5.61, N 9.45

Example 452

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt;

Step 452a. 2-Benzyl-3a-nitro-octahydroisoindole

(10.0 mmol) of 1-nitro-1-cyclohexene (Aldrich) sample and 2.38 g (10.0 mmol) of N-benzyl-N (methoxymethyl) -trimethylsilylmethylamine were dissolved in methylene chloride and the solution was purged with nitrogen Flush and cool to 0 ° C. 10 ml of methylene chloride containing 1 N TFA is added to the solution over 10 minutes and the mixture is stirred at 0 &lt; 0 &gt; C for 0.5 hour and at room temperature for 15 hours. 497 g (2 mmol) of N-benzyl-N- (methoxymethyl) -trimethylsilylmethylamine are further added and the solution is stirred for 5 hours. The mixture is washed with 5% NaHCO ₃ and brine, dried and concentrated to give 2.935 g of the title compound.

Step 452b. 2-Benzyl-3-amino-octahydroisoindole

520 mg of the compound obtained from step 425a is dissolved in 30 and treated with ammonium formate and 10% Pd / C for 1 hour according to the method of step 445b to isolate 550 mg of the title compound.

Step 452c. 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt;

Amino-pyrrolidine was replaced with 0.550 g of 2-benzyl-3a-amino-octahydroisoindole obtained from step 448b and the product was treated with di-t- Butyl dicarbonate, and the BOC-protected product is treated as in step 253k l to give 66 mg of the title compound.

Elemental analysis for C ₂₂ H ₂₆ FN ₃ O ₃ .HCl. 2H ₂ O:

Calculated: C 55.99, H 6.62, N 8.90

Found: C 55.56, H 6.30, N 8.95

Example 453

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydro- Chloride [Isomer (I)]

Step 453a. 1- (2-Bromoethyl) -2-oxo-cyclopentanecarboxylic acid

4.68 g (30 mmol) of 2-oxo-cyclopentanecarboxylic acid sample and 28.18 g (150 mmol) of 1,2-dibromoethane are dissolved in 100 ml of acetone. K ₂ CO ₃ 20.73 (150 mmol) is added and the mixture is heated under reflux for 4 hours. The mixture is filtered and concentrated. The residue was chromatographed on silica gel to give 4.52 g of the title compound.

Step 453b. 2-aza-2-benzyl-spiro [3.3] nonane-1,6-dione

4.07 g of the compound sample obtained from Step 453a and 4.98 g of benzylamine are dissolved in 50 ml of toluene and the mixture is heated under reflux for 8 hours in the presence of 14 g of 4A molecular sieve. 36.6 ml of 2 M HCl are added to the mixture and the mixture is stirred at room temperature for 1 hour. The mixture is filtered and the organic layer is separated and washed with 2M HCl, then dried and evaporated. The residue was chromatographed on silica gel to give 1.69 g of the title compound.

Step 453c. 2-aza-2-benzyl-spiro [3.3] nonan-

1.18 g (4.85 mmol) of the compound sample obtained from step 453b are dissolved in 15 ml of anhydrous THF and 14.6 ml (14.55 mmol) of LAH (1M in ether) is added dropwise. The mixture is heated to reflux for 2 hours and the reaction is quenched by successive addition of 0.55 ml of water, 0.55 ml of 15% NaOH and 1.65 ml of water. The mixture is stirred for 1 hour and filtered. The filtrate was dried and concentrated to give 1.13 g of the title compound.

Step 453d. 2-aza-2-benzyl-spiro [3.3] nonan-6-

1.13 g of the compound obtained from step 453c are dissolved in 35 ml of acetone, the solution is cooled to 0 &lt; 0 &gt; C and 0.25 ml of sulfuric acid is added. The mixture is added dropwise to the mixture and the reaction is added dropwise at room temperature for 4 hours. Isopropanol was added, the acetone was removed under reduced pressure, and 6.5 ml of 6N sodium hydroxide was added. The mixture was filtered and the filtrate was washed with water and brine, then dried and concentrated to give 845 mg of the title compound.

Step 453e. 6-Amino-2-aza-2-benzyl-spiro [3.3] nonane

845 mg of the compound sample obtained from Step 453d, 173 mg of NaBH ₃ CN and 2.84 g of ammonium acetate are dissolved in distilled methanol and the mixture is stirred at room temperature for 16 hours. The mixture is concentrated and the mixture is stirred at room temperature for 16 hours. The mixture is concentrated and 200 ml of methylene chloride are added. The solution is filtered and the filtrate is washed with 5% NaHCO ₃ and brine, dried and concentrated to give 853 mg of the title compound.

Step 453f. 6- (BOC-amino) -2-aza-2-benzyl-spiro [3.3] nonane

847 mg of the compound sample obtained from step 453e are dissolved in 24 ml of methanol and 6 ml of water and 1.6 g of di-t-butyl dicarbonate are added. The mixture is stirred under nitrogen at room temperature for 3 hours. The mixture is concentrated and the residue is dissolved in methylene chloride. The solution was washed with 5% NaHCO ₃ , dried and concentrated to give 1.40 g of the title compound.

Step 453g. 6- (BOC-amino) -2-aza-spiro [3.3] nonane

138 g of the compound sample obtained from step 453f is dissolved in 30 and treated with ammonium formate and 10% Pd / C according to the method of step 445b to give 105 mg of the title compound.

Step 453h. 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydro- Chloride

Amino-pyrrolidine was replaced by 138 mg of 6- (BOC-amino) -2-aza-2-benzyl-spiro [3.3] nonane obtained from step 453g, The resulting product is treated as in step 253k l to give 57 mg of the title compound. Stereoisomers are separated by HPLC. Isomer (I):

Elemental analysis for C ₂₂ H ₂₆ FN ₃ O ₃ ^- HCl ^- 1.5 H ₂ O:

Calculated: C 57.08, H 6.53, N 9.08

Found: C 56.85, H 6.41, N 8.84

Example 454

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydro- Chloride

Step 454a. 1-Benzyl-3-trifluoromethylpyrrolidine-3-carboxylic acid

2.48 g of 2- (trifluoromethyl) acrylic acid sample is dissolved in 40 ml of anhydrous methylene chloride and a solution of 4.75 g of N-benzyl-N- (methoxymethyl) -trimethylsilylmethylamine in 20 ml of anhydrous methylene chloride is added dropwise at 0 [ . 2 ml of trifluoroacetic acid are added to the mixture and the mixture is stirred at room temperature for 2 hours. The product is filtered off, washed and dried to give the title product.

Step 454b. L-Benzyl-3- (BOC-amino) -3-trifluoromethylpyrrolidine

A mixture of 1.42 g of the compound obtained from Step 454a, 1.71 g of diphenylphosphoryl azide, 12.3 g of t-butanol and 0.627 g of trimethylamine is heated under reflux for 24 hours under nitrogen. The mixture is concentrated to dryness and the residue is dissolved in methylene chloride. Then washed with saturated NaHCO ₃ solution and water and concentrated. The residue was chromatographed on silica gel to give 1.73 g of the title compound.

Step 454c. 3- (BOC-amino) -3-trifluoromethylpyrrolidine

413 mg of the compound sample obtained from step 447c is treated with ammonium formate and 10% Pd / C according to the method of step 445b to give 282 mg of the title compound.

Step 454d 8- (3-Amino-3-trifluoromethylpyrrolidin-l-yl) -l-cyclopropyl-7-fluoro-4H- Carboxylic acid hydrochloride

Amino-pyrrolidine was replaced with 227 mg of 3- (BOC-amino) -3-trifluoromethylpyrrolidine obtained from step 453g and the product obtained was purified by analogy to the procedure described in step 253k 1, 79 mg of the title compound is obtained.

Example 455

8- (3- (S) -hydroxymethylazetidin-l-yl) -l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-

Following the procedure of Example 253j replacing BOC-amino-pyrrolidine with 540 mg of 3- (S) -hydroxymethylazetidine and treating the obtained product as in step 253k, 102 mg of the title compound is obtained .

Elemental analysis for C ₁₈ H ₁₉ FN ₂ O ₄ ^- 0.25H ₂ O:

Calculated: C 61.62, H 5.60, N 7.98

Found: C 61.71, H 5.55, N 7.81

Example 456

Yl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3- Carboxylic acid hydrochloride

Step 456a. 1-Benzyl-3-trifluoromethylpyrrolidine-3-carboxylic acid

2.48 g (20 mmol) of 2- (trifluoromethyl) acrylic acid was dissolved in 30 ml of anhydrous methylene chloride and a solution of 4.75 g (20 mmol) of N-benzyl-N- (methoxymethyl) -trimethylsilylmethylamine in 20 ml of anhydrous methylene chloride The solution is added dropwise at 0 &lt; 0 &gt; C under nitrogen. To the solution is added 2 ml of trifluoroacetic acid and the solution is stirred at room temperature for 2 hours. The white precipitate was collected, washed and dried to give 3.22 g of the title compound.

Step 456b. Benzyl-3-trifluoromethylpyrrolidine-3-methanol

2.32 g of the compound obtained from step 456a are dissolved in 60 ml of anhydrous THF, 1.12 equivalents of LAH (1M in ether) are added and the reaction is stirred under nitrogen for 3 hours. The reaction is quenched by successive dropwise addition of 0.35 ml of water, 0.35 ml of 15% NaOH and 1.3 ml of water, then the mixture is stirred for 1 hour and filtered. The filtrate was dried and concentrated to give 2.2 g of the title compound.

Step 456c. 1-Benzyl-3-trifluoromethyl-3- (toluenesulfonyloxymethyl) pyrrolidine

1.61 g of the compound obtained from Step 456b are dissolved in anhydrous pyridine and the solution is cooled to 0 &lt; 0 &gt; C. To this solution is added 1.458 g of p-toluenesulfonyl chloride in 4 ml of anhydrous pyridine and the reaction is stirred at 0 &lt; 0 &gt; C for 4 days. The mixture is diluted with 300 ml of methylene chloride, washed with water and brine, and then dried. Removal of the solvent gave 2.81 g of the title compound.

Step 456d. 1-Benzyl-3-trifluoromethyl-3- (azidomethyl) pyrrolidine

2.43 g of the compound obtained from step 456c are dissolved in acetonitrile and reacted with tetrabutylammonium azide at 80 DEG C for 16 hours. The mixture is diluted with methylene chloride, washed with water and brine, and dried. The solvent was removed to give 0.751 g of the title compound.

Step 456e. L-Benzyl-3- (BOC-aminomethyl) -3-trifluoromethyl-pyrrolidine

248 mg of the compound obtained from step 456c and 262 mg of di-t-butyl dicarbonate are dissolved in acetic anhydride and added to a suspension of Pd / C (29 mg) in 10 ml of acetic acid. The reaction was stirred at room temperature under nitrogen for 4 hours, filtered and the filtrate was washed with 5% NaHCO ₃ and brine, dried and concentrated, and then. The residue was purified by chromatography on silica gel to give 172 mg of the title compound.

Step 456f. 3- (BOC-aminomethyl) -3-trifluoromethyl-pyrrolidine

300 mg of the compound sample obtained from step 447c is treated with ammonium formate and 10% Pd / C according to the method of step 445b to give 222 mg of the title compound.

Step 456g was prepared in an analogous manner to that described in Example 1, using 8- (3-aminomethyl) -3-trifluoromethyl-pyrrolidin- 1 -yl) -l-cyclopropyl-7-fluoro-4H- Chloro-3-carboxylic acid hydrochloride

Amino-pyrrolidine was replaced by 3- (BOC-aminomethyl) -3-trifluoromethyl-pyrrolidine obtained from step 456f and the resulting product was treated with 253k and l to give 47 mg of the title compound.

Elemental analysis for C ₂₀ H ₂₁ F ₄ N ₃ O ₃ ^- HCl ^- 1.75H ₂ O:

Calculated: C 48.49, H 5.19, N 8.48

Found: C 48.48, H 4.99, N 8.49

Example 457

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt; / RTI &gt;

Step 457a. N-benzyl-3,4-pyrrolidinedicarboxylic acid diethyl ester

7.44 g (40 mmol) of diethylglutaconate are dissolved in 60 ml of anhydrous methylene chloride and a solution of 9.52 g (40 mmol) of N-benzyl-N- (methoxymethyl) -trimethylsilylmethylamine in 20 ml of anhydrous methylene chloride is added dropwise at 0 Deg. To the solution is added 2 ml of 1N trifluoroacetic acid in methylene chloride, and the solution is stirred at room temperature for 2 hours. The solution was washed with 5% NaHCO ₃ and brine, dried and concentrated to give the title compound 12.48g.

Step 457b. 2-benzyl-4,6-dioxo-octahydropyrrolo [3.4-c] pyridine

To prepare a solution of Na 9.00mmol aqueous NH ₃ at -78 ℃. 15 mg of FeCl ₃ is added to the solution, and the reaction mixture is warmed to -40 ° C. To this stirred solution under nitrogen was added a cooled (-40 &lt; 0 &gt; C) solution of 957 mg of the compound from step 457a in THF over 10 minutes and the reaction mixture was stirred at -33 [deg.] C for 3 hours. Ammonium chloride 1.5 g is added with stirring, the mixture is allowed to warm to room temperature and the excess ammonia is evaporated. 60 ml of water are added to the mixture and the mixture is extracted with methylene chloride. The extract is washed with brine, dried and concentrated. The residue was chromatographed on silica gel to give 425 mg of the title compound.

Step 457c. 2,5-dibenzyl-4,6-dioxo-octahydropyrrolo [3,4-c] pyridine

To a mixture of 905 mg of K ₂ CO _{3 in} 5 ml of DMF and 400 mg of the compound obtained from Step 457b is added 308 mg of benzyl bromide and the reaction mixture is stirred at room temperature for 6.5 hours under nitrogen. The mixture was diluted with ethyl acetate, washed with water and brine, dried and concentrated to give 610 mg of the title compound.

Step 457d. 5-benzyl-4, 6-dioxoctahydro pyrrolo [3.4-c] pyridine

700 mg of the compound sample obtained from step 447c is treated with ammonium formate and 10% Pd / C for 2 hours according to the method of step 445b to isolate 540 mg of the title compound.

Step 457e. 5-benzyl-octahydropyrrolo [3.4-c] pyridine

A suspension of 266 mg of LAH in 10 ml of ether is stirred at 10 [deg.] C under nitrogen. To the suspension was added 540 mg of the compound obtained in Step 457d, which was dissolved in 10 ml of methylene chloride. The mixture is stirred under nitrogen for 1.5 hours. The reaction is quenched by successive addition of 0.3 ml of water, 0.3 ml of 15% NaOH and 0.6 ml of water, and the mixture is stirred for 1 hour and filtered. The filtrate was dried and concentrated to give 389 mg of the title compound.

Step 457f. 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt; / RTI &gt;

Amino-pyrrolidine was replaced by 5-benzyl-octahydropyrrolo [3.4-c] pyridine from step 457e and the product obtained was treated as in step 253k l To give 22 mg of the title compound.

Example 458

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt;

Step 458a. L-benzyl-3- (cyclopropylmethyl) aminopyrrolidine

1.75 g (10 mmol) of a 1-benzyl-3-pyrrolidinone sample was dissolved in methylene chloride and 1.44 g of anhydrous magnesium sulfate was added. The mixture is stirred at 0 &lt; 0 &gt; C under nitrogen and 634 mg cyclopropylamine is added dropwise. The mixture was stirred at room temperature for 5 hours, then added to 10ml of methanol and then NaBH ₄ portionwise to 534mg. The mixture is stirred for 1 hour and diluted with methylene chloride. The solution was washed with 5% NaHCO ₃ and brine, dried and concentrated to give 2.12 g of the title compound.

Step 458b. Benzyl-3- (N-BOC-N- (cyclopropylmethyl) amino) pyrrolidine

The compound of step 458 is treated with di-t-butyl dicarbonate in acetonitrile for 2 hours, the compound is extracted and then chromatographed on silica gel to give the title compound (2.11 g).

Step 458c. Benzyl-3- (N-BOC-N- (cyclopropylmethyl) amino) pyrrolidine

2.11 g of the compound of Step 458b is treated with ammonium formate and 10% Pd / C for 2 hours according to the procedure of Step 445b and the title compound (1.92 mg) is isolated.

Step 458d. 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt;

The title compound was prepared in analogy to Example 253j but using 1-benzyl-3- (N-BOC-N- (cyclopropylmethyl) amino) pyrrolidine from step 458c instead of BOC- aminopyrrolidine The reaction is carried out according to the procedure and the product is worked up as in steps 253k and 253l to give the title compound.

Example 459

The title compound was prepared in analogy to example 7 from 8- (6-amino-2-aza-spiro [3.3] non-3-yl) Chloride (the isomer (II))

The second isomer from Example 453 (isomer (II)) is obtained by HPLC. Isomer (II):

Elemental analysis for C ₂₂ H ₂₆ FN ₃ O ₃ · HCl · H ₂ O

Calculated: C, 58.21; H, 6.44; N, 9.26.

Found: C, 58.00; H, 6.29; N, 8.86.

Example 460

7-yl) - 1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine- Chloride / isomer A

7-BOC-2-CBZ-2,7-diazabicyclo [3.3.0] octane is prepared according to Example 444. The prepared compound is separated into two isomers by HPLC. Isomer A is worked up as in steps 444b and 444c to give the title compound (194mg).

Elemental analysis for C ₂₀ H ₂₂ FN ₃ O ₃ · HCl · 1.75H ₂ O

Calculated: C 55.66; H 6.08; N 9.56.

Found: C 54.68; H 5.73; N 9.54.

Example 461

7-yl) - 1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine- Chloride / isomer B

7-BOC-2-CBZ-2,7-diazabicyclo [3.3.0] octane is prepared according to Example 444. The prepared compound is separated into two isomers by HPLC. Isomer B is worked up as in steps 444b and 444c to give the title compound (263mg).

Elemental analysis for C ₂₀ H ₂₂ FN ₃ O ₃ · HCl · 1.5H ₂ O

Calculated: C 55.24; H 6.03; N 9.66.

Found: C 55.37; H 5.79; N 9.59.

Example 462

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid &lt; Hydrochloride

Step 462a. 1- (1- (R) -phenylethyl) pyrrolidine-3- (R) -methanol

Pyrrolidinecarboxylic acid ethyl ester (prepared as described in the literature, see: DR Johnson et al., J. Heterocyclic &lt; (R) &gt; 2.95 g (10 mmol) of a sample of Lewis acid, Chem., 29: 1481 (1992)] and 0.95 g of LAH are suspended in 20 ml of anhydrous THF and the reaction mixture is stirred at room temperature for 16 hours. The mixture is extracted with ether, washed with water, dried and concentrated to give the title compound (1.8 g) as an oil.

A sample of the compound from step 462a was dissolved in methanol, was added 10% Pd / C, the mixture is then hydrogenated at room temperature at 4 atm H ₂ for 16 hours. The solution is filtered and the solvent is removed. Take the residue and use it immediately in the next step.

Step 462c. 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid &lt; Hydrochloride

The reaction was carried out according to the procedure of Example 253j but using 3- (R) -pyrrolidine methanol from step 463b instead of BOC-amino-pyrrolidine and the product was obtained in steps 253k and 253l Treatment is carried out in the same manner to give the title compound.

Example 463

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid (2-fluoro- Hydrochloride

Step 463a. 1- (1- (R) -phenylethyl) pyrrolidine-3- (S) -methanol

Pyrrolidinecarboxylic acid ethyl ester (prepared as described in the literature, see DR Johnson et al., J. Heterocyclic Chem., &Lt; RTI ID = 0.0 &gt; (10 mmol) of LAH and 0.95 g of LAH are suspended in 20 ml of anhydrous THF and the reaction mixture is stirred at room temperature for 16 hours. The reaction is diluted with water, 15% NaOH and water The mixture is extracted with ether, washed with water, dried and concentrated to give the title compound (1.8 g) as an oil.

Step 463b. 3- (S) -Pyrrolidine &lt; / RTI &gt;

A sample of the compound from Step 462a was dissolved in methanol, was added 10% Pd / C, the mixture is then hydrogenated for 16 hours at room temperature at 4 atm H _2. The solution is filtered and the solvent is removed. Take the residue and use it immediately in the next step.

Step 463c. 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid (2-fluoro- Hydrochloride

The reaction was carried out according to the procedure of Example 253j but using 3- (R) -pyrrolidine methanol from step 463b instead of BOC-amino-pyrrolidine and the product was obtained in steps 235k and 253l Treatment is carried out in the same manner to give the title compound.

Example 464

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid &lt; Hydrochloride

The reaction was carried out according to the procedure of Example 253j but using 2- (R) -pyrrolidine methanol (Aldrich, Aldrich) instead of BOC-amino-pyrrolidine and the product was purified by analogy to steps 253k and 253l To give the title compound.

Example 465

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid &lt; Hydrochloride

The reaction was carried out according to the procedure of Example 253j but using 2- (S) -pyrrolidine methanol (Aldrich, Aldrich) instead of BOC-amino-pyrrolidine and the product was purified by analogy to steps 253k and 253l To give the title compound.

Example 466

7-fluoro-4H-9-methyl-4-oxo-quinolyl] -3- &lt; / RTI &gt; carboxylic acid hydrochloride

Following the procedure of Example 253j but substituting 2- (R) - (BOC-aminomethyl) pyrrolidine (prepared according to JP 87-236335) in place of BOC-amino-pyrrolidine The reaction is carried out and the product is worked up as in steps 253k and 253l to give the title compound.

_{C 19 H 23 FN 3 O 3} HRMS (M + H) ⁺ for

Calculated: 360.1723

Found: 360.1713

Example 467

7-fluoro-4H-9-methyl-4-oxo-quinolyl] -3- &lt; / RTI &gt; carboxylic acid hydrochloride

The title compound was prepared following the procedure of Example 253j but using 2- (S) - (BOC-iminomethyl) pyrrolidine (prepared according to JP 87-236335) instead of BOC-amino-pyrrolidine The reaction is followed and the product is worked up as in steps 253k and 253l to give the title compound.

_{C 19 H 23 FN 3 O 3} HRMS (M + H) ⁺ for

Calculated: 360.1723

Found: 360.1730

Example 468

7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride &lt;

Step 468a. (R) - (1- (BOC-amino) cyclopropyl) pyrrolidine-2-thione and 4- (S)

Described in U.S. Patent No. 5,098,912 to Hayakawa, issued March 24, 1992, to a solution of 4- (1- (BOC-amino) cyclopropyl) -pyrrolidin- And 3.987 g of Lawesson's Reagent are suspended in 41 ml of THF and the reaction mixture is stirred at room temperature for 3 hours under a nitrogen atmosphere. The solvent was stirred and the residue was dissolved in 1% methanol in methylene chloride and purified by chromatography on silica gel to afford 30773 g of the title compound. MS: 257 (M + H) ⁺ . This compound is subjected to chiral HPLC to separate R isomer and S isomer.

Step 468b. 3- (R) - (1- (BOC-amino) cyclopropyl) pyrrolidine

A sample of R isomer (203 mg) from Step 468a and 1.51 g of NiCl ₂ .6H ₂ O are dissolved in 10 ml of a methanol: THF mixture (1: 1) and the solution is cooled in an ice bath. 720 mg of NaBH _{4 is} added in small portions and the reaction mixture is stirred at room temperature for 2 hours. The solvent was removed and the residue was purified by chromatography on silica gel to give the title compound.

Step 468c. Pyrrolidinyl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride

The reaction was carried out according to the procedure of Example 253j but using 3- (R) - (1- (BOC-amino) cyclopropyl) pyrrolidine from step 468b instead of BOC-amino-pyrrolidine And the product is worked up as in steps 253k and 253l to give the title compound. The spectroscopic data is similar to that for the racemic mixture of Example 311.

Example 469

7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride &lt;

Step 469a. 3- (s) - (1- (BOC-amino) cyclopropyl) pyrrolidine

A sample of isomer from Example 468a (197 mg) and 1.46 g of NiCl ₂ .6H ₂ O are dissolved in 10 ml of a methanol: THF mixture (1: 1) and the solution is cooled in an ice bath. NaBH ₄ was added to 690mg The reaction mixture is stirred at room temperature for 2 hours. The solvent was removed and the residue was purified by chromatography on silica gel to give the title compound.

Step 469b. Pyrrolidinyl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride

The reaction was carried out according to the procedure of Example 253j but using 3- (S) - (1- (BOC-amino) cyclopropyl) pyrrolidine from step 468b instead of BOC-imino-pyrrolidine And the product is worked up as in steps 253k and 253l to give the title compound. The spectroscopic data is similar to that for the racemic mixture of Example 311.

Example 470

7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydroxide was prepared in accordance with the general method of example 1 from 8- (3- Chloride

Step 470. l-Cyclopropyl-prop-2-en-1-one

A sample (5 g, 59 mmol) of 1-cyclopropylmethyl ketone (Aldrich) is dissolved in 59 ml of THF and the solution is heated under reflux under a nitrogen atmosphere and then cooled. A solution of 7.97 g of formalin and 19.57 g of N-methylpyridinium trifluoroacetate is then prepared. Half of the second solution is added to the first cooled solution, and the resulting mixture is heated under reflux for 30 minutes. The reaction mixture is cooled and the other half of the second solution is added and the reaction mixture is heated under reflux for 7 hours. The mixture is cooled and ether (100 ml) is slowly added with stirring to obtain a crude phase precipitate. Polish the rubber with ether. The ether solution is combined and extracted with aqueous NaHCO ₃ . The ether solution is dried, filtered and concentrated. The residue was triturated with ether and the ether solution was again dried, filtered and concentrated to give 4.60 g of the title compound.

Step 470b. (L-Benzyl-pyrrolidin-3-yl) -cyclopropyl-methanone

2 g of a sample of the compound from step 470a and 4.94 g of N-benzyl-N- (methoxymethyl) -trimethylsilylmethylamine are dissolved in methylene chloride and the solution is cooled in an ice bath. To this solution is added 2.1 ml of TFA (1N in methylene chloride) and the reaction mixture is stirred at room temperature for 2 hours. The mixture is diluted with methylene chloride and the solution is washed with NaHCO ₃ , water and brine, and then concentrated. The residue was purified by chromatography on silica gel to give 2,037 g of the title compound.

Step 470c. (L-Benzyl-pyrrolidin-3-yl) -cyclopropyl-methylamine

1 g of a sample of the compound from step 470b and 3.37 g of ammonium acetate and 274 mg of NaBH ₃ CN are dissolved in 15 ml of methanol and 1.2 g of 4 A molecular sieves are added and the mixture is stirred at room temperature for 16 hours under a nitrogen atmosphere. The mixture is filtered, the molecular sieve is washed with methanol, and the washing solution and the filtrate are combined and concentrated. The residue is dissolved in 100 ml of methylene chloride and 30 ml of 15% NaOH are added. Combine the second aqueous cleaning solution on the organic phase is dried and washed with water and brine to the next, MgSO _4. The solvent was removed and the residue was chromatographed on silica gel to give the title compound.

Step 470d. N-BOC-l- (l-Benzyl-pyrrolidin-3-yl) -cyclopropyl-methylamine

The compound from step 470c is treated with di-t-butyl dicarbonate in methylene chloride and triethylamine for 2 hours and chromatographed on silica gel to give the title compound (640 mg).

Step 470e. 3- (1- (BOC-amino) -l-cyclopropyl-methyl) pyrrolidine

A sample (548 mg) of the compound from step 470d is dissolved in methanol, 140 mg of 10% Pd / C are added and the mixture is hydrogenated at room temperature under a 4atm hydrogen atmosphere for 42 hours. The solution was filtered and the solvent was removed to give 140 mg of the title compound.

Step 470f. 7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydroxide was prepared in accordance with the general method of example 1 from 8- (3- Chloride

The reaction was carried out according to the procedure of Example 253j but using 3- (1- (BOC-amino) -l-cyclopropyl-methyl) pyrrolidine from step 470e instead of BOC-amino-pyrrolidine And the product is worked up as in steps 253k and 253l to give the title compound.

_{C 22 H 27 FN 3 O 3} HRMS (M + H) ⁺ for

Calculated: 400.2036

Found: 400.2030

Example 471

7-fluoro-9-methyl-4-oxo-4H-pyrrolo [2,3- -Quinolizine-3-carboxylic &lt; / RTI &gt; acid hydrochloride

Step 471a, 3- (R) - (1-BOC-2- (S) -pyrrolidinyl) -4-nitrobutanol

(US Pat. No. 5,098,912 to Hayakawa, issued Mar. 24, 1992) discloses the preparation of ethyl 3- (R) - (1-BOC-2- (S) -pyrrolidinyl) -4-nitrobutanoate Prepared as described) in 7.5 ml of ether is dissolved in 35 ml of ether and treated with 0.76 g of LAH. After careful quenching of the excess reagent, the title compound is extracted and purified by chromatography (4.5 g).

Step 471b. 3- (R) - (1-BOC-2- (S) -pyrrolidinyl) -4-nitrobutanylmethylsulfonyl ether

3.5 g of the alcohol sample from step 471a are dissolved in 25 ml of methylene chloride and treated with methanesulfonyl chloride and TEA at 0 &lt; 0 &gt; C for 24 h. The reaction mixture was washed with water, NaHCO ₃ solution and the solvent is removed. The residue was chromatographed on silica gel to give 3 g of the title compound.

Step 471c. 3- (R) - (1-BOC-pyrrolidin-2- (S) -yl) pyrrolidine

Hydrogenation of the ether compound from step 471a on Pd / C in methanol under a 4atm hydrogen atmosphere affords the title compound.

Step 471d. 7-fluoro-9-methyl-4-oxo-4H-pyrrolo [2,3- -Quinolizine-3-carboxylic &lt; / RTI &gt; acid hydrochloride

The title compound was prepared in analogy to example 253j but using 3- (R) - (1- (BOC-pyrrolidin-2- (S) -yl) pyrrolidine from step 471c instead of BOC-amino- , And the product is worked up as in steps 253k and 253l to produce the title compound.

Example 472

7-fluoro-9-methyl-4-oxo-4H-quinazoline-3-carboxylic acid hydrochloride &lt;

Step 472a. 3- (BOC-aminomethyl) -1-diphenylmethyl-azetidine

3-Aminomethyl-1-diphenylmethyl-azetidine (prepared according to literature, see Anderson and Lok, J. Org. Chem., 37: 3393-5 (1972)] was treated with di-t-butyl carbonate in methylene chloride and triethylamine for 2 hours and chromatographed on silica gel to give the title compound (450 mg) .

Step 472b. 3- (BOC-aminomethyl) -azetidine

A sample of the compound from step 473a is treated with 4atm hydrogen at room temperature in the presence of Pd / C in methanol. The mixture is filtered and the solvent is removed to give the title compound.

Step 472c. 7-fluoro-9-methyl-4-oxo-4H-quinazoline-3-carboxylic acid hydrochloride &lt;

The reaction was carried out according to the procedure of Example 253j but using 3- (BOC-aminomethyl) azetidine from step 472b instead of BOC-amino-pyrrolidine and the product was obtained in steps 253k and 253l Treatment is carried out in the same manner to give the title compound.

Example 473

6-Amino-8- (3-aminopyrrolidine) -l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride

Step 473a. 4-t-butoxy-6-dibenzylamino-2,5-difluoro-3-methylpyridine

4-t-butoxy-2,5,6-trifluoro-3-methylpyridine from step 253c is reacted with dibenzylamine in ethanol at reflux temperature. The solvent is removed and the residue is dissolved in methylene chloride and washed with water. The product is purified by column chromatography.

Step 473b. 6-dibenzylamino-8- (3-aminopyrrolidine) -l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride

4-t-butoxy-2,5-difluoro-3-methylpyridine was prepared from 4-t-butoxy-6-dibenzylamino-2,5-difluoro-3-methylpyridine from step 473a The reaction was carried out according to the procedure for Example 253e but replacing the product and work-up of the product as in steps e to l of Example 253 afforded the title compound.

Step 473c. 6-Amino-8- (3-aminopyrrolidine) -l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride

The sample from step 473d is heated with ammonium formate in the presence of 10% Pd / C in ethanol. After the reaction is complete, the mixture is filtered and the filtrate is concentrated and treated with HCl in ether to give the title compound.

Example 474

6-Amino-8- (7-amino-5-azaspiro [2,4] heptan-5-yl) -l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine Carboxylic acid hydrochloride

Amino-5-azaspiro [2.4] heptane (prepared as described in J. Med. Chem. 1994, 37, 3344) was used instead of 3-BOC-aminopyrrolidine The reaction is carried out according to the procedure of Example 473 and the product is worked up to give the title compound.

Example 475

8-Bicyclo [4.3.0] nonyl) -1-salicylopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine Carboxylic acid hydrochloride

Example 473 was followed except that 2,8-diaza-8-bicyclo [4.3.0] nonane (prepared as described in U.S. Patent No. 5,095,597) was used instead of 3-BOC-aminopyrrolidine , And the product is worked up to give the title compound.

Example 476

6-Amino-8- (3,5-cis-dimethylpiperazin-l-yl) -l-cyclopropyl-7,9- difluoro-4H-4-oxo-quinolizine-3-carboxylic acid hydrochloride

4-t-butoxy-2,3,5,6-tetrafluoropyridine from Example 274b was used instead of 4-t-butoxy-2,5,6, -trifluoro-3-methylpyridine The reaction was carried out according to the procedure for Example 473a but replacing 3-BOC-aminopyrrolidine with 3,5-cis-dimethylpiperazine in Example 473b and 473c And the resulting product is worked up to give the title compound.

Example 477

7-fluoro-9-methyl-4H-4-oxo-quinolizine-3-carboxylic acid hydrochloride

Step 477a. Methyl-4-oxo-4H-quinolizine-3-carboxylic &lt; / RTI &gt; acid ethyl ester

To a suspension of NaH in DMF cooled in an ice bath is added di-t-butyl malonate. Thereafter, 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester from Example 253i is added. After this, the reaction is heated to 50-60 &lt; 0 &gt; C and the mixture is poured into water and acidified. The product is extracted in methylene chloride, dried over MgSO _4. After removal of the solvent, the residue is dissolved in methylene chloride and trifluoroacetic acid at room temperature. The solvent is removed in vacuo and the product is treated with methylene chloride and diphenyldiazomethane in methanol. After the reaction has been quenched, the solvent is removed in vacuo and the product is subjected to column chromatography to give the title compound.

Step 477b, 1-Cyclopropyl-8- (1-diphenylmethoxycarbonylmethyl- 1 -vinyl) -7-fluoro-9-methyl-4-oxo-4H- quinolizine-

The product from step 477a is heated with 35% formaldehyde in DMF in the presence of sodium bicarbonate. After the reaction was completed, the product is extracted in methylene chloride, washed with water, dried over MgSO _4. The solvent is removed and the residue is dissolved in methylene chloride. Triethylamine is added under ice-cooling, and then methanesulfonyl chloride is added. Thereafter, the reaction is stirred at room temperature, then poured into water and acidified. The mixture is extracted with ethylene chloride and the solvent is removed to give a crude product which is subjected to column chromatography.

Step 477c. 1-cyclopropyl-8- (1-diphenylmethoxycarbonylmethyl- 1 -cyclopropyl) -7-fluoro-9-methyl-4-oxo-4H- quinolizine-

To the NaH solution in stirred DMSO is added trimethylsulfonium iodide at 0 &lt; 0 &gt; C and the resulting solution is stirred at room temperature. The product from step 477b is added and the mixture is stirred at 50 &lt; 0 &gt; C. The mixture is quenched with water and the product is extracted to give the title compound.

Step 477d. 1-cyclopropyl-8- (1-hydroxycarbonyl-1-cyclopropyl) -7-fluoro-9-methyl-4-oxo-4H- quinolizine-

The product from step 477c is dissolved in a mixture of anisole and trifluoroacetic acid and stirred at room temperature. The solvent was removed and the residue was purified by column chromatography to give the title compound.

Step 477e. (1-BOC-amino-1-cyclopropyl) -7-fluoro-9-methyl-4-oxo-4H-quinolizine-

A sample of the product from step 477d is heated with diphenylphosphoryl azide, t-butanol, triethylamine and dioxane. The solvent is removed under vacuum. The residue was dissolved in methylene chloride and washed with water, and dried with MgSO ₄ and then concentrated in vacuo. The resulting title compound is chromatographed on silica gel.

Step 477f. 1-Cyclopropyl-8- (1-amino-1-cyclopropyl) -7-fluoro-9-methyl-4-oxo-4H-quinolizine-

The product from step 477e is worked up according to steps k to l of example 253 to give the title compound.

Example 478

3H, 6H-oxo-pyrano [2,3,4-ij] quinolizine-5- Carboxylic acid hydrochloride

(R) -10-chloro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester from Example 281e instead of 8- Following the procedure of Example 477, but using 3-methyl-2H, 3H, 6H-6-oxo-pyrano [2,3,4 .- ij] quinolizine-5-carboxylic acid ethyl ester The reaction is carried out to give the title compound.

Example 479

7-fluoro-9-methoxy-4H-4-oxo-quinolizine-3-carboxylic acid hydrochloride

Chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester from Example 275 in place of 8- -Fluoro-9-methoxy-4H-4-oxo-quinolizine-3-carboxylic acid ethyl ester The title compound is obtained by following the procedure in Example 477. [

Example 480

7-fluoro-9-methyl-4H-4-oxo-quinolizine-3-carboxylic acid hydrochloride

Step 480a. 7-fluoro-9-methyl-4H-4-oxo-quinolizine-3-carboxylic acid ethyl ester

The product from Example 477d is treated with oxalylchlorideide in methylene chloride and then quenched with aqueous ammonia. An aqueous work-up affords the amide which is treated with POCl ₃ at room temperature to give the title compound.

Step 480b. 8- (1-BOC aminomethyl-1-cyclopropyl) -l-cyclopropyl-7-fluoro-9-methyl-4H-4-oxo-quinolizine-

The product from step 480a is treated with Raney nickel under a hydrogen atmosphere. After removal of the solvent, the residue is treated with di-t-butyl dicarbonate in a mixture of methanol and water. The reaction was extracted in methylene chloride, washed with water, dried over MgSO _4, then concentrated under vacuum. The resulting title compound is purified by chromatography on silica gel.

Step 480c. 7-fluoro-9-methyl-4H-4-oxo-quinolizine-3-carboxylic acid hydrochloride

The product from step 480b is treated according to steps k to l of example 253 to give the title compound.

Examples 481 to 565

The reaction was carried out according to steps 253j, 253k and 253l using the appropriate unprotected or BOC-protected reagent instead of 3-BOC-aminopyrrolidine in step 253j to give Examples 481-565 as shown in the following Table 13A &Lt; / RTI &gt; In each case where a particular chiral isomer is indicated, it is to be understood that these examples also include the opposite stereoisomer and diastereomer thereof.

[Table 13Aa]

[Table 13Ab]

[Table 13 Ac]

[Table 13Ad]

[Table 13Ae]

Example 566

7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-l- Quinolizine-3-carboxylic acid hydrochloride

Step 566a. 1-Benzyl-4-cyclopropylpyrrolidine-3-carboxylic acid ethyl ester

(3.00 g, 50.0 mmol, prepared according to literature, see J. Org. Chem. 1987, 52, 2629) and N-benzyl-N- (methoxymethyl) trimethylsilylmethylamine (11.85 g, 50.0 mmol) is dissolved in methylene chloride (100 ml) and the resulting solution is cooled to 0 &lt; 0 &gt; C and flushed with nitrogen. Trifluoroacetic acid (5.0 mL of a 1N solution in methylene chloride) is added dropwise at 0 &lt; 0 &gt; C over 10 minutes and the reaction mixture is stirred under a nitrogen atmosphere for 2 hours while allowing the reaction temperature to rise to room temperature. The mixture is stirred for an additional 18 h, washed with 5% NaHCO ₃ and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by chromatography on silica gel, eluting with ether: hexane (1: 3) to give the title compound (9.30 g, oil).

Step 566b. 1-Benzyl-4-cyclopropylpyrrolidine-3-carboxylic acid

A sample of the compound from step 566a (5.46 g) is dissolved in methanol (100 ml) and 15% aqueous NaOH (100 ml) is added dropwise over 20 minutes at room temperature. The mixture is stirred for 2 hours 30 minutes and methanol is removed under vacuum. The aqueous solution is washed with methylene chloride, adjusted to pH 4 with 6N HCl, saturated with NaCl and extracted with isopropanol: methylene chloride (1: 3). The extract is washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was dried in vacuo to give the title compound (4.758 g).

Step 566c. Benzyl-3- (BOC-amino) -4-cyclopropylpyrrolidine

The compound from step 566b is dissolved in t-butanol under a nitrogen atmosphere. Triethylamine (5.34 ml, 38.4 mmol) and DPPA (6.08 g, 22.1 mmol) are added and the mixture is heated at 90 &lt; 0 &gt; C for 24 h under a nitrogen atmosphere. The solvent was removed and the residue was purified by chromatography on silica gel, eluting with 5% methanol in methylene chloride to give the title compound (4.77 g).

Step 566d. 3- (BOC-Imino) -4-cyclopropylpyrrolidine

The compound from step 566c (6.952 g, 22 mmol) is dissolved in methanol (100 ml). The solution is flushed with nitrogen, ammonium formate (6.93 g, 110 mmol) and 10% Pd / C (695 mg) are added and the mixture is heated at 80 &lt; 0 &gt; C for 26 h. The mixture is cooled, diluted with methylene chloride and filtered. The solvent was removed and the title compound (5.80 g) was obtained.

Step 566e. Benzyloxycarbonyl-3- (BOC-amino) -4-cyclopropyl

The compound from step 566d (2.0 g, 11.9 mmol) and K ₂ CO ₃ (1.88 g, 17.8 mmol) are dissolved in 50% aqueous dioxane (40 ml), the solution is flushed with nitrogen and cooled to 0 ° C. Benzyl chloroformate (2.43 g, 14.2 mmol) is added dropwise over 10 minutes and the mixture is stirred at 0 &lt; 0 &gt; C for 5 hours under a nitrogen atmosphere. The mixture was dissolved in ether and washed with water, 1N HCl and water and dried with Na ₂ SO _4. The solvent was removed and the residue was purified by chromatography on silica gel, eluting with acetate: hexane (1: 3) to give the title compound (1.96 g, oil).

Subsequent separation of the diastereomeric mixture by preparative HPLC (Chiralpak AS column eluting with 2.5% ethanol in hexanes) gave pure 3- (S) -4- (R) - and 3- (R) -4- (S) -stere isomer.

Step 566f. 3- (S) - (BOC-amino) -4- (R) -cyclopropylpyrrolidine

The 3- (S) -4- (R) - compound from step 566e is dissolved in methanol (40 ml). The solution is flushed with nitrogen, ammonium formate (1.04 g, 16.5 mmol) and 10% Pd / C (208 mg) are added and the mixture is heated under reflux for 1 hour. The mixture is cooled, diluted with methylene chloride and filtered. The solvent was removed to give the title compound (795 mg).

Step 566g. 7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-l- Quinolizine-3-carboxylic acid hydrochloride

Following the procedure of Example 253j but substituting 3- (S) - (BOC-amino) -4- (R) -cyclopropylpyrrolidine from step 566f for BOC-amino-pyrrolidine The reaction is carried out and the product is worked up as in steps 253k and 253l to give the title compound (3.20 g).

Elemental analysis for C ₂₁ H ₂₄ N ₃ O ₃ F · HCl · 1 1 / 4H ₂ O

Calculated: C 56.76; H 6.24; N 9.45.

Found: C 56.99; H 6.13; N 9.38.

Example 567

7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-l- Quinolizine-3-carboxylic acid hydrochloride

Step 567a. 3- (R) - (BOC-amino) -4- (S) -cyclopropylpyrrolidine

A sample (640 mg) of 3- (R) -4- (S) -lbenzyloxycarbonyl-3- (BOC-amino) -4-cyclopropylpyrrolidine in step 566e was treated as in example 566f To give the title compound (465 mg).

Step 567b. 7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-l- Quinolizine-3-carboxylic acid hydrochloride

Following the procedure of Example 253j but substituting 3- (R) - (BOC-amino) -4- (S) -cyclopropylpyrrolidine from step 567a for BOC-amino-pyrrolidine The reaction is carried out and the product is worked up as in steps 253k and 253l to give the title compound (318mg).

Elemental analysis for C ₂₁ H ₂₄ N ₃ O ₃ F · HCl · 1 1 / 4H ₂ O

Calculated: C 56.76; H 6.24; N 9.45.

Found: C 56.80; H 6.12; N 9.38.

Example 568

A solution of 8- (trans-3- (S) -amino-4- (R) -methylpyrrolidin- 1 -yl) -l-cyclopropyl-7-fluoro-4H-9- 3-carboxylic acid &lt; / RTI &gt; hydrochloride

Step 568a. Trans-3- (BOC-amino) -1-benzyl-4-methylpyrrolidine

4-methylpyrrolidine (1.5 g, 41.3 mmol, prepared according to the method described in Cesare, TD, et al., J. Med. Chem. 35 : 4205-4213 (1992)) is dissolved in aqueous methanol at 0 &lt; 0 &gt; C and treated with t-butyloxycarbonic anhydride (9.9 g) and stirred for 16 hours. After filtration and extraction with methylene chloride, the product is collected to give the title compound which is dried and used directly in the next step.

Step 568b. Trans-3- (BOC-amino) -4-methylpyrrolidine

The compound from step 568a (8.65 g, 29.8 mmol) is dissolved in anhydrous methanol. The solution is flushed with nitrogen and ammonium formate (9.39, 749 mmol) and 10% Pd / C (86.5 mg) are added and the mixture is heated at 80 &lt; 0 &gt; C for 2 hours. The mixture is cooled, diluted with methylene chloride and filtered. Removal of the solvent gave the title compound (6.51 g). MS m / z 201 (M + H) &lt; ⁺ & gt ^; .

Step 568c. Trans-3- (BOC-amino) -1-CBZ-4-methylpyrrolidine

The compound from step 568b (6.51 g, 29.8 mmol) is dissolved in 90 ml of 50% aqueous dioxane and K ₂ CO ₃ (4.74 g, 44.7 mmol) is added. The solution is stirred at 0 &lt; 0 &gt; C under a nitrogen atmosphere and benzyloxycarbonyl chloride (6.10 g, 35.76 mmol) is added dropwise over 15 minutes. The solution was stirred at 0 &lt; 0 &gt; C for 5 hours under a nitrogen atmosphere and then diluted with ether. The solution is washed with water and brine, dried and concentrated. The solvent was removed and the residue purified by chromatography on silica gel to give the title compound (8.88 g, oil).

Subsequent separation of the enantiomeric mixture by preparative HPLC (Chiralpak AD column eluting with 5% ethanol in hexanes) afforded pure 3- (S) -4- (R) - and 3- (R) - 4- (S) -isomer.

Step 568d. 3- (S) - (BOC-amino) -4- (R) -methylpyrrolidine

(S) - (BOC-amino) -1-CBZ-4- (R) -methylpyrrolidine (501 mg, 1.50 mmol) from step 568c is dissolved in methanol (15 ml). The solution is flushed with nitrogen, ammonium formate (472 mg, 7.50 mmol) and 10% Pd / C (100 mg) are added and the mixture is stirred at room temperature for 26 hours. The mixture is cooled, diluted with methylene chloride and filtered. The solvent was removed to give the title compound (380 mg).

Step 568e. A solution of 8- (trans-3- (S) -amino-4- (R) -methylpyrrolidin- 1 -yl) -l-cyclopropyl-7-fluoro-4H-9- 3-carboxylic acid &lt; / RTI &gt; hydrochloride

(S) - (BOC-amino) -4- (R) -methylpyrrolidine from step 568d instead of BOC-amino-pyrrolidine was used in the procedure of Example 253j The reaction is followed and the product is worked up as in steps 253k and 253l to give the title compound (2.63mg).

Elemental analysis for C ₁₉ H ₂₂ N ₃ O ₃ F · HCl · H ₂ O

Calculated: C 55.14; H 6.09; N 10.15.

Found: C 54.98; H 5.86; N 9.91.

Example 569

7-fluoro-4H-9-methyl-4-oxo-quinazolin-3- 3-carboxylic acid &lt; / RTI &gt; hydrochloride

Step 569a. Trans-3- (R) - (BOC-amino) -4- (S) -methylpyrrolidine

(S) -methylpyrrolidine (501 mg, 1.50 mmol) from step 568c is dissolved in methanol (15 ml). The solution is flushed with nitrogen, ammonium formate (472 mg, 7.50 mmol) and 10% Pd / C (100 mg) are added and the mixture is stirred at room temperature for 26 hours. The mixture is cooled, diluted with methylene chloride and filtered. The solvent was removed to give the title compound (380 mg).

Step 569b. A solution of 8- (trans-3- (R) -amino-4- (S) -methylpyrrolidin- 1 -yl) -l-cyclopropyl-7-fluoro-4H- 3-carboxylic acid &lt; / RTI &gt; hydrochloride

The procedure of Example 253j was followed except that trans-3- (R) - (BOC-amino) -4- (S) -methylpyrrolidine from step 569a was used instead of BOC-amino-pyrrolidine The reaction is followed and the product is worked up as in steps 253k and 253l to give the title compound (246mg).

Example 570

7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-l- Quinolizine-3-carboxylic acid hydrochloride

Step 570a. Ethyl N-benzyl-4-cyclopropyl-3-pyrrolinecarboxylate

Synthesis, 66: 173 (1987)) and N-benzyl-N- (methoxymethyl) propanoate (2.76 g, 20.0 mmol, prepared according to the method described in the literature, ) Trimethylsilylmethylamine (4.76 g, 20.0 mmol) is dissolved in methylene chloride, cooled to 0 &lt; 0 &gt; C and flushed with nitrogen. TFA (2.0 ml, 1N in methylene chloride) is added dropwise over 10 minutes at 0 ° C, and the mixture is stirred under nitrogen at 0 ° C for 2 hours and at room temperature for 22 hours. The mixture is washed with 5% aqueous NaHCO ₃ and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by chromatography on silica gel eluting with ethyl acetate: hexane (1: 2 to 1: 1) to give the title compound (2.72 g, oil).

Step 570b. (Cis) -ethyl N-benzyl-4-cyclopropyl-3-pyrrolidinecarboxylate

Dissolving the compound (2.72g) from step 570a in ethanol and then hydrogenated over PtO ₂ under 4atm H _2. The mixture is filtered, the solvent is removed and the residue is dried to give the title compound (2.36 g, oil).

Step 570c. (Cis) -ethyl 4-cyclopropyl-3-pyrrolidinecarboxylate

The compound from step 570b (2.36 g, 8.64 mmol) is dissolved in methanol (30 ml). The solution is flushed with nitrogen, ammonium formate (2.72 g, 43.2 mmol) and 10% Pd / C (300 mg) are added and the mixture is stirred at 80 &lt; 0 &gt; C for 3 h 30 min. The mixture is cooled, diluted with methylene chloride and filtered. The solvent was removed to give the title compound (1.85 g).

Step 570d. (Cis) -ethyl N-CBZ-4-cyclopropyl-3-pyrrolidinecarboxylate

The compound from step 570c (1.85 g, 10.1 mmol) is dissolved in 20 ml of 50% aqueous dioxane and K ₂ CO ₃ (1.59 g, 15.0 mmol) is added. The solution is stirred at 0 &lt; 0 &gt; C under a nitrogen atmosphere and benzyloxycarbonyl chloride (2.04 g, 12.0 mmol) is added dropwise over 10 minutes. The solution is stirred at 0 &lt; 0 &gt; C for 4 hours under a nitrogen atmosphere and then diluted with ether. The solution is washed with water and brine, dried and concentrated. The solvent was removed and the residue was purified by chromatography on silica gel to give the title compound (1.79 g, oil).

Step 570e. (Cis) -N-CBZ-4-cyclopropyl-3-pyrrolidinecarboxylate

The compound from step 570c (1.79 g, 5.65 mmol) is dissolved in methanol (40 ml) and 15% aqueous NaOH (40 ml) is added dropwise over 10 minutes at room temperature. The mixture is stirred for 4 h, the methanol is removed under vacuum and the aqueous residue is extracted with ether. The aqueous phase is adjusted to pH 3 with 6N HCl and extracted with methylene chloride. The extract was washed with brine, dried and concentrated to give the title compound (719 mg).

Step 570f. (Cis) -3- (BOC-amino) -1-CBZ-4-cyclopropylpyrrolidine

The compound from step 570d (648 mg, 2.24 mmol) is dissolved in t-butanol under a nitrogen atmosphere. Triethylamine (0.623 ml, 4.48 mmol) and DPPA (740 mg, 2.69 mmol) were added and the mixture was heated at 90 &lt; 0 &gt; C for 60 h under a nitrogen atmosphere. The solvent was removed and the residue was purified by chromatography on silica gel, eluting with ethyl acetate: hexane (1: 2) to give the title compound (563 mg).

The racemic mixture was then separated by preparative HPLC (Chiralpak AS column eluting with 2.5% ethanol in hexanes) to give pure 3- (S) -4- (S) - and 3- (R) 146 mg and 120 mg of the 4- (R) -enantiomer, respectively, are obtained.

Step 570g. Cis-3- (S) - (BOC-amino) -4- (S) -cyclopropylpyrrolidine

The (cis) -3- (S) - (BOC-amino) -1-C-4- (S) -cyclopropylpyrrolidine from step 570e is dissolved in methanol (10 ml). The solution is flushed with nitrogen, ammonium formate (125 mg, 1.986 mmol) and 10% Pd / C (28.6 mg) are added and the mixture is stirred at room temperature for 1 hour. The mixture is diluted with methylene chloride and filtered. Removal of the solvent gave the title compound.

Step 570h. 7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-l- Quinolizine-3-carboxylic acid hydrochloride

Following the procedure of Example 253j but substituting 3- (S) - (BOC-amino) -4- (S) -cyclopropylpyrrolidine from step 570f for BOC-amino-pyrrolidine The reaction is carried out and the product is worked up as in steps 253k and 253l to give the title compound (16mg).

Example 571

7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-1-carboxylic acid ethyl ester was prepared from 8- (cis-3- (R) -amino-4- (R) -cyclopropylpyrrolidin- Quinolizine-3-carboxylic acid hydrochloride

Step 571a. Cis-3- (R) - (BOC-amino) -4- (R) -cyclopropylpyrrolidine

(94 mg, 0.261 mmol) from step 570e is dissolved in methanol (10 ml). The solution is flushed with nitrogen, ammonium formate (82 mg, 1.305 mmol) and 10% Pd / C (19 mg) are added and the mixture is stirred at room temperature for 1 hour. The mixture is cooled, diluted with methylene chloride and filtered. Solvent was removed to give the title compound (81 mg).

Step 571b. 7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-1-carboxylic acid ethyl ester was prepared from 8- (cis-3- (R) -amino-4- (R) -cyclopropylpyrrolidin- Quinolizine-3-carboxylic acid hydrochloride

The procedure of Example 253j was followed except that cis-3- (R) - (BOC-amino) -4- (R) -cyclopropylpyrrolidine from step 571a was used instead of BOC-amino- , And the product is worked up as in steps 253k and 253l to give the title compound (54mg) [mp: 225 [deg.] C (decomposition)].

Example 572

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt; The diastereomer A

Step 572a. 2-pentenoic acid ethyl ester

Propionaldehyde (5.8 g) and (carbethoxymethylene) triphenylphosphorane (35 g) are dissolved in methylene chloride (100 ml) and the mixture is refluxed overnight. The product is distilled off from the reaction mixture.

Step 572b. Trans-3- (BOC-amino) -1-CBZ-4-ethyl-pyrrolidine

The reaction is carried out according to the procedure of step 435b except that 2-pentenoic acid ethyl ester from step 572a is used instead of 4-fluoro-2-butenoic acid ethyl ester and the product is treated as in steps 435c and 435d Work-up afforded the title compound. Subsequently, the diastereomer is separated by HPLC on a Chiralpak AS ( ^TM ) column and the diastereoisomer A (without observing chirality) is used in the next step.

The diastereoisomer B (without observing chirality) is used in Example 573.

Step 572c. Trans-3- (BOC-amino) -4-ethyl-pyrrolidine

After the compound from step 572b is hydrogenated with Pd / C in ethanol as in step 435c, the title compound is isolated.

Step 572d. 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt;

The reaction was carried out according to the procedure for Example 435e but using trans-3- (BOC-amino) -4-ethyl-pyrrolidine from step 572c instead of BOC-amino-pyrrolidine, Are worked up as in steps 253k and 253l to give the title compound. MS m / z 474 (M + H) &lt; ⁺ & gt ^; .

Example 573

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt; Diastereomer B

Step 573a. Trans-3- (BOC-amino) -4-ethyl-pyrrolidine diastereomer B

After the diastereomeric B compound from step 572b is hydrogenated with Pd / C in ethanol as in step 435c, the title compound is isolated.

Step 573b. 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt; Diastereomer B

The title compound was prepared according to the procedure of Example 435e but using trans-3- (BOC-amino) -4-ethyl-pyrrolidine diastereomer B compound from step 572c instead of BOC-amino-pyrrolidine And the product is worked up as in steps 253k and 253l to give the title compound.

Example 574

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt; The diastereomer A

Step 574a. 1-CBZ-3-pyrroline

3-Pyrroline (Aldrich, 65% purity) is dissolved in a mixture of dioxane and water (1: 1). Add Na ₂ CO ₃ . The reaction mixture is then flushed with nitrogen and cooled to 0 &lt; 0 &gt; C. Benzyl chloroformate is added dropwise and the mixture is stirred at 0 &lt; 0 &gt; C for several hours. The reaction mixture is warmed to room temperature and stirred for a further 2 hours. Then, ethyl acetate was added to wash the reaction mixture with H ₂ O and brine. Dry the organic layer with MgSO ₄ and concentrated in vacuo purified by column chromatography with hexane / EtOAc solution to give the title compound (purity 65%).

Step 574b. 3,4-epoxy-1-CBZ-pyrroline

5 g of crude 1-CBZ-3-pyrroline from step 574a is dissolved in 25 ml of CH ₂ Cl ₂ . 3-chloroperoxybenzoic acid is added dropwise over 5 minutes. The reaction mixture is stirred at room temperature for 22 hours. After this time, the reaction mixture is filtered and the filtrate is diluted with 30 ml of CH ₂ Cl ₂ and washed with Na ₂ S ₂ O ₃ solution, NaHCO ₃ solution and H ₂ O. The organic layer is dried over MgSO ₄ and is concentrated in vacuo and chromatographed, eluting with hexane / EtOAc solution on silica gel. The title compound is obtained in 76% yield. MS m / z 220 (M + H) &lt; ⁺ & gt ^; .1H

Step 574c. Cis-3- (hydroxy) -1-CBZ-4-ethyl-pyrrolidine

The compound from step 574b (2.0 g) is dissolved in 20 ml of THF and CuCN (0.081 g) is added. The mixture is cooled to -70 占 and 5.5 ml of EtMgCl solution is added over 20 minutes. The mixture is heated to -50 &lt; 0 &gt; C and stirred at the same temperature for 1 hour. Thereafter, the solution is heated to -20 占 폚 over 1 hour. Finally, the solution is allowed to stir at room temperature overnight. The next morning, the reaction is quenched with 2N HCl. Add EtOAc and separate the layers. The organic layer was washed with H ₂ O and saturated NaCl solution, dried over MgSO ₄ , concentrated in vacuo and chromatographed on silica gel to give the title compound (88%). MS m / z 250 (M + H) &lt; ⁺ & gt ^;

Step 574d. Cis-3- (phthalimide) -1-CBZ-4-ethyl-pyrrolidine

(5.22 g), PPh ₃ (8.24 g) and phthalimide (4.0 g) from Step 574b are introduced into a flask and flushed with nitrogen, cooled to 0 ° C and dissolved in 50 ml of THF. DEAD (4.3 ml) is added dropwise over 25 min. The resulting solution is stirred at room temperature for 51 hours. Subsequently, the solvent was removed in vacuo and the product was purified by column chromatography to give the title compound in 86% yield.

Example 574 e. Cis-3- (BOC-amino) -1-CBZ-4-ethyl-pyrrolidine

The compound from step 574c (6.56 g) is dissolved in EtOH, NH ₂ NH ₂ .H ₂ O (2.7 ml) is added and the mixture is refluxed for 5.5 hours. The reaction mixture is cooled, filtered and the filtrate is concentrated in vacuo. The residue is dissolved in 20 ml of CH ₂ Cl ₂ and cooled to 0 ° C. BOC ₂ O (4.9 g), Et ₃ N (3.0 ml) and a catalytic amount of DMAP are added and the mixture is allowed to warm to room temperature overnight. The next day, the amino, CH ₂ Cl ₂ is added and the mixture is washed with NaHCO ₃ solution and H ₂ O and brine. The organic layer is dried over MgSO ₄ and concentrated in vacuo and purified by column chromatography with hexane / EtOAc solution. The diastereomer is separated by HPLC on a Chiralpak AS ( ^TM ) column. Separate stereoisomer A is used in the next step.

The diastereoisomer B is used in Example 575.

Step 574f. Cis-3- (BOC-amino) -4-ethyl-pyrrolidine

After hydrogenation of the compound from step 574d to Pd / C in ethanol as in step 435c, the title compound is isolated. MS m / z 215 (M + H) &lt; ⁺ & gt ^; .

Step 574g. 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt;

The reaction was carried out according to the procedure of Example 253j but using cis-3- (BOC-amino) -4-ethyl-pyrrolidine from step 574e instead of BOC-amino-pyrrolidine, Are worked up as in steps 253k and 253l to give the title compound. MS m / z 374 (M + H) &lt; ⁺ & gt ^; .

Example 575

7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt; Diastereomer B

Step 575a. Cis-3- (BOC-amino) -3-ethyl-pyrrolidine

After the diastereomeric B compound from step 574d is hydrogenated with Pd / C in ethanol as in step 435c, the title compound is isolated. MS m / z 215 (M + H) &lt; ⁺ & gt ^; .

Step 575b. 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride &lt;

The reaction was carried out according to the procedure of Example 253j but using cis-2- (BOC-amino) -3-ethyl-pyrrolidine from step 575b instead of BOC-amino-pyrrolidine, Are worked up as in steps 253k and 253l to give the title compound. MS m / z 374 (M + H) &lt; ⁺ & gt ^; .

Example 576

7-fluoro-4H-9-methyl-4-oxo-quinazolin-3- 3-carboxylic acid &lt; / RTI &gt; hydrochloride

Step 576a. Cis-3- (BOC-amino) -4-methyl-pyrrolidine

Cis-3- (BOC-amino) -4-methyl-benzylpyrrolidine (prepared according to the method described in the literature, see Cesare. TD, et al., J. Med. Chem. 35: 4205-4213 (1992)) is converted to Pd / C in ethanol as in step 435c, the title compound is isolated. The title compound was treated with benzyl chloroformate and HPLC on a Chiralpak AS ( ^TM ) column to separate the diastereomers and deprotect each compound according to the procedure described in Example 568 steps c and d. The 3S, 4S-compound is used in the next step. MS 201 (M + H) &lt; ⁺ & gt ^; . H ¹

The 3R, 4R-compound is used in Example 576.

Step 576b. 7-fluoro-4H-9-methyl-4-oxo-quinazolin-3- 3-carboxylic acid &lt; / RTI &gt; hydrochloride

The reaction is carried out according to the procedure of Example 253j but using the compound from step 576a instead of BOC-amino-pyrrolidine and the product is worked up as in steps 253k and 253l to give the title compound .

Example 577

The title compound was prepared from 8- (cis-3 (R) -amino-4 (R) -methylpyrrolidin- 1- yl) -l-cyclopropyl-7-fluoro-4H- Carboxylic acid hydrochloride

Step 577a. Cis-3- (BOC-amino) -4-methyl-pyrrolidine

After hydrogenating the 3R, 4R compound from step 576a with Pd / C in ethanol as in step 435c, the title compound is isolated.

Step 577b. 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride

The reaction is carried out as in Example 253j except that the compound from Step 577a is used instead of BOC-amino-pyrrolidine and the product is worked up as in Steps 253k and 253l to give the title compound .

Example 578

In vitro test for antimicrobial activity

The in vitro assay for the antimicrobial activity against the compounds according to the invention is described below: The minimum inhibitory concentration (MIC) is determined by the agar dilution method. Twelve Petri dishes are prepared for this method and each dish contains a continuous aqueous two-fold dilution of the test compound mixed with 10 ml of sterile Brain Heart Infusion (BHI) agar. Each dish was diluted 1: 100 (or a low-growth strain, mainly Micrococcus) of 32 species of microorganisms using a Stirrer replicator block calibrated to generate about 10 ⁴ colony forming units (CFU) 1: 10] dilution for Streptococcus. The inoculated dishes are incubated at about 35-37 [deg.] C for 20-24 hours. Also, at the end of each test, a control dish containing no test compound is prepared and incubated using BHI agar. As a control (Cntl), a quinolone antifungal ciprofloxacin is used.

After incubation, each Petri dish is observed for the presence of microbial growth. The MIC is defined as the minimum concentration of the test compound that does not cause any growth (compared to a slightly turbid or rarely isolated colony at the spot of the inoculum) as compared to the growth of a control containing no test compound.

The results of this test are shown in the following Tables 14, 15 and 16, which demonstrate that the compounds of the present invention are surprisingly effective in inhibiting bacterial growth. Furthermore, the 9-methylquinolizone compound of the present invention (wherein A is CR ⁶ - and R ⁶ is methyl) in Staphylococcus aureus 1775 which is resistant to ciprofloxacin , Demonstrating the potential utility of the compounds of this invention in treating infections that are not resolved by these widely used drugs.

[Table 14a]

[Table 14b]

[Table 14c]

[Table 14d]

[Table 15a]

[Table 15b]

[Table 15c]

[Table 15d]

[Table 15e]

[Table 15f]

[Table 15g]

[Table 16a]

[Table 16b]

[Table 16c]

[Table 16d]

[Table 16e]

[Table 16f]

[Table 16g]

[Table 16h]

[Table 16i]

[Table 16j]

[Table 16k]

[Table 16l]

[Table 16n]

[Table 16m]

[Table 16o]

[Table 16p]

[Table 16q]

[Table 16r]

[Table 16s]

[Table 16t]

[Table 16u]

[Table 16v]

[Table 16w]

[Table 16x]

[Table 16y]

[Table 16z]

[Table 16aa]

[Table 16ab]

[Table 16ac]

Some of the compounds of the present invention show particular superiority over the previously applied exemplified compounds. For example, the compounds of Examples 420 and 566 through 577 are identical to or superior to the criteria shown in Table 1 except for Candida albicans microorganisms (MIC data should be greater than 100) Activity (i. E., The MIC value is smaller). Comparative data for ciprofloxacin is also shown. These scales are chosen because compounds with this MIC profile exhibit exceptional activity against a representative group of clinically problematic microorganisms.

[Table 17]

The compounds of Examples 254, 257, 263, 271 and 341 are also suitable for this scale. However, these latter compounds are not superior to the compounds of Examples 420 and 566 to 577 for reasons.

Example 254: Induces that the in vitro cell characteristics obtained from the standard calf thymus topoisomerase II assay are not suitable for a cytotoxicity scale of 2 / / ml.

The compound of Example 257: LD ₅₀ (IP) toxicity data obtained from a standard mouse model appears to be lower than the LD ₅₀ scale of ₅₀ mg / kg.

Compound of Example 263: The LD ₅₀ (IP) toxicity data obtained from a standard mouse model appears to be lower than the LD ₅₀ scale of ₅₀ mg / kg.

The compound of Example 271: the solubility of this compound does not appear to fit the solubility measure above 0.08 mg / ml.

Compound of Example 341: Whole cell cytotoxicity data from a standard Chinese hamster ovarian test appears to be unsuitable for a cytotoxicity scale of 70 μg / ml.

The foregoing detailed description and accompanying examples are merely illustrative and are not intended to limit the scope of the invention as defined in the appended claims and the like. The skilled artisan can make various changes and modifications to the described embodiments. Such changes and modifications are possible without departing from the spirit and scope of the invention, including, without limitation, chemical structures, substituents, derivatives, intermediates, syntheses, combinations and / or methods of use of the invention.

Claims (33)

A compound of formula I or a pharmaceutically acceptable salt, ester or amide thereof. (I) (Ia) (Ib) In the above formulas I, Ia and Ib, R ¹ is selected from the group consisting of lower alkyl (a), lower alkenyl (b), halo (lower-alkyl) (c), lower alkoxy (d), cycloalkyl (I), nitro (j), bicycloalkyl (k), lower alkynyl (l), lower alkoxycarbonyl (m), nitrogen containing aromatic heterocycle (n) ), halo-substituted nitrogen-containing aromatic heterocycle, (o), cyclic 4 W, 5-or 6-ether (p) and -RN ⁷ R ⁸ (q) (wherein, R ⁷ and R ⁸ are independently hydrogen, Lower alkyl and alkanoyl of 1 to 8 carbon atoms, or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached may form a 5-membered, 6-membered or 7-membered heterocycle , R ² is selected from the group consisting of halogen (a), lower alkyl (b), lower alkenyl (c), cycloalkyl having 3 to 8 carbons, cycloalkenyl having 4 to 8 carbons, (K), (lower alkyl) amino (1), aryl (lower alkyl), aryl (lower alkyl) (N), phenyl (o), substituted phenyl (p), acyclic nitrogen containing heterocycle (q), nitrogen containing aromatic heteroatom (s) The cycle (r) is selected from the nitrogen-containing heterocycle (s) of formula (Ia) and the nitrogen-containing heterocycle (t) x is 0, 1, 2 or 3, R ⁹ is _{(i) - (CH 2)} m - ( wherein, m is 1, 2 or 3) or _{(ii) (CH 2) n} R 13 (CH 2) p - ( wherein, R ¹³ is -S -, -O-, and -NH-), &lt; / RTI &gt; R ¹⁰ is CH ₂ , When R ⁹ is selected from (i) O, S and N, n is 1 or 2, p is 1 or 2, R ³¹ is - (CH ₂ ) _q R ³² -, wherein R ³² is -S- or -O- and q is 1, 2 or 3, Radical Y is each independently selected from the group consisting of (i) lower alkyl, (ii) hydroxy, (iii) halogen, (iv) halo (lower alkyl), (v) hydroxy substituted lower alkyl, (lower alkyl), (xi) lower alkoxy (lower alkoxy) (lower alkyl), (xii) lower alkylamino, (viii) lower alkoxy, (Xii) imino, (xiv) alkoxycarbonyl, (xv) carbamoyl, (xvi) aryl (lower alkyl), (xvii) aminoxy, (xxii) halo (lower alkyl) amino, (xx) halo (lower alkyl) amino (lower alkyl), (xxi) thio lower alkoxy (lower alkyl), (xxii) aminothio lower alkoxy, (Xxiv) cycloalkyl, (xxv) cycloalkylamino, (xxvi) phenyl, (xxvii) substituted phenyl, contain (Xxx) -NR ¹¹ R ¹² wherein R ¹¹ and R ¹² are independently selected from hydrogen and lower alkyl, or when one of R ¹¹ and R ¹² is hydrogen, the other is selected from the group consisting of C 1-8 of alkanoyl, alpha-amino acid or amino acid number 2 to 5, the polypeptide moiety) and ^{(xxxi) -C (R 21)} (R 22) NH 2 [ where, R ²¹ and R ²² are independently hydrogen, lower alkyl (Lower alkyl), lower alkoxy (lower alkyl), thio lower alkoxy (lower alkyl), cycloalkyl of 3 to 6 carbon atoms, and lower alkyl substituted by nitrogen containing aromatic heterocycle , R &lt; ²¹ &gt; and R &lt; ²² &gt; together with the carbon atoms to which they are attached form a ring structure selected from a cycloalkyl and a nitrogen-containing heterocycle having from 3 to 6 carbon atoms, R &lt; ³ &gt; is selected from the group consisting of hydrogen, halogen and lower alkoxy, R ⁴ is selected from the group consisting of hydrogen, lower alkyl, pharmaceutically acceptable cations and prodrug ester groups, R ⁵ is hydrogen (a), a halogen (b), hydroxy (c), lower alkyl (d), halo (lower alkyl) (e), lower alkoxy (f), and -NR ¹³ R ¹⁴ (g) (wherein , R ¹³ and R ¹⁴ are independently selected from the group consisting of hydrogen, lower alkyl, hydroxy-substituted lower alkyl, lower alkoxy (lower alkyl) and alkanoyl having 1 to 8 carbon atoms, A is = N- or = CR ⁶ (wherein, R ⁶ is hydrogen (a), a halogen (b), lower alkyl (c), halo (lower alkyl) (d), hydroxy-substituted lower alkyl (e), R is selected from the group consisting of lower alkoxy (lower alkyl) (f), lower alkoxy (h) and amino (lower alkyl) (i), or R ¹ and R ⁶ , together with the atoms to which they are attached, And forming a six-membered saturated ring optionally substituted by lower alkyl] Provided that when R &lt; ⁵ &gt; is hydrogen and A is = CH-, R &lt; ¹ &gt; is not unsubstituted phenyl. The method of claim 1 wherein, A is = CR ⁶ - to and R ⁶ is halogen, lower alkyl, halo (lower alkyl), hydroxy substituted lower alkyl, lower alkoxy (lower alkyl), lower alkoxy and amino (lower alkyl) &Lt; / RTI &gt; ^3. The compound according to claim 2, wherein R &lt; ³ &gt; is halogen. A compound according to claim 3, wherein R ⁵ is selected from the group consisting of hydrogen, lower alkyl, halo (lower alkyl) and -NR ¹³ R ¹⁴ wherein R ¹³ and R ¹⁴ are as defined in claim 1. 5. A compound according to claim 4, wherein R &lt; ¹ &gt; is selected from the group consisting of cycloalkyl having 3 to 8 carbon atoms and substituted phenyl. ^6. A compound according to claim 5 wherein R &lt; ⁶ &gt; is selected from the group consisting of halogen, lower alkyl and lower alkoxy. 7. The compound of claim 6 wherein R &lt; ² &gt; is selected from the group consisting of an acyclic nitrogen containing heterocycle and a nitrogen containing heterocycle of formula (Ic). (Ic) In formula (Ic) above, R ⁹ , Y and x are as defined in claim 1. 8. The compound of claim 7, wherein R &lt; ^{2 &gt;} is (Wherein Y and x are as defined in claim 1). A compound according to claim 8, wherein x is 1 or 2 and Y is -NR ¹¹ R ¹² and -C (R ²¹ ) (R ²² ) NH ₂ wherein R ¹¹ , R ¹² , R ²¹ and R ²² are as previously defined Lt; / RTI &gt; 3. A compound according to claim 2, wherein R &lt; ⁶ &gt; is methyl. 11. The compound according to claim 10, wherein R &lt; ³ &gt; is halogen. 12. The method of claim 11 wherein, R ⁵ is hydrogen, lower alkyl, halo (lower alkyl) and -NR ¹³ R ¹⁴ compound is selected from the group consisting of (wherein, R ¹³ and R ¹⁴ are as defined in claim 1). 13. The compound of claim 12 wherein R &lt; ¹ &gt; is selected from the group consisting of cycloalkyl having 3 to 8 carbon atoms and substituted phenyl. 14. The compound of claim 13, wherein R &lt; ² &gt; is selected from the group consisting of an acyclic nitrogen containing heterocycle and a nitrogen containing heterocycle of formula (Ic). (Ic) In formula (Ic) above, R ⁹ , Y and x are as defined in claim 1. 15. The compound of claim 14, wherein R &lt; ^{2 &gt;} is (Wherein Y and x are as defined in claim 1). 16. The method of claim 15, x is 1 or 2 and Y is -NR ¹¹ R ¹² and ^{-C (R 21) (R 22} ) NH 2 ( ^{wherein, R 11, R 12, R} 21 and R ²² is a first anti- Lt; / RTI &gt; are as defined in formula (I). The compound according to claim 1, wherein the compound is of formula (Id) or a pharmaceutically acceptable salt, ester or amide thereof. (Id) In the above formula (Id) R ² is selected from the group consisting of an acyclic nitrogen containing heterocycle and a nitrogen containing heterocycle of formula (Ic). (Ic) In formula (Ic) above, R ⁹ , Y and x are as defined in claim 1. 18. The compound of claim 17 wherein R &lt; ^{2 &gt;} is (Wherein Y and x are as defined in claim 1). 19. The method of claim 18, x is 1 or 2 and Y is -NR ¹¹ R ¹² and ^{-C (R 21) (R 22} ) NH 2 ( ^{wherein, R 11, R 12, R} 21 and R ²² is a first anti- Lt; / RTI &gt; are as defined in formula (I). The compound according to claim 1, wherein the compound is of formula (Ie) or a pharmaceutically acceptable salt, ester or amide thereof. (Ie) In the above formula (Ie) Z is -CH ₂ - is selected from the group consisting of, -O-, and -S-, R &lt; ¹⁶ &gt; is lower alkyl, R ² , R ³ , R ⁴ and R ⁵ are as defined in claim 1. 21. The compound of claim 20, wherein Z is -O- and R &lt; ² &gt; is a nitrogen containing heterocycle of formula (Ic). (Ic) In formula (Ic) above, R ⁹ , Y and x are as defined in claim 1. The method according to claim 1, -6-Hexano-pyrido [l, 2-a] pyrimidine-l- 7-carboxylic acid; (H) -6-oxo-pyrido [l, 2-a] pyrimidin- Pyrimidine-7-carboxylic acid; 3-Fluoro-9-cyclopropyl-2- (4-methylpiperazin-l-yl) -6 (H) -6-oxo-pyrido [l, 2-a] pyrimidine-7-carboxylic acid; 8- (3-Aminopyrrolidin-1-yl) -1-ethyl-4H-quinolizin-4-one-3-carboxylic acid; 2- (3-Aminopyrrolidin-l-yl) -9-cyclopropyl-3-fluoro-6H-6-oxo-pyrido [l, 2-a] pyrimidine-7-carboxylic acid; 2- (3-Aminopyrrolidin-l-yl) -9-cyclopropyl-3-fluoro-6H-6-oxo-pyrido [l, 2-a] pyrimidine-7-carboxylic acid; 6H-6-oxopyrido [l, 2-a] pyrimidin-7 (4-fluorophenyl) -Carboxylic acid; 6H-6-oxopyrido [l, 2-a] pyrimidine-lH- 7-carboxylic acid; (2,4-difluorophenyl) -3-fluoro-6H-6-oxopyrido [1, 2-dihydroxypyrrolidin- , 2-a] pyrimidine-7-carboxylic acid; 6H-6-oxopyrido [l, 2-a] pyrimidine-lH- 7-carboxylic acid; 9-Cyclopropyl-3-fluoro-2- (4-methylpiperazin-l-yl) -6H-6-oxo-pyrido [l, 2-a] pyrimidine-7-carboxylic acid; 9-Cyclopropyl-3-fluoro-2- (piperazin-1-yl) -6H-6-oxo-pyrido [l, 2-a] pyrimidine-7-carboxylic acid; 9-Cyclopropyl-3-fluoro-2- (morpholin-l-yl) -6H-6-oxo-pyrido [l, 2-a] pyrimidine-7-carboxylic acid; 6-oxopyrido &lt; / RTI &gt; (3-fluoro-phenyl) [L, 2-a] pyrimidine-7-carboxylic acid; (2,4-difluorophenyl) -3-fluoro-6H-6-oxopyrido &lt; / RTI &gt; [L, 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 [l, 2-a] pyrimidine-7-carboxylic acid; 2-methylpyrrolidin-1-yl) -9- (2,4-difluorophenyl) -3-fluoro-6H-6-oxo Pyrido [l, 2-a] pyrimidine-7-carboxylic acid; 6H-6-oxopyrido [l, 2-a] pyrimidine-lH-pyrrolo [ 7-carboxylic acid; 2-methylpyrrolidin-1-yl) -9- (2,4-difluorophenyl) -3-fluoro-6H-6-oxopyrido [L, 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- (Aminomethyl) 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- (l, 2,3,4-tetrahydro-2-isoquinolinyl) -4H-quinolizine-3-carboxylic acid; 1-Cyclopropyl-7-fluoro-9-methyl-4-oxo-8- (4-amino-1-piperidinyl) -4H-quinolizine-3-carboxylic acid; 1-Cyclopropyl-7-fluoro-9-methyl-4-oxo-8- (3-amino-1-piperidinyl) -4H-quinolizine-3-carboxylic acid; 1-Cyclopropyl-7-fluoro-9-methyl-4-oxo-8- (4- (aminomethyl) -1-piperidinyl) -4H-quinolizine-3-carboxylic acid; 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; Yl) -7-fluoro-9-methyl-4-oxo-4H-quinolizine-l- 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 [ 5-carboxylic acid; (3R) -9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -2H, 3H, 6H-6-oxo-pyrano [ 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 [ 5-carboxylic acid; 3 (S) -10- (3-Aminomethyl-1-pyrrolidinyl) -9-fluoro-3-methyl-2H, 3H, 6H-6-oxo-pyrano [ 5-carboxylic acid; 3-methyl-2H-3H, 6H-6-oxo-pyrano (2S, [2,3,4-ij] quinolizine-5-carboxylic acid; 3 (S) -9-fluoro-10- (3-hydroxy-1-pyrrolidinyl) -3-methyl-2H, 3H, 6H-6oxo-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) -l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid; 8- (3- (Methylamino) -1-piperazinyl) -l-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; 7-fluoro-9-methyl-4-oxo-4H-quinolizine-3 -Carboxylic acid; 7-fluoro-9-methyl-4-oxo-4H-quinolizine-l- 3-carboxylic acid; 7-fluoro-9-methyl-4-oxo-4H-quinolizine-l- 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; Methyl-4-oxo-4H-quinolizine-3-carboxylic acid (5-fluoro-4- ; 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, 1 R) -8- (3- (1-aminoethyl) pyrrolidinyl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid; (3R, 1 R) -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- ; Pyrrolidinyl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolin- 3-carboxylic acid; 7-fluoro-9-methyl-4-oxo-4H-quinolizine-l- 3-carboxylic acid; 8- (3- (1-aminocyclopropyl) pyrrolidinyl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid; Pyrrolidinyl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine 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) -norbornylamino) pyrrolidinyl) -4H-quinolizine-2-carboxylic acid 3-carboxylic acid; 3 (S) -I-Cyclopropyl-7-fluoro-9-methyl-4-oxo-8- 3-carboxylic acid; 3 (S) -Ilanyl- (S) -alaninylamino) pyrrolidinyl) -7-fluoro- -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) -l-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; 4-oxo-8- (3- (1,2,3-triazol-1-yl) -1-pyrrolidinyl) -quinolizine 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- (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; 8-Bicyclo [4.3.0] nonyl) -4-oxo-quinolizine-l- 3-carboxylic acid; Cyclopropyl-7-fluoro-4H-8- ((11S, 4S) -2,5-diaza- bicyclo [2.2.1] heptan- 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)) - -4H-9- methyl-1-cyclopropyl-7-fluoro -4-oxo-quinolizine-3-carboxylic acid; 8- ((1R ^* , 2R ^* , 6R ^* ) - 2-amino-8-azabicyclo [4.3.0] nonan- -4-oxo-quinolizine-3-carboxylic acid; 6-amino-3-azabicyclo [3.1.0] hexan-3-yl)) - 1- cyclopropyl- 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; (Spiro-1, 3-dioxacyclopentane [2.3] -1-piperidinyl) -1-cyclopropyl-7-fluoro-4H- 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) -l-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-Pyrrolipiperidinyl) -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; 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) methylpiperidinyl) -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; Methyl-4-oxo-quinolizine-3-carboxamide &lt; / RTI &gt; Carboxylic acid; Methyl-1 ', 3'-dioxolanyl) piperidinyl) -7-fluoro-9-methyl- 4H-quinolizine-3-carboxylic acid; 6-methylbicyclo [3.3.0] octan-1-yl) -7-fluoro-9-methyl-4-oxo-4H-quinazolin- 3-carboxylic acid; 1-Cyclopropyl-8- (3-fluoromethylpiperidinyl) -7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid; 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; Cyclopropyl-8- ((2-aza-4- (dimethylaminomethyl) bicyclo [4.3.0] non-2-yl) -7-fluoro- Anthraquinone carboxylic acid; (3-aza-6- (L-alaninylamino) -6-methylbicyclo [3.3.0] octane) -7- Quinolizinecarboxylic acid; Pyrrolidinyl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolyl (2R, 3-carboxylic acid; (3R, 1S) -8- (3- (1-Amino-2-methoxyethyl) pyrrolidinyl) -1-cyclopropyl-7-fluoro-9- 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- ; 8-Bicyclo [4.3.0] nonyl) -7-fluoro-4H-9-methyl-4-oxo-quinolizine- 3-carboxylic acid; 8-Bicyclo [4.3.0] nonyl) -7-fluoro-4H-9-methyl-4-oxo-quinolizine- 3-carboxylic acid; 3-aza-bicyclo [3.1.0] hexan-3-yl) -7-fluoro-4H-9-methyl-4-oxo-quinolizine- -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; -7-fluoro-4H-9-methyl-4-oxo-quinolizine-l- 3-carboxylic acid hydrochloride; 4-oxo-quinolizine-1-carbonitrile The title compound was prepared in analogy to the procedure described for the synthesis of 8- (7- (R) -amino-5-aza- spiro [2.4] heptan- 3-carboxylic acid hydrochloride; Pyrrolidinyl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine- 3-carboxylic acid; (S ^* ) - (1- (S ^* ) - amino-2,2,2-trifluoroethyl) pyrrolidinyl) -1-cyclopropyl-7-fluoro- 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- (R) -aminopiperidinyl) -l-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- (octahydropyrrolo [3,2-b] pyridin- l-yl) -l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid; 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid &lt;; 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-hydroxypyrrolidinyl-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-l-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-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; 7-fluoro-4H-9-methyl-4-oxo-quinolizine (prepared according to the method described in &lt; Carboxylic acid; 8- (3- (2-fluoroethyl) aminopyrrolidin-1-yl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid; Yl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3 -Carboxylic acid; 7-fluoro-4H-9-methyl-4-oxo-quinolizine-l- 3-carboxylic acid; 7-fluoro-4H-9-methyl-4-oxo-quinolizine-l- 3-carboxylic acid; 8- (3-amino-octahydroisoindol-2-yl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid; 3-carboxylic acid (prepared as described for the synthesis of 8- (6-amino-2-aza- spiro [3.3] non-2-yl) -l-cyclopropyl-7-fluoro-4H- Isomer (I)); 8- (3-Amino-3-trifluoromethylpyrrolidin-l-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; 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxamide was prepared from 8- (3-aminomethyl-3- trifluoromethyl- 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; 3-carboxylic acid (prepared as described for the synthesis of 8- (6-amino-2-aza- spiro [3.3] non-2-yl) -l-cyclopropyl-7-fluoro-4H- Isomer (II)); 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; 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid &lt;; 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid (2-fluoro- ; 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid &lt;; 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid &lt;; 8- (2- (R) -aminomethyl-pyrrolidin-l-yl) -l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid; 8- (2- (S) -Aminomethyl-pyrrolidin-l-yl) -l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid; 8- (3- (R) - (1-aminocyclopropyl) pyrrolidinyl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-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; 7-fluoro-9-methyl-4-oxo-4H-pyrrolo [2,3- - 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-l-yl) -l-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- Carboxylic acid; -7-fluoro-4H-9-methyl-4-oxo-quinolizine-l- 3-carboxylic acid; 4-oxo-quinolizine-1-carbonitrile The title compound was prepared in analogy to the procedure described for the synthesis of 8- (7- (R) -amino-5-aza- spiro [2.4] heptan- 3-carboxylic acid; 7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-l- Quinolizine-3-carboxylic acid; 7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-l- Quinolizine-3-carboxylic acid; A solution of 8- (trans-3- (S) -amino-4- (R) -methylpyrrolidin- 1 -yl) -l-cyclopropyl-7-fluoro-4H-9- 3-carboxylic acid; 7-fluoro-4H-9-methyl-4-oxo-quinazolin-3- 3-carboxylic acid; 7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-l- Quinolizine-3-carboxylic acid; 7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-1-carboxylic acid ethyl ester was prepared from 8- (cis-3- (R) -amino-4- (R) -cyclopropylpyrrolidin- Quinolizine-3-carboxylic acid; 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomeric mixture of 8- (trans-3-amino-4-ethylpyrrolidin- 1 -yl) Isomer A; 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomeric mixture of 8- (trans-3-amino-4-ethylpyrrolidin- 1 -yl) Isomer B; 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomer &lt;A; 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomer &lt;B; 7-fluoro-4H-9-methyl-4-oxo-quinolin-2- -Carboxylic acid and 7-fluoro-4H-9-methyl-4-oxo-quinolin e (1 H) Carboxylic acid, and pharmaceutically acceptable salts, esters and amides thereof. 23. The method of claim 22, 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- ; 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- Carboxylic acid; 1-Cyclopropyl-7-fluoro-9-methyl-4-oxo-8- (4-amino-1-piperidinyl) -4H-quinolizine-3-carboxylic acid; 1-Cyclopropyl-7-fluoro-9-methyl-4-oxo-8- (4- (aminomethyl) -1-piperidinyl) -4H-quinolizine-3-carboxylic acid; 1-Cyclopropyl-7-fluoro-9-methyl-4-oxo-8- (3-amino-1-piperidinyl) -4H-quinolizine-3-carboxylic acid; 8- (3- (S) -aminopiperidinyl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-3-carboxylic acid; 6-methylbicyclo [3.3.0] octan-1-yl) -7-fluoro-9-methyl-4-oxo-4H-quinolin- 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)) - -4H-9- methyl-1-cyclopropyl-7-fluoro -4-oxo-quinolizine-3-carboxylic acid; 8- ((1R ^* , 2R ^* , 6R ^* ) - 2-amino-8-azabicyclo [4.3.0] nonan- -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- 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, 1 R) -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, 1 R) -8- (3- (1-aminoethyl) pyrrolidinyl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid; 8-Bicyclo [4.3.0] nonyl) -7-fluoro-4H-9-methyl-4-oxo-quinolizine- 3-carboxylic acid; 8-Bicyclo [4.3.0] nonyl) -7-fluoro-4H-9-methyl-4-oxo-quinolizine- 3-carboxylic acid; 3-aza-bicyclo [3.1.0] hexan-3-yl) -7-fluoro-4H-9-methyl-4-oxo-quinolizine- -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-fluoromethylpyridin-l-yl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid; 8- (cis-3-Amino-4-fluoromethylpyridin-l-yl) -l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid; 7-fluoro-4H-9-methyl-4-oxo-quinolizine-l- 3-carboxylic acid; 7-fluoro-4H-9-methyl-4-oxo-quinolizine-l- 3-carboxylic acid; 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid &lt;; 8- (2- (R) -aminomethyl-pyrrolidin-l-yl) -l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid; (8- (3-Amino-4-methyl-piperidin-l-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- Carboxylic acid; -7-fluoro-4H-9-methyl-4-oxo-quinolizine-l- 3-carboxylic acid; 4-oxo-quinolizine-1-carbonitrile The title compound was prepared in analogy to the procedure described for the synthesis of 8- (7- (R) -amino-5-aza- spiro [2.4] heptan- 3-carboxylic acid; 7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-l- Quinolizine-3-carboxylic acid; 7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-l- Quinolizine-3-carboxylic acid; A solution of 8- (trans-3- (S) -amino-4- (R) -methylpyrrolidin- 1 -yl) -l-cyclopropyl-7-fluoro-4H-9- 3-carboxylic acid; 7-fluoro-4H-9-methyl-4-oxo-quinazolin-3- 3-carboxylic acid; 7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-l- Quinolizine-3-carboxylic acid; 7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-1-carboxylic acid ethyl ester was prepared from 8- (cis-3- (R) -amino-4- (R) -cyclopropylpyrrolidin- Quinolizine-3-carboxylic acid; 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomeric mixture of 8- (trans-3-amino-4-ethylpyrrolidin- 1 -yl) Isomer A; 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomeric mixture of 8- (trans-3-amino-4-ethylpyrrolidin- 1 -yl) Isomer B; 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomer &lt;A; 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomer &lt;B; 7-fluoro-4H-9-methyl-4-oxo-quinolin-2- -Carboxylic acid and 7-fluoro-4H-9-methyl-4-oxo-quinolin e (1 H) Acyl-3-carboxylic acid, and pharmaceutically acceptable salts, esters and amides thereof. 23. The method of claim 22, 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- 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; Cyclopropyl-8- (S, S, -2,8-diaza-8-bicyclo [4.3.0] nonyl) -7-fluoro-4H-9-methyl-4-oxo-quinolizine Carboxylic acid; 8-Bicyclo [4.3.0] nonyl) -7-fluoro-4H-9-methyl-4-oxo-quinolizine Carboxylic acid; 3-aza-bicyclo [3.1.0] hexan-3-yl) -7-fluoro-4H-9-methyl-4-oxo-quinolizine- -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-fluoromethylpyridin-l-yl) -1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid; 8- (cis-3-Amino-4-fluoromethylpyridin-l-yl) -l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid; 7-fluoro-4H-9-methyl-4-oxo-quinolizine-l- 3-carboxylic acid; 7-fluoro-4H-9-methyl-4-oxo-quinolizine-l- 3-carboxylic acid; 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid &lt;; 8- (2- (R) -aminomethyl-pyrrolidin-l-yl) -l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid; (8- (3-Amino-4-methyl-piperidin-l-yl) -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid; 7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid &lt;; -7-fluoro-4H-9-methyl-4-oxo-quinolizine-l- 3-carboxylic acid; 4-oxo-quinolizine-1-carbonitrile The title compound was prepared in analogy to the procedure described for the synthesis of 8- (7- (R) -amino-5-aza- spiro [2.4] heptan- 3-carboxylic acid; 7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-l- Quinolizine-3-carboxylic acid; 7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-l- Quinolizine-3-carboxylic acid; A solution of 8- (trans-3- (S) -amino-4- (R) -methylpyrrolidin- 1 -yl) -l-cyclopropyl-7-fluoro-4H-9- 3-carboxylic acid; 7-fluoro-4H-9-methyl-4-oxo-quinazolin-3- 3-carboxylic acid; 7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-l- Quinolizine-3-carboxylic acid; 7-fluoro-4H-9-methyl-4-oxo-pyrrolidine-1-carboxylic acid ethyl ester was prepared from 8- (cis-3- (R) -amino-4- (R) -cyclopropylpyrrolidin- Quinolizine-3-carboxylic acid; 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomeric mixture of 8- (trans-3-amino-4-ethylpyrrolidin- 1 -yl) Isomer A; 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomeric mixture of 8- (trans-3-amino-4-ethylpyrrolidin- 1 -yl) Isomer B; 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomer &lt;A; 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid diastereomer &lt;B; 7-fluoro-4H-9-methyl-4-oxo-quinolin-2- -Carboxylic acid and 7-fluoro-4H-9-methyl-4-oxo-quinolin e (1 H) Acyl-3-carboxylic acid, and pharmaceutically acceptable salts, esters and amides thereof. A pharmaceutical composition comprising a compound according to claim 1 in combination with a pharmaceutically acceptable carrier. 11. A pharmaceutical composition comprising a compound according to claim 10 in combination with a pharmaceutically acceptable carrier. 22. A pharmaceutical composition comprising a compound according to claim 22 in combination with a pharmaceutically acceptable carrier. 26. A pharmaceutical composition comprising a compound according to claim 25 in combination with a pharmaceutically acceptable carrier. A method of treating a bacterial infection in a human or diseased livestock, comprising administering to the human or diseased animal a therapeutically effective amount of a compound according to claim 1. A method of treating a bacterial infection of a human or diseased livestock, comprising administering to a human or diseased animal a therapeutically effective amount of a compound according to claim 10. 26. A method of treating a bacterial infection in a human or diseased livestock, comprising administering to the human or diseased animal a therapeutically effective amount of a compound according to claim 22. 26. A method of treating a bacterial infection of a human or diseased livestock, comprising administering to the human or diseased animal a therapeutically effective amount of a compound according to claim 25. 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; Diethyl ester of 2- (2- (4-chloro-5-fluoro-3-methyl-2-pyridinyl) -2-cyclopropylethylidinyl) -1,3-propanedicarboxylic acid and 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4h-quinolizine-3-carboxylic acid ethyl ester.