ZA200509147B - Use of oxazolidinone-quinoline hybrid antibiotics for the treatment of anthrax and other infections - Google Patents

Description

Use of oxazolidinone-quinoline hybrid antibiotics for the treatment of anthrax and other infections

The present invention describes the use of compounds in which the pharmacophores of quinolone and oxazolidinone are chemically linked together through a linker that is stable under physiological conditions for the treatment of anthrax and other infections.

Anthrax is an acute infectious disease caused by the spore-forming bacterium Bacillus anthracis. Anthrax most commonly occurs in wild and domestic lower vertebrates (cattle, sheep, goats, camels, antelopes, and other herbivores), but it can also occur in humans when they are exposed to infected animals or tissue from infected animals.

Bacillus anthracis, the etiologic agent of anthrax, is a large, gram-positive, non-motile, spore-forming bacterial rod.

The three virulence factors of B. anthracis are edema toxin, lethal toxin and a capsular antigen. Human anthrax has three major clinical forms: cutaneous, inhalation, and gastrointestinal. If left untreated, anthrax in all forms can lead to septicemia and death. Recently, anthrax has become of considerable interest, because it is considered to be a potential agent for use in biological warfare.

The present invention provides the use of compounds of

Formula (I) for the treatment of anthrax and other infections:

RT O o

R2

LTT] ™

HF

~y = R3 (I) wherein

A is a direct bond, a NH, O, S, SO, SO;, SO;NH, POs, -NH-

CO-NH-, -CO-NH-, -CO-, -CO-O-, -NH-CO-0-, -0O-Z-hetero- cycloalkylen, an alkylen group, an alkenylen group, an alkinylen group, a heterocalkylen group, an arylen group, a heteroarylen group, a cycloalkylen group, a heterocycloalkylen group, an alkylarylen group or a heteroarylalkylen group or a combination of two or more of these atoms or groups:

I. is selected from the following groups: 8 \ 8 ‘ 8 * }

R4 RNT RSNA Ron

Pe IES ° ° oO : ° 0 0 8 s 8 : ) 8 N o 0 ut “~T NT

O-N (0) b

X is CRS or N; ¥Y is CR6 or N;

U is F or Cl;

Z is a C,.. alkylene group, a Cz. alkenylene group, a Ci-4 alkynylene group or a Ci. heteroalkylene group, all of

S which may be substituted by one or more hydroxy or amino groups; nis 0, 1, 2 or 3;

Rl is H, F, Cl, Br, I, OH, NH;, an alkyl group or a heteroalkyl group;

R2 is H, F or Cl;

R3 is H, an alkyl group, an alkenyl group, an alkinyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an alkylaryl group or a heteroarylalkyl group; all of which may be substituted with one, two or more halogen atoms like F or Cl;

R4 is a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an alkylaryl group or a heteroarylalkyl group;

RS is H, F, Cl, OH, NH;, an alkyl group or a heteroalkyl group, OY

R3 and RS5 can be linked via an alkylen, an alkenylen or a heteroalkylen group or be a part of a cycloalkylen or heterocyclo-alkylen group; in case R3 is no H and R5 is no H, F, OH, NH, or Cl;

R6 is H, F, Cl or OMe;

R8 is a C;.¢ heteroalkyl or a heteroarylalkyl group; or a pharmacologically acceptable salt, solvate, hydrate or formulation thereof.

It should be appreciated that certain compounds of

Formula (I), or Formula (II) or (III) of the present application, may have tautomeric forms from which only one might be specifically mentioned or depicted in the following description, different geometrical isomers (which are usually denoted as cis/trans isomers or more generally as (E) and (2) isomers) or different optical isomers as a result of one or more chiral carbon atoms (which are usually nomenclatured under the Cahn-Ingold-Prelog or R/S system). Further, some compounds may display polymorphism. All these tautomeric forms, geometrical or optical isomers (as well as racemates and diastereomers) and polymorphous forms are included in the invention.

The term alkyl refers to a saturated or unsaturated (i.e. alkenyl and alkinyl) straight or branched chain alkyl group, containing from one to ten, preferably one to six carbon atoms for example methyl, ethyl, propyl, iso-propyl, butyl, iso- butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl n-hexyl, 2,2-dimethylbutyl, n-octyl; ethenyl (vinyl), propenyl (allyl), iso-propenyl, n-pentyl, butenyl, isoprenyl or hexa-2-enyl;

ethinyl, propinyl or butinyl groups. Any alkyl group as defined herein may be substituted with one, two or more substituents, for example F, Cl, Br, I, NH;, OH, SH or NO,. 5 The terms alkenyl and alkinyl refer to an unsaturated straight or branched chain alkyl group (having one, two or more double and/or triple bonds, an alkenyl preferably having one or two double bonds and an alkinyl preferably having one or two triple bonds), containing from two to ten, preferably two to six carbon atoms for example: ethenyl (vinyl), propenyl (allyl), iso-propenyl, n-pentenyl, butenyl, isoprenyl or hexa- 2-enyl; ethinyl, propinyl or butinyl groups. Any alkenyl or alkinyl group as defined herein may be substituted with one, two or more substituents, for example F, Cl, Br, I, NH, OH, SH or NO,.

The term heteroalkyl refers to an alkyl group as defined herein where one or more carbon atoms are replaced by an oxygen, nitrogen, phosphorous or sulphur atom for example an alkoxy group such as methoxy, ethoxy, propoxy, iso-propoxy, butoxy or tert.-butoxy, an alkoxyalkyl group such as methoxymethyl, ethoxymethyl, 1-methoxyethyl, 1l-ethoxyethyl, 2- methoxyethyl or 2-ethoxyethyl, an alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino or diethylamino, an alkylthio group such as methylthio, ethylthio or isopropylthio or a cyano group. It may also refer to one of the above groups containing a keto group. The term heteroalkyl furthermore refers to a group derived from a carboxylic acid or carboxylic acid amide such as acetyl, propionyl, acetyloxy, propionyloxy, acetylamino or propionylamino, a carboxyalkyl group such as carboxymethyl,

carboxyethyl or carboxypropyl, a carboxyalkyl ester, an alkylthiocarboxyamino group, an alkoxyimino group, an alkylaminothiocarboxyamino group or an alkoxycarbonylamino group. Any heteroalkyl group as defined herein may be substituted with one, two or more substituents, for example F,

Cl, Br, I, NH,, OH, SH or NO,.

The term cycloalkyl refers to a saturated or partially unsaturated (having one, two or more double and/or triple bonds), cyclic group with one, two or more rings, having three to 14 carbon ring-atoms, preferably from five or six to ten carbon ring-atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetralin, cyclopentenyl or cyclohex- 2-enyl groups. Any cycloalkyl group as defined herein may be substituted with one, two or more substituents, for example F,

Cl, Br, I, OH, NH,, SH, Nj, NO, alkyl groups such as methyl or ethyl, heteroalkyl groups such as methoxy, methylamino, dimethylamino, cyanide, or a group of the formula -OR7, wherein R7 is hydrogen, a group of formula POs;R’; or SO;R' or a heteroalkyl group carrying at least one OH, NH, SO,R'®, POsRY, or COOH group, wherein R? is H, alkyl, cycloalkyl, aryl, aralkyl, and wherein R*® is H, alkyl, cycloalkyl, aryl, aralkyl.

The term heterocycloalkyl refers to a cycloalkyl group as defined herein where one, two or more carbon ring-atoms are replaced by one, two or more oxygen, nitrogen, phosphorous or sulphur atoms or S(0);., groups for example piperidino, morpholino or piperazino groups, preferably such groups contain 1 or 2 nitrogen atoms.

The term aryl refers to an aromatic cyclic group with one, two or more rings, having five to 14 carbon ring-atoms preferably from five or six to ten carbon ring-atoms, for example phenyl or naphthyl groups. Any aryl group as defined herein may be substituted with one, two or more substituents, for example F, Cl, Br, I, OH, NH, SH, N3, NO, alkyl groups such as methyl or ethyl, heteroalkyl groups such as methoxy, methylamino, dimethylamino or cyanide. ’

The term heteroaryl refers to an aryl group as defined herein where one, two or more ring-carbon atoms are replaced by an oxygen, nitrogen, boron, phosphorous or sulphur atom, for example pyridyl, imidazolyl, ©pyrazolyl, quinolinyl, isoquinolinyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl and pyridazinyl groups.

The terms arylalkyl, alkylaryl and heteroarylalkyl, heteroalkylaryl refer to groups that comprise both aryl or, respectively, heteroaryl as well as alkyl and/or heteroalkyl and/or cycloalkyl and/or heterocycloalkyl groups.

Preferred embodiments of the present invention are compounds of Formula (I), wherein

A is a bond, a NH, 0, S, SO, SO,, SO,NH, POs, -NH-CO-NH-, -CO-NH-, -CO-, -CO0-0-, =-NH-CO-0-, an alkylen group, an alkenylen group, an alkinylen group, a heteroalkylen group, an arylen group, a heteroarylen group, a cycloalkylen group, a heterocycloalkylen group, an alkylarylen group or a heteroarylalkylen group or a combination of two or more of these atoms or groups;

R4

NA

O( :

L is Oo ;

X is CR5 or N;

Y is CR6 or N;

U is F or Cl; n is 0, 1, 2 or 3;

Rl is H, F, C1, Br, I, OH, NH, an alkyl group or a heteroalkyl group;

R2 is H, F or Cl;

R3 is H, an alkyl group, an alkenyl group, an alkinyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an alkylaryl group or a heteroarylalkyl group;

R4 is a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an alkylaryl group or a heteroarylalkyl group;

RS is H, F, Cl, OH, NH,, an alkyl group or a heteroalkyl group, Ox

R3 and R5 can be linked via an alkylen, an alkenylen or a heteroalkylen group or be a part of a cycloalkylen or heterocyclo-alkylen group; in case R3 is no H and R5 is no H, F, OH, NH; or Cl;

R6 is H, F, Cl or OMe; or a pharmacologically acceptable salt, solvate, hydrate or formulation thereof for the treatment of anthrax.

Preferred and/or advantageous embodiments of the invention are subject-matter of the subclaims.

Preferred are compounds of Formula (I), wherein Rl is H or NH, (especially H).

Further preferred are compounds of Formula (I), wherein

R2 is H or F (especially F).

Moreover preferred are compounds of Formula (I), wherein

R3 is an ethyl, a 2-propyl, a C3-Cé cycloalkyl, a phenyl or a pyridyl group. All these groups may be substituted by one, two or more fluorine atoms or amino groups.

Moreover preferred are compounds of Formula (I), wherein

R3 is a cyclopropyl group.

Further preferred are compounds of Formula (I), wherein

R3 and R5 together form a bridge of the formula -O-CH,-N{(Me) -

or ~O-CHp;-CH{Me)-. Herein, the preferred stereochemistry at the chiral center is the one giving the (S) configuration in the final compound.

Further preferred are compounds of Formula (I), wherein

R4 is a group of the formula -NHCOCH=CHAryl, —-OHeteroaryl (especially -oxa-3-oxazol), -NHSO;Me, -NHCOOMe, NHCS;Me,

NHCSNH;, -NHCSOMe or -NHCOMe.

Especially preferred are compounds of Formula (1), wherein R4 is an acetylamino group.

Further preferred are compounds of Formula (I), wherein the absolute configuration at C-5 of the oxazolidinone ring is (S) according to the Cahn-Ingold-Prelog nomenclature system.

Moreover preferred are compounds of Formula (I), wherein

R5 is H, F, Cl or a methoxy group which may be substituted by one, two or three fluorine atoms or a CF; group.

Further preferred are compounds of Formula (I), wherein X is N or CH.

Further preferred are compounds of Formula (I), wherein Y is N or CF (especially CF).

Further preferred are compounds of Formula (I), wherein n is O.

Further preferred are compounds of Formula (I), wherein A is a bond.

Further preferred are compounds of Formular (I), wherein

A is a group of the formula -Bo-1 TD = Eo-1 Fw - Gout — Ko-1— wherein the group B is NH, O, S, SO, SO, SO;NH, an alkylene, which may be substituted by one, two or more fluorine atoms or a heteroalkylen group, which may be substituted by one, two or more fluorine atoms and/or at the optionally present nitrogen atoms by an alkyl or an acyl group; the groups D independently of each other are optionally anellated heterocycloalkylen groups with 1, 2, 3 or 4 nitrogen atoms, which heterocycloalkylen groups may each be substituted by one, two or more fluorine atoms and/or which each may be substituted at one, two, three or four nitrogen atoms by an alkyl or an acyl group; the groups E independently of each other are NH, O, §,

SO, 802, SO;NH, an alkylene, which may be substituted by one, two or more fluorine atoms or a heteroalkylen group, which may be substituted by one, two or more fluorine atoms and/or at the optionally present nitrogen atoms by an alkyl or an acyl group; the groups G independently of each other are optionally anellated heterocycloalkylen groups with 1, 2, 3 or 4 nitrogen atoms, which heterocycloalkylen groups may each be substituted by one, two or more fluorine atoms and/or which each may be substituted at one, two, three or four nitrogen atoms by an alkyl or an acyl group;

the group K is NH, O, S, SO, S02, SO,NH, an alkylene, which may be substituted by one, two or more fluorine atoms or a heteroalkylen group, which may be substituted by one, two or more fluorine atoms and/or at the optionally present nitrogen atoms by an alkyl or an acyl group; and m = 1,2,3 or 4.

Moreover preferred are compounds of Formula (I), wherein

A is a cycloalkylen or a alkylcycloalkylen group that contains 2, 3 or 4 heteroatoms (preferred O, N and S) and may be substituted by one, two or more fluorine atoms and the nitrogen atoms may be substituted by an alkyl or an acyl group.

Further preferred are compounds of Formula (I), wherein A is selected from the following groups which may be further substituted by one, two or more fluorine atoms or by an alkyl group which may be substituted by one, two or more fluorine atoms, and wherein the amino groups may be substituted by an alkyl or an acyl group:

Ie A iN oO a _ N ~~ \ N ; N N ‘ _ ha _ NL : / +n » /\ _ N N ; N N * \_/ Ny ) [J [} . 0s TH ee W "NS

' J [] NN [] Q 0

HE Nt =O ; :

HE T TO\ NT AN NT lo) 0 ~~ Oo . ; : : \ )g x iy Dat NY ~S o ’ A\} .° . ‘ ~ BD ~S.. +0 + N ’ h s ' . . ' . [] 0 +n >—ot +n s+ +n —s4 0 : +n O—3 =o al 0 i ' ’

TR nN >—/ Font 0 L} : : o. +L \

NY ok ; 0+ x

FN — +N 0"

. H | , A

LN *" hill Fun - iu fN AS [v \__/ > ¥ Se : i : H “N Rp i. i in ow + N ~N N — HN J

Moreover preferred are compounds of Formula (I), wherein

A is a group of the formula ~V-W-, wherein V is a direct bond or a group of the formula NH, O, S, S80, SO, SO,NH, PO,, -NH-

CO-NH-, -CO-NH-, -CO-, -CHy~, -CO-0-, = (CH3) 1-3-0~, -CH=CH-C (0)- + Or -NH-CO-0- and W is a heterocycloalkyl group with 4 to 7 ring atoms or a alkylheterocycloalkyl group with 4 to 7 ring atoms and 1 to 4 carbon atoms in the alkyl chain; all these groups may be substituted by 1, 2, 3 or 4 fluorine atoms, methyl or methoxy groups.

Further preferred are compounds of Formula (I), wherein Aa is a group of the formula (CH,),\ “+v—(cH,),— N+ (CH,), . wherein V is a group of the formula NH, O, Ss, SO, SO, SO,NH,

POs, -NH-CO-NH-, -CO-NH-, -CO-, =-CH,-, -CO-0-, = (CHz) 1-3-0-, ~CH=CH-C(0)~, or -NH-CO-0-; a is 0, 1, 2, 3 or 4; b is 0, 1, 2, 3 or 4; ¢c is 0, 1, 2, 3 or 4 and 1, 2, 3 or 4 hydrogen atoms may be substituted by F, a methyl- or a methoxy group.

Moreover preferred are compounds as described here, wherein Vv is NH, 0, S, SO or S0,.

Especially preferred are compounds as described here, wherein V is O or NH; a is O or 1; b is 1 or 2 and c is 1 or 2.

Moreover preferred are compounds as described here, wherein A is a group of the formula OCH;Het, wherein Het is an optionally substituted heterocycloalkylen group with 4, 5, 6 or 7 ring atoms.

Another preferred embodiment of the present invention are compounds of Formula (II):

R7 R2 R1 0_JAcH),

WZ W—” \ _o — Ho ny’ " = eX ps

F AN

R3 OH (II) wherein

L is selected from following groups: 8 \ 8 . 8 '

R ~"w ~~ R NN x R'< N N ‘ \ 0 0 0 o oO o 8 p )

R [} 8 . 8 1 \

X is CR5 or N;

Y is CR6 or N;

Z is a Cj;-4 alkylene group, a Cig alkenylene group, a Ca. alkynylene group or a Ci, heteroalkylene group, all of which may be substituted by one or more hydroxy or amino groups; b is 1, 2 or 3; c is 1, 2 or 3;

Rl is H, F, Cl, Br, I, OH, NH, an alkyl group or a heteroalkyl group;

R2 is H, F or Cl;

R3 is H, an alkyl group, an alkenyl group, an alkinyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an alkylaryl group or a heteroarylalkyl group; all of which may be substituted with one, two or more halogen atoms like F or Cl.

R5 is H, F, Cl, OH, NH, an alkyl group or a heteroalkyl group, or

R3 and R5 can be linked wia an alkylen, an alkenylen or a heteroalkylen group or be a part of a cycloalkylen or heterocyclo-alkylen group; in case R3 is no H and RS is no H, F, OH, NH; or Cl;

R6 is H, F, Cl or OMe; 3

R7 is hydrogen, a group of formula POsR’, or SOsRY? or a heteroalkyl group carrying at least one OH, NH,, SO;R?,

POsR’, or COOH group, wherein R® is H, alkyl, cycloalkyl, aryl, aralkyl, and wherein RR}? is H, alkyl, cycloalkyl, aryl, aralkyl,

R8 is a Ci-¢ heteroalkyl or a heteroarylalkyl group; - or a pharmacologically acceptable salt, solvate, hydrate or formulation thereof.

Further preferred are compounds of Formula (II), wherein

R1 is H.

Further preferred are compounds of Formula (II), wherein

R2 is F or H.

Moreover preferred are compounds of Formula (II), wherein

R3 is an ethyl, a 2-propyl, a C3-Cé cycloalkyl, a phenyl or a pyridyl group. All these groups may be substituted by one, two or more fluorine atoms or amino groups.

Moreover preferred are compounds of Formula (II), wherein

R3 is a cyclopropyl group.

Further preferred are compounds of Formula (II), wherein

R3 and RS together form a bridge of the formula —-0-CHz-N (Me) - or -O-CH;-CH(Me)-. Herein, the preferred stereochemistry at the chiral center is the one giving the S configuration in the final compound.

Moreover preferred are compounds of Formula (II), wherein

R7 is hydrogen or a group of formula POsH, ,SOsRY®, POsRY,,

CH20PO3H, or COCH.CH,COOH, wherein R® is H, alkyl, cycloalkyl, aryl, aralkyl, and wherein RY is H, alkyl, cycloalkyl, aryl, aralkyl or together with the oxygen to which it is bound forms an ester of a naturally occurring amino acid or a derivative thereof (e.g dimethyl aminoglycine).

Further preferred are compounds of Formula (II), wherein

R® is a group of the formula ~CH,NHCOCH=CHAryl, -

CH,OHeteroaryl (especially -oxa-3~oxazol), —CH,NHSO,Me, —CH,NHCOOMe, -CH,NHCS,Me, -CH,NHCSNH,, -CH,NHCSOMe or -CH,NHCOMe.

Especially preferred are compounds of Formula (II), wherein L has the following structure: o ) 4 a al

H o—4 0

Moreover preferred are compounds of Formula (II), wherein

R53 is H, F, Cl or a methoxy group which may be substituted by one, two or three fluorine atoms.

Further preferred are compounds of Formula (IT), wherein

X is N or CH.

Moreover preferred are compounds of Formula (II), wherein

Y is CH.

Further preferred are compounds of Formula (II), wherein

Z is CHy; or CH,CH,.

Especially preferred are compounds of Formula (III)

R7 F 0 ) o o H N 5

XY oH pr N \ 9)

LN 0 cH) xx

HN c 0

V/

F N

3R OH (ITI) wherein Z is CH; or CH,CH,; X is CH, N or C-OMe and R3 is cyciopropyl or X is CRS and R5 and R3 together form a bridge of the formula -0-CH3-CH (Me) —-, wherein, the preferred stereochemistry at the chiral center is the one giving the 8 configuration in the final compound and b, c¢ and R7 are the same as defined above.

The present invention also relates to pharmacologically acceptable salts, or solvates and hydrates, respectively, and to compositions and formulations of compounds of Formula (I), (II), or (III). The present invention describes procedures to produce pharmaceutically useful agents, which contain these compounds, as well as the use of these compounds for the production of pharmaceutically useful agents.

The pharmaceutical compositions according to the present invention contain at least one compound of Formula (I), (II) or (III) as the active agent and optionally carriers and/or diluents and/or adjuvants. Optionally the pharmaceutical compositions according to the present invention may also contain additional known antibiotics.

Examples of pharmacologically acceptable salts of sufficiently basic compounds of Formula (I) and of compounds 100 of Formula (II) or (III) are salts of physiologically ac- ceptable mineral acids like hydrochloric, hydrobromic, sul- furic and phosphoric acid; or salts of organic acids like methanesulfonic, p-toluenesulfonic, lactic, acetic, trifluoro- acetic, citric, succinic, fumaric, maleic and salicylic acid.

Further, a sufficiently acidic compound of Formula (I) may form alkali or earth alkaline metal salts, for example sodium, potassium, lithium, calcium or magnesium salts; ammonium salts; or organic base salts, for example methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, meglumin, piperidine, morpholine, tris-(2-hydroxyethyl)amine, lysine or arginine salts; all of which are also further examples of salts of

Formula (II) or (III). Compounds of Formula (I), (II) or (IIT) may be solvated, especially hydrated. The hydratisation can occur during the process of production or as a consequence of the hygroscopic nature of the initially water free compounds of Formula (I), (II) or (IIl). The compounds of Formula (I), (II) or (III) contain asymmetric C-atoms and may be present either as achiral compounds, mixtures of diastereomers, mixtures of enantiomers or as optically pure compounds.

The present invention also relates to pro-drugs which are composed of a compound of Formula (I), (II) or (III) and at least one pharmacologically acceptable protective group which will be cleaved off under physiological conditions, such as an alkoxy-, aralkyloxy-, acyl-, acyloxymethyl group (e.g. pivaloyloxymethyl), an 2-alkyl-, 2-aryl- or 2-aralkyl- oxycarbonyl-2-alkylidene ethyl group or an acyloxy group as defined herein, e.g. ethoxy, benzyloxy, acetyl or acetyloxy or, especially for a compound of Formula (I), for hydroxy group (ROH), a sulfate, a phosphate (ROPO; or ROCH,OPO;) or an ester of an amino acid. Especially preferred are pro-drugs of the hydroxy group of a compound of Formula (II) or (III) wherein R7 is H.

As mentioned above, therapeutically useful agents that contain compounds of Formula (I), (II) or (III), their solvates, salts or formulations are also comprised in the scope of the present invention. In general, compounds of

Formula (I), (II) or (III) will be administered by using the known and acceptable modes known in the art, either alone or in combination with any other therapeutic agent. Such therapeutically useful agents can be administered by one of the following routes: oral, e.g. as tablets, dragees, coated tablets, pills, semisolids, soft or hard capsules, for example soft and hard gelatine capsules, aqueous or oily solutions, emulsions, suspensions or syrups, parenteral including intravenous, intramuscular and subcutaneous injection, e.g. as an injectable solution or suspension, rectal as suppositories, by inhalation or insufflation, e.g. as a powder formulation, as microcrystals or as a spray (e.g. liquid aerosol), trans- dermal, for example via an transdermal delivery system (TDS)

such as a plaster containg the active ingredient or intranasal. For the production of such tablets, pills, semisolids, coated tablets, dragees and hard, e.g. gelatine, capsules the therapeutically useful product may be mixed with pharmaceutically inert, inorganic or organic excipients as are e.g. lactose, sucrose, glucose, gelatin, malt, silica gel, starch or derivatives thereof, talc, stearinic acid or their salts, dried skim milk, and the like. For the production of soft capsules one may use excipients as are e.g. vegetable, petroleum, animal or synthetic oils, wax, fat, polyols. For the production of liquid solutions, emulsions or suspensions

Or syrups one may use as excipients e.g. water, alcohols, aqueous saline, aqueous dextrose, polyols, glycerin, lipids, phospholipids, cyclodextrins, vegetable, petroleum, animal or synthetic oils. Especially preferred are lipids and more preferred are phospholipids (preferred of natural origin; especially preferred with a particle size between 300 to 350 nm) preferred in phosphate buffered saline (pH = 7 to 8, preferred 7.4). For suppositories one may use excipients as are e.g. vegetable, petroleum, animal or synthetic oils, wax, fat and polyols. For aerosol formulations one may use compressed gases suitable for this purpose, as are e.g. oxygen, nitrogen and carbon dioxide. The pharmaceutically useful agents may also contain additives for conservation, stabilisation, e.g. UV stabilizers, emulsifiers, sweetener, aromatisers, salts to change the osmotic pressure, buffers, coating additives and antioxidants.

A daily dosage per patient of about 1 mg to about 4000 mg especially about 50 mg to 3 g is usual with those of ordinary skill in the art appreciating that the dosage will depend also upon the age, conditions of the mammals, and the kind of diseases being treated or prevented. The daily dosage can be administrated in a single dose or can be divided over several doses. An average single dose of about 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg and 2000 mg can be contemplated.

The invention also relates to a method of treating a disorder selected from a bacterial infection, a protozoal infection, and disorders related to bacterial infections or protozoal infections, in a mammal, fish, or bird which comprises administering to the mammal, fish or bird a combination comprising a compound of Formula (I), (II) or (ITI) and another antibiotic, wherein the amounts of the compound and of the other antibiotic are together therapeutically effective in treating the disorder. In further embodiments, the compound of the invention may administered prior to, with or after the other antibiotic. Examples of suitable other antibiotics include, but are not limited to, beta-lactams, vancomycin, aminoglycosides, quinolones, chloramphenicol, tetracyclines and macrolides.

The term “treating”, as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term “treatment”, as used herein, refers to the act of treating, as “treating” is defined immediately above.

As used herein, unless otherwise indicated, the terms or phrases “infection(s)”, “bacterial infection(s)"“, “protozoal infection(s)"“, and “disorders related to bacterial infections

Or protozoal infections” include the following: pneumonia, otitis media, sinusitus, bronchitis, tonsillitis, and mastoiditis related to infection by Streptococcus pneumoniae,

Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, Enterococcus faecalis, E. faecium, E. casselflavus, 8S. epidermidis, S. haemolyticus, or Peptosfreptococcus spp.: pharyngitis, rheumatic fever, and glomerulonephritis related to infection by Streptococcus pyogenes, Groups CC and G streptococci, Corynebacferium diphtheriae, or Acfinobacillus haemolyticum; respiratory tract infections related to infection by Mycoplasma pneumoniae, Legionella pneumophila,

Streptococcus pneumoniae, Haemophilus influenzae, or Chlamydia pneumoniae; blood and tissue infections, including endocarditis and osteomyelitis, caused by S. aureus, 8. haemolyficus, E. faecalis, BE. faecium, E. durans, including strains resistant to known antibacterials such as, but not limited to, beta-lactams, vancomycin, aminoglycosides, quinolones, chloramphenicol, tetracyclines and macrolides; uncomplicated skin and soft tissue infections and abscesses, and puerperal fever related to infection by Staphylococcus aureus, coagulase-negative staphylococci (i.e., S. epidermidis, S. hemolyticus, etc.), Streptococcus pyogenes ,

Streptococcus agalactiae, Streptococcal groups C-F (minute colony streptococci), viridans streptococci, Corynebacterium minutissimum, Closfridium spp., or Bartonella henselae; uncomplicated acute urinary tract infections related to infection by Staphylococcus aureus, coagulase-negative staphylococcal species, or Enterococcus Spp.; urethritis and cervicitis; sexually transmitted diseases related to infection by Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidurn, Ureaplasma urealyticum, or Neiserria gonorrheae;

toxin diseases related to infection by S. aureus (food

Poisoning and toxic shock syndrome), or Groups A, B, and C streptococci; ulcers related to infection by Helicobacter pylori; systemic febrile syndromes related to infection by

Borrelia recurrentis; Lyme disease related to infection by

Borrelia burgdorferi; conjunctivitis, keratitis, and dacrocystitis related to infection by Chlamydia trachomatis,

Neisseria gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes,

H. influenzae, or Listeria spp.; disseminated Mycobacterium avium complex (MAC) disease related to infection by

Mycobacterium avium, or Mycobacterium intracellulare; infections caused by Mycobacferium tuberculosis, M. leprae, M. baratuberculosis, M. kansasii, or M. chelonei; gastroenteritis related to infection by Campylobacter jejuni; intestinal protozoa related to infection by Cryptosporidium spp. odontogenic infection related to infection by viridans streptococci; persistent cough related to infection by

Bordetella pertussis; gas gangrene related to infection by

Closfridium perfringens or Bacteroides spp. and atherosclerosis or cardiovascular disease related to infection by Helicobacter pylori or Chlamydia pneumoniae.

Preferred is the use of a compound according to Formula (I), (II) or (III) for the treatment of infections that are mediated by Gram-negative bacteria such as E. coli, Klebsiella pneumoniae and other enterobacteriaceae, Haemophilus influenzae, Mcraxella catarrhalis, Acinetobacter sSpp.,

Stenothrophomonas maltophilia, Neisseria gonorrhoeae,

Neisseria menigitidis, Helicobacter pylori, Campylobacter spp., Mycoplasma spp. and Legionella pneumophilia or Gram- positives such as Bacillus cereus, Bacillus anthracis, Strep.

pneumoniae, Corynebacterium SPP., Propionibacterium acnes and

Listeria monocytogenes.

In the following the invention is described in more 5S detail with ‘reference to examples. These examples are intended for illustration only and are not to be construed as any limitation. The Examples were synthesized according to the procedures described in WO03032962,W003031443, US 60/530,822% and C, Hubschwerlen et al. Bioorg. Med. Chem. 2003, 11, 2313- 2319.

The compounds of Formula (11) and (III) can be synthesized according to the following reaction scheme:

OH F

TO" 1.0 —e

F o 9 = 5 a

A l ge 1 ge 0, o o

VAN 0 0 ocopr ie; 1 _—— ——— in ~ - —

HO— Mso— 4 Rr - . F R F of ws oJ 0 OH © CH Ca" en, o J AX Nz [0]

Jy 0’ N Mo CH, ) o WN J —— +)

N= = = — 0 * WO 2005/058888 : Amended sheet: 8 December 2006 :

R* eo o \ om ‘ NA OH ° jo (CH,),, Ry (CHL Ng. I ° N —_— on len! A v 0 o & JA 1) o={ Nan

N=

Reaction conditions:

Step 1: CHxClp, KOH (50%), 3h, rt; 97%. step 2: Hp, Pt/C, 20h, rt; followed by z-Cl1, acetone/water, NaHCO;, 12h, rt, 98%. step 3: n-BuLi, -60°C, 24h, 80%. step 4: MsCl, triethylamine,

CHClz; 100%. step 5: NaN; in DMF, 90°C, cat. Buy,NI, 5h, 90%. step 6: Hy, Pd(OH),, THF, MeOH, 24h, followed by AcOH, Ac,0, rt, 2h, 70%. step 7: DMF, NaH, 70°C, 12h, 75%. step 8: Hy, Pd (OH),,

MeOH, THF, 24h, RT, 100%. step 09: N-Methylpyrrolidinone, 1-Cyclopropyl-7-chloro-6-fluoro-1, 4~dihydro-4-oxo-1, 8-napht- hydrin-3-carboxylic acid (commercially available), TMS-C1,

Hinig Base or K,CO3, 80°C, 5h, 80%.

Examples

EXAMPLE 1: 7-(4-{4-[5-(acetylamino-methyl)~2-oxo-oxazolidin-3- yll-2-fluoro-phenyl}-piperazin-1-yl)-l-cyclopropyl-6~fluoro—4- oxo-1,4-dihydro-quinoline-3-carboxylic acid:

fo F F 0 0X at N 74 A\ Q

H Lo MN 7 —

NO nt on

EXAMPLE 2: 9-(4-{4-([5-(acetylamino-methyl)-2-oxo-oxazolidin-3— yl]-2-fluoro-phenyl}-piperazin-1-yl)-8-fluoro-3-methyl-6-oxo- 2,3-dihydro-6éH-1l-oxa-3a-aza-phenalene-5-carboxylic acid: 0 F F

Pe 0 oA 0

H LN N N

ON — /

N oO N OH

EXAMPLE 3: 7-((3R,8)=3-{4-[ (58) ~5~ (acetylamino-methyl) -2-oxo- oxazolidin-3-yl]-2-fluoro-phenylcarbamoyl}-piperazin-1-yl)-1- cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid. [o ~ F

F

- Wand . oO NH 0 N V4

T i or

EXAMPLE 4: 7-[(3R)-3-{4-[(5S)~5-(Acetylamino-methyl)—-2-oxo- oxazolidin-3-yl]-2-fluoro-phenylamino}-pyrrolidin-1-yl]- lcyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-l-carboxylic acid.

F o

F N \=

NNN @ ow N J OH © % ~ ~y 4 0 H

EXAMPLE 5: 7-(4-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo- oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-6-fluoro-1- (5-fluoro-pyridin-2-yl)-4-oxo-1,4-dihydro-quinoline-3- . carboxylic acid:

F

O F o oX I~ \ o

LN NN v — / x" N OH

N

N

F

EXAMPLE 6: 7-(4-{(58)-5-(Acetylamino-methyl)-2-oxo-oxazolidin- 3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-1-(2, 4-difluoro- 10. phenyl) -6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid:

F

O F oO 04 ® NN [o) : pi \—/ / 5" N OH 9

F

EXAMPLE 7: 7-(4-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo- oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-1l-cyclo-

propyl-8-methoxy-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid: jo]

Vi F 0 oO /\

Pn N j > 0 n/ N i _0

A

5 EXAMPLE 8: 9-(4-{4-[(5S)-5-(Acetylamino~methyl)-2~-oxo- oxazolidin-3-yl]-2~-fluoro-phenyl}-piperazin-1-yl)-8-fluoro-3- methyl-6-oxo0-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5- carboxylic acid:

A 0 o /\

Ho JN N N

ON \—/ N J “ou

Y F 0} ’ \—N \

EXAMPLE 9: 7-{(3RS)-3-[{{4-[(5S)-5-(Acetylamino-methyl)-2-oxo- oxazolidin-3-yl]-2-fluoro-phenyl}-ethyl-amino)methyl]- piperazin-1l-yl}-l-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro- quinoline-3-carboxylic acid. '. HN

LO

N \ oO N : —/ F wr N ° — V7 =o 0 HO

EXAMPLE 10: 7-(4-{[(58)-5- (Acetylamino-methyl)~2-oxo- oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-1- cyclopropyl-6-fluoro-4-oxo~1, 4-dihydro-[1, 8} naphthyridine-3- carboxylic acid: 0 F F o

COOH

H —— . °X" —— ~/ N N y/ OH

EXAMPLE 11: 7-{4-[2-(4-{4~[5- (Acetylamino-methyl)-2-ox0o- oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-ethyl]- piperazin-l-yl}-l-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro- quinoline-3-carboxylic acid:

O F

F

ONG \"

H / \ 0] o) He ry aod

YN —/ 0 4

MN OH

EXAMPLE 12: 7-[4-(4-{4-[(55)-5-(Acetylamino-methyl)-2-oxo- oxazolidin~3-yl]-2-fluoro-phenyl}-piperazin~-1-yl)-piperidin-1- yl]-1l-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline~3- carboxylic acid:

o (0) F

YY oA /\ p ” L_» NON N 0) 0 ae ’ \_/ /

F N OH

EXAMPLE 13: 7-[(3R, 4R) and (3S, 4S)-3-{4-[(5S)-5- (Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}~- 4-aminomethyl-pyrrolidin-1-yl]-l-cyclopropyl—-6-fluoro-4-oxo- 1,4-dihydro-quinolin-3-carboxylic acid.

H,N fo) Fo y | N o N 0

H Lr F

N

~~ NZ (o} © V OH

EXAMPLE 14: 7-{4-[2-(4-{4-[ (59) ~-5- (Acetylamino-methyl) -2-oxo~- oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-2-oxo- ethyl]-piperazin-1-yl}-1l-cyclopropyl-6~fluoro-4-oxo-1, 4- dihydro-quinolone-3-carboxylic acid: ) 0) oA /~—\ 0 F

I N N /\ lo)

I” —/ N N o

NH F \_/ y, hg N—7 on lo] A

EXAMPLE 15: 7-(3-{4-[5(S)~5-(Acetylamino-methyl)-2-oxo- oxazolidin-3-yl]-2-fluoro-phenylamino}-azetidin-1-yl)-1- cyclopropyl-6-fluoro-4-oxo-1,4-dihydro~(1, 8}naphthyridine-3- carboxylic acid: o) 04 oO 0

N Lr F

Da (LT z ° ey, NTN

N

F H A

EXAMPLE 16: 7-[(3R)-3-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo- oxazolidin-3-yl]-2-fluoro-phenylamino}-pyrrolidin-1-yl]-1- cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1, 8] -naphthyridine-3- carboxylic acid: o)

F 0]

N lo) | | OH

PN NI NZ

NH F N

= { 7 A

N o—{ ar 0

EXAMPLE 17: 7-[(3R, 4S ) and (3S, 4R)-3-(-4{4-[(58)-5- (Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro- phenyl}piperazine~l-carbonyl)-4-aminomethyl-pyrrolidin-1-yl]- l-cyclopropyl-6-fluoro—~4-oxo-1,4~dihydro-quinoline carboxylic acid oN

COO)

NS NG

J SN

~{ NA°

No \vA o H OH

EXAMPLE 18: 7-[(3R, 4S) and (3S, 4R)-3-(4-{4-[(5S)-5- (Acetylamino-methyl) -2-oxo-oxazolidin-3-yl}-2-fluoro-phenyl}- piperazine-l-carbonyl)-4-aminomethyl-pyrrolidin-1-yl)1- cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-[1, 8] naphthyridine-3- carboxylic acid o PL

CO

NS N a pu Na 0 o TN o

N. ~~ oA 7 0 OH

EXAMPLE 19: 7-(4-{5-[(5S)-5-(Acetylamino-methyl)~2-oxo- oxazolidin-3-yl]-pyridin-2-yl}-1l-piperazin-1-~yl)-1- cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-(1, 8lnaphthyridine-3- carboxylic acid

0 F ~~ 0

H OAS w—l No

Oa Na =N ~~ N= Pa

Y MN OH

EXAMPLE 20: 7-(4-{5-((58)-5-(Acetylamino-methyl)-2-oxo- oxazolidin-3-yl]-pyridin-2-yl}-piperazin-1-yl)-1l-cyclopropyl- 6-fluoro-4-~oxo-1, 4~-dihydro-quinoline-3-carboxylic acid. fo) F 0 oA 7 7 Ny 0

H eo NJ

NG =N °Y ~~ J / OH

EXAMPLE 21: 7=[(3R)-3-(4-{4([(5S)-5-(Acetylamino-methyl) -2-oxo- oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1~-yl)-pyrrolidin- l1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro- (1,8]naphthyridine-3-carboxylic acid:

Oo F oA /\ /\ LP

LAN N —~) i \_/ N= p (o] ~~" F N OH o

EXAMPLE 22: 1-Cyclopropyl-6-fluoro-7- (4-{2-fluoro-4-[ (5R)-5- (methansulfonylamino-methyl)-2-oxo-oxazolidin-3-yl]-phenyl}- piperazin-1-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3- carboxylic acid.

Jo) F ° oA Nd 0

Wg MN F N OH a 4 oO

EXAMPLE 23: 7-(4-{4-[(5S)~5-(Acetylamino-methyl)-2-oxo- oxazolidin-3-yl]-2-fluoro-phenylamino}-piperidin-1-yl)-1- cyclopropyl-6-fluoro-4-oxo-1, 4~dihydro-[1, 8] naphthyridine-3- carboxylic acid:

Oo 0

F

NSN

0 F ¢ A

H oO og HL ' ri

EXAMPLE 24: 1-Cyclopropyl-6-fluoro-7-(4-{2-fluoro-4-[(5S)-5- (methoxythiocarbonylamino-methyl)-2-oxo-oxazolidin-3-y1]- phenyl}-piperazin~l-yl)-4-oxo-1,4-dihydro-[1, 8] -naphthyridine- 3—-carboxylic acid:

oO 0 oA f= F 0

N LL" \ | TN

S ot

YO ¢ MN N= [on 0 F Ny ~ 4

EXAMPLE 25: 1-Cyclopropyl-6-fluoro-7-(4-{2-fluoro-4-((5S5)-5- (methylsulfanylthiocarbonylamino-methyl)-2-oxo-oxazolidin=-3- yl]-phenyl}-piperazin-1-yl)-4-oxo-1,4dihydro- [1,8]naphthyridine-3-carboxylic acid:

Oo

F 0 0X —\ N 0

H LN N N /

Sy \ / N= J OH

N .

Ss F A

EXAMPLE 26: 1-Cyclopropyl-6-fluoro-{4-[2-fluoro-4-{(5S)-2-oxo-

S-thioureidomethyl-oxazolidin~3-yl}-phenyl]-piperazin-1-yl}-4- oxo-1,4-dihydro-[1, 8] naphthyridine-3-carboxylic acid: 0] yi F 0 © o FY

Hoo" Ne NN = [[ “ow sy n_/ N N

NH, F A

EXAMPLE 27: 7-(4-{4-{5(S)-5-(Acetylamino-methyl)-2-oxo- oxazolidin=-3-yl]-2~fluoro-phenoxy}-piperidin-1-yl)-1~ cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1, 8] naphthyridine-3- carboxylic acid:

J

0 0

WF Q (0)

N F

~~ OH ~

Tear 0)

F

EXAMPLE 28: 7-(4-{4-[5(S)-5-(Acetylamino-methyl)-2-oxo- oxazolidin-3-yl]-2-fluoro-phenoxy}-piperidin-1-yl)-1- cyclopropyl-6-fluoro-4-oxo-1,4~-dihydro-quinoline-3-carboxylic acid: oO \ H \, °°

LIN [eo] [a] n i

OH

N N

’ A

F

EXAMPLE 29: 7-(4-{4-[5(S)-5-(Acetylamino-methyl)-2-oxo~- oxazolidin-3~yl]-2-fluoro-phenylsulfanyl}-piperidin-1-yl)-1- cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:

0]

Ja 0.0

Ye” F QO 0

N F

OH

LI

A

F

EXAMPLE 30: 7-(4-{4-[5(S)-5(Acetylamino-methyl)-2-oxo- oxazolidin-3-yl]-2-fluoro-phenylsulfanyl}-piperidin-1-yl)-1- cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1, 8) naphthyridine-3- carboxylic acid: (o) > 0 oO

Nive, F 0] (o} = OH oA

S

A

EXAMPLE 31: 7-(4-{4-[5-(Acetylamino-methyl)-2-oxo-oxazolidin- 3-yl]-2-fluoro-benzoyl}-piperazin~1-yl)-l-cyclopropyl—6- fluoro-4-oxo-1,4~-dihydro-[1, 8] naphthyridine-3-carboxylic acid:

F

0] NN fo) 0 _N / A\ oO

A N= 0) J] E N OH

X

NH o=

EXAMPLE 32: 1-Cyclopropyl-6-~fluoro-7-{4-[2-fluoro-4-(5- 'guanidinomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-piperazin-1- yl}-4-oxo-1, 4-dihydro-{1, 8] naphthyridine-3~-carboxylic acid: 0 F oA - \ avs N / N o ) — NX JT

WN F N

NH <

EXAMPLE 33: 7-(4-{4-(5-(Acetylamino-methyl)-2-oxo-oxazolidin- 3-yl]-2-fluoro-benzenesulfinyl}-piperidin-1-yl)~-1l-cyclopropyl- 6-fluoro-4-oxo-1,4-dihydro-[1, 81 naphthyridine-3-carboxylic acid: 0} 0 0) H [0] oN o~¢ Fr OH ely | 1

QT) ; A “"

F (o]

EXAMPLE 34: 7-(3-{4-[5-(Acetylamino-methyl)-2-oxo-oxazolidin- 3-yl]-2-fluoro-phenoxy}-azetidin-1-yl)-1l-cyclopropyl-6-fluoro- 4-oxo-1,4-dihydro-{1,8]naphthyridine-3-carboxylic acid: 0

Lr J

O N

\ J FN TT

N Ns o

NH

N. ~~ 0 0= ved

OH

A suspension of 100 mg N-{ (5S5)-3-[4~(Azetidin-3-yloxy)-3- fluoro--phenyl]-2-oxo-oxazolidin-5-yl methyl}-acetamide (MW: 323.32, 0.31 mmol), 73 mg 7-chloro-l-cyclopropyl-6-fluoro-1, 4- dihydro-4-oxo-1,8-Naphthyridine-3-carboxylic acid (MW: 282.66, 0.25 mmol) 0.066 ml trimethylchlorosilane (MW:108.64, d=0.859, 0.51 mmol) and 0.108 ml triethylamine (MW:101.19, d=0.726, 0.77 mmol) in 2 ml N-methyl-pyrrolidin-2-one was heated under stirring in a micro wave oven at 150 °C for 7 min. The N-methyl-pyrrolidin-2-one was evaporated, the residue was purified by chromatography. Yield: 55 mg, 30 %. MS: 570.5 (M+H)¥, Method ESI*. Molecular Weight =570

EXAMPLE 35: 7-(3-{4-[5-(Acetylamino-methyl)~-2-oxo-oxazolidin- 3-yl]-2-fluoro-phenoxy}-pyrrolidin-1-yl)-1i-cyclopropyl-6- fluoro-4-oxo-1, 4-dihydro-[1, 8]naphthyridine-3~carboxylic acid: 0 os F + i oe

NH o °X N_Z

Tk

A suspension of 185 mg N-{ (5S8)-3-[-3-fluoro-4{3-(S)- (pyrrolidin-3-yloxy) }-phenyl]-2-oxo-oxazolidin-5-y1 methyl} - acetamide (337.35, 0.55 mmol), 141 mg 7-chloro-l-cyclopropyl- 6-fluoro-1, 4-dihydro-4-oxo-1, 8-Naphthyridine-3-carboxylic acid (MW: 282.66, 0.5 mmol) 0.126 ml trimethylchlorosilane (MW:108.64, d=0.859, 1 mmol) and 0.209 ml triethylamine (MW:101.19, d=0.726, 1.5 mmol) in 2 ml N-methyl-pyrrolidin- 2-one was heated under stirring in a micro wave oven at 150 °c for 7 min. The N-methyl-pyrrolidin-2-one was evaporated, the residue was purified by chromatography. Molecular Weight =584;

Yield: 140 mg, 48 %; MS: 584.5 (M+H)*, Method ESI'.

EXAMPLE 36: 7-(3-{4-[5-(Acetylamino-methyl)-2-oxo-oxazolidin- 3-yl]~-2-fluoro-phenoxy}-pyrrolidin-1-yl)-l-cyclopropyl-6- fluoro-4-oxo-1, 4-dihydro~-quinoline-3-carboxylic acid:

L Pye ° 0” "N Ow ~ ; ©

A o

NH NZ x J

EXAMPLE 37: 7-(4-{4-[5-(Acetylamino-methyl)-2-oxo-oxazolidin- 3-yll-2-fluoro-phenoxymethyl}-piperidin-1-yl)-1-cyclopropyl-6- fluoro-4-oxo-1,4~-dihydro-{1, 8] naphthyridine-3~carboxylic acid: o oA ; .

HOA

N= 5x" F N J on q

EXAMPLE 38: 7-(4-{4~[5-(Acetylamino-methyl)-2-oxo-oxazolidin- 3-yl]—-2-fluoro-phenoxymethyl}-piperidin-1-yl)-1-cyclopropyl-6~ fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid:

7 F oA 0

NM Q

Se 0 { ? \ /

F OH ht 4

EXAMPLE 39: 9-(3-{4-[5-(Acetylamino-methyl)~-2-oxo-oxazolidin- 3-yli-2-fluoro-phenoxy}-pyrrolidin-1-yl)-8-fluoro-3-methyl-6- oxo-2,3-dihydro-6H-l-oxa-3a-aza-phenalene-5-carboxylic acid: 0) jig Opn

Oo N Cn $ F o \

NH MALO

°=

OH .

EXAMPLE 40: 9-(4-{4-[5-(Acetylamino-methyl)-2-oxo-oxazolidin- 3-yl]l-2-fluoro-phenoxy}-piperidin-1-yl)-8-fluoro-3-methyl-6- 0x0-2,3-dihydro-6H-1-oxa-3a-aza-phenalene-5-carboxylic acid: o

LOCC oj F N $d 0

R oO

NH N = oO o=X{

OH

EXAMPLE 41: 9-(3-{4-[5-(Acetylamino-methyl)-2-oxo-oxazolidin- 3-yl}-2-fluoro-phenoxy}-piperidin-1-yl)-8-fluoro-3-methyl-6- ox0-2,3-dihydro-6H-1-oxa-3a-aza-phenalene-5-carboxylic acid:

F oO 0

A ok ( \ J © N who [o) / (0) N OH

F ~~

EXAMPLE 42: 7-(3-{4-[5-(Acetylamino-methyl)-2-oxo-oxazolidin- 3-yl}-2-fluoro-phenoxy}-pyrrolidin-1-yl)-1l-cyclopropyl=-6- fluoro-4-oxo-1,4-dihydro-{1, 8) naphthyridine-3-carboxylic acid:

F oO { N 7 o oA Q N> t N \ 8) hg NEN © NZ 0 : Vo on

EXAMPLE 43: 9-(3-{4-[5- (Acetylamino-methyl)-2-oxo~oxazolidin- 3-yl]l-2-fluoro-phenoxy}-pyrrolidin-1-yl)-8-fluoro-3-methyl-6- 0X0-2,3-dihydro-6H-1-oxa-3a-aza-phenalene-5-carboxylic acid: o F 0

We! Cr) e ed UN < 0 oO 0 Oo

NZ

F ~ OH

EXAMPLE 44: 9-(3-{4-[5-(Acetylamino-methyl)-2-oxo-oxazolidin- 3-yl]-2-fluoro-phenoxy}-azetidin-1-yl)-8-fluoro-3-methyl-6- oxo-2,3-dihydro-6H-1-oxa-3a-aza-phenalene-5-carboxylic acid:

0 pu 0) AN -om oO

Md CF \

N F )

N

LN o> oO

F

EXAMPLE 45: 9-(4-{4-[5-(Acetylamino-methyl)-2-oxo-oxazolidin- 3-yl]-2-fluoro-phenylsulfanyl}-piperidin-1-yl)-8-fluoro-3- methyl-6-ox0-2, 3-dihydro-6H-1-oxa-3a~aza~phenalene=-5- carboxylic acid: 0] Ss

LLL

N

A 0 ©

NH

N o={ N a A)

OH

EXAMPLE 46: 7-(3-{4-[5- (Acetylamino-methyl)-2-oxo-oxazolidin- 3-yl]-2-fluoro-phenoxymethyl}-pyrrolidin-1-yl)-1l-cyclopropyl- 6~-fluoro-4-oxo-1,4~dihydro-[1, 8 naphthyridine-3-carboxylic acid: oO O 0 Fr OH

H 0X N Li N

N oy Q- A

F

A suspension of 179 mg N-{(5S)-3-[3-fluoro- 4-[3- (RS) - (pyrrolidin-3-ylmethoxy)]-phenyl]-2-oxo-oxazolidin-5-y1 methyl}-acetamide (MW: 351.38, 0.55 mmol), 141 mg 7-chloro-1- cyclopropyl-6-fluoro~1, 4~dihydro-4-oxo-1, 8-Naphthyridine-3- carboxylic acid (MW: 282.66, 0.5 mmol), 0.128 ml trimethylchlorosilane (MW:108.64, d=0.859, 1.0 mmol) and 0.200 ml triethylamine (MW:101.19, d=0.726, 1.5 mmol) in 2 ml N- methyl-pyrrolidin-2-one was heated under stirring in a micro wave oven at 150 °C for 7 min. The N-methyl-pyrrolidin-2-one was evaporated, the residue was purified by chromatography.

Yield: 241 mg, 81 %. MS: 598.5 (M+H)*, Method ESI‘. Molecular

Weight =598.

EXAMPLE 47: 9-(3-{4-[5-(Acetylamino-methyl)-2-oxo-oxazolidin- 3-yl]-2-fluoro-phenoxymethyl}-pyrrolidin-1-yl)-8-fluoro-3- methyl-6-ox0-2,3-dihydro-6H-1-oxa-3a-aza-phenalene-5- carboxylic acid: » 0 oO 0 F OH 0. _N 74 FE

Te SS

F

A suspension of 179 mg N-{(5S)-3-[3-fluoro- 4-[3-(RS)- (pyrrolidin-3-ylmethoxy) ]-phenyl]-2~oxo-oxazolidin-5-yl methyl}-acetamide (MW: 351.38, 0.55 mmol), 140 mg 9-10- difluoro-2, 3-dihydro-3-methyl-7-oxo~7H-pyrido(1l,2,3-de]-1, 4- benzoxazine-6-carboxilic acid (MW: 281.21, 0.5 mmol), 0.128 ml trimethylchlorosilane (MW:108.64, d=0.859, 1.0 mmol) and 112 mg 1,4-diazabicyclo[2.2.2]octane (MW:112.18, 1.0 mmol) in 2 ml N-methyl-pyrrolidin-2-one was heated under stirring in 3 micro wave oven at 150 °C for 7 min. The N-methyl-pyrrolidin-

2-one was evaporated, the residue was purified by crystallisation. Yield: 161 mg, 52 $%. MS: 613.5 (M+H)*, Method

ESI. Molecular Weight =613.

EXAMPLE 48: 9-(4-{4-[5-(Acetylamino-methyl)-2-oxo-oxazolidin- 3-yl]-2-fluoro-phenoxymethyl}-piperidin-1-yl)-8-fluoro-3- methyl-6-oxo0-2, 3-dihydro-6H-1-oxa-3a-aza-phenalene-5- carboxylic acid: 0

F

0 A N 9 o

Oo — =e 0 \ / 0 NH F o Ny OH

EXAMPLE 49: 7-[4-(3-{4-[5-(Acetylamino-methyl)-2-oxo- oxazolidin-3-yl]-2-fluoro-phenoxy}-propyl)-piperidin-1-yl}-1- cyclopropyl-6-fluoro-4-oxo~1,4-dihydro-[1, 81 naphthyridine-3- carboxylic acid:

A

F

0] o)

N o

Ay Cr 7 N\ ) v N= /

F

OH lo) X NH 4

EXAMPLE 50: 9-[4-(3-{4-[5-(Acetylamino-methyl)-2-oxo- oxazolidin-3-yl]-2-fluoro~phenoxy}-propyl)-piperidin-1-y1l]-8- fluoro-3-methyl-6-oxo0-2, 3-dihydro-6H-1-oxa-3a-aza-phenalene-5- carboxylic acid:

0

A ] 0 0" Tn o I 0) — NE / \ F o M OH ox" —

EXAMPLE 51: 7-(4-{4-[5-(Acetylamino-methyl)-2-oxo~oxazolidin- 3-yl]-2-fluoro-phenoxy}-azepan-1-yl)-1l-cyclopropyl-6-fluoro-4-

S oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid:

F

0 N—7 \ o

N N ©

Nr NEN - NF o <7 OH

F

EXAMPLE 52: 9~(4-{4-[5-(Acetylamino-methyl)-2-oxo-oxazolidin- 3-yl]-2-fluoro-phenoxy}-azepan-1-yl)-8-fluoro-3-methyl-6-oxo- 2,3-dihydro-6H-1-oxa-3a-aza-phenalene-5-carboxylic acid: 0] lo] oc H 0 F [o)

N , LAN

YT Nu \ON {7 / OH

N

© °c

F

EXAMPLE 53: 7-[4-(2-{4-[ (58) ~ (Acetylamino-methyl) -2-oxo- oxazolidin-3-yl]-2-fluoro-phenoxy}-ethyl)-piperidin-1-yl]-1- cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1, 8] naphthyridine-3- carboxylic acid:

F

0] y N~7 \ (8)

We J NS

TSAO © 0 NF (o] vA

OH

F

A suspension of 100 mg N-{(5S)-3-[3-fluoro- 4-[4-(piperazin-4- yl-ethoxy)]-phenyl]-2~-oxo-oxazolidin-5-ylmethyl}-acetamide (MW: 379.43, 0.263 mmol), 68 mg 7-chloro-l-cyclopropyl-6- fluoro-1, 4-dihydro-4-oxo~1, 8-Naphthyridine-3-carboxylic acid (MW: 282.66, 0.239 mmol), 0.060 ml trimethylchlorosilane (MW:108.64, d=0.859, 0.47 mmol) and 0.1 ml triethylamine (MW:101.19, d=0.726, 0.71 mmol) in 2 ml N-methyl-pyrrolidin-2- one was heated under stirring in a micro wave oven at 150 °C for 7 min. The N-methyl-pyrrolidin-2-one was evaporated, the residue was purified by chromatography. Yield: 30 mg, 20 %.

MS: 626.5 (M+H)', Method ESI*. Molecular Weight =626

EXAMPLE 54: 9-[4-(2-{4-[5- (Acetylamino-methyl)-2-oxo- oxazolidin-3-yl}-2-fluoro-phenoxy}-ethyl)-piperidin-1-yl]-8- fluoro-3-methyl-6-oxo-2, 3-dihydro-6H-1-oxa-3a-aza-phenalene-5- carboxylic acid: o (0) iL x OO F

N

0] ] F N $s 0} \ 0

NH NA o= OH

EXAMPLE 55: 7-[3(R,S)~-(2~{4~[(5S)-(Acetylamino-methyl)-2-oxo~ oxazolidin-3-yl]-2-fluoro-phenoxy}-ethyl)-pyrrolidin-i-yl}-1- cyclopropyl-6-fluoro-4-oxo-1,4-dihydro~[1, 8] naphthyridine-3- carboxylic acid: . ; oO

HN Lr F 0) N \ N= 0" N —7 - <

A suspension of 120 mg N-{(5S)-3-[3-fluoro- 4-[4(R,S)-4- (piperazin-4-yl-ethoxy) ]-phenyl]-2-oxo-oxazolidin-5-ylmethyl}- acetamide (MW: 365.40, 0.33 mmol), 85 mg 7-chloro-1- cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1, 8-Naphthyridine-3- carboxylic acid (MW: 282.66, 0.3 mmol), 0.075 ml trimethylchlorosilane (MW:108.64, d=0.859, 0.6 mmol) and 0.127 ml triethylamine (MW:101.19, d=0.726, 0.9 mmol) in 3 ml N- methyl-pyrrolidin-2-one was heated under stirring in a micro wave oven at 150 °C for 7 min. The N-methyl-pyrrolidin-2-one was evaporated, and the residue dissolved in dichloromethane.

The organic layer was washed with water and brine, dried over

Mg sulfate, filtered and the filtrate evaporated. The residue was digested in ethyl acetate, the resulting colourless solid was filtered and dried. Yield: 159 mg, 86 %. Molecular Weight 612.

EXAMPLE 56: 9-[3-(2-{4-[5-(Acetylamino-methyl)- 2-oxo- oxazolidin-3-yll-2-fluoro-phenoxy}-ethyl)-pyrrolidin-1-y1]-8- fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3a~aza-phenalene-5- carboxylic acid:

ie GE o” °N o

YJ E N 0]

N y un o N OH o= (

EXAMPLE 57: 7-(3-{4-[5-(Acetylamino-methyl)-2-0oxo-oxazolidin- 3-yll-2-fluoro-phenoxymethyl}-pyrrolidin-1-yl)-1l-cyclopropyl- 6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:

Oo F Oo 0 N 2 wk _N o [| won yr (o] 4

F

A suspension of 176 mg N-{(58)~3-[3-fluoro- 4-[3-(RS)- (pyrrolidin-3-ylmethoxy) ]-phenyl]-2-oxo-oxazolidin-5-y1 methyl}-~acetamide (MW: 351.38, 0.5 mmol), 205 mg 7-chloro- 6- fluoro-l-cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylato- boron diacetate (MW: 409.56, 0.5 mmol ), and 0.341 ml N- ethyldiisopropylamine (MW:129.25, d=0.755, 2 mmol) in 2 ml N- methyl-pyrrolidin-2-one was heated under stirring in a micro wave oven at 150 °C for 7 min. The N-methyl-pyrrolidin-2-one was evaporated, the residue was purified by chromatography and crystallisation from ethanol. Yield: 120 mg, 40 %. MS: 587.5 (M+H)", Method ESI*. Molecular Weight =597.

EXAMPLE 58: 7-[3-(2-{4-[5-(Acetylamino-methyl)- 2-oxo- oxazolidin-3-yl]-2-fluoro-phenoxy}-ethyl)-pyrrolidin-1-yl}-1~ cyclopropyl-6-fluoro—-4-oxo-1, 4-dihydro~quinoline-3~carboxylic acid: 10) 5, TQ;

N

0 J F

No ° o= Vv °

HO

EXAMPLE 59: 7-(3-{4-[5-(Acetylamino-methyl)-2-oxo-oxazolidin- 3-yl]-2-fluoro-phenoxymethyl}-pyrrolidin-1-yl)-1l-cyclopropyl=- 8-methoxy-4-oxo-1, 4-dihydro-quinoline-3~carboxylic acid: 0)

Oo 04 \ ° pio N /

Oo

Y NH O- o —0 N OH

F 4

A suspension of 100 mg N-{ (5S)-3-[3-fluoro-4-[3- (RS) - (pyrrolidin-3-ylmethoxy) ]-phenyl]-2-0x0-0oxazolidin-5-yl methyl} ~acetamide (MW: 351.38, 0.284 mmol), 115 mg 1- cyclopropyl-7-fluoro-8-methoxy-4-oxo-1, 4-dihydro-quinoline-3- carboxylatoboron diacetate (MW: 405.14, 0.284 mmol) and 0.097 ml N-ethyldiisopropylamine (MW:129.25, d=0.755, 0.57 mmol) in 2 ml N-methyl-pyrrolidin-2-one was heated under stirring in a micro wave oven at 150 °C for 7 min. The N-methyl-pyrrolidin- 2-one was evaporated, the residue was purified by chromatography and crystallisation from ethanol. Yield: 40 mg, 23 %. MS: 609.5 (M+H)*, Method ESI*. Molecular Weight =609.

EXAMPLE 60: 7-(3-{4-[5-(Acetylamino-methyl)-2-oxo-oxazolidin- 3-yll-2-fluoro-phenoxy}-pyrrolidin-1-yl)-6~fluoro-1- (4~ hydroxy-phenyl)-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid: lo] 0 OH (e] .

H pai. 0° \

A F N

N

N lo) LO

F OH

EXAMPLE 61: 7-(3-{4-[5-(Acetylamino-methyl)-2-oxo-oxazolidin- 3~yl]l-2-fluoro-phenoxymethyl}-pyrrolidin-1-yl)-1l-cyclopropyl- 6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:

F

O jo) ok Cy 0

N oy pa /) lo) N OH

F \ 4

EXAMPLE 62: 7-[4-(2-{4-[5~(Acetylamino-methyl)- 2-oxo- oxazolidin-3-yl]-phenyl}-2-oxo-ethyl)-piperazin-1-yl]-1- cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid: 0)

F

0 A 2 0

AN A o N N 0 oO Y NH N OH

EXAMPLE 63: 7-(3(S)-{4-[5(S)-(Acetylamino-methyl)-2-oxo- oxazolidin-3-yl]-2-fluoro-phenoxymethyl}-pyrrolidin-1-yl)-1- cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-[1, 8] naphthyridine-3- carboxylic acid: 0] lo] 0 F

Te - Ly © Nol N Aan NTN

T o J A

F

A suspension of 737 mg N-{(5S)-3-{3-fluoro- 4-[3-(S)~ (pyrrolidin-3-ylmethoxy) ] -phenyl]-2-oxo-oxazolidin-5-y1 methyl}-acetamide (MW: 351.38, 2.1 mmol), 566 mg 7-chloro-1- cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1, 8-Naphthyridine-3- carboxylic acid (MW: 282.66, 2 mmol), 0.505 ml trimethyl- chlorosilane (MW:108.64, d=0.859, 4 mmol) and 0.840 ml triethylamine (MW:101.19, d=0.726, 6 mmol) in 15 ml N-methyl- pyrrolidin-2-one was heated under stirring at 150 °C for 2 hrs. The N-methyl-pyrrolidin-2-one was evaporated, and the residue dissolved in dichloromethane. The organic layer was washed with water and brine, dried over Mg sulfate, filtered and the filtrate evaporated. The residue was purified by crystallisation from an ethanol and dichloromethane mixture.

Yield: 972 mg, 81 %. MS: 598.5 (M+H)', Method ESI*. Molecular

Weight 598.

EXAMPLE 64: 7-(3(R)-{4-[5(S)~-(Acetylamino-methyl)-2-oxo- oxazolidin-3-yl]-2-fluoro-phenoxymethyl}-pyrrolidin-1-yl)-1- cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid:

Ji J 0 Ye o Ho F je

X vio

HO

A suspension of 1.228 gg N-{{(5S)-3-[3-fluoro- 4-[3-(R)~ (pyrrolidin-3-ylmethoxy)l-phenyl]-2-oxo-oxazolidin-5-yl methyl}-acetamide (MW: 351.38, 3 mmol), 1.054 g 7-chloro- 6-. fluoro-l-cyclopropyl-4-oxo-1, 4-dihydroquinoline-3-carboxylato- boron diacetate (MW: 409.56, 3 mmol ), and 2 ml N-ethyl- diisopropylamine (MW:129.25, d=0.755, 12 mmol) in 30 ml N- methyl-pyrrolidin-2-one was heated under stirring at 150 °C for 2 hrs. The N-methyl-pyrrolidin-2-one was evaporated, and the residue dissolved in dichloromethane. The organic layer was washed with O0.1N HCl and with brine, dried over Mg sulfate, filtered and the filtrate evaporated to dryness. The residue was digested in warm ethyl acetate, the crystals filtered (DCl). The solid was crystallised from ethanol.

Yield: 728 mg, 41 %. MS: 597.5 (M+H)*, Method ESI*. Molecular

Weight 597.

EXAMPLE 65: 7-[4-(2-{4-(5-(Acetylamino-methyl)-2-oxo- oxazolidin-3-yl]-2-fluoro-phenoxy}-ethylidene)-piperidin-1- y11-1l-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-{1,8]- naphthyridine-3-carboxylic acid:

~~ £ x ng ~~ “OY pa 0X, Or ° vA OH :

EXAMPLE 66: 7-(3-{4-[5-(Acetylamino-methyl)-2-oxo-oxazolidin- 3-yl]-2-fluoro-phenoxymethyl}-azetidin-1-yl)-1l-cyclopropyl-6- fluoro-4-oxo-1,4-dihydro-(1, 8]lnaphthyridine-3-carboxylic acid:

F

Ji 9 a% ~ . Pw Ns 0 a po

HO

A suspension of 179 mg N-{(5S)-3-[4-(Azetidin-3-ylmethoxy)-3- fluoro--phenyl]-2-oxo-oxazolidin-5-yl methyl}-acetamide (MW: 337.35, 0.31 mmol), 100 mg 7-chloro-l-cyclopropyl-6-fluoro- 1,4-dihydro-4-oxo-1,8-Naphthyridine-3-carboxylic acid (MW: 282.66, 0.25 mmol), 0.134 ml trimethylchlorosilane (MW:108.64, d=0.859, 1.059 mmol) and 0.197 ml triethylamine (MW:101.19, d=0.726, 1.41 mmol) in 2 ml N-methyl-pyrrolidin-2-one was heated under stirring in a micro wave oven at 150 °C for 7 min. The N-methyl-pyrrolidin-2-one was evaporated, the residue was purified by chromatography. Yield: 82 mg, 40 %. MS: 583.5 (M+H)*, Method ESI*. Molecular Weight =584

EXAMPLE 67: 7-(2-{4-[5-{Acetylamino-methyl)-2~oxo-oxazolidin- 3-yl]-2-fluoro-phenoxymethyl}-l-oxa-6-aza-spiro[2.5]oct-6-yl)-

l-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-{1l, 8lnaphthyridine-3- carboxylic acid:

A F ; ©

N

A Ug Non

LE A

EXAMPLE 68: 7-(3-{4-[5-(Acetylamino-methyl)-2-oxo-oxazolidin- 3-yli-2-fluoro-phenoxy}-4-methoxy-pyrrolidin-1-yl)-l-cyclo- propyl-6-fluoro-4-oxo—1i, 4-dihydro-[1, 8] -naphthyridine-3- carboxylic acid: > oS o \ 0] 0] OH

UI

( ~~ \ nN N

N IN o

F H

—~0

EXAMPLE 69: 7-(3(R)-{4-[5(S)-(Acetylamino-methyl)-2-oxo- oxazolidin-3-yl]-2-fluoro-phenoxymethyl}-pyrrolidin-1-yl)-1- cyclopropyl-6-fluoro-4-oxo~1, 4-dihydro-{1,8]naphthyridine-3- carboxylic acid: 0 [o]

Oo

H O F

Ou-N =< X

T el UN / _ | OH

NOH

" A

Claims (1)

1. Claims

   1. Use of a compound of Formula (I): Ri O 10) R2 h pp SOS (I) . wherein : A is a bond, a NH, O, S, SO, 80, SO,NH, PO4, -NH-CO-NH-, -CO-NH-, -CO-, -CO0-0-, ~-NH-CO-0-, -0O-Z-heterocyclo- alkylen, an alkylen group, an alkenylen group, an alkinylen group, a heterocalkylen group, an arylen group, a heteroarylen ~ group, a cycloalkylen group, a heterocycloalkylen group, an alkylarylen group or a heteroarylalkylen group or a combination of two or more of these atoms or groups; L is selected from the following groups: 8 \ 8 , 8 : Ra RNY RN Rn “\— : o— 0 0 N=: 0 : ° 0 0 8 [} R ) Rr® . 8 \ O-N 0 o

   ~~ WO02004/096221 PCT/EP2004/003650 X is CRS or N; Y is CR6 or N;

   5 . . U is F or C1; Z is a C;.4 alkylene group, a C;.4 alkenylene group, a Cz alkynylene group or a C;.4 heteroalkylemne group, all of which may be substituted by one or more hydroxy or amino groups; nis 0, 1, 2 or 3; Rl is H, F, Cl, Br, I, OH, NH, an alkyl group or a heteroalkyl group; R2 is H, F or Cl; R3 is H, an alkyl group, an alkenyl group, an alkinyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an alkylaryl group or a heteroarylalkyl group; all of which may be substituted with one, two or more halogen atoms; R4 is a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an alkylaryl group or a heteroarylalkyl group; Amended sheet: 8 December 2006

   R5 is H, F, Cl, OH, NH,, an alkyl group or a heteroalkyl group, or R3 and R5 can be linked via an alkylen, an alkenylen or a heteroalkylen group or be a part of a cycloalkylen or heterocyclo-alkylen group; in case R3 is no H and R5 is no H, F, OH, NH, or Cl; R6 is H, F, Cl or OMe; R8 is a Cj;.¢ heteroalkyl or a heteroarylalkyl group; or a pharmacologically acceptable salt, solvate, hydrate or formulation thereof in the manufacture of a medicament for use in the treatment of anthrax.

   2. Use of a compound according to Claim 1, wherein the halogen atoms are F or Cl.

   3. Use of a compound according to Claim 1 or 2, wherein R1 is

   H.

   4. Use of a compound according to any one of the preceding claims, wherein R2 is F or H.

   5. Use of a compound according to any one of the preceding claims, wherein R3 is an ethyl, a 2-propyl, a C3-Cs cycloalkyl, a phenyl or a pyridyl group, all of which may be substituted by one, two or more fluorine atoms or amino groups.

   6. Use of a compound according to any one of the preceding claims, wherein R3 is a cyclopropyl group. Amended sheet: 8 December 200¢

   7. Use of a compound according to any one of the preceding claims, wherein R3 and R5 together form a group of the formula -0-CH,-N{(Me)- or -0-CH,-CH(Me)-.

   8. Use of a compound according to any one of the preceding claims, wherein R4 is an acetylamino group.

   9. Use of a compound according to any one of the preceding claims, wherein the absolute configuration at C-5 of the oxazolidinone ring is (S) according to the Cahn-Ingold- Prelog nomenclature system.

   10. Use of a compound according to any one of the preceding claims, wherein X is N or CH.

   11. Use of a compound according to any one of the preceding claims, wherein Y is CF or CH.

   12. Use of a compound according to any one of the preceding claimg, wherein n is 0.

   13. Use of a compound according to any one of claims 1-12, wherein A is a group of the formula -Bo-1 +p ~ Boor Fm - Gop - Ko-1- wherein the group B is an alkylene, which may be substituted by one, two or more fluorine atoms, an 0, 8S, SO, 80,, SO,NH group, or a heterocalkylen group, which may be substituted Amended sheet: 8 December 2006 :

   by one, two or more fluorine atoms and/or at the optionally present nitrogen atoms by an alkyl or an acyl group;

   the groups D independently of each other are optionally anellated heterocycloalkylen groups with 1, 2, 3 or 4 nitrogen atoms, which heterocycloalkylen groups may each be substituted by one, two or more fluorine atoms and/or which each may be substituted at one, two, three or four nitrogen atoms by an alkyl or an acyl group; the groups E independently of each other are an alkylene, which may be substituted by one, two or more fluorine atoms, an O, 8S, SO, SO,, SO,NH group, or a heteroalkylen

   1S group, which may be substituted by one, two or more fluorine atoms and/or at the optionally present nitrogen atoms by an alkyl or an acyl group; the groups G independently of each other are optionally anellated heterocycloalkylen groups with 1, 2, 3 or 4 nitrogen atoms, which heterocycloalkylen groups may each be substituted by one, two or more fluorine atoms and/or which each may be substituted at one, two, three or four nitrogen atoms by an alkyl or an acyl group; .

   the group K is an alkylene, which may be substituted by one, two or more fluorine atoms, an O, §, SO, SO, SO;NH group, or a heteroalkylen group, which may be substituted by one, two or more fluorine atoms and/or at the optionally present nitrogen atoms by an alkyl or an acyl group; and m = 1,2,3 or 4.

   14. Use of a compound according to any one of Claims 1-12, wherein A is a group of the formula -V-W-, wherein V is a direct bond or a group of the formula NH, O, S, SO, SO, SO;NH, POs, -NH-CO-NH-, -CO-NH-, -CO-, -CH,-, -CO-0-, - (CHz),-3-0-, -CH=CH-C(0)-, or -NH-CO-O- and W is a heterocycloalkyl group with 4 to 7 ring atoms or a alkylheterocycloalkyl group with 4 to 7 ring atoms and 1 to 4 carbon atoms in the alkyl chain; all these groups may be substituted by 1, 2, 3 or 4 fluorine atoms, methyl or methoxy groups.

   15. Use of a compound according to any one of Claims 1-12, wherein A is a group of the formula ; (CH,)p\ , “FV—(cH)— NT (CH,), wherein V is a group of the formula NH, 0, S, SO, SO,, SO.NH, PO, -NH-CO-NH-, -CO-NH-, -CO-, -CH,-, -CO-0-, -(CH;);.3-0-, -CH=CH-C(0) -, or -NH-CO-0O-; a is 0, 1, 2, 3 or 4; b is 0, 1, 2, 3 or 4; ¢c is 0, 1, 2, 3 or 4 and 1, 2, 3 or 4 hydrogen atoms may be substituted by F, a methyl- or a methoxy group.

   16. Use of a compound according to Claims 14 or 15, wherein V is NH, O, S, SO or SO0,. Amended sheet: 8 December 2006

   17. Use of a compound according to Claims 14 or 15, wherein V is OoOr NH; a is 0 or 1; bis 1 or 2 and c is 1 or 2.

   18. Use of a compound according to any one of Claims 1-12, wherein A is selected from the following groups which may be substituted by one, two or more fluorine atoms or by an alkyl group which may be substituted by one or more fluorine ‘atoms, and wherein the amino groups may be substituted by an alkyl or an acyl group:

   10 .

   H . , 3 Ll gd 3 N NY * NT +N N+ S N 1 \ , 1 H ‘ q [] [] pd x 34 ER NYT ys HN -~ \ . an! 0 . a TL, a [ LJ ya VAR Nn N : ~N N T \—/ NY [ [] [] Y, \ H —+N N+ —+N N N+ Amended sheet: 8 December 2006

   : CN ' H 3 lo} N ] § N= + nh Rl - Li +O 0 0

   ‘ . R }] oN ) ~0y¢ Li | ) —Sy¢ La ) ~Sy¢ Oo, ,o0 Ls, 4 , +o : SOP Ber On fn in —o-+ Fn —s+ +n—s+ HOt HO do<Unt 0 [] ' 0 NY No ot | * nD N o-

   ~ WO2004/096221 PCT/EP2004/003650

   19. Use of a compound according to any one of claims 1-7 and 9-11, wherein the compound is represented by Formula (II): R7 R2 0 Jew), Ri —Y, 4 PN— | fo) — N-o cry X= -_ c y Oo F AN R3 OH (II) wherein LI is selected from following groups: R® \ RS ' R® . ~ NT NN x ~N NN ‘ o— 0— 0 oO 0) 0) 8 M . R [) 8 ry 8 [) \ b is 1, 2 or 3; c is 1, 2 or 3; R7 is hydrogen, a group of formula PO;R’ or SO;RY or a heteroalkyl group carrying at least one OH, NH;, SOR, POsR®, or COOH group, wherein R’ is H, alkyl, cycloalkyl, aryl, aralkyl, and wherein RY is H, alkyl, cycloalkyl, aryl, aralkyl; Amended sheet: 8 December 2006

   Co 96 X, Y, z, Rl, R2, R3, R5, R6, R8, and the possible linkage between R3 and R5 are as defined in any one of claims 1-7 and 9-11; or a pharmacologically acceptable salt, solvate, hydrate or formulation thereof in the manufacture of a medicament for use in the treatment of anthrax.

   20. Use of compounds according to Claim 19, wherein R7 is hydrogen or a group of the formula SO0sH, PO3H,, PO3 (CH2C¢Hs) 2, CH,OPO3H or COCH,CH,COOH, or together with the oxygen to which it is bound forms an ester of a naturally occurring amino acid or a derivative thereof.

   21. Use of compounds according to Claims 19 or 20, wherein RS is a group of the formula ~CH,NHCOCH=CHAryl, -CH,OHeteroaryl, —CH,;NHSO,Me, -CH,;NHCOOMe, -CH,;NHCS;,Me, -CH,NHCSNH;, -CH,NHCSOMe or -CH,NHCOMe.

   22. Use of compounds according to any one of Claims 19-21, wherein L is a group of the following formula: 0) ‘ PN ANT N 4 oO

   23. Use of compounds according to any one of Claims 19-22, wherein R5 is H, F, Cl or a methoxy group which may be substituted by one, two or three fluorine atoms.

   24. Use of compounds according to any one of Claims 19-23, wherein Z is CH, or CH,CH,. Amended sheet: 8 December 2006

   0 + 97

   25. Use of a pharmaceutical composition AL a compound according to any one of the preceding claims and optionally carriers and/or adjuvants and/or diluents for the treatment of anthrax.

   26. Use of pro-drugs, which contain a compound according to any one of claims 1-24 and at least one pharmacologically acceptable protective group in the manufacture of a medicament for use in the treatment of anthrax. Amended sheet: 8 December 2006