WO1998001446A1 - Substituted piperazinyl-phenyl-oxazolidinone derivatives and their use as anti-bacterial agents - Google Patents

Abstract

The invention concerns a compound of formula (I) wherein, for example: R1 is of the formula -NHC(=O)Ra wherein Ra is for example (1-4C)alkyl; R?2 and R3¿ are independently hydrogen or fluoro; R?4 and R5¿ are independently hydrogen or methyl; R6 is a 6-membered heteroaryl ring containing 2 or 3 ring nitrogen atoms as the only ring heteroatoms, and optionally substituted by substituents selected from (1-4C)alkyl (optionally substituted), halo, trifluoromethyl, (1-4C)alkylS(O)¿n?- (wherein n is 0, 1 or 2), (1-4C)alkylS(O)2amino, (1-4C)alkanoylamino, carboxy, hydroxy, amino, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-4C)alkoxycarbonyl, carbamoyl, N-(1-4C)alkylcarbamoyl, di-(N-(1-4C)alkyl)carbamoyl [wherein the (1-4C)alkyl group or groups in the last two-mentioned carbamoyl substituents is optionally substituted by hydroxy, (1-4C)alkoxy or (1-4C)alkoxycarbonyl], (2-4C)alkenyl (optionally substituted by carboxy or (1-4C)alkoxycarbonyl), (1-4C)alkoxy, cyano or nitro; pharmaceutically-acceptable salts, suitable N-oxides and in-vivo-hydrolysable esters thereof; processes for their preparation; pharmaceutical compositions containing them and their use as antibacterial agents.

Description

SUBSTITUTED PIPERAZINYL-PHENYL-OXAZOLIDTNONE DERIVATIVES AND THEIR USE AS ANTI-BACTERIAL AGENTS

The present invention relates to antibiotic compounds and in particular to antibiotic compounds containing an oxazolidinone ring. This invention further relates to processes for their preparation, to intermediates useful in their preparation, to their use as therapeutic agents and to pharmaceutical compositions containing them.

The international microbiological community continues to express serious concern that the evolution of antibiotic resistance could result in strains against which currently available antibacterial agents will be ineffective. In general, bacterial pathogens may be classified as either Gram-positive or Gram-negative pathogens. Antibiotic compounds with effective activity against both Gram-positive and Gram-negative pathogens are generally regarded as having a broad spectrum of activity. The compounds of the present invention are regarded primarily as effective against Gram-positive pathogens because of their particularly good activity against such pathogens. Gram-positive pathogens, for example Staphylococci, Enterococci. Streptococci and mycobacteria. are particularly important because of the development of resistant strains which are both difficult to treat and difficult to eradicate from the hospital environment once established. Examples of such strains are methicillin resistant staphylococcus (MRSA). methicillin resistant coagulase negative staphylococci (MRCNS). penicillin resistant streptococcus pneumoniae and multiply resistant Enterococcus faecium.

The major clinically effective antibiotic for treatment of such resistant Gram-positive pathogens is vancomycin. Vancomycin is a glycopeptide and is associated with nephrotoxicity and ototoxicity. Furthermore, and most importantly, antibacterial resistance to vancomycin and other glycopeptides is also appearing. This resistance is increasing at a steady rate rendering these agents less and less effective in the treatment of Gram-positive pathogens.

The present inventors have discovered a class of antibiotic compounds containing an oxazolidinone ring which has useful activity against Gram-positive pathogens including MRSA and MRCNS and. in particular, against various strains exhibiting resistance to vancomycin and against E. faecium strains resistant to both aminogiycosides and clinically used β-lactams. We have now discovered a range of compounds that have good activity against a broad range of Gram-positive pathogens including organisms known to be resistant to most commonly used antibiotics. In comparison with compounds described in the art (for example Walter A. Gregory et al in J.Med.Chem. 1990. 33. 2569-2578 and Chung-Ho Park et al in J.Med.Chem. 1992. 35. 1 156-1 165) the compounds also possess a favourable toxicological profile.

Accordingly the present invention provides a compound of the formula (I )

wherein:

R¹ is hydroxy. chloro. fluoro, ( l-4C)alkanesulfonyloxy. amino. azido, ( l -4C)alkoxy.

(l-4C)alkylthio, (l-4C)alkylaminocarbonyloxy. or of the formula -NHC(=O)R^a wherein R'^η is hydrogen. ( l-4C)alkoxy, amino. chloromethyl, dichloromethyl. cyanomethyl, methoxymethyl. acetylmethyl. methylamino. dimethylamino or ( l-4C)alkyl or R' is of the formula -N(Me)C(=O)R^b wherein R is hydrogen, methyl or methoxy or R' is of the formula

-NHS(0),,( 1 -4C)alkyl wherein n is 0. 1 or 2:

R" and R are independently hydrogen or fluoro:

R⁴ and R⁵ are independently hydrogen or methyl:

R⁶ is a 6-membered heteroaryl ring containing 2 or 3 ring nitrogen atoms as the only ring heteroatoms. linked via a ring carbon atom and optionally substituted on a ring carbon atom by one. two or three substituents independently selected from ( l -4C)alkyl (optionally substituted by trifluoromethyl, ( l-4C)alkylS(O)„- (wherein n is 0. 1 or 2), ( 1 -4C)alkoxy, carboxy. hydroxy.

(l-4C)alkoxycarbonyl. carbamoyl. N-(l -4C)alkylcarbamoyl. di-(N-(l -4C)alkyl)carbamoyl. cyano. nitro. amino. N-( 1 -4C)alkylamino. di-(N-( 1 -4C)alkyl)amino or

(2-4C)alkanoyiamino). halo, trifluoromethyl. ( l -4C)alkylS(O)„- (wherein n is 0. 1 or 2). ( l -4C)alkylS(O)-amino. ( 1 -4C)alkanoylamino, carboxy. hydroxy. amino. ( l-4C)aikylamino. di-( l -4C)alkylamino. ( C)alkoxycarbonyl. carbamoyl. N-( l -4C)alkylcarbamoyl. di-(N-( l-4C)alkyl)carbamoyl [wherein the (l-4C)alkyl group or groups in the last two- mentioned carbamoyl substituents is optionally substituted by hydroxy, ( l -4C)alkox or ( l-4C)alkoxycarbonyl], (2-4C)alkenyl (optionally substituted by carboxy or ( 1 -4C)alkoxycarbonyl), ( 1 -4C)alkoxy. cyano or nitro: pharmaceutically-acceptable salts thereof: and suitable N-oxides thereof.

In this specification the term "alkyl" includes straight chained and branched structures. For example. (l-6C)alkyl includes propyl. isopropyl and tert-butvl. However. references to individual alkyl groups such as "propyr are specific for the straight chained version only, and references to individual branched chain alkyl groups such as ^'"isopropyl" are specific for the branched chain version only.

In this specification a 6-membered heteroaryl ring containing 2 or 3 ring nitrogen atoms as the only ring heteroatoms, includes pyrimidine. pyridazine. pyrazine. 1.2.3-triazine. 1.2.4-triazine and 1.3.5-triazine.

Examples of ( l-4C)alkyl include methyl, ethyl, propyl. isopropyl and tert-butvl: examples of halo include fluoro. chloro. bromo and iodo: examples ofN-( l - 4C .alkylcarbamoyl include methyicarbamoyl. ethylcarbamoyl and propylcarbamoyl: examples of di-(N-( l -4C alkyl)carbamoyl include di-(methyl)carbamoyl and di-(ethyl)carbamoyl: examples of the ( l -4C)alkyl group or groups in N-(l-4C)alkylcarbamoyl and di-(N-( l -4C)alkyl)carbamoyl being optionally substituted by hydroxy. ( l-4C)alkoxy or ( 1 -4C)alkoxycarbonyl include 2-hydroxyethylaminocarbonyl. bis-(2-hydroxyethyl )aminocarbonyl, 2-methoxyethylaminocarbony 1 and methoxycarbonylmethylaminocarbonyl; examples of (l-4C)alkylS(O)_n include methylthio, ethylthio. methylsulfinyl. ethylsulfinyl, methylsulfonyl and ethylsulfonyl; examples of ( 1 -4C a_kylS(O)-,amino include methylsulfonylamino and ethylsulfonylamino: examples of (2-4C)alkenyl include allyl and vinyl: examples of (l-4C)alkoxy include methoxy, ethoxy and propoxy: examples of (l -4C)alkanoylamino include formamido. acetamido and propionylamino: examples of (2-4C)alkanoylamino include acetamido and propionylamino: examples of N-( l-4C)alkylamino include methylamino and ethylamino: examples of di-(N-( l - 4C)alkyl (amino include di-N-methylamino. di-(N-ethyl)amino and N-ethyi-N-methylamino: examples of ( l-4C)alkoxycarbonyl include methoxycarbonyl. ethoxycarbonyl. n- and tert- butoxycarbonyl : examples of ( l-4C)alkanesulfonyloxy include methanesulfonyloxy and ethanesulfonyloxy: and examples of (l-4C)alkylaminocarbonyloxy include methylaminocarbonyloxy and ethylaminocarbonyloxy.

Suitable pharmaceutically-acceptable salts include acid addition salts such as methanesulfonate. fumarate. hydrochloride. hydrobromide. citrate, maleate and salts formed with phosphoric and sulfuric acid. In another aspect suitable salts are base salts such as an alkali metal salt for example sodium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine. morpholine. N- methylpiperidine. N-ethylpiperidine. procaine. dibenzylamine. N.N-dibenzylethylamine or amino acids for example lysine. There may be more than one cation or anion depending on the number of charged functions and the valency of the cations or anions. A preferred pharmaceutically-acceptable salt is the sodium salt. However, to facilitate isolation of the salt during preparation, salts which are less soluble in the chosen solvent may be preferred whether pharmaceutically-acceptable or not.

In this specification a suitable N-oxide refers to the N-oxides which may be formed on an available nitrogen atom in either the piperazine ring or in the heteroaryl ring R". A suitable N-oxide may be optionally in the form of a pharmaceutically-acceptable salt. The compounds of the formula (I) may be administered in the form of a pro-drug which is broken down in the human or animal body to give a compound of the formula (I). Examples of pro-drugs include in-vivo hydrolysable esters of a compound of the formula (I). An in-vivo hydrolysable ester of a compound of the formula (I) containing carboxy or hydroxy group is. for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically- acceptable esters for carboxy include (l-6C)alkoxymethyl esters for example methoxymethyl. ( I -6C)alkanoyloxymethyl esters for example pivaloyloxymethyl. phthalidyl esters. (3- 8C)cycloalkoxycarbonyloxy(l-6C)alkyl esters for example 1-cyclohexylcarbonyloxyethyl; 1.3-dioxoten-2-onylmethyl esters for example 5-methyl-1.3-dioxolen-2-onylmethyi: and (1 - 6C)alkoxycarbonyloxyethyi esters for example 1 -methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention. An in-vivo hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and α-acyloxyalkyl ethers and related compounds which as a result of the in-vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2.2-dimethylpropionyloxymethoxy. A selection of in-vivo hydrolysable ester forming groups for hydroxy include ( 1 - 10C)alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, (l-lOC)alkoxycarbonyl (to give alkyl carbonate esters). di-( l- 4C)alkylcarbamoyl and N-(di-(l-4C)alkylaminoethyl)-N-( l-4C)alkylcarbamoyl (to give carbamates). di-(l-4C)alkylaminoacetyI and carboxyacetyl. Examples of substituents on benzoyl include morpholino or piperazino linked from a ring nitrogen atom via methylamino to the 3- or 4- position of the benzoyl ring.

The compounds of the present invention have a chiral centre at the C-5 position of the oxazolidinone ring. The pharmaceutically active enantiomer is of the formula (IA):

(IA)

The present invention includes the pure enantiomer depicted above or mixtures of the 5R and 5S enantiomers. for example a racemic mixture. If a mixture of enantiomers is used, a larger amount (depending upon the ratio of the enantiomers) will be required to achieve the same effect as the same weight of the pharmaceutically active enantiomer. For the avoidance of doubt the enantiomer depicted above could be either 5R or 5S depending upon the value of R . For example, when R is acetamido. the enantiomer depicted above is the 5S enantiomer and when R is hydroxy, the enantiomer depicted above is the 5R enantiomer. Furthermore. some compounds of the formula (I) may have other chiral centres. It is to be understood that the invention encompasses all such optical and diastereo-isomers that possess antibacterial activity.

The invention relates to all tautomeric forms of the compounds of the formula (I) that possess antibacterial activity.

It is also to be understood that certain compounds of the formula (I) can exist in solvated as well as unsolvated forms such as. for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which possess antibacterial activity. In a further aspect of the invention there is provided a compound of the formula (I) wherein:

R' is hydroxy. chloro. fluoro. (l -4C)alkanesulfonyloxy. amino, azido. ( l-4C)alkox> . or R' is of the formula -NHC(=O)R^a wherein R^a is hydrogen. ( l -4C)alkoxy, chloromethyl, dichloromethyl, cyanomethyl, methoxymethyl, acetylmethyl or ( l -4C)alkyl or R' is of the formula -NHSO_:( 1 -4C)alkyl

R² and R are independently hydrogen or fluoro;

R⁴and R' are independently hydrogen or methyl;

R⁶ is a 6-membered heteroaryl ring containing 2 or 3 ring nitrogen atoms as the

ring heteroatoms. linked via a ring carbon atom and optionally substituted on a ring carbon atom by one. two or three substituents independently selected from (l -4C)alkyl [optionally substituted by trifluoromethyl. (l -4C)alkylS(O)„- (wherein n is 0, 1 or 2), ( l -4C alkoxy. carboxy. hydroxy.

( l-4C)alkoxycarbonyl. carbamoyl. N-( l -4C)alkylcarbamoyl, di-(N-(l-4C)alkyl)carbamoyl. cyano. nitro. amino, N-(l-4C)aIkylamino. di-(N-( l -4C)alkyl)amino or (2-4C)alkanoylamino], halo, trifluoromethyl. (l -4C)alkylS(O)„- (wherein n is 0. 1 or 2). ( l-4C alkylSO₂amino. ( 1 -4C)alkanoylamino. carboxy, hydroxy, amino. ( l -4C)alkylamino, di-( l-4C .alkylamino. ( l-4C)alkoxycarbonyl. carbamoyl. N-( l-4C)alkylcarbamo\ l. di-(N-(l-4C)alkyl)carbamoyl [wherein the (l-4C)alkyl group or groups in the last two- mentioned carbamoyl substituents is optionally substituted by hydroxy. ( l -4C)alkoxv or ( l -4C alkoxycarbonyi], (2-4C)alkenyl [optionally substituted by carboxy or ( 1

1]. ( 1 -4C)alkoxy. cyano or nitro: pharmaceutically-acceptable salts thereof: and suitable N-oxides thereof.

In another further aspect of the invention there is provided a compound of the formula (I). or a pharmaceutically-acceptable salt thereof, as defined in the above aspects of the invention, except that suitable N-oxides are excluded. In a yet further aspect of the invention there is provided a compound of the formula

(I), or a pharmaceutically-acceptable salt or suitable N-oxide thereof, as defined anywhere above, except that the following optional substituents on R'¹. namely

( l -4C)a!koxy, (l -4C)alkylSO₂amino, ( 1 -4C)alkanoylamino and those

N-( 1 -4C alkylcarbamoyl and di-(N-(l -4C)alkyl)carbamoyl substituents with the ( l -4C)alkyl group or groups substituted by hydroxy, (l-4C)alkoxy or ( l-4C)alkoxycarbonyl. are excluded: and the number of optional substituents on R⁶ is restricted to one or two. For the avoidance of doubt, in the preceding yet further aspect of the invention suitable N-oxides are optionally excluded.

In a preferred aspect of the invention there is provided a compound of the formula (I), or a pharmaceutically-acceptable salt or suitable N-oxide thereof, wherein the substituents R' to R⁶ and other optional substituents mentioned above have the values disclosed hereinbefore, or any of the following values :

(a) Preferably R¹ is hydroxy. chloro, fluoro. methanesulfonyloxy, amino. azido. methoxy, methylthio. methylaminocarbonyloxy, or of the formula -NHC(=O)R^a wherein R^a is hydrogen. methoxy. amino, chloromethyl. dichloromethyl, cyanomethyl, methoxymethyl, acetylmethyl. methylamino, dimethylamino or ( l-4C)alkyl or R¹ is of the formula -N(Me)C(=O)R^b wherein R is hydrogen, methyl or methoxy or R' is of the formula - NHS(O)_n(l-4C)alkyl wherein n is 0. 1 or 2.

(b) More preferably R' is hydroxy, chloro. fluoro, methanesulfonyloxy, or of the formula -NHC(=0)R^a wherein R^a is hydrogen, methoxy, amino, chloromethyl. dichloromethyl, cyanomethyl, methoxymethyl, acetylmethyl or (l -4C)alkyI or R¹ is of the formula - NHS(O),,(l-4C)alkyl wherein n is 0. 1 or 2.

(c) Yet more preferably R' is hydroxy, or of the formula -NHC(=O)R^a wherein R^a is ( 1 -4C)alk> 1 or R¹ is of the formula -NHS(O)„(l-4C)alkyl wherein n is 0. 1 or 2. (d) When R¹ is of the formula -NHS(O),,( 1 -4C)alkyl wherein n is 0. 1 or 2. n is preferably 2. (e) Yet more preferably R¹ is of the formula -NHC(=0)(l-4C)alkyl.

(f) Most preferably R¹ is acetamido.

(g) In another aspect R¹ is hydroxy.

(h) Preferably one of R² and R' is hydrogen and the other is fluoro. (i) Preferably at least one of R⁴ and R³ is hydrogen.

(j) Preferably R⁴ and R⁵ are both hydrogen.

(k) Preferably the heteroaryl ring in R⁶ is pyrimidine. pyridazine or pyrazine.

(1) Yet more preferably the heteroaryl ring in R" is pyrimidine or pyrazine.

(m) Still more preferably the heteroaryl ring in R⁶ is pyrimidin-2-yl or pyrazin-2-yl. (n) Most preferably the heteroaryl ring in R⁶ is pyrimidin-2-yl.

(o) Preferably optional substituents on the heteroaryl ring are not positioned in the 2- position relative to the ring carbon atom which is attached to the piperazine ring.

(p) Preferably the optional substituents on the heteroaryl ring are independently selected from ( l-4C)alkyI (optionally substituted by ( l-4C)alkoxy or (2-4C)alkanoylamino). ( 1- 4C)alkylthio. halo, carboxy, (l -4C)alkoxycarbonyl. and carbamoyl.

(q) More preferably the optional substituents on the heteroaryl ring are independently selected from methyl or ethyl (each optionally substituted by methoxy. ethoxy or acetamido). methylthio. ethylthio. chloro, bromo, carboxy, methoxycarbonyl. ethoxycarbonyl and carbamoyl. (r) Yet more preferably the optional substituents on the heteroaryl ring are independently selected from methyl, ethyl, methoxymethyl, 2-(acetamido)ethyl. methylthio. chloro. bromo. carboxy. methoxycarbonyl and carbamoyl.

(s) Most preferably the optional substituents on the heteroaryl ring are independently selected from ( l -4C)alkyl (preferably methyl), halo (preferably chloro). nitro. cyano. carbamoyl.

N-( 1 -4C)alkylcarbamoyI and di-(N-(l-4C)alkyl)carbamoyl.

(t) Preferably the heteroaryl ring is unsubstituted or substituted by one substituent.

(u) Most preferably the heteroaryl ring is unsubstituted.

Therefore, especially preferred compounds of the formula (I), or a pharmaceutically - acceptable salt or suitable N-oxide thereof, are those defined above wherein R¹ is acetamido. one of R² and R is hydrogen and the other is fluoro. R⁴ and R' are both hydrogen. R⁶ is pyrimidine or pyrazine and the optional substituents on the heteroaryl ring are independently selected from methyl, chloro. nitro. cyano. carbamoyl.

N-( l -4C alkylcarbamoyl and di-(N-( l -4C)alkyl)carbamoyl. Particular compounds of the present invention include :

N-[(5S)-3-(3-Fluoro-4-(4-(pyrimidin-2-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5- ylmethyljacetamide:

N-[(5S)-3-(3-Fluoro-4-(4-(pyrimidin-4-yl)piperazin-l -yl)phenyl)-2-oxooxazolidin-5- ylmethyl]acetamide: N-[(5S)-3-(3-Fluoro-4-(4-(pyrimidin-5-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5-yl- methyl]acetamide:

N-[(5S)-3-(3-Fluoro-4-(4-(5-nitropyrimidin-2-yl)piperazin-l -yl)phenyl)-2-oxooxazolidin-5- ylmethyl]acetamide:

N-[(5S)-3-(3-Fluoro-4-(4-(5-methylpyrimidin-2-yl)piperazin-l -yl)phenyl)-2-oxooxazolidin-5- ylmethyljacetamide:

N-[(5S)-3-(3-Fluoro-4-(4-(4-amino-5-cyanopyrimidin-2-yl)piperazin-l -yl)phenyl)-2- oxooxazolidin-5-ylmethyl]acetamide:

N-[(5S)-3-(3-Fluoro-4-(4-(2-methylpyrimidin-5-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5- ylmethyl]acetamide: N-[(5S)-3-(3-Fluoro-4-(4-(4-methylpyrimidin-5-yl)piperazin-l -yl)phenyl)-2-oxooxazolidin-5- ylmethyljacetamide;

N-[(5S)-3-(3-Fluoro-4-(4-(2-methylpyrimidin-4-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5- ylmethyl]acetamide;

N-[(5S)-3-(3-Fluoro-4-(4-(5-methylpyrimidin-4-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5- ylmethyl]acetamide:

N-[(5S)-3-(3-Fluoro-4-(4-(6-methylpyrimidin-4-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5- ylmethyljacetamide:

N-[(5S)-3-(3.5-Difluoro-4-(4-(pyrimidin-2-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5-yl- methyl]acetamide: N-[(5S)-3-(3.5-Difluoro-4-(4-(pyrimidin-4-yl)piperazin- 1 -yl)phenyl)-2-oxooxazolidin-5-yl- methyljacetamide: N-[(5S)-3-(3.5-Difluoro-4-(4-(pyrimidin-5-yl)piperazin-l -yl)phenyl)-2-oxooxazolidin-5-yl- methyl]acetamide;

N-[(5S)-3-(4-(4-(pyrimidin-2-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]- acetamide: N-[(5S)-3-(4-(4-(pyrimidin-4-yl)piperazin-l -yl)phenyl)-2-oxooxazolidin-5-ylmethyl]- acetamide:

N-[(5S)-3-(4-(4-(pyrimidin-5-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5-ylmethylj- acetamide: and pharmaceutically-acceptable salts, and suitable N-oxides, thereof. Further particular compounds of the present invention include :

N-[(5S)-3-(3-Fluoro-4-(4-(pyrazin-2-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]- acetamide:

N-[(5S)-3-(3-Fluoro-4-(4-(3-methylpyrazin-2-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5- ylmethyl]acetamide: N-[(5S)-3-(3-Fluoro-4-(4-(5-methylpyrazin-2-yl)piperazin-l -yl)phenyl)-2-oxooxazolidin-5- ylmethyljacetamide:

N-[(5S)-3-(3-Fluoro-4-(4-(6-methylpyrazin-2-yl)piperazin-l -yl)phenyl)-2-oxooxazolidin-5- ylmethyljacetamide:

N-[(5S)-3-(4-(4-(pyrazin-2-yl)piperazin-l -yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide: N-[(5S)-3-(3.5-Difluoro-4-(4-(pyrazin-2-yl)piperazin- 1 -yi)phenyl)-2-oxooxazolidin-5- y l ethy 1] acetamide ;

N-[(5S)-3-(3-Fluoro-4-(4-(6-methylpyridazin-3-yl)piperazin-l -yl)phenyl)-2-oxooxazolidin-5- ylmethyljacetamide:

N-[(5S)-3-(3-Fluoro-4-(4-(6-chloropyridazin-3-yl)piperazin-l -yl)phenyl)-2-oxooxazolidin-5- ylmethyl]acetamide; and pharmaceutically-acceptable salts, and suitable N-oxides, thereof. Especially preferred compounds of the invention include

N-[(5S)-3-(3-Fluoro-4-(4-(pyrimidin-2-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5- y [methyljacetamide: N-[(5S)-3-(3-Fluoro-4-(4-(pyrazin-2-yl)piperazin-l-yl)phenyI)-2-oxooxazolidin-5-ylmethyl]- acetamide: and pharmaceutically-acceptable salts, and suitable N-oxides. thereof.

In a further aspect the present invention provides a process for preparing a compound of the formula (I), a pharmaceutically-acceptable salt, suitable N-oxide or in-vivo hydrolysable ester thereof. The compounds of the formula (I), a pharmaceuticalh -acceptable salt, suitable N-oxide or in-vivo hydrolysable ester thereof may be prepared by deprotecting a compound, containing at least one protecting group, of the formula (II). a pharmaceutically- acceptable salt, suitable N-oxide or in-vivo hydrolysable ester thereof :

(II) wherein R² , R³, R⁴ and R⁵ are as hereinabove defined. R⁷ is R⁶ or protected R⁶ and R¹⁰ is R¹ or protected R' and thereafter if necessary forming a pharmaceutically-acceptable salt, suitable N- oxide or in-vivo hydrolysable ester.

Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.

Specific examples of protecting groups are given below for the sake of convenience, in which "lower" signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned is of course within the scope of the invention.

A carboxy protecting group may be the residue of an ester- forming aliphatic or araliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms). Examples of carboxy protecting groups include straight or branched chain ( ! -12C)alkyl groups (eg isopropyl. tert-butvl); lower alkoxy lower alkyl groups (eg methoxymethyl. ethoxymethyl. isobutoxy methyl: lower aliphatic acyloxy lower alkyl groups, (eg acetoxymethyl. propionyloxymethyl. butyryloxymethyl, pivaloyloxymethyl): lower alkoxycarbonyloxy lower alkyl groups (eg 1-methoxycarbonyloxyethyl.

1 -ethoxycarbonyloxy ethyl): aryl lower alkyl groups (eg g-methoxybenzyl, < nitrobenzyl, r nitrobenzyl. benzhydryl and phthalidyl): tri(lower alkyDsilyl groups (eg trimethylsilyl and tert-butvldimethylsilyl); triOower alkyl)silyl lower alkyl groups (eg trimethylsilylethyl): and (2-6C)alkenyl groups (eg allyl and vinylethyl). Methods particularly appropriate for the removal of carboxyl protecting groups include for example acid-, metal- or enzymically-catalysed hydrolysis.

Examples of hydroxy protecting groups include lower alkenyl groups (eg allyl): lower alkanoyl groups (eg acetvl); lower alkoxycarbonyl groups (eg tert-butoxvcarbonyl ); lower alkenyloxycarbonyl groups (eg allyloxycarbonyl); aryl lower alkoxycarbonyl groups (eg benzoyloxycarbonyl, r methoxybenzyloxycarbonyl, ( nitrobenzyloxycarbonyl. r nitrobenzyloxycarbonyl): tri lower alkyl/arylsilyl groups (eg trimethylsilyl. tert- butyldimethylsilyl. tert-butvldiphenvlsilyl); aryl lower alkyl groups (eg benzyl) groups: and triaryl lower alkyl groups (eg triphenylmethyl).

Examples of amino protecting groups include formyl. aralkyl groups (eg benzyl and substituted benzyl, eg r methoxybenzyl. nitrobenzyl and 2.4-dimethoxybenzyl. and triphenylmethyl); di-r anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (eg tert- butoxycarbonyl); lower alkenyloxycarbonyl (eg allyloxycarbonyl); aryl lower alkoxycarbonyl groups (eg benzyloxycarbonyl. r methoxybenzyloxycarbonyl, c iitrobenzyloxycarbonyl, r nitrobenzyloxycarbonyl; trialkylsilyl (eg trimethylsilyl and tert-butvldimethvlsihT): alkylidene (eg methylidene): benzylidene and substituted benzylidene groups.

Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, metal- or enzymically-catalysed hydrolysis, for groups such as o_-nitrobenzyioxycarbonyl. photolytically and for groups such as silyl groups, fluoride. Examples of protecting groups for amide groups include aralkoxymethyl (eg. benzyloxymethyl and substituted benzyloxymethyl); alkoxymethyl (eg. methoxymethyl and trimethylsilylethoxymethyl); tri alkyl/arylsilyl (eg. trimethylsilyl. tert-butvldimethylsilyl. by reacting the amide with the appropriate chloride and removing with acid, or in the case of the silyl containing groups fluoride ions. The alkoxyphenyl and alkoxybenzyl groups are conveniently introduced by arylation or alkylation with an appropriate halide and removed by oxidation with eerie ammonium nitrate. Finally alk-1-enyl groups may be introduced by reacting the amide with the appropriate aldehyde and removed with acid.

For further examples of protecting groups see one of the many general texts on the subject, for example. 'Protective Groups in Organic Synthesis^' by Theodora Green (publisher: John Wiley & Sons).

In another aspect of the present invention the compounds of the formulae (I) and (II). pharmaceutically-acceptable salts, suitable N-oxides and in-vivo hydrolysable esters thereof can be prepared:

(a) by modifying a substituent in or introducing a substituent into another compound of formula (I) or (II);

(b) when R¹ or R^,0 is of the formula - NHS(O)_n( l-4C)alkyl. wherein n is 1 or 2. by oxidising a compound of the formula (I) wherein n is 0 or. when n is 2 by oxidising a compound of the formula (I) or (II) wherein n is 1 ;

(c) when R¹ or R¹⁰ is azido, by reacting a compound of the formula (III) with a source of azide:

(III)

(d) when R' or R'° is amino, by reducing a compound of the formula (I) or (II) wherein R' or R¹⁰ is azido;

(e) when R' or R'° is of the formula -NHC(=O)R\ by introducing -C(=O)R^a into a compound of the formula (I) or (II) wherein R¹ or R^l0is amino: (f) when R¹ or R'° is of the formula -NHS(O)„ (l -4C)alkyl by introducing

-S(O)„ ( l -4C)alkyl into a compound of the formula (I) or (II) wherein R¹ or R¹⁰ is amino: (g) when R¹ or R'° is chloro. fluoro. ( 1 -4C)alkanesulfonyloxy or ( 1 -

4C)alkylaminocarbonyloxy. from a compound of the formula (I) or (II) wherein R^: or R'° is hydroxy:

(h) when R' or R^iϋ is chloro. ( 1 -4C)alkylthio or ( C)alkoxy. from a compound of the formula (III): (i) when R' or R^l0is hydroxy. by reacting a compound of the formula (IV) with a compound of the formula (V):

(IV) (V)

(j) by reacting a compound of the formula (VI) with a compound of the formula (VII):

(VI) (VII)

(k) when R¹⁰ is of the formula -N(CO2R^{1 5})CO(l-4C)alkyl; from a compound of the

formula (I) and (II) wherein R or R is hydroxy;

(1) when R¹ or R^lϋ is of the formula -N(Me)C(=O)R^b. by introducing the group -

C(=O)R^b into a compound of the formula (VIII):

(VIII) and (m) when a suitable N-oxide is required, by preparation directly from a corresponding parent compound of the formula (I) or (II). or by assembly from suitable N-oxide starting materials: wherein R² - R³ and R and R¹⁰ are as hereinabove defined. R¹² is mesvloxy or tosyloxy. R^π is (l-6C)alkyl or benzyl. R^l4 is (l-6C)alkyl. R¹⁵ is (l-4C)alkyl or benzyl and L¹ is a leaving goup and thereafter if necessary: i) removing any protecting groups; ii) forming a pharmaceutically-acceptable salt, suitable N-oxide or in-vivo hydrolysable ester.

Methods for converting substituents into other substituents are known in the art. For example, an alkylthio group may be oxidised to an alkylsulfinyl or alkysulfonyl group, a cyano group reduced to an amino group, a nitro group reduced to an amino group, an amino group converted to an acetamido or sulfonamido group, a hydroxy group alkylated to a methoxy group, a carboxy group converted to a carbamoyl group, an N-(l-4C)alkyicarbamoyl or di-(N-( 1 -4C)alkyl)carbamoyl group, or a bromo group converted to an alkylthio group. Also for example, a chloro group may be introduced at an unsubstituted position in R . or a chloro group may be removed from R⁷ (by, for example, hydrogenation as in Examples 9 and 31 ).

Compounds of the formula (I) or (II) wherein R¹ or R'° is -NHS(O)„ ( l-4C)alkyl can be prepared by oxidising a compound of the formula (I) or (II) with standard reagents known in the art for the oxidation of a thio group to a sulfinyl or suifonyl group. For example, a thio group may be oxidised to a sulfinyl group with a peracid such as m-chloroperoxybenzoic acid and oxidising agents such as potassium permanganate w ill convert a thio group to a sulfonyl group. Compounds of the formula (I) or (II) wherein R¹ or R'°is -NHS(l -4C)alkyl can be prepared by reacting compounds of the formula (I ) or (II) wherein R¹ or R¹" is amino with a reagent such as ( l-4C)alkylSCl.

A compound of the formula (I) or (II) wherein R' or R^l() is azido may be prepared. for example, by reacting a compound of the formula (III) with sodium azide in an inert solvent such as DMF in a temperature range of ambient to 100°C. normally in the region of 75°C - 85°C. A compound of the formula (III) may be prepared by converting the hydroxy group in a compound of the formula (I) or (II) wherein R' or R'° is hydroxy into a tosyloxy or mesvloxy group by standard methods known in the art. For example, by reacting the compound of the formula (I) or (II) with tosyl chloride or mesyl chloride in the presence of a mild base such as triethylamine. or pyridine.

Suitable reducing agents for reducing azido to amino in a compound of the formula (I) or (II) include triethylamine/hydrogen sulfide. triphenylphosphine or phosphite ester, or hydrogen in the presence of a catalyst. More specifically the reduction of the azido group may be carried out by heating it in an aprotic solvent, such as 1,2-dimethoxyethane. in the presence of P(OMe), and subsequently heating in 6N aqueous hydrochloric acid, or reacting it with hydrogen in the presence of palladium on carbon in a solvent such as DMF or ethyl acetate. For further details on the reduction of azides to amines see USP 4,705.799. The azido compound may be reduced and converted to a compound of the formula (I) or (II). wherein R¹ or R¹" is acetamido. in situ using acetic anhydride in DMF.

When R^π is ( l-4C)alkyl, the group -C(=O)(l-4C)alkyl may be introduced into a compound of the formula (I) or (II) wherein R¹ or R'° is amino by standard acetylation procedures. For example, the amino group may be acetylated to give an acetamido group using the Schotten-Baumann procedure i.e. reacting the compound of the formula (I) or (II) wherein R' or R¹⁰ is amino with acetic anhydride in aqueous sodium hydroxide and THF in a temperature range of 0°C to ambient temperature. Preferably the acylation is carried out in situ following the catalytic hydrogenation of a compound of the formula (I) or (II) wherein R¹ or R^ιcι is azido. by performing the hydrogenation in the presence of acetic anhydride (for example using similar methods to those used in Example 15). When R^a is hydrogen, the -CHO group may be introduced into the compound of the formula (I) or (II) wherein R' or R¹⁰ is amino (amino compound) by reacting the latter compound with formic acetic anhydride, in an inert organic solvent such as THF. in a temperature range of 0°C to ambient temperature, or by reacting it with ethyl formate in an inert organic solvent in the temperature range of 50-100°C.

When R^a is ( 1 -4C)alkoxy, the -COO( l-4C)alkyl group may be introduced into the amino compound by reacting the latter compound with ( l-4C)alkyl chloroformate. in the presence of an organic base such as triethylamine. in an organic solvent such as dichloromethane and in a temperature range of 0°C to ambient temperature.

When R^a is amino, the -CONH₂ group may be introduced into the amino compound by reacting the latter compound either with potassium cyanate in aqueous acid (eg hydrochloric acid) in a temperature range of ambient temperature to 40°C or with phenyi carbamate in glyme at reflux.

When R^a is chloromethyl. dichloromethyl. cyanomethyl or methoxymethyl. the -C(=0)R^a group may be introduced into the amino compound by reacting the latter compound with the appropriate acid chloride under standard conditions. The acid chloride may be prepared from the appropriate acid. When R^a is acetylmethyl, the -C(=O)R^a group may be introduced into the amino compound by reacting the latter compound with diketene. in an inert organic solvent such as THF, in a temperature range of 0°C to ambient temperature.

Alternatively, the amino compound may be reacted with the appropriate acid anhydride, in dichloromethane or THF, in the presence of an organic base such as triethylamine and in a temperature range of 0°C to ambient temperature, or the amino compound may be reacted with the appropriate acid in the presence of l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and an organic base such as triethylamine, in an organic solvent such as dichloromethane, in a temperature range of 0°C to ambient temperature. When R^a is methylamino, the -CONHMe group may be introduced into the amino compound by reacting the latter compound with methyl isocyanate in an organic solvent such as THF or acetonitrile. in a temperature range of 0°C to ambient temperature.

When R^a is dimethylamino, the -CONMe₂ group may be introduced into the amino compound my reacting the latter compound with dimethylcarbamoyl chloride and triethylamine in an organic solvent such as THF or acetonitrile. in a temperature range of 0°C to ambient temperature. Standard reaction conditions for the conversion of a compound of the formula (I) or (II) wherein R¹ or R¹⁰ is amino to a compound of the formula (I) or (II) wherein R or R¹⁰ is sulfonamido are known in the art. For example, a compound of the formula (I) or (II) wherein R¹ or R'° is amino could for example be converted to a compound of the formula (I) or (II) wherein R¹ or R"^J is ( 1 -4C)alkylSO,NH- by reacting the former compound with a sulfonyl chloride, for example, mesyl chloride, in a mild base such as pyridine. Alternatively compounds of the formula (I) or (II) wherein R¹ or R¹⁰ is ( l -4C)alkylSO_:!NH- or (l-4C)alkylSONH- may be prepared by reacting a compound of the formula (I) or (II) wherein R¹ is amino with a compound of the formula ( l-4C)alkylSO .L² or (1 -4C)SOL² wherein L is a phthalimido group.

The phthalimido compound may be prepared by oxidising a compound of the formula (IX):

with standard oxidising agents known for the conversion of a thio group to a sulfinyl or sulfonyl group.

Compounds of the formula (IX) can be prepared by reacting phthalimide with an alkylthiochloride (( l -4C)alkylSCl).

A compound of the formula (I) or (II) wherein R' or R'° is fluoro may be prepared by reacting a compound of the formula (I) or (II) wherein R¹ or R^lϋ is hydroxy (hydroxy compound) with a fluorinating agent such as diethylaminosulfur trifluoride in an organic solvent such as dichloromethane in the temperature range of 0°C to ambient temperature.

When R' or R¹⁰ is chloro. the compound of the formula (I) or (II) may be formed by reacting the hydroxy compound with a chlorinating agent. For example, by reacting the hydroxy compound with thionyl chloride in a temperature range of ambient temperature to reflux, optionally in a chlorinated solvent such as dichloromethane or by reacting the hydroxy compound with carbon tetrachloride/triphenyl phosphine in dichloromethane. in a temperature range of 0°C to ambient temperature. The ( l -4C)alkanesulfonyloxy compound may be prepared by reacting the hydroxy compound with (l -4C)alkanesulfonyl chloride in the presence of a mild base such as triethylamine or pyridine.

The ( l -4C)al ylaminocarbonyloxy compound may be prepared by reacting the hydroxy compound with (l-4C)alkyl cyanate in an organic solvent such as THF or acetonitrile. in the presence of triethylamine, in a temperature range of 0°C to 50°C.

A compound of the formula (I) or (II) wherein R¹ or R¹⁰ is chloro may also be prepared from a compound of the formula (III), by reacting the latter compound with lithium chloride and crown ether, in a suitable organic solvent such as THF. in a temperature range of ambient temperature to reflux. A compound of the formula (I) or (II) wherein R¹ or R'° is (1 - 4C)alkylthio or ( l-4C)alkoxy may be prepared by reacting the compound of the formula (III) with sodium thio( l-4C)alkoxide or sodium (l -4C)alkoxide respectively, in an alcohol or THF. in a temperature range of 0°C to reflux.

Compounds of the formulae (IV) and (V) are conveniently reacted together in the presence of a strong base such as butyl lithium, lithium bistrimethylsilylamide. sodium hydride, lithium tert-butoxide or lithium diisopropylamide. The reaction is conveniently carried out in an inert solvent such as tetrahydrofuran (THF), dimethylformamide (DMF), N,N'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidone in a temperature range of - 78°C to -50°C for the deprotonation and cyclisation. Suitable values for R¹³ include ethyl and benzyl and suitable values for R'⁴ include ethyl and n-propyl, preferably n-propyl. A compound of the formula (IV) is conveniently prepared by reacting a chloroformate of the formula (ClCOORⁿ) with a compound of the formula (IVA):

(IVA) wherein R² - R⁵ and R are as hereinabove defined. The reaction is conveniently carried out in the presence of an inorganic or organic base such as sodium bicarbonate or an amine base such as dimethylaniline. the former in a solvent such as acetone/water and the latter in an organic solvent such as THF. toluene. DMF or acetonitrile.

A compound of the formula (IVA) may be prepared by reducing a compound of the formula (IVB):

(IVB) wherein R² - R' and R are as hereinabove defined.

Many reduction methods suitable for the reduction of a nitro to an amino group are known in the art, for example catalytic hydrogenation. metal reductions or with reducing agents such as sodium hvdrosulfite. Suitable catalysts in catalytic hydrogenation include

Raney nickel, platinum metal and its oxide, rhodium, palladium-on-charcoal and Wilkinson^'s catalyst RhCl (Ph,P) Catalyst hydrogenation is conveniently carried out in the temperature range 0°C - 150°C. but preferably at ambient temperature at slightly above atmospheric pressure. A compound of the formula (IVB) is conveniently prepared by reacting together compounds of the formulae (X) and (IVC):

R⁴

wherein R² - R^" and R are as hereinabove defined and L is a leaving group, preferably halo and in particular fluoro. The reaction between compounds of the formulae (X) and (IVC) is carried out in the presence of an organic or inorganic base such as sodium bicarbonate, potassium carbonate or an amine base such as diisopropylethylamine. in an inert solvent such as acetonitrile. DMF. DMPU or N-methylpyrrolidone. in a temperature range of 50°C - 150°C. Compounds of the formula (X) are conveniently prepared by reacting the appropriate piperazine ring with a compound of the formula (VII) using similar conditions to those described (see later) for the reaction between compounds of the formulae (VI) and (VII). It may be advantageous to protect one of the ring nitrogen atoms in the piperazine ring prior to the reaction with a compound of the formula (VII) and remove the protecting group thereafter. For compounds of the formula VII in which L¹ is not activated for displacement, more vigorous reaction conditions may be necessary, for example the Buchwald reaction using a strong base (such as potassium tert-butoxide or lithium bistrimethylsilylamide) and a catalyst (such as Pd(0)). as illustrated in Example 15. It is within the ordinary skill of an organic chemist to recognise when such reaction conditions are necessary. Alternatively, a compound of the formula (IVB) may be formed by reacting the appropriate piperazine ring in which one of the ring nitrogen atoms is protected (with for example a ( 1 -4C)alkoxycarbonyl group) with a compound of the formula (IVC). The ring nitrogen-protecting group may then be removed and R⁷ introduced onto the ring nitrogen by reacting the product of the deprotection with a compound of the formula (VII). Compounds of the formula (VII) may be prepared by introducing substituents into or modifying substituents in a known optionally substituted heteroaryl ring. Such conversions are well known to the skilled chemist, for example a cyano group may be hydrolysed to a carboxy group which in turn may be converted to a carbamoyl or alkoxycarbonyl group or reduced to a hydroxymethyl group; an amino group may be acylated to an alkanoylamino group: a thio group may be alkylated to an alkylthio group which in turn may be oxidised to an alkylsulfinyl or alkylsulfonyl group and a hydroxyalkyl group may be alkylated to an alkoxyalkyl group.

The reaction between compounds of the formulae (VI) and (VII) is conveniently carried out in the presence of a base, in an aprotic polar solvent; preferably one with a high boiling point, such as acetonitrile or dimethylformamide. Suitable bases include amine bases such as triethylamine. The reaction is preferably carried out in the temperature range 50°C - 150°C. Suitable leaving groups for this reaction include halo. ( l-4C)alkylthio. ( l -4C)alkanesuIfιnyl. ( l-4C)alkanesulfonyl or phenoxy. Preferably the leaving group is fluoro. chloro or ( 1 -4C)alkanesulfonyl such as methanesulfonyl. A compound of the formula (II) wherein R is of the formula

-N(CO2R )CO( 1 -4C)alkyl is conveniently prepared by reacting a compound of the formula

(I) and (II) wherein R or R is hydroxy with an amide of the formula

HN(CO2R )CO( I -4C)aIkyl under Mitsunobu conditions. For example, in the presence of tri-n-butylphosphine and 1.1 ^"-(azodicarbonyl)dipiperidine in an organic solvent such as THF. and in the temperature range 0°C - 60°C. but preferably at ambient temperature. Details of analogous Mitsunobu reactions are contained in Tsunoda et al. Tet. Letts.. 34. 1639. ( 1993).

Amides of the formula HN CO2R )CO(I-4C)alkyl may be prepared by standard procedures of organic chemistry which are within the ordinary skill of an organic chemist.

The group -C(=O) R^b may be introduced into a compound of the formula (VIII) to give the appropriate compound of the formula (I) or (II) wherein R'or R^lϋ is of the formula -N(Me)C(=0)R^b using similar methods to those described for the introduction of the appropriate -C(=0)R^a group into the compound of the formula (I) or (II) wherein R¹ or R¹" is amino.

The compound of the formula (VIJI) may be prepared by reacting a compound of the formula (I) or (II) wherein R¹ or R^lϋ is amino with formaldehyde and sodium borohydride or sodium cyanoborohydride. in an alcholic solvent such as ethanol or isopropanol. in a temperature range of 0°C to ambient temperature.

Suitable N-oxides of compounds of the formula (I) or (II) may be prepared directly from a corresponding parent compound of the formula (I) or (II) using techniques well known to the ordinary skilled organic chemist, such as, for example, using a peracid (such as m- chloroperbenzoic acid) or perphthaiic acid in a suitable solvent (such as dioxan or a mixture of water and THF) at a suitable temperature (such as ambient temperature). Example 36 also illustrates possible suitable reagents and conditions for preparing suitable N-oxides. The preparation of suitable N-oxides by assembly from suitable N-oxide starting materials and the use of the processes described in this specification is within the skill of the ordinary skilled organic chemist, and is illustrated by. for example. Example 18.

It is also possible to convert one R 7 group i •nto another R 7 group as a final step in the preparation of a compound of the formula (I) or (II) (see the specific examples). When an optically active form of a compound of the formula (I) is required, it may be obtained by carrying out one of the above procedures using an optically active starting material, or by resolution of a racemic form of the compound or intermediate using a standard procedure.

According to a further feature of the invention there is provided a compound of the formula (I), or a pharmaceutically-acceptable salt, suitable N-oxide or in-vivo hydrolysable ester thereof, for use in a method of treatment of the human or animal body by therapy.

According to a further feature of the present invention there is provided a method for producing an antibacterial effect in a warm blooded animal, such as man. in need of such treatment, which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically-acceptable salt, suitable N-oxide or in-vivo hydrolysable ester thereof.

The invention also provides a compound of the formula (I), or a pharmaceutically- acceptable salt, suitable N-oxide or in-vivo hydrolysable ester thereof, for use as a medicament: and the use of a compound of the formula (I) of the present invention, or a pharmaceutically-acceptable salt, suitable N-oxide or in-vivo hydrolysable ester thereof, in the manufacture of a medicament for use in the production of an antibacterial effect in a warm blooded animal, such as man.

In order to use a compound of the formula (I) or a pharmaceutically-acceptable salt, suitable N-oxide or in-vivo hydrolysable ester thereof for the therapeutic treatment of mammals including humans, in particular in treating infection, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I) or a pharmaceutically-acceptable salt, suitable N-oxide or in-vivo hydrolysable ester thereof and a pharmaceutically-acceptable diluent or carrier. The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, rectal or parenteral administration. For these purposes the compounds of this invention may be formulated by means known in the art into the form of. for example, tableis. capsules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.

In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain or be co-administered with one or more known drugs selected from other clinically useful antibacterial agents (for example β-lactams or aminogiycosides). These may include penicillins, for example oxacillin or flucloxacillin and carbapenems. for example meropenem or imipenem. to broaden the therapeutic effectiveness against methicillin-resistant staphylococci. Compounds of this invention may also contain or be co-administered with bactericidal/permeability-increasing protein product (BPI) or efflux pump inhibitors to improve activity against gram negative bacteria and bacteria resistant to antimicrobial agents.

A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between lOOmg and lg of the compound of this invention.

In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.

Each patient may receive, for example, a daily intravenous, subcutaneous or intramuscular dose of 5 rngkg-* to 20 mgkg-1 of the compound of this invention, the composition being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.

Antibacterial Activity The pharmaceutically-acceptable compounds of the present invention are useful antibacterial agents having a good spectrum of activity in vitro against standard Gram-positive organisms. which are used to screen for activity against pathogenic bacteria. Notably, the pharmaceutically-acceptable compounds of the present invention show activity against enterococci. pneumococci and methicillin resistant strains of S. aureus and coagulase negative staphylococci. The antibacterial spectrum and potency of a particular compound may be determined in a standard test system.

The antibacterial properties of the compounds of the invention may also be demonstrated in-vivo in conventional tests. No overt toxicity or other untoward effects are observed when compounds of the formula I are so tested at conventional daily dose levels.

The following results were obtained on a standard in-vitro test system. The activity is described in terms of the minimum inhibitory concentration (MIC) determined by the agar-dilution technique with an inoculum size of 10^ CFU/spot.

Staphylococci were tested on agar. using an inoculum of 10^ CFU/spot and an incubation temperature of 37°C for 24 hours - standard test conditions for the expression of methicillin resistance. Streptococci and enterococci were tested on agar supplemented with 5% defibrinated horse blood, an inoculum of 10^ CFU/spot and an incubation temperature of 37°C in an atmosphere of 5% carbon dioxide for 48 hours - blood is required for the growth of some of the test organisms.

Organism MIC (ug/ml)

Example 1

Staphylococcus aureus:

Oxford 0.5 Novb. Res 1.0

MRQR 1.0

Coagulase Negative Staphylococci

MS 0.25

MR 0.5 Streptococcus pyogenes

C203 1.0 Enterococcus faecalis 1.0

Bacillus subtilis 0.25

Novb. Res = Novobiocin resistant MRQR = methicillin resistant quinolone resistant MR = methicillin resistant MS = methicillin sensitive

The invention is now illustrated but not limited by the following Examples in which unless otherwise stated :- i) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids by filtration: (ii) operations were carried out at ambient temperature, that is in the range 18-26°C and in air unless otherwise stated, or unless the skilled person would otherwise work under an inert atmosphere; (iii) column chromatography (by the flash procedure) was performed on Merck

Kieselgel silica (Art. 9385) unless otherwise stated:

(iv) yields are given for illustration only and are not necessarily the maximum attainable: (v) the structure of end-products of the formula I were generally confirmed by NMR and mass spectral techniques [proton magnetic resonance spectra were determined in DMSO- D6 unless otherwise stated using a Varian Gemini 2000 spectrometer operating at a field strength of 300 MHz. or a Bruker AM250 spectrometer operating at a field strength of 250 MHz: chemical shifts are reported in parts per million downfield from tetramethysilane as an internal standard (δ scale) and peak multiplicities are shown thus: s. singlet; d, doublet; AB or dd. doublet of doublets: t, triplet, m, multiplet: fast-atom bombardment (FAB) mass spectral data were obtained using a Platform spectrometer (supplied by Micromass) run in electrosprav and. where appropriate, either positive ion data or negative ion data were collected]: (vi) intermediates were not generally fully characterised and purity was in general assessed by thin layer chromatographic. infra-red (IR), mass spectral (MS) or NMR analysis: and

(vii) in which :- ® is a Trademark

DMF is N.N-dimethylformamide DMA is N.N-dimethylacetamide TLC is thin layer chromatography DMSO is dimethylsulfoxide CDCI3 is deuterated chloroform MS is mass spectroscopy ESP is electrospray THF is tetrahydrofuran TFA is trifluoroacetic acid NMP is N-methylpyrrolidone dba is dibenzylideneacetone DMPU is N.N-dimethylpropyleneurea.

Example 1 : N-|(5S)-3- 3-Fluoro-4-(4-(pyriιnidin-2-yl)piperazin-l-vπphenyl)-2- oxooxazolidin-5-ylmethvI|acetamide

N-[(5S)-3-(3-Fluoro-4-(piperazin-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide 1.5 trifluoroacetate salt (500 mg. 1 mM) was dissolved in ethanol (20 ml). 2-Chloropyrimidine ( 125 mg. 1.1 mM) was added, followed by triethylamine (0.36 ml. 2.6 mM) and water (2 ml. to aid solubility), and the solution stirred at ambient temperature for 24 hours. Further 2- chloropyrimidine (62 mg, 0.5 mM) was added, and the mixture refluxed for 16 hours. The solution was evporated to dryness. water (20 ml) added to the residue, and the pH adjusted to 12 with 1 sodium hydroxide solution. The solution was extracted with ethyl acetate (2 x 20 ml), and the combined organic layers dried over magnesium sulfate. and evaporated. The white residue was chromatographed on silica, eluting with a gradient increasing in polarity from 0 to 5% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the title product (270 mg).

MS (ESP): 415 (MH⁺) NMR (DMSO-D6) δ: 1.83 (s, 3H); 3.03 (t. 4H): 3.40 (t. 2H); 3.70 (dd, IH); 3.87 (t. 4H): 4.08 (L lH): 4.69 (m. lH); 6.65 (t. lH); 7.09 (t. IH); 7.17 (dd. IH): 7.49 (dd. I H): 8.19 (t. I H); 8.38 (d, 2H).

The N-[(5S)-3-(3-fluoro-4-(piperazin- 1 -yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide 1.5 trifluoroacetate salt starting material was prepared as follows :-

N-[(5S)-3-(3-Fluoro-4-(4-tert-butoxycarbonylpiperazin- l -yl)phenyl)-2-oxooxazolidin-5- ylmethyljacetamide (PCT patent application WO 93/23384 Example 1 (j), 1 g_^ 2.3 mM) was dissolved in dichloromethane (50 ml) under argon, and cooled in an ice-bath. TFA (12.7 ml) was added, and the mixture stirred at 0°C for 30 minutes. Solvent was evaporated, and the residue treated four times by evaporation with 30 ml portions of ethyl acetate to remove TFA. The required starting material as a remaining solid analysed for 1.5 moles of residual TFA.

MS (ESP ): 337 (MH+).

NMR (DMSO-D6 + CD.COOD) δ: -1.8 (obscured by solvent): 3.21 (t, 4H): 3.28 (t. 4H); 3.45 (t. 2H): 3.74 (dd. IH): 4.19 (t. IH); 4.73 (m. IH): 7.12 (t. IH): 7.21 (dd. I H): 7.52 (dd. I H). Example 2 : N-|(5S)-3-(3-Fluoro-4-(4-(5-chloroDyrimidin-2-vπpiperazin-l-yl)phenyl)-2- oxooxazolidin-5-ylmethyllacetamide

N-[(5S)-3-(3-Fluoro-4-(piperazin-l -yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide trifluoroacetate salt (6.73 g, 15 mM) was dissolved in DMA ( 100 ml). Triethylamine (4.37 ml. 31.4 mM) was added, and the whole mixture stirred at ambient temperature under argon for 10 minutes. 2,5-Dichloropyrimidine (2.23 g, 15 mM) was added, and the solution heated to 100°C for 8 hours. After cooling, solvent was evaporated, and the residue slurried with water for 1 hour. Solid was filtered, washed with water (2 x 100 ml) and dried. The residue was chromatographed twice on silica by dry flash chromatography. eluting with a gradient increasing in polarity from 0 to 4% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the title product (3.04 g). Microanalvsis: Found: C. 53.4; H, 4.8; N, 18.6%.

Required for C₂₀H_::C1FN₆O,: C. 53.6; H, 4.9; N. 18.7%.

MS (ESP): 449 (MH÷) for C₂₀H_:2C1FN₆O, NMR . DMSO-D6) δ: 1.82 (s, 3H); 3.02 (t, 4H); 3.39 (t. 2H); 3.69 (dd. IH); 3.86 (t, 4H): 4.06 (t. lH): 4.68 (m. lH); 7.08 (t. lH); 7.16 (dd, IH); 7.48 (dd. IH); 8.19 (t. lH): 8.43 (s. 2H).

The N-[(5S)-3-(3-fluoro-4-(piperazin-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide trifluoroacetate salt starting material was prepared as follows :-

N-[(5S)-3-(3-Fluoro-4-(4-tert-butoxycarbonylpiperazin-l-yl)phenyl)-2-oxooxazolidin-5- ylmethyljacetamide (PCT patent application WO 93/23384, 34 g, 78 mM) was dissolved in dichloromethane (500 ml), and cooled in an ice-bath. TFA (50 ml) was added, and the mixture stirred at 0°C for 1.5 hours. Solvent was evaporated, and the residual oil dissolved in ethyl acetate (40 ml). Diethyl ether was added to turbidity (-75 ml), and the solution left to crystallise. Filtration gave product as the mono trifluroacetate salt (32.5 g). Microanalvsis: Found : C. 47.5; H. 5.0; N. 1 1.8 C₁₈H_::F_{J 4}0₅ requires : C. 48.0; H, 4.9; N. 12.4 Example 3 : N-K5S)-3-f3-Fluoro-4-(4-(4.6-dimethylpyr_midin-2-yl)p.perazin-l- yl)phenyl.-2-oxooxazolidin-5-vimethyllacetaπ_.de

N-[(5S)-3-(3-Fluoro-4-(piperazin-l-yl)phenyl)-2-oxooxazolidin-5- lmethyl]acetamide trifluoroacetate salt (90 mg, 0.2 mM) was dissolved in DMA (3 ml). Triethylamine (58 μL. 0.42 mM) was stirred in, then 2-chloro-4.6-dimethylpyrimidine (28.5 mg. 0.2 mM ) was added, and the solution heated under argon at 160°C for 5 hours. After cooling, solvent was evaporated, and the residue chromatographed on a 5 g silica Mega Bond F-.lut® column, eluting with a gradient increasing in polarity from 0 to 3% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the title product (50 mg). MS (ESP): 443 (MH⁺) for C₂₂H₂ -FN₆O,

NMR f CDCK) δ: 2.03 (s. 3H); 2.31 (s. 6H): 3.09 (t. 4H): 3.60-3.71 (m. 2H): 3.75 (dd. I H); 3.99 (t. 4H): 4.02 (t, I H); 4.76 (m. I H): 6.09 (brt. I H): 6.29 (s. I H); 6.95 (t. IH); 7.08 (dd. I H): 7.44 (dd. I H).

Example 4 : N-fr5S)-3-(3-Fluoro-4-(4-(3,5-dichloropyridazin-4-vπpiperazin-l-vhphenyl)- 2-oxooxazol_din-5-yln_ethyl|acetamide

N-[(5S)-3-(3-Fluoro-4-(piperazin-l -yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide trifluoroacetate salt (450 mg. 1 mM) was dissolved in DMA ( 15 ml). Triethylamine (306 μL. 2.2 mM) was stirred in. then 3,4.5-trichloropyridazine ( 184mg, 1 mM) was added, and the solution heated to 100°C for 16 hours. After cooling, the mixture was diluted with water (50 ml) and extracted weith ethyl acetate (2 x 25 ml). The combined extracts were dried over magnesium sulfate. evaporated, and the residue chromatographed on a 20 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 5% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the title product (280 mg).

MS (ESP): 483 (MH⁺) for C_:oH₂₁Cl₃FN₆O,

NMR (DMSO-Dό) δ: 1.83 (s. 3H); 3.13 (t. 4H); 3.39 (t. 2H); 3.57 (t. 4H); 3.69 (dd. IH); 4.06 (t. I H); 4.70 (m. IH); 7.10 (t. IH); 7.18 (dd. IH); 7.49 (dd. IH): 8.21 (brt. IH): 9.01 (s, IH). Example 5 : N-f(5S)-3-(3-Fluoro-4-(4-(6-chloropyridazin-3-yl)piperazin-l-yl)phenyl)-2- oxooxazo_id-n-5-ylmethvHacetam.de

N-[(5S)-3-(3-Fluoro-4-(piperazin-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide trifluoroacetate salt (0.9 g, 2 M) was dissolved in NMP (25 ml), triethylamine (0.28 ml. 2 mM) and 3.6-dichloropyridazine (298 mg. 2 mM) were added, and the solution heated to 1 10°C for 24 hours. After cooling, solvent was evaporated, and the residue chromatographed on a 20 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 4% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the title product (165 mg). MS (ESP): 449 (MH⁺) for CjoHr_.ClFN₆O .

NMR (DMSO-Dό) δ: 1.83 (s. 3H); 3.06 (t. 4H); 3.39 (t, part obscured. 2H); 3.73 (t + m. 5H): 4.07 (t, IH); 4.68 ( , IH); 7.09 (t. IH); 7.17 (dd. I H); 7.42 (d. I H); 7.48 (dd. I H); 7.54 (d. IH): 8.21 (t. IH).

Example 6 : N-f(5S)-3-(3-Fluoro-4-(4-(pyridazin-3-yl)piperazin-l-V-)phenv0-2- oxooxazoltdin-5-ylmethyl)acetaπ_ide

N-[(5S)-3-(3-FIuoro-4-(4-(6-chloropyridazin-3-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5- ylmethyl]acetamide (247 mg, 0.55 mM) was dissolved in ethanol (25 ml), and treated with triethylamine (77 μL. 0.55 mM). Palladium catalyst (10% on charcoal. 100 mg) was added. and the mixture hydrogenated under balloon pressure for 18 hours. Catalyst was filtered off through celite, solvent evaporated, and the residue chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 2.5% to 5% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the title product (79 mg). MS (ESP): 415 (MH+) for C,₀H₂₃FN₆O₃

NMR (DMSO-D6) δ: 1.81 (s, 3H); 3.06 (t. 4H); 3.38 (t. 2H); 3.70 (br, 5H); 4.06 (t. lH); 4.68 (m. l H); 7.10 (t. lH); 7.16 (dd, IH); 7.29 (d. lH); 7.38 (dd. IH); 7.49 (dd. IH); 8.18 (brt. IH) 8.55 (d. IH). Example 7 : N-l(5S)-3-(3-Fluoro-4-,4-(6-carbamoylpyridazin-3-yl)piperazin-l- vI)Dhenyl)-2-oxooxazolidin-5-ylmethvI]acetaπιide

N-[(5S)-3-(3-Fluoro-4-(piperazin-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide trifluoroacetate salt (225mg, 0.5 mM) was dissolved in DMA ( 15 ml), triethylamine ( 101 mg. 1 mM) was added, and the whole mixture stirred at ambient temperature under argon for 15 minutes. 3-Chloropyridazine-6-carboxarnide (Heterocycles. 1992. 34. 225; 79 mg. 0.5 mM) was added, and the solution heated to 120°C for 6 hours. After cooling, solvent was evaporated, the residue dissolved in dichloromethane. and washed with saturated sodium bicarbonate solution. The organic layer was dried (magnesium sulfate) and evaporated, and the residue chromatographed on silica, eluting with a gradient increasing in polarity from 0% to 10% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the title product ( 150 mg).

MS (ESP): 458 (MID for C_2lH₂₄FN₇O,

NMR (DMSO-D6) δ: 1.82 (s, 3H); 3.08 (t. 4H); 3.37 (t. 2H); 3.69 (dd. IH); 3.86 (t. 4H); 4.07 (t. l H); 4.69 (m. lH); 7.10 (t. l H); 7.18 (dd. I H); 7.39 (d, lH); 7.50 (dd. IH); 7.53 (brs. I H): 7.86 (d. I H): 8.14 (brs. I H); 8.21 (brt, I H).

Example 8 : N-[(5S)-3-(3-Fluoro-4-(4-(6-/ι-butyloxycarbonylyridazin-3-yl)Diperazin-l- yl)phenyl)-2-oxooxazolidin-5-ylmethv_)acetanιidc Using the method and scale of Example 7. but replacing the 3-chloropyridazine-6- carboxamide with n-butyl 3-chloropyridazine-6-carboxylate (PCT patent application WO 96/03380; 108 mg, 0.5 mM), the title product (162 mg) was obtained after chromatography as in Example 7.

MS (ESP): 515 (MH⁺) for C₂₅H„FN₆O₅ NMR (DMSQ-D6) δ: 0.92 (t. 3H); 1.40 (hextet. 2H); 1.68 (quintet. 2H): 1.81 (s. 3H); 3.09 (t. 4H): 3.38 (t, 2H): 3.69 (dd. IH); 3.89 (t. 4H); 4.06 (t. lH): 4.68 (m. l H); 7.10 (t. lH); 7.20 (dd. IH); 7.33 (d. I H); 7.50 (dd. IH); 7.82 (d. I H): 8.20 (brt. I H). Example 9 : N-[(5S)-3-(3-Fluoro-4-(4-(pyrazin-2-yl)piperazin-l-yl)phenyl)-2- oxooxazolidin-5-yltnethvIlacetamide

N-[(5S)-3-(3-Fluoro-4-(4-(3-chloropyrazin-2-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5- ylmethyljacetamide (Example 25. 0.67 g. 1.5 mM) was dissolved in a mixture of ethanol (100 ml) and DMF (50 ml), and treated with triethylamine (208 μL. 1.5 mM). Palladium catalyst ( 10% on charcoal, 100 mg) was added, and the mixture hydrogenated under balloon pressure for 18 hours. Catalyst was filtered off through celite. solvent evaporated, and the residue azeotroped dry with toluene ( 100 ml). The residue was chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0% to 5% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the title product (235 mg).

MS (ESP): 415 (MH⁺) for C₂₀H₂,FN₆O₃

NMR (DMSO-D6) δ: 1.82 (s, 3H); 3.06 (t, 4H); 3.39 (t. 2H); 3.71 (t - m. 5H); 4.07 (t. lH): 4.68 (m. lH); 7.10 (t. lH); 7.18 (dd, IH); 7.49 (dd, IH); 7.85 (d. lH): 8.10 (t. lH); 8.20 (brt. IH); 8.39 (d, IH).

Examples 10-14

Examples 10-14 were all prepared using the following procedure :-

Triethylamine (2 mM) was added to a stirred solution of N-[(5S)-3-(3-fluoro-4-(piperazin-l - yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide trifluoroacetate salt (450 mg, 1 mM) in DMA (20 ml) under argon. The resultant mixture was stirred at room temperature for 15 minutes, and the appropriate halo-heterocycle ( 1 mM) added. The mixture was heated with stirring at 1 10°C for 6 hours. After cooling the solvent was removed by centrifugal evaporation. The residue was mixed with water and the solid filtered. The crude solids were dissolved or slurried in dichloromethane and purified by silica Mega Bond Elut® chromatography. eluting with a gradient increasing in polarity from 0% to 10% methanol in dichloromethane. The relevant fractions were combined and the solvent evaporated to give the following compounds :- Example 10 : N-[(5S)-3-(3-Fluoro-4-(4-(6-methylaminocarbonylpyridazin-3- yl)p_perazin-l-vOphenv.)-2-oxooxazolidin-5-ylmethyl)acetam-de

MS (ESP): 472 (MH~) for C,H₂₆FN,O₄

NMR (DMSO-D6) δ: 1.82 (s. 3H): 2.79 (d. 3H): 3.08 (t, 4H); 3.38 (t. 2H); 3.69 (dd. I H); 3.84 (t. 4H): 4.06 (t. I H); 4.69 (m. l H); 7.09 (t. I H); 7.18 (dd. IH): 7.38 (d. IH): 7.50 (dd. IH); 7.85 (d. lH); 8.19 (brt. IH): 8.77 (brq. I H).

The appropriate halo-heterocycle. 3-chloro-6-methylaminocarbonylpyridazine. was prepared as follows :-

n-Butyl 3-chioropyridazine-6-carboxylate (429 mg. 2 mM) was dissolved in ethanol (10 ml). and a solution of methylamine in ethanol (2M. 4 ml) added. The mixture was stirred at ambient temperature for 1 hour, and solvent removed. The residue was chromatographed on a

10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0% to 3% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired halo-heterocycle product (304 mg).

NMR (DMSO-D6) δ: 2.81 (d. 3H); 8.06 (d. lH); 8.20 (d. lH); 9.17 (brs. IH).

Example 11 : N-|(5S)-3-(3-Fluoro-4-(4-(6-(2-methoxyethylaminocarbonvπpyridazin-3- yl)n_perazin-l-yl)phenvD-2-oxooxazolidin-5-ylmethyl|acetamide

MS (ESP): 516 (MH^) for C₂₄H,₀FN.O₅

NMR (DMSO-D6) δ: 1.81 (s. 3H); 3.09 (t. 4H); 3.26 (s, 3H); 3.39 (t, 2H); 3.47 (m. 4H); 3.69 (dd. IH); 3.88 (t. 4H): 4.08 (t, I H); 4.69 (m. l H); 7.10 (t, lH): 7.18 (dd. I H); 7.40 (d. IH); 7.50 (dd. I H): 7.86 (d. I H): 8.20 (brt. IH): 8.70 (brs, IH).

The appropriate halo-heterocycle. 3-chloro-6-(2-methoxyethylaminocarbonyl)pyridazine, was prepared as follows :-

n-Butyl 3-chloropyridazine-6-carboxylate (429 mg, 2 mM) was dissolved in ethanol ( 10 ml). and 2-methoxyethylamine ( 150 mg. 2 mM) added. The mixture was stirred at ambient temperature for 48 hours, and solvent then removed. The residue was chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0% to 10% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired halo-heterocycle product (76 mg).

MS (ESP): 216 (MH⁺) for C₈H_!0ClN,O₂ NMR (DMSO-D6) δ: 3.26 (s, 3H); 3.49 (m. 4H); 8.08 (d. lH); 8.21 (d, IH); 9.14 (brs. IH).

Example 12 : N-[(5S)-3-(3-Fluoro-4-(4-(6-(2-hvdroxyethylaminocarbonyl)pyridazin-3- yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5-ylmethvHacetamide MS (ESP): 502 (MH⁺) for C₂₁H₂₈FN₇O₅

NMR (DMSO-D6) δ: 1.81 (s, 3H); 3.08 (t. 4H): 3.37 (m, 4H); 3.51 (q. 2H); 3.69 (dd. I H); 3.85 (t. 4H); 4.07 (t. lH); 4.67 (m, IH); 4.74 (t. lH); 7.09 (U H); 7.18 (dd. IH): 7.40 (d, I H); 7.49 (dd. I H); 7.86 (d, IH): 8.20 (U H); 8.67 (t. lH).

The appropriate halo-heterocycle. 3-chloro-6-(2-hydroxyethylaminocarbonyl)pyridazine. was prepared as follows :-

n-Butyl 3-chloropyridazine-6-carboxylate (858 mg, 4 mM) was dissolved in ethanol (20 ml), and 2-hydroxyethylamine (488 mg, 8 mM) added. The mixture was stirred at ambient temperature for 48 hours, and solvent removed. The residue was chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient from 0 to 10% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired halo- heterocycle product (637 mg).

MS (ESP): 202 (MH⁺) for C,H₈ClN₃O, NMR (DMSO-D6) δ: 3.39 (q. 2H); 3.55 (q, 2H); 4.75 (t, IH); 8.08 (d. IH); 8.21 (d, I H); 9.08 (brt. IH).

Example 13 : N-[r5S)-3-(3-Fluoro-4-(4-(6-( κ-(2- hvdroxyethvhaminocarbonvπpyridazin-3-vπpiDerazin-l-yl)phenyl)-2-oxooxazolidin-5- ylmethyl] acetamide

MS (ESP): 546 (MH^*) for C_2?H₁₂FN ^Jb H NMR (DMSO - D6) : 1.83 (s. 3H): 3.08 (t. 4H); 3.40 (t. 2H); 3.49 (t. 2H); 3.55 (overlapping. 8H); 3.69 (dd. I H): 3.81 (t. 3H): 4.08 (t. IH): 4.69 (m. I H): 4.78 (t. I H): 7.12 (t. I H): 7.19 (t. IH); 7.38 (d. I H); 7.51 (dd. I H): 7.55 (t. I H): 8.19 (t. IH).

The appropriate halo-heterocycle. 3-chloro-6-(A._s-(2-hydroxyethyl)aminocarbonyl)pyridazine. was prepared as follows :-

n-Butyl 3-chloropyridazine-6-carboxylate (858 mg. 4 mM) was dissolved in ethanol (20 ml), and bis-(2-hydroxyethyl)amine (488 mg, 8 mM) added. The mixture was stirred at ambient temperature for 48 hours, and solvent removed. The residue was chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 10% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired halo-heterocycle product (637 mg).

MS (ESP.: 202 (MH⁺) for C.HgClN NMR (DMSO-D6) δ: 3.39 (q, 2H); 3.55 (q. 2H): 4.75 (t. lH): 8.08 (d. IH); 8.21 (d. IH); 9.08 (brt. I H).

Example 14 : N-|(5S)-3-(3-Fluoro-4-(4-(6-methoxycarbonylmethylaminocarbonyl)- pyridazin-3-yl)piperazin-l-vπphenyl)-2-oxooxazolidin-5-ylmethyl)acetamide MS (ESP): 530 (MH^"*^") for C₂₄H₂₈FN₇O_f,

NMR (DMSO-D6) δ: 1.81 (s. 3H): 3.10 (t. 4H): 3.37 (t. 2H); 3.63 (s. 3H); 3.69 (dd, IH); 3.87 (t. 4H); 4.03 (d. 2H); 4.07 (t, lH); 4.68 (m, IH); 7.10 (t, I H); 7.18 (dd, IH): 7.40 (d. I H); 7.50 (dd. IH); 7.86 (d. I H); 8.20 (t. lH); 9.13 (t. IH).

The appropriate haloheterocycle, 3-chloro-6-methoxycarbonylmethylaminocarbonyl- pyridazine. was prepared as follows :-

n-Butyl 3-chloropyridazine-6-carboxylate (858 mg, 4 mM) was dissolved in ethanol (20 ml), and glycine methyl ester hydrochloride (1 g. 8 M), and triethylamine (808 mg. 8 mM) added. The mixture was stirred at ambient temperature for 18 hours, and solvent removed. The residue was chromatographed on a 20 g silica Mega Bond EluttB column, eluting with a gradient increasing in polarity from 0 to 10% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired halo-heterocycle product (85 mg). NMR (DMSO-D6) δ: 3.65 (s. 3H); 4.08 (d. 2H); 8.13 (d. I H) 8.23 (d. I H): 9.58 (brt. I H).

Example 15 : N-l(5S)-3-(3-Fluoro-4-(4-.pyrim.d-5-yl)p„perazin-l-yl)phenyl.-2- oxooxazolidin-5-ylmethyllacetamide

(5R)-5-Azidomethyl-3-(3-fluoro-4-(4-pyrimid-5-ylpiperazin-l -yl)phenyl)oxazolidin-2-one (430 mg. 1.08 mM) was dissolved in DMF (25 ml) and the solution purged with argon. Palladium ( 10% on carbon, 50 mg) was added, followed by acetic anhydride (240 μL. 2.16 mM) and the mixture hydrogenated at ambient temperature under hydrogen confined in a balloon for 6 hours. The mixture was filtered through celite. evaporated to dryness. and the residue chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0% to 10% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the title product (340 mg). MS (ESP): 415 (MFT) for C₂₀H₂₃FN₆O₃

NMR (DMSO-D6) δ: 1.82 (s, 3H); 3.08 (t, 4H); 3.39 (m, 6H); 3.68 (dd, IH); 4.07 (t, lH); 4.69 (m. lH); 7.10 (t. lH); 7.18 (dd, IH); 7.49 (dd, IH); 8.20 (t, lH): 8.53 (s. 2H): 8.61 (s. I H).

The (5R)-5-azidomethyl-3-(3-fluoro-4-(4-pyrid-2-ylpiperazin-l-yl)phenyl)oxazolidin-2-one used as starting material was prepared as follows :-

Tris(dba)dipalladium (1.0 g, 1.09 mM) was added to a degassed, stirred solution of 5- bromopyrimidine (12.19 g, 77 mM), jV-benzylpiperazine (40.5 g, 0.23 M), and tri-o- tolylphosphine ( 1.29 g. 4.24 mM) in toluene (500 ml) under argon. A solution of lithium bis(trimethylsilylamide) (1M in THF, 230 ml) was added dropwise with stirring at ambient temperature. The mixture was then heated with stirring at 100°C for 5 hours. After cooling, the mixture was partitioned between dilute hydrochloric acid (2N, 500ml) and diethyl ether (500 ml). The aqueous phase was separated, made basic with aqueous sodium hydroxide, and extracted with diethyl ether (3 x 500 ml). The combined organic extracts were washed with brine (250 ml), dried over magnesium sulfate. filtered and evaporated to dryness. The residue was chromatographed on silica by dry flash chromatography. eluting with a gradient increasing in polarity from 0 to 2.5%) methanol in dichloromethane. Relevant fractions were combined and evaporated to give l -benzyl-4-(pyrimid-5-yl)piperazine as an oil (5.15 g), which the NMR spectrum showed to be contaminated with l-benzyl-4-(pyrimid-2- 5 yl)piperazine. The mixture was used without further purification.

MS (ESP): 254 (MH⁺) for C_{l 5}H₎₈N₄

NMR (DMSO-D6) δ: 2.62 (t. 4H); 3.35 (t, 4H): 7.32 (m. 5H): 8.34 (s. 2H); 8.68 (s. IH).

Crude l -benzyl-4-(pyrimid-5-yl)piperazine (5.3 g. 20 mM) and ammonium formate (5.26 g.

10 0.08 M) were dissolved in a mixture of methanol ( 100 ml) and water (0.5 ml), and treated with palladium ( 10%> on carbon. 1.3 g) under argon. The mixture was heated to reflux for 3 hours, cooled, filtered through celite. and evaporated to dryness. The residue was treated with aqueous sodium carbonate (2M. 50 ml), and extracted with dichloromethane (3 x 50 ml). The combined extracts were dried (magnesium sulfate) and evaporated, to give an oil containing

15 l-(pyrimid-5-yl)piperazine, mixed with l -(pyrimid-2-yl)piperazine (3.35 g). The mixture was used as such in the next stage. MS (ESP): 165 (MH⁺) for C₈H,₂N₄

3.4-Difluoronitrobenzene ( 1.53 ml. 1.38 M) was dissolved in acetonitrile (60 ml).

20 N.N-diisopropylethylamine (6.93 ml, 40 mM). and the above mixture of piperazines (2.72 g. 16.6 mM) added, and the mixture heated to reflux for 18 hours. Solvent was evaporated, and the residue rougly purified by chromatography on silica by dry flash chromatography. eluting with dichloromethane. Relevant fractions were combined and evaporated. This residue was split into three equal portions (500 mg) which were further purified by chromatography on a

25 90 g Biotage iloprep® silica column, eluting with 2.5%> methanol in dichloromethane. Relevant fractions were combined to give 3-fiuoro-4-(4-(pyrimid-5-yl)piperazin-l- yl)nitrobenzene (1.2 g).

MS (ESP): 304 (MH+) for C_MH_uFN,O₂

NMR (DMSO-D6) δ: 3.43 (s. 8H); 7. 23 (t. IH): 8.02 (m. 2H); 8.53 (s. 2H); 8.61 (s. IH).

30 3-Fluoro-4-(4-(pyrimid-5-yl)piperazin-l-yl)nitrobenzene (2.08 g. 6.8 mM) was dissolved in a mixture of ethyl acetate (300 ml) and DMF (20 ml), and the solution flushed with argon. Palladium ( 10%> on carbon, 125 mg) was added, and the mixture hydrogenated at ambient temperature and pressure to greater than the theoretical uptake of gas. The mixture was filtered through celite. washed with water (2 x 150 ml), then brine ( 100 ml), dried (magnesium sulfate) and evaporated to dryness. to give 5-amino-2-(4-(pyrimid-5-yl)piperazin- l-yl)fluoro-benzene as a solid (1.7 g), which was used as such in the next stage.

MS (ESP): 274 (MH⁺) for C₁₄H₁₆FN₅

NMR (DMSO-D6) δ: 2.96 (t, 4H); 3.36 (t, 4H); 4.98 (s. 2H); 6.31 (dd, I H): 6.36 (dd, IH); 6.80 (t. lH); 8.50 (s. 2H); 8.58 (s. lH).

5-Amino-2-(4-(pyrimid-5-yl)piperazin-l -yl)fluorobenzene (1.7 g. 6.2 mM) was dissolved in dry dichloromethane (40 ml) under argon, and cooled to -4°C. Pyridine (0.63 ml. 7.79 mM) was added, followed by benzyl chloroformate (0.98 ml, 6.85 mM). The mixture was stirred for 72 hours at ambient temperature. The resulting suspension was diluted with 5% methanol in dichloromethane ( 100 ml), washed with water (2 x 50 ml), dried (magnesium sulfate), and evaporated to dryness. The residue was chromatographed on a 20 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 2.5% to 10% methanol in dichloromethane. Relevant fractions were combined and evaporated to give 5-benzyloxycarbonyl- amino-2-(4-(pyrimid-5-yl)piperazin-l-yl)fluorobenzene ( 1.31 g).

MS (ESP): 408 (MH+) for C₂₂H₂₂FN,O₂

NMR .DMSO-D6) δ: 3.34 (m. 8H); 5.13 (s, 2H); 7.01 (t, IH); 7.16 (d. IH); 7.35

(complex. 6H): 8.52 (s. 2H); 8.59 (s, lH); 9.92 (s, lH).

tert-Butanol (0.354 g. 3.19 mM) and dry THF (25 ml) were stirred under argon, and cooled to -10°C. n-Butyl lithium (1.6 M in zsohexane. 2.39 ml, 3.83 mM) was added dropwise. the mixture was stirred 10 minutes, then cooled to -70°C. A solution of 5-benzyloxycarbonyl- amino-2-(4-(pyrimid-5-yl)piperazin-l -yl)fluorobenzene (1.3 g, 3.19 mM) dissolved in dry DMPU (20 ml) was added dropwise. After stirring for 10 minutes, a solution of (R)-glycidyl- butyrate (0.55 g. 3.83 mM) in dry THF (10 ml) was added, and stirring continued at -78°C for 30 minutes. The temperature was allowed to rise to ambient over 16 hours, the mixture treated with methanol (10 ml), and stirred for 10 minutes. The reaction was diluted with saturated aqueous sodium bicarbonate (20 ml) and extracted with ethyl acetate (3 x 25 ml). The combined extracts were washed with brine, dried over magnesium sulfate. and evaporated. The residue, still containing DMPU. was chromatographed on a 20 g silica Mega Bond Elut I. column, eluting with a gradient increasing in polarity from 0% to 5% methanol in dichloromethane. Relevant fractions were combined and evaporated to give (5R)-3-(4-(4- (pyrimid-5-yl)piperazin- l-yl)-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one (0.70 g).

MS (ESP): 374 (MH⁺) for C_lgH,₀FN,O,

NMR (DMSO-D6) δ: 3.10 (m. 4H); 3.40 (m. 4H); 3.53 (m. l H): 3.65 (m, IH): 3.77 (t. I H) 4.03 (t. lH) 4.66 (m. l H): 5.19 (t. lH); 7.10 (t, l H); 7.21 (d. I H): 7.54 (d. I H); 8.21 (s. 2H): 8.60 (s. I H).

(5R)-3-(4-(4-(pyrimid-5-yl)piperazin-l -yl)-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one (0.654 g. 1.75 mM) was dissolved in pyridine (15 ml), and cooled under argon to 0°C. Triethylamine (0.292 ml. 2.1 mM) and methanesulfonyl chloride (0.163 ml. 2.1 mM) were added, and stirring continued at 0°C for 10 minutes, before allowing the temperature to reach ambient over 2 hours. Solvent was evaporated, and the residue dissolved in dichloromethane (50 ml). The solution was washed with water (3 x 40 ml), brine (25 ml), dried (magnesium sulfate) and evaporated. The solid residue was triturated with diethyl ether (20 ml), and (5R)- 3-(3-fluoro-4-(4-(pyrimid-5-yl)piperazin-l -yl)phenyl)-5-(methanesulfonyloxymethyI )- oxazolidin-2-one filtered off (0.65 g).

MS (ESP): 452 (MH⁺) for C^H^FN^O.S

NMR (DMSO-Dό) δ: 3.13 (m. 4H); 3.23 (s, 3H): 3.42 (m. 4H); 3.80 (dd, IH); 4.16 (t, IH): 4.47 (m. 2H); 4.98 (m. lH); 7.14 (t. l H); 7.22 (dd. IH); 7.50 (dd. I H); 8.54 (s, 2H); 8.61 (s. I H).

(5R)-3-(3-Fluoro-4-(4-(pyrimid-5-yl)piperazin-l -yl)phenyI)-5-(methanesulfonyloxymethyl)- oxazolidin-2-one (0.6 g. 1.33 mM) was dissolved in dry DMF ( 15 ml), sodium azide (520 mg. 8 mM) was added, and the mixture was heated at 80°C under argon for 7 hours. Solvent was evaporated, and the residue partitioned between ethyl acetate (50 ml) and water (50 ml). The organic layer was separated, reextracted with ethyl acetate (2 x 25 ml), dried (magnesium sulfate) and evaporated, to give (5R)-5-azidomethyl-3-(3-fluoro-4-(4-(pyrimid-5-yl)piperazin- l -yl)phenyl)oxazolidin-2-one as a solid (0.46 g).

MS (ESP): 399 (MW) for C₁₈H,₉FN₈O₂

NMR (DMSO-D6) δ: 3.12 (t, 4H); 3.41 (t, 4H); 3.66 (dd. I H); 3.73 (complex. 2H): 4.1 1 (t, IH); 4.86 (m, IH): 7.1 1 (t, IH); 7.21 (dd. IH); 7.52 (dd. IH): 8.53 (s, 2H): 8.61 (s, IH).

Examples 16-26

Examples 16-26 (all of which are (5S) chiral compounds are summarised in Table 1 below) were prepared using the following procedure which employed a Zymark robotic system for multiple parallel synthesis :-

Triethylamine (2 mM) was added to a stirred solution of N-[(5S)-3-(3-fluoro-4-(piperazin-l - yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide trifluoroacetate salt (450 mg, 1 mM) in DMA ( 15 ml) under argon. The resultant mixture was stirred at room temperature for 10 minutes. This solution was then added to the appropriate halo-heterocycle (1 mM) and the mixture heated with stirring at 1 10°C for 6 hours. After cooling the solvent was removed by centrifugal evaporation (SAVANT AES2000) with radiant heating for 5 hours. The residue was mixed with water and the solid filtered. The purity at this stage was assessed by TLC. Impure materials were dissolved in a mixture of dichloromethane and methanol and purified by silica Mega Bond Elut® chromatography. using a suitable mixture of the two solvents, as determined from the TLC. The relevant fractions were combined and the solvent removed by centrifugal evaporation (SAVANT AES2000 ) on medium heat for 3 hours. Compounds so prepared were generally characterised by the presence of the correct molecular ion for MH^* in their electrospray mass spectra, and by their HPLC retention time (in minutes), using the following system and elution parameters. Column HYPERSIL ODS 5m

Flow rate 1.0 ml/min Time % Solvent .4 % Solvent B Detector Wavelength 2541 0 95 5 Solvent A 1 mMol TF A/FLO .1 95 5 Solvent B 1 mMol TFA/CH,CN 17 5 95

18 95 5

20 95 5

Table 1

Table 1 continued

Table 1 continued

1. Further purified by chromatography on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity in the range from 0% to 10% methanol in dichloromethane.

2. Obtained pure directly from reaction.

3. Characterised by NMR N-r(5S)-3-(3-Fluoro-4-(4-(2,4-dimethoxypyrimid-6-yl)piperazin-l-yl)phenyl)-2- oxooxazolidin-5-ylmethyllacetamide

NMR(DMSO-D6) δ: 1.81 (s.3H): 3.00 (t.4H); 3.37 (t, 2H); 3.51 (dd. IH); 3.67 (t.4H); 3.79 (2 xs.6H); 4.06 (t. IH): 4.68 (m. IH); 5.77 (s.lH); 7.07 (t.lH); 7.16 (dd. IH); 7.47 (dd. IH): 8.21 (t. IH).

4. Characterised by NMR

N-[(5S)-3-(3-Fluoro-4-(4-(4-amino-5-cvanopyrimid-2-yl)piperazin-l-yl)phenyl)-2- oxooxazolidin-5-ylmethvπacetamide

NMR.DMSO-D6) δ: 1.82 (s.3H); 3.00 (t.4H); 3.39 (t.2H); 3.69 (dd, IH); 3.89 (t.4H);

4.08 (t.lH): 4.70 (m.lH); 7.08 (t.lH); 7.17 (dd, IH); 7.29 (br, 2H): 7.49 (dd. IH); 8.08 (d. IH): 8.21 (t, IH); 8.28 (s, IH).

5. Characterised by NMR

N-[(5S)-3-(3-Fluoro-4-(4-(3-chloropyrazin-2-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5- ylmethyllacetamide NMR (DMSO-D6) ό: 1.82 (s, 3H): 3.13 (t. 4H): 3.39 (t. 2H); 3.52 (t. 4H): 3.70 (dd. IH); 3.89 (t. 4H): 4.08 (t. I H): 4.70 (m. l H): 7.08 (t. l H): 7.17 (dd. I H): 7.29 (br. 2H ): 7.49 (dd. I H): 8.08 (d. I H): 8.21 (t. I H): 8.28 (s. I H).

6. Characterised by NMR

N-f(5S)-3-(3-Fluoro-4-(4-(4.6-dimethoxy-1.3.5-triazin-2-yl)piperazin-l -yl)phenyl)-2- oxooxazolidin-5-ylmethyl]acetamide

NMR (CDC1,) δ: 2.02 (s, 3H); 3.13 (t. 4H); 3.55-3.70 (m. 2H): 3.76 (dd. I H); 3.97 (s, 6H); 4.02 (t + m. 5H); 4.77 (m. lH); 6.10 (brt. IH); 6.95 (t. IH); 7.09 (dd. I H): 7.46 (dd. I H).

7. Preparation of starting material: J. Chem. Soc. 1951. 1218.

8. The appropriate haloheterocycle, 2-trifluoromethyl-4-chloropyrimidine. was prepared as follows :-

2-Trifluoromethyl-4-hydroxypyrimidine (1.06 g. 6.5 mM) was dissolved in thionyl chloride (10 ml) and DMF (10 drops) added. The mixture was heated to reflux for 1 hour, cooled, and solvent evaporated. The residue was partitioned between aqueous 2N potassium carbonate solution (50 ml) and dichloromethane (50 ml). The organic layer was separated. . dried over sodium sulfate and evaporated to give the desired product, slightly contaminated with DMF (0.9 g). NMR .CDC1.) δ: 7.57 (d, IH); 8.80 (d, IH).

9. The appropriate haloheterocycle. N-(n-propyl)-3-chloropyridazine-6-carboxamide. was prepared as follows :-

Ethyl 3-chloropyridazine-6-carboxylate (Ref: Bull. Soc.Chim. France 1959, p 1793: 4.2 g, 22.6 mM) was dissolved in dry 1.2-dimethoxyethane (25 ml), n-propylamine (5 ml, 61 mM) added, and the mixture stirred at ambient temperature for 3 days. Solvent was removed, and the residue purified by dry column chromatography. using diethyl ether as eluant. Relevant fractions were combined and evaporated, and the residue recrystallised from a mixture of diethyl ether and petrol, to give the desired product, mp 128.5°C-129.5°C (1.71 g). Microanalvsis: Found: C. 48.1 : H. 5.4: N. 21.3: Cl. 18.1% C₈H₈CINO_: requires: C. 48.1 ; H. 5.0; N. 21.1 ; Cl, 17.8%

10. Preparation of starting material: J. Amer. Chem. Soc, 1953. 75. 1909.

1 1. Characterised by NMR and MS N-f(5S)-3-(3-Fluoro-4-(4-(2-ethylamino-6-trifluoromethylpyrimidin-4-vπpiperazin-l- yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide MS (ESP): 526 (MH+) for C ,H₂.F₄N₇O,

NMR (DMSO-Dό δ: 1.07 (t, 3H); 1.81 (s, 3H); 3.00 (t, 4H); 3.23 (q. 2H); 3.37 (t. 2H): 3.68 (dd. IH); 3.77 (t. 4H); 4.06 (t, l H); 4.65 (m. lH); 6.42 (s. lH) 7.07 (t. l H): 7.10 (br. I H); 7.17 (dd. I H); 7.48 (dd. IH); 8.18 (t, IH).

Example 27 : N-[(5S)-3-(3-Fluoro- -(4-(6-(/>/s(2-hvdroxyethylamino)carbonyl)pyridazin-

3-yl)DiDerazin-l-vDphenvD-2-oxooxazolidin-5-ylmethyl]acetamide

Using the method and scale of Examples 10-14. the title product (248 mg) was obtained after chromatography. MS (ESP): 546 (MH^~. for C₅H,_:FN₇O₆

NMR (DMSO-Dόl δ: 1.85 (s, 3H); 3.09 (t, 4H); 3.39 (t, 2H); 3.55 (m, 8H); 3.70 (dd. I H); 3.83 (t. 4H): 4.08 (t. IH); 4.68 (m, lH); 4.77 (t, 2H); 7.12 (t. l H); 7.18 (dd. IH): 7.37 (d. IH) 7.51 (dd. IH); 7.55 (d. IH); 8.19 (t, IH).

The appropriate haloheterocycle, 3-chloro-6-(bis(2-hydroxyethyl)aminocarbonyl)pyridazine. was prepared as follows :-

n-Butyl 3-chloropyridazine-6-carboxylate (858 mg, 4 mM) was dissolved in ethanol (20 ml), and bis(2-hydroxyethyl)amine (841 mg, 8 mM) added. The mixture was stirred at ambient temperature for 24 hours, and solvent removed. The residue was chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient from 0% to 10% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired haloheterocycle product (896 mg).

NMR (DMSO-D6) δ: 3.43 (s. 4H): 3.58 (q. 2H): 3.64 (q. 2H); 4.63 (t. IH); 4.82 (t. IH): 7.84 (d. I H); 8.01 (d. I H).

Example 28 : N-|(5S)-3-(3-Fluoro-4-(4-(6-methylpyridazin-3-yl)piperazin-l-yl)phenyl)-2- oxooxazolidin-5-ylmethyllacetamide

N-[(5S)-3-(3-Fluoro-4-(piperazin-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide trifluoroacetate salt (0.9 g, 2 mM) was dissolved in DMA ( 10 ml), and triethylamine (0.556 ml. 4 mM) added. 3-Chloro-6-methylpyridazine (257 mg, 2 mM) was added and the mixture heated to 100°C for 18 hours. Solvent was evaporated, and the residue chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 1 % to 10% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (61 mg), slightly contaminated with N-[(5S)-3-(3-fluoro-4-(4- formy lpiperazin- 1 -y l)phenyl)-2-oxooxazolidin-5-ylmethy 1 Jacetamide

MS (ESP): 429 (MH⁺) for C^H-_jN FO,

NMR . DMSO-D6) δ: 1 .81 (s, 3H); 2.42 (s. 3H); 3.06 (t. 4H); 3.37 (t. 2H); 3.66 (t overlapping m. 5H): 4.06 (t. IH); 4.68 (m. IH): 7.05 (t. IH); 7.15 (dd. IH): 7.23 (d. I H): 7.29 (d. I H): 7.48 (dd. I H); 8.19 (t. I H).

Example 29 : N-((5S)-3-(3-Fluoro-4-(4-(4-ehloro-6-methylpyrimidin-2-yl)piperazin-l- yl)phenyl)-2-oxooxazolidin-5-ylmethyl|acetamide and N-[(5S)-3-(3-Fluoro-4-(4-(2- chloro-6-methylpyrimidin-4-yl)piperazin-l-vπphenyl)-2-oxooxazolidin-5- ylmethyllacetamide

N-[(5S)-3-(3-Fluoro-4-(piperazin- l -yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide trifluoroacetate salt ( 1.35 g. 3 mM) was dissolved in DMA (30 ml), and triethylamine (606 mg. 6 mM) added under argon. 2.4-Dichloro-6-methylpyrimidine (489 mg, 3 mM) was added and the mixture heated to 1 10°C for 6 hours. Solvent was evaporated, and the residue dissolved in dichloromethane ( 100 ml). The solution was washed with water (50 ml), dried over magnesium sulfate and evaporated. The residue was purified by chromatography on a 90 g Biotage iloprep® silica column. Elution with 2.5% methanol in dichloromethane gave N-[(5S)-3-(3-fluoro-4-(4-(4-chloro-6-methylpyrimidin-2-yl)piperazin-l -yl)phenyl)-2- oxooxazolidin-5-ylmethyllacetamide (312 mg) - Example 29A.

MS ⁽ESP⁾: 463 ( /OT) for C,,H₂₄ClFN₆O. NMR (DMSO-D6 δ: 1.82 (s. 3H); 2.27 (s. 3H): 2.99 (t. 4H); 3.37 (t. 2H): 3.68 (dd. IH); 3.83 (t. 4H): 4.06 (t. lH); 4.68 (m. lH); 6.65 (s. IH); 7.08 (t. lH): 7.16 (dd. IH): 7.48 (dd. I H); 8.18 (UH).

Further elution with 5% methanol in dichloromethane gave N-[(5S)-3-(3-fluoro-4-(4-(2- chloro-6-methylpyrimidin-4-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide (838 mg) - Example 29B.

MS (ESP): 463 (MPP) for C₂,H_:.,ClFN₆O,

NMR (DMSO-D6 δ: 1.80 (s. 3H); 2.23 (s, 3H); 3.00 (t, 4H); 3.37 (t. 2H): 3.68 (dd. IH): 3.72 (t. 4H); 4.05 (t. lH); 4.68 (m. lH); 6.76 (s, lH); 7.07 (t, IH); 7.16 (dd. IH); 7.47 (dd. I H); 8.18 (t, IH).

Example 30 : N-K5S)-3-(3-Fluoro-4-(4-(2-methyl-6-chloropyrimidin-4-yl)piperazin-l- yl)phenyl)-2-oxooxazo-idin-5-ylmethyllacetamide

N-[(5S)-3-(3-Fluoro-4-(piperazin-l -yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide trifluoroacetate salt ( 1.35 g, 3 M) was dissolved in DMA (30 ml), and triethylamine (606 mg. 6 mM) added under argon. 4.6-Dichloro-2-methylpyrimidine (489 mg, 3 mM) was added and the mixture heated to 1 10° for 6 hours. Solvent was evaporated, and the residue dissolved in dichloromethane (100 ml). The solution was washed with water (50 ml), dried over magnesium sulfate and evaporated to give the desired product plus residual DMA.

MS (ESP): 463 (MH⁺) for C₂,H₂₄ClFN₆O NMR (DMSO-D6 δ: 1.81 (s, 3H); 2.34 (s, 3H); 2.99 (t, 4H); 3.37 (t. 2H); 3.68 (dd. IH); 3.76 (t. 4H): 4.05 (t. IH); 4.67 (m. lH); 6.79 (s. lH); 7.06 (t, lH); 7.16 (dd. I H): 7.48 (dd. I H); 8.18 (t. IH). Example 31 : N-l(5S)-3-(3-Fluoro-4-(4-(4-methylnyrimidin-2-yl)piperazin-l-yl)phenyl)- 2-oxooxazolidin-5-ylmethvIlacetamide

N-[(5S)-3-(3-Fluoro-4-(4-(4-chloro-6-methylpyrimidin-2-yl)piperazιn-l -yl)phenyl)-2- oxooxazolidin-5-ylmethylJacetamide (Example 29A. 153 mg, 0.33 mM) was dissolved in a mixture of ethanol (40 ml) and DMF ( 10 ml). Triethylamine (92 μL. 0.66 mM) and palladium catalyst ( 10% on charcoal. 100 mg) were added, and the mixture hydrogenated under balloon pressure for 18 hours. Catalyst was filtered off through celite. solvent evaporated. The residue was dissolved in dichloromethane (200 ml), washed with water, dried over magnesium sulfate and evaporated to give the title product (90 mg). MS ⁽ESP⁾: 429 (MH⁺) for C_{2 l}H^, _sFN₆O,

NMR (DMSO-Dό) δ: 1.81 (s. 3H); 2.26 (s. 3H): 2.98 (t. 4H); 3.37 (t. 2H); 3.68 (dd. IH); 3.84 (t. 4H): 4.06 (t. lH); 4.68 (m. lH): 6.52 (d. IH); 7.07 (U H); 7.16 (dd. IH): 7.48 (dd. IH); 8.18 (t. IH); 8.21 (d. IH).

Example 32 : N-[(5S)-3-(3-Fluoro-4-(4-(6-methylpyrimidin-4-yl)piperazin-l-vI)phenyl)- 2-oxooxazolidin-5-ylmethyl)acetamide

Using the same technique as Example 31, but starting with N-[(5S)-3-(3-Fluoro-4-(4-(2- chloro-6-methylpyrimidin-4-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide (Example 29B. 692 mg. 1.5 mM) the title product was obtained (470mg). MS (ESP): 429 (MH^) for C₂₁H₂ FN_ήO,

NMR (DMSO-D6) δ: 1.81 (s. 3H); 2.25 (s, 3H); 2.99 (t, 4H); 3.37 (t. 2H); 3.67 (dd. I H): 3.73 (t. 411); 4.05 (U H); 4.68 (m. lH); 6.73 (s, lH); 7.07 (t. Ill); 7.16 (dd. IH): 7.47 (dd. IH); 8.18 (t. IH); 8.37 (s. IH).

Example 33 : N-f(5S)-3-(3-Fluoro-4-(4-(2-methylpyrimidin-4-v0piperazin-l-yl)phenyl)- 2-oxooxazolidin-5-ylmethyl]acetamide

Using the same technique as Example 31. but starting with N-[(5S)-3-(3-Fluoro-4-(4-(2- methyl-6-chloropyrimidin-4-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide (Example 30. 1.34 g. 2.69 mM) the title product was obtained (690mg). MS (ESP): 429 (MH⁺) for C_:1H₂₅FKA NMR . DMSO-D6. δ: 1.82 (s. 3H); 2.36 (s, 3H): 3.00 (t. 4H); 3.37 (t. 2H); 3.68 (dd. I H); 3.72 (t. 4H): 4.07 (t. lH): 4.68 (m. lH); 6.66 (d. IH); 7.08 (t. l H); 7.17 (dd. I H): 7.48 (dd. I H); 8.08 (d. IH); 8.19 (t, IH).

Example 34 : N-|(5S.-3-(3-Fluoro-4-(4-(l,2,4-triazin-3-yl piperazin-l-vπphenyl)-2- oxooxazolidin-5-ylmethyllacetamide

Triethylamine (0.5 ml. 3.6 mM) was added to a stirred solution of N-[(5S)-3-(3-fluoro-4- (piperazin-l -yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide trifluoroacetate salt ( 157 mg, 0.34 M) in acetonitrile (5 ml), and 3-methylsulfinyl-1.2.4-triazine (50 mg, 0.34 mM) added. The resultant mixture was heated with stirring at 75°C for 18 hours. After cooling the solvent was evaporated, the residue dissolved in dichloromethane and chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0% to 5% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the title product ( 106 mg). MS (ESP): 416 (MH⁺) for C₁₉H_:,FN₇O,

NMR (DMSO-D6 δ: 1.82 (s, 3H); 3.06 (t. 4H); 3.38 (t. 2H); 3.69 (t. l H); 3.94 (t. 4H); 4.07 (t. l H); 4.69 (m. lH); 7.08 (t. l H); 7.16 (dd. I H): 7.50 (dd. IH): 8.18 (t. l H): 8.34 (d. IH); 8.63 (d. I H).

The 3-methylsulfιnyl-1.2.4-triazine used as starting material was prepared as follows :-

3-Methylthio-1.2.4-triazine (J. Het. Chem.. 1970, 7, 767; 254 mg, 2 mM) was dissolved in dichloromethane (5 ml) and stirred at ambient temperature. 3-Chloroperoxybenzoic acid (50% strength. 690 mg, 2 mM) was added in portions over 30 minutes. The mixture was washed with saturated aqueous sodium bicarbonate (5 ml), dried (magnesium sulfate). and chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0% to 10% methanol in dichloromethane. Relevant fractions were combined and evaporated to give 3-methylsulfιnyl-1.2.4-triazine as a gum (60 mg).

MS (ESP): 144 (MH⁺) for C₄H₅N,OS NMR (DMSO-D6. δ: 2.97 (s. 3H): 9.05 (d. I H): 9.58 (d. IH). Example 35 : N-[(5S)-3-(3-Fluoro-4-(4-(l,3,5-triazin-2-yl)piperazin-l-yπphenyl)-2- oxooxazolidin-5-ylmethyl)acetamide

Triethylamine (0.21 ml. 1.5 mM) was added to a stirred solution of N-[(5S)-3-(3-fluoro-4- (piperazin-l -yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide trifluoroacetate salt (450 mg. 1 mM) in 1.4-dioxane (20 ml), and 2-phenoxy -1.3.5-triazine (J. Amer. Chem. Soc. 1975. 97. 1851 : 173 mg. 1 mM) added. The resultant mixture was heated to reflux for 4 hours. After cooling the solvent was evaporated, the residue dissolved in 5% methanol in dichloromethane and chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 3% to 1 1% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the product contaminated with phenol, which was rechromatographed as above eluting with a gradient increasing in polarity from 0% to 7% methanol in dichloromethane to give a pure sample (38 mg).

MS (ESP): 416 (MH^{^}) for C,„H_:_.FN₇O,

NMR (DMSO-D6) δ: 1.81 (s. 3H); 3.02 (t. 4H); 3.37 (t, 2H); 3.68 (dd. I H): 3.92 (t. 4H): 4.07 (t. l H); 4.68 (m. lH); 7.08 (t. lH); 7.19 (dd. I H); 7.50 (dd. I H); 8.23 (t. l H): 8.58 (s. 2H).

Example 36 : N-[(5SK3-(3-Fluoro-4-(l-oxo-4-(pyrimidin-2-vhpiperazin-l-vDphenvD-2- oxooxazolidin-5-ylmethyl|aeetamide N-[(5S)-3-(3-Fluoro-4-(4-(pyrimidin-2-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5- ylmethyljacetamide (Example 1. 207 mg, 0.5 mM) was dissolved in a mixture of methanol (10 ml) and dichloromethane (5 ml), and magnesium monoperoxyphthalate.6H_:0 (90%. 279 mg, 0.51 mM) was added. After stirring for 4 hours, precipitated phthalic acid was filtered off. and solvents removed. Solvent was evaporated, the residue preabsorbd on silica, and chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 5% to 20% methanol in dichloromethane. Relevant fractions were combined and evaporated to give title product (38 mg) slightly contaminated with phthalic acid.

MS (ESP): 431 (MH+) for C,₀H₂,FN_ΛO NMR (DMSO-D6) δ: 1.82 (s. 3H); 3.05 (d. 2H); 3.39 (t, 2H): 3.75 (dd. IH); 3.92 (quintet. 4H); 4.13 (t. IH); 4.62 (d. 2H): 4.74 (m. IH): 6.72 (t. IH): 7.42 (dd. IH); 7.64 (dd. IH): 8.22 (t. IH); 8.42 (d. 2H); 8.63 (t. I H).

Example 37 : N-f(5S)-3-(3-Fluoro-4-(4-(2-chloro-5-methylpyrimidin-4-vDpiperazin-l- yl)Dhenyl -2-oxooxazolidin-5-ylmethyllacetamide and N-f(5S)-3-(3-Fluoro-4-(4-(4- chloro-5-methylpyrimidin-2-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl|- acetamide

N-[(5S)-3-(3-Fluoro-4-(piperazin-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide trifluoroacetate salt (900 mg, 2 mM) was dissolved in DMA (20 ml), and triethylamine (610 mg. 6 mM) added. 2.4-Dichloro-5-methyipyrimidine (326 mg, 2 mM) was added and the mixture heated to 100°C for 18 hours. Solvent was evaporated, and the residue partitioned between dichloromethane (40 ml) and water (20 ml). The organic layer was dried over magnesium sulfate and evaporated. The residue was purified by dry column chromatography on silica eluting with a gradient increasing in polarity from 0% to 7% methanol in dichloromethane. The minor, less polar component (13 mg) was N-[(5S)-3-(3-fluoro-4-(4-(4- chloro-5-methylpyrimidin-2-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide (Example 37A).

MS (ESP): 463 (MH⁺) for C„H₃₄ClFN₆O, NMR (CDCK) δ: 2.02 (s. 3H); 2.17 (s. 3H): 3.09 (t. 4H); 3.56-3.71 (m. 2H); 3.75 (dd. IH); 3.93 (t. 4H); 4.03 ( H); 4.76 (m, IH): 6.04 (t. IH); 6.94 (t, IH); 7.08 (dd. I H); 7.46 (dd. IH); 8.10 (s. IH).

The major, more polar component (400 mg) was N-[(5S)-3-(3-fluoro-4-(4-(2-chloro-5- methylpyrimidin-4-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide (Example 37B).

MS ⁽ESP⁾: 463 (MH⁺) for C_2lH₂.,ClFN₆O,

NMR (CDCU) δ: 2.02 (s, 3H); 2.24 (s, 3H): 3.14 (t, 4H); 3.57-3.69 (m, 2H): 3.74 (t overlapping m. 5H); 4.03 (t. l H): 4.78 (m. IH); 6.24 (t. lH); 6.94 (t. lH); 7.08 (dd. I H); 7.45 (dd. I H); 7.97 (s. I H). Example 38 : N-[(5S)-3-(3-Fluoro-4-(4-(5-methylpyrimidin-4-yl)piperazin-l-yl)phenyl)- 2-oxooxazolidin-5-ylmethyllacetamide

N-[(5S)-3-(3-Fluoro-4-(4-(2-chloro-5-methylpyrimidin-4-yl)piperazin-l-yl)phenyl)-2- oxooxazolidin-5-ylmethyl]acetamide (Example 37B; 380 mg. 0.82 mM) was dissolved in methanol (30 ml), and treated with triethylamine (230 μL. 1.7 mM). Palladium catalyst ( 10% on charcoal. 40 mg) was added, and the mixture hydrogenated under balloon pressure for 18 hours. Catalyst was filtered off through celite. solvent evaporated, and the residue partitioned between dichloromethane (20 ml) and water ( 10 ml). The organic layer was dried over magnesium sulfate and evaporated to give the title product (290 mg). MS (ESP): 429.4 (MH⁺) for C₂₁H-,FN₆O,

NMR (CDC1/) δ: 2.03 (s. 3H); 2.26 (s. 3H): 3.17 (t. 4H); 3.63 (t overlapping m. 6H); 3.76 (dd. I H): 4.03 (t, I H); 4.77 (m, I H); 6.29 (t. I H): 6.96 (t. I H); 7.09 (dd. I H): 7.45 (dd, I H); 8.16 (s. IH); 8.63 (s, IH).

Example 39

The following illustrate representative pharmaceutical dosage forms containing the compound of formula I. or a pharmaceutically-acceptable salt thereof (hereafter compound X). for therapeutic or prophylactic use in humans:

(a) Tablet I mg/tablet Compound X 100

Lactose Ph.Eur 179

Croscarmellose sodium 12

Polyvinylpyrrolidone 6

Magnesium stearate 3

(b) Tablet II mg/tablet

Compound X 50

Lactose Ph.Eur 229

Croscarmellose sodium 12 Polyvinylpyrrolidone 6

Magnesium stearate 3 (c) Tablet III mg/tablet

Compound X 1

Lactose Ph.Eur 92 Croscarmellose sodium 4

Polyvinylpyrrolidone 2

Magnesium stearate 1

(d) Capsule mg/capsule Compound X 10

Lactose Ph.Eur 389

Croscarmellose sodium 100

Magnesium stearate 1

(e) Injection I (50 mg/ml)

Compound X 5.0% w/v

Isotonic aqueous solution to 100%

Buffers, pharmaceutically-acceptable cosolvents such as polyethylene glycol, polypropylene glycol. glycerol or ethanol or complexing agents such as hydroxy-propyl β cyclodextrin may be used to aid formulation.

Note

The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.

Claims

1 . A compound of the formula (I)

⁽I) wherein:

R¹ is hydroxy, chloro. fluoro, (l-4C)alkanesulfonyloxy. amino. azido. ( 1 -4C)alkoxy.

( 1 -4C)alkylthio. ( 1 -4C)alkylaminocarbonyloxy. or of the formula -NHC(=O)R^a wherein R^a is hydrogen. ( l -4C)alkoxy. amino. chloromethyl. dichloromethyl. cyanomethyl. methoxymethyl. acetylmethyl, methylamino. dimethylamino or ( l-4C)alkyl or R' is of the formula -N(Me)C(=O)R^b wherein R^b is hydrogen, methyl or methoxy or R¹ is of the formula

-NHS(O)„(l -4C)alkyl wherein n is 0. 1 or 2;

R² and R' are independently hydrogen or fluoro:

R⁴ and R" are independently hydrogen or methyl:

R⁶ is a 6-membered heteroaryl ring containing 2 or 3 ring nitrogen atoms as the only ring heteroatoms. linked via a ring carbon atom and optionally substituted on a ring carbon atom by one. two or three substituents independently selected from ( l -4C)alkyI (optionally substituted by trifluoromethyl, ( l-4C)alkylS(O)„- (wherein n is 0. 1 or 2), ( l-4C)alkoxy, carboxy. hydroxy,

( l-4C)alkoxycarbonyl, carbamoyl, N-(l-4C)alkylcarbamoyl. di-(N-(l -4C)alkyl)carbamoyl, cyano. nitro. amino. N-(l -4C)aIkylamino. di-(N-(l-4C)alkyl)amino or

(2-4C)alkanoylamino). halo, trifluoromethyl, (l-4C)alkylS(O)„- (wherein n is 0. 1 or 2),

( l-4C)alkylS(O)₂amino. ( 1 -4C)aIkanoylamino. carboxy. hydroxy, amino, (l -4C)alkylamino. di-( l -4C)alkylamino. ( l -4C)alkoxycarbonyl. carbamoyl. N-( l -4C)alkylcarbamoyl. di-(N-( l -4C)alkyl)carbamoyl [wherein the ( l-4C)alkyl group or groups in the last two- mentioned carbamoyl substituents is optionally substituted by hydroxy. ( l -4C)alkoxy or

( l -4C)alkoxycarbonyl], (2-4C)alkenyl (optionally substituted by carboxy or

( 1 -4C .alkoxvcarbonvl ). ( 1 -4C)alkoxy . cyano or nitro: pharmaceutically-acceptable salts thereof; suitable N-oxides thereof and in-vivo-hydrolysable esters thereof.

2. A compound of the formula (I), as claimed in claim 1. wherein: R¹ is hydroxy. chloro. fluoro. ( l-4C)alkanesulfonyloxy, amino. azido. ( l -4C)alkoxy. or R¹ is of the formula -NHC(=O)R^a wherein R^a is hydrogen, ( l -4C)alkoxy. chloromethyl. dichloromethyl, cyanomethyl, methoxymethyl. acetylmethyl or (l-4C)alkyl or R¹ is of the formula -NHSO₂(l-4C)alkyl; R² and R' are independently hydrogen or fluoro; R and R^" are independently hydrogen or methyl; R^b is a 6-membered heteroaryl ring containing 2 or 3 ring nitrogen atoms as the only ring heteroatoms. linked via a ring carbon atom and optionally substituted on a ring carbon atom by one. two or three substituents independently selected from (l-4C)alkyl [optionally substituted by trifluoromethyl, (l -4C)alkylS(O)_n- (wherein n is 0, 1 or 2), ( l-4C)alkoxy. carboxy. hydroxy, (1 -4C)alkoxycarbonyl. carbamoyl, N-( 1 -4C)alkylcarbamoyl. di-(N-( 1 -4C)alkyl)carbamoyl. cyano. nitro. amino. N-(l-4C)alkylamino, di-( -(l-4C)alkyl)amino or (2-4C)alkanoylamino], halo, trifluoromethyl, (l-4C)alkylS(O)„- (wherein n is 0. 1 or 2). ( l -4C)alkylSO amino. (l-4C)alkanoylamino. carboxy, hydroxy, amino. ( l-4C)alkylamino. di- (l -4C)alkylamino, ( 1 -4C)alkoxycarbonyl, carbamoyl, N-( l-4C)alkylcarbamoyl. di- N-( l -4C)alkyl)carbamoyl [wherein the (lτ4C)alkyl group or groups in the last two- mentioned carbamoyl substituents is optionally substituted by hydroxy, ( i-4C)alkoxy or ( l-4C)alkoxycarbonyl]. (2-4C)alkenyl [optionally substituted by carboxy or ( l -4C)alkoxycarbonyl]. ( 1 -4C)alkoxy, cyano or nitro; pharmaceutically-acceptable salts thereof; suitable N-oxides thereof and in-vivo-hydrolysable esters thereof.

3 A compound of the formula (I), or a pharmaceutically-acceptable salt, suitable

N-oxide or in-vivo-hydrolysable ester thereof, as claimed in claims 1 and 2. except that the following optional substituents on R⁶. namely (l-4C)alkoxy, (l-4C)alkylSO,amino. (l -4C)alkanoylamino and those N-( 1 -4C)alkylcarbamoyl and di-(N-(l -4C)alkyl)carbamoyl substituents with the ( 1 -4C)alkyl group or groups substituted by hydroxy. ( l-4C)alkoxy or ( l -4C)alkoxycarbonyl. are excluded: and the number of optional substituents on R" is restricted to one or two.

4. A compound of the formula (I), or a pharmaceutically-acceptable salt or suitable N-oxide thereof as claimed in claims 1 -3. wherein : R¹ is acetamido. one of R² and R' is hydrogen and the other is fluoro. R⁴ and R^" are both hydrogen. R⁶ is pyrimidine or pyrazine and the optional substituents on the heteroaryl ring are independently selected from methyl, chloro. nitro. cyano. carbamoyl. N-( l -4C)alkylcarbamoyl and di-(N-(l -4C)alkyl)carbamoyl.

5. A compound of the formula (I), as claimed in claims 1 -3. selected from N-[(5S)-3-(3-Fluoro-4-(4-(pyrimidin-2-yl)piperazin-l -yl)phenyl)-2-oxooxazolidin-5- ylmethyljacetamide:

N-[(5S)-3-(3-Fluoro-4-(4-(pyrimidin-4-yl)piperazin-l -yl)phenyl)-2-oxooxazolidin-5- ylmethyljacetamide;

N-[(5S)-3-(3-Fluoro-4-(4-(pyrimidin-5-yl)piperazin-l -yl)phenyl)-2-oxooxazolidin-5-yl- methyljacetamide:

N-[(5S)-3-(3-Fluoro-4-(4-(5-nitropyrimidin-2-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5- ylmethyljacetamide:

N-[(5S)-3-(3-Fluoro-4-(4-(5-methylpyrimidin-2-yl)piperazin-l -yl)phenyl)-2-oxooxazolidin-5- ylmethyljacetamide: N-[(5S)-3-(3-Fluoro-4-(4-(4-amino-5-cyanopyrimidin-2-yl)piperazin-l-yl)phenyl)-2- oxooxazolidin-5-ylmethyl]acetamide;

N-[(5S)-3-(3-Fluoro-4-(4-(2-methylpyrimidin-5-yl)piperazin-l -yl)phenyl)-2-oxooxazolidin-5- ylmethyljacetamide;

N-[(5S)-3-(3-Fluoro-4-(4-(4-methylpyrimidin-5-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5- ylmethyljacetamide;

N-[(5S)-3-(3-Fluoro-4-(4-(2-methylpyrimidin-4-yl)piperazin-l -yl)phenyl)-2-oxooxazolidin-5- ylmethyljacetamide:

N-[(5S)-3-(3-Fluoro-4-(4-(5-methylpyrimidin-4-yl)piperazin-l -yl)phenyl)-2-oxooxazolidin-5- ylmethyljacetamide; N-[(5S)-3-(3-Fluoro-4-(4-(6-methylpyrimidin-4-yl)piperazin-l-yl)phenyl)-2-oxoo.\azolidin-5- ylmethyljacetamide: N-[(5S)-3-(3.5-Difiuoro-4-(4-(pyrimidin-2-yl)piperazin-l -yl)phenyl)-2-oxooxazolidin-5-yl- methyljacetamide;

N-[(5S)-3-(3.5-Difluoro-4-(4-(pyrimidin-4-yl)piperazin-l -yI)phenyl)-2-oxooxazolidin-5-yl- methyljacetamide: N-[(5S)-3-(3.5-Difluoro-4-(4-(pyrimidin-5-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5-yl- methyljacetamide:

N-[(5S)-3-(4-(4-(pyrimidin-2-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5-ylmethylj- acetamide;

N-[(5S)-3-(4-(4-(pyrimidin-4-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5-ylmethylj- acetamide:

N-[(5S)-3-(4-(4-(pyrimidin-5-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]- acetamide: and pharmaceutically-acceptable salts and suitable N-oxides thereof.

6. A compound of the formula (I), as claimed in claims 1 -3. selected from N-[(5S)-3-(3-Fluoro-4-(4-(pyrazin-2-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5-ylmethylj- acetamide:

N-[(5S)-3-(3-Fluoro-4-(4-(3-methylpyrazin-2-yl)piperazin-l -yl)phenyl)-2-oxooxazolidin-5- ylmethyljacetamide:

N-[(5S)-3-(3-Fluoro-4-(4-(5-methylpyrazin-2-yl)piperazin-l -yl)phenyl)-2-oxooxazolidin-5- ylmethyljacetamide:

N-[(5S)-3-(3-Fluoro-4-(4-(6-methylpyrazin-2-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5- ylmethyljacetamide:

N-[(5S)-3-(4-(4-(pyrazin-2-yl)piperazin-l -yl)phenyl)-2-oxooxazolidin-5-ylmethyljacetamide:

N-[(5S)-3-(3.5-Difluoro-4-(4-(pyrazin-2-yl)piperazin-I -yl)phenyl)-2-oxooxazolidin-5- ylmethyljacetamide;

N-[(5S)-3-(3-Fluoro-4-(4-(6-methylpyridazin-3-yl)piperazin-l -yl)phenyl)-2-oxooxazolidin-5- ylmethyijacetamide:

N-[(5S)-3-(3-Fluoro-4-(4-(6-chloropyridazin-3-yl)piperazin-l -yl)phenyl)-2-oxooxazolidin-5- ylmethyljacetamide; and pharmaceutically-acceptable salts, and suitable N-oxides. thereof.

7. A compound of the formula (I), or a pharmaceutically-acceptable salt or suitable N-oxide thereof, as claimed in claims 1-3. selected from

N-[(5S)-3-(3-Fluoro-4-(4-(pyrimidin-2-yl)piperazin-l -yl)phenyl)-2-oxooxazoIidin-5- ylmethyljacetamide: and

N-[(5S)-3-(3-Fluoro-4-(4-(pyrazin-2-yl)piperazin-l -yl)phenyl)-2-oxooxazolidin-5-\ lmethylj- acetamide.

8. A process for the preparation of a compound of the formula (I), as claimed in claim

1 , which comprises :-

(a) the deprotection of a compound, containing at least one protecting group, of the formula (II). a pharmaceutically-acceptable salt . suitable N-oxide or in-vivo hydrolysable ester thereof :

(ID

(b) the modification of a substituent in or the introduction of a substituent into another compound of formula (I) or (II);

(c) when R¹ or R'" is of the formula - NHS(O),,( l-4C)alkyl. wherein n is 1 or 2. the oxidation of a compound of the formula (I) wherein n is 0 or, when n is 2 the oxidation of a compound of the formula (I) or (II) wherein n is 1 ;

(d) when R' or R¹⁰ is azido. the reaction of a compound of the formula (III) with a source of azide:

(HI) (e) when R¹ or R'° is amino. the reduction of a compound of the formula (I) or (II) wherein R¹ or R'° is azido;

(f) when R' or R¹⁰ is of the formula -NHC(=O)R^a. the introduction of -C(=0)R^a into a compound of the formula (I) or (II) wherein R¹ or R'° is amino: (g) when R¹ or R^ιc is of the formula -NHS(O),, ( l-4C)alkyl the introduction of

-S(O)„ ( l-4C)alkyl into a compound of the formula (I) or (II) wherein R¹ or R'° is amino; (h) when R¹ or R¹⁰ is chloro. fluoro. (l-4C)alkanesulfonyloxy or

( 1 -4C)alkylaminocarbonyloxy, from a compound of the formula (I) or ( II) wherein R' or R'° is hydroxy; (i) when R' or R'° is chloro, ( 1 -4C)alkylthio or ( l-4C)alkoxy, from a compound of the formula (III):

(j) when R' or R'° is hydroxy, the reaction of a compound of the formula (IV) with a compound of the formula (V):

(IV) (V)

(k) the reaction of a compound of the formula (VI) with a compound of the formula

(VII):

R 7'- IL I (VI) (VII)

(1) when R¹⁰ is of the formula -N(CO2R¹⁵)CO(l-4C)alkyl: from a compound of the

formula (I) and (II) wherein R or R is hydroxy; (m) when R¹ or R¹⁰ is of the formula -N(Me)C(=O)R^b, by the introduction of the group

-C(=O)R^b into a compound of the formula (VIII):

(VIII) and

(n) when a suitable N-oxide is required, by preparation directly from a corresponding parent compound of the formula (I) or (II), or by assembly from suitable N-oxide starting materials: wherein R^: . R\ R and R⁵ are as hereinabove defined, R⁷ is R" or protected R⁶. R'° is R' or protected R'. R'² is mesvloxy or tosyloxy. R is (l-6C)alkyl or benzyl. R^u is ( l -6C)alkyl.

R^{1 '} is ( l -4C)alkyl or benzyl and L¹ is a leaving goup and thereafter if necessary: i) removing any protecting groups; ii) forming a pharmaceutically-acceptable salt, suitable N-oxide or in-vivo hydrolysable ester; and when an optically active form of a compound of the formula (I) is required it may be obtained by carrying out one of the above procedures using an optically active starting material, or by resolution of a racemic form of the compound or intermediate using a standard procedure.

9. A pharmaceutical composition which comprises a compound of the formula (1) or a pharmaceutically-acceptable salt, suitable N-oxide or in-vivo-hydrolysable ester thereof, as claimed in claims 1 -7 and a pharmaceutically-acceptable diluent or carrier.

10. A method for producing an antibacterial effect in a warm blooded animal, such as man. in need of such treatment, which comprises administering to said animal an effective amount of a compound of the formula (I), or a pharmaceutically-acceptable salt, suitable N- oxide or in-vivo-hydrolysable ester thereof, as claimed in claims 1 -7.

1 1. The use of a compound of the formula (I), or a pharmaceutically-acceptable salt, suitable N-oxide or in-vivo-hydrolysable ester thereof, as claimed in claims 1 -7. in the manufacture of a medicament for use in the production of an antibacterial effect in a warm blooded animal, such as man.