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3 Amino 6 (1 Amino Ethyl) Tetrahydropyran Derivatives

Abstract: The invention relates to antibacterial compounds of formula I wherein R1 represents halogen or alkoxy; U and W each represent N, V represents CH and R2 represents H or F, or U and V each represent CH, W represents N and R2 represents H or F, or U represents N, V represents CH, W represents CH or CRa and R2 represents H, or also, when W represents CH, may represent F; Ra represents CH2OH or alkoxycarbonyl; A represents the group CH=CH-B, a binuclear heterocyclic system D, a phenyl group which is mono substituted in position 4 by alkyl, or a phenyl group which is disubstituted in positions 3 and 4, wherein each of the substituents is independently selected from alkyl and halogen, B representing a mono- or di-substituted phenyl group wherein each substituent is a halogen atom and D representing the group wherein Z represents CH or N, and Q represents O or S; and to salts of such compounds.

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Patent Information

Application #
Filing Date
08 January 2010
Publication Number
35/2010
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
Parent Application
Patent Number
Legal Status
Grant Date
2017-11-10
Renewal Date

Applicants

ACTELION PHARMACEUTICALS LTD
GEWERBESTRASSE 16, CH-4123 ALLSCHWIL

Inventors

1. HUBSCHWERLEN, CHRISTIAN
15, RUE DE LA GENDARMERIE, 68480 DURMENACH
2. RUEEDI, GEORG
WIRTSGARTENWEG 44, 4123 ALLSCHWIL
3. SURIVET, JEAN-PHILIPPE
3, IMPASSE DES ROSSIGNOLS, 68680 KEMBS
4. ZUMBRUNN ACKLIN, CORNELIA
ALEMANNENGASSE 57, BASEL-CH-4058

Specification

3-AMINO-6-(1-AMINO.ETHYL)-TETRAHYDROPYRAN DERIVATIVES The present invention concerns novel 3-amino-6-(l-amino-ethyl)-tetrahydropyran derivatives, a pharmaceutical antibacterial composition containing them and the use of these compounds in the manufacture of a medicament for the treatment of infections (e.g. bacterial infections). These compounds are useful antimicrobial agents effective against a variety of human and veterinary pathogens including among others Gram positive and Gram negative aerobic and anaerobic bacteria and mycobacteria. The intensive use of antibiotics has exerted a selective evolutionary pressure on microorganisms to produce genetically based resistance mechanisms. Modern medicine and socio-economic behaviour exacerbates the problem of resistance development by creating slow growth situations for pathogenic microbes, e.g. in artificial joints, and by supporting long-term host reservoirs, e.g. in immuno-compromised patients. In hospital settings, an increasing number of strains of Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus spp., and Pseudomonas aeruginosa, major sources of infections, are becoming multi-drug resistant and therefore difficult if not impossible to treat: - S. aureus is resistant to B-lactams, quinolones and now even to vancomycin; - S. pneumoniae is becoming resistant to penicillin or quinolone antibiotics and even to new macrolides; - Enteroccocci are quinolone and vancomycin resistant and B-lactam antibiotics are inefficacious against these strains; - Enterobacteriacea are cephalosporin and quinolone resistant; - P. aeruginosa are B-lactam and quinolone resistant. Furthermore, the incidence of multi-drug-resistant Gram negative strains such as Enterobacteriacea and Pseudomonas aeruginosa, is steadily increasing and new emerging organisms like Acinetobacter spp., which have been selected during therapy with the currently used antibiotics, are becoming a real problem in hospital settings. Therefore, there is a high medical need for new antibacterial agents which overcome multidrug- resistant Gram negative bacilli such as A. baumannii, ESBL-producing E. coli and Klebsiella species and Pseudomonas aeruginosa (Clinical Infectious Diseases (2006), 42657-68). In addition, microorganisms that are causing persistent infections are increasingly being recognized as causative agents or cofactors of severe chronic diseases like peptic ulcers or heart diseases. WO 2006/032466 discloses antibacterial compounds that may possess almost all structural motifs of the compounds of the instant invention, except however, on the one hand, the amino group on the ethane-l,2-diyl chain that is located between the quinoline or naphthyridine motif and the tetrahydropyran motif of the molecules and, on the other hand, the hydroxymethyl or alkoxycarbonyl side chain on the quinoline motif when such motif is present. WO 2006/125974 discloses generically antibacterial compounds that may possess all structural motifs of the compounds of the instant invention. In this document, there is however no concrete example of a compound comprising an amino group on the ethane-1,2-diyl chain that is located between the quinoline or naphthyridine motif and the tetrahydropyran motif of the molecules. Besides, WO 2006/046552 discloses similar antibacterial compounds that may feature a hydroxymethyl or alkoxycarbonyl side chain on the quinoline motif when such motif is present in the molecules. Unlike the compounds of the instant invention, the antibacterial compounds described in this document do however not comprise a tetrahydropyran motif and their quinoline or naphthyridine motif does not bear a substituted 2-amino-ethyl motif. Various embodiments of the instant invention are presented hereafter: i) The invention firstly relates to compounds of formula I W, /)—CH2~CH ( ) N—CH2—A I wherein R2 represents halogen or alkoxy; U and W each represent N, V represents CH and R2 represents H or F, or U and V each represent CH, W represents N and R2 represents H or F, or U represents N, V represents CH, W represents CH or CR" (and notably CR") and R2 represents H, or also, when W represents CH, may represent F; R" represents CH2OH or alkoxycarbonyl; A represents the group CH=CH-B (the group CH=CH-B being preferably (E)-configurated), a binuclear heterocyclic system D, a phenyl group which is mono substituted in position 4 by a (C1-C4)alkyl group, or a phenyl group which is disubstituted in positions 3 and 4, wherein each of the two substituents is independently selected from the group consisting of (C1-C4)alkyl and halogen; B represents a mono- or di-substituted phenyl group wherein each substituent is a halogen atom; D represents the group s. Q H wherein Z represents CH or N, and Q represents O or S; and to salts (in particular pharmaceutically acceptable salts) of compounds of formula I. The compounds of formula I may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms. Substituents at a double bond may be present in the Z- or £-configuration unless indicated otherwise. The compounds of Formula I may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art. The following paragraphs provide definitions of the various chemical moieties for the compounds according to the invention and are intended to apply uniformly throughout the specification and claims, unless an otherwise expressly set out definition provides a broader or narrower definition: ♦ The term "alkyl", used alone or in combination, refers to a straight or branched chain alkyl group, containing from one to six and preferably one to four carbon atoms. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, wo-propyl, n-butyl, wo-butyl, sec-butyl, ferf-butyl, n-pentyl, tso-pentyl, n-hexyl or 2,2-dimethyIbutyl. The term "(CrCx)alkyl" (x being an integer) refers to a straight or branched chain alkyl group of 1 to x carbon atoms. ♦ The term "alkoxy", used alone or in combination, refers to a straight or branched chain alkoxy group, containing from one to six and preferably one to four carbon atoms. Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, wo-propoxy, /j-butoxy, «o-butoxy, sec-butoxy, ?ert-butoxy or «-hexyloxy. The term "(C]-Cx)alkoxy" refers to a straight or branched chain alkoxy group of 1 to X carbon atoms. ♦ The term "alkoxycarbonyl" refers to an alkoxycarbonyl group wherein the alkoxy group is a saturated straight or branched chain alkoxy group containing from one to four carbon atoms. The term "[(CrCx)alkoxy]carbonyl" refers to an alkoxycarbonyl group wherein the alkoxy group is a straight or branched chain alkoxy group of 1 to x carbon atoms. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl and ethoxycarbonyl. ♦ The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably to fluorine or bromine and more preferably to fluorine. ♦ When in the formula W, /)—CHg—CH ( ) N—CH2—A \f I V_/ " \ NH2 R2 A represents the radical CH=CH-B, this means specifically that the terminal CH of the CH=CH-B radical is attached to the CH2 group. ♦ In this patent application, a bond interrupted by a wavy line shows the point of attachment of the radical drawn. For example, the radical drawn below wherein R1 represents methoxy is the 6-methoxy-quinolin-4-yl group. Besides, the term "room temperature" as used herein refers to a temperature of 25 "C. Unless used regarding temperatures, the term "about" placed before a numerical value "X" refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X. In the particular case of temperatures, the term "about" placed before a temperature "Y" refers in the current application to an interval extending from the temperature Y minus 10 °C to Y plus 10 °C, and preferably to an interval extending from Y minus 5 °C to Y plus 5°C. ii) In particular, the invention relates to compounds of formula I that are also compounds of formula ICE r< W /)—CHa—CH ( ) N—CH2—A ICE wherein R1 represents halogen (in particular fluorine) or (C1-C4)alkoxy (in particular methoxy); U and W each represent N, V represents CH and R2 represents H or F, or U and V each represent CH, W represents N and R2 represents H or F, or U represents N, V represents CH, W represents CH or CR2 (and notably CR") and R2 represents H, or also, when W represents CH, may represent F; R2 represents CH2OH or [(C1-C4)alkoxy]carbonyl (preferably CH2OH or methoxycarbonyl and particularly methoxycarbonyl); A represents the group CH=CH-B (the group CH=CH-B being preferably (£)-configurated), a binuclear heterocyclic system D, a phenyl group which is mono substituted in position 4 by a (C1-C4)alkyl group (and preferably by a (C1-C2)alkyl group), or a phenyl group which is disubstituted in positions 3 and 4, wherein each of the two substituents is independently selected from the group consisting of (C1-C4)alkyl and halogen (and preferably from the group consisting of (C1-C2)alkyl and fluorine); B represents a di-substituted phenyl group wherein each substituent is a halogen atom (especially a fluorine atom); D represents the group s Q v / W H wherein Z represents CH or N, and Q represents O or S; and to salts (in particular pharmaceutically acceptable salts) of compounds of formula ICE- iii) According to a preferred embodiment of this invention, the compounds of formula I as defined in embodiment i) or ii) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that R2 is (C1-C4)alkoxy or fluorine (and preferably (C1-C3)alkoxy, in particular methoxy or ethoxy, especially raethoxy). iv) Another preferred embodiment of this invention relates to the compounds of formula I as defined in embodiment i), ii) or iii) above or their salts (among which the pharmaceutically acceptable salts will be preferred) wherein U and W each represent N, V represents CH and R2 represents H or F (and especially F). v) Yet another preferred embodiment of this invention relates to the compounds of formula I as defined in embodiment i), ii) or iii) above or their salts (among which the pharmaceutically acceptable salts will be preferred) wherein U and V each represent CH, W represents N and R2 represents H or F (and especially F). vi) Yet another preferred embodiment of this invention relates to the compounds of formula I as defined in embodiment i), ii) or iii) above or their salts (among which the pharmaceutically acceptable salts will be preferred) wherein U represents N, V represents CH, W represents CH or CR" and R" represents H, or also, when W represents CH, may represent F. vii) According to one variant of embodiment vi), the compounds of formula I as defined in embodiment i), ii) or iii) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that U represents N, V and W each represent CH and R2 represents H or F (and especially F). viii) According to another variant of embodiment vi), the compounds of formula I as defined in embodiment i), ii) or iii) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that U represents N, V represents CH, W represents CR° and R2 represents H. ix) Preferably, the compounds of formula 1 as defined in embodiment viii) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that R" represents CH2OH or methoxycarbonyl (and especially CH2OH). x) A further preferred embodiment of this invention relates to the compounds of formula I as defined in embodiment i), ii) or iii) above or their salts (among which the pharmaceutically acceptable salts will be preferred) wherein U and W each represent N, V represents CH and R2 represents H or F or U and V each represent CH, W represents N and R2 represents H or F. xi) According to a first main variant of this invention, the compounds of formula I as defined in one of embodiments i) to x) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that A represents the group CH=CH-B. xii) Preferably, the compounds of formula I as defined in embodiment xi) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that B represents a di-substituted phenyl group wherein each substituent is a halogen atom (especially a fluorine atom). xiii) More preferably, the compounds of formula I as defined in embodiment xi) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that B represents 2,5-difluoro-phenyl. xiv) Besides, the compounds of formula I as defined in one of embodiments xi) to xiii) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will preferably be such that the group CH=CH-B is (£')-configurated. xv) According to a second main variant of this invention, the compounds of formula I as defined in one of embodiments i) to x) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that A represents a binuclear heterocyclic system D. xvi) Preferably, the compounds of formula I as defined in embodiment xv) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that A is selected from the group consisting of 3-oxo-4i/'benzo[l,4]oxazin-6-yl, 3-oxo-3,4,4a,8a-tetrahydro-2//-pyrido[3,2-fe][l,4]thiazin-6-yl and 3-oxo-3,4,4a,8a-tetrahydro-2//-pyrido[3,2-6][l,4]oxazin-6-yl (and in particular 3-oxo-3,4,4a,8a-tetrahydro-2//-pyrido[3,2-fe][l,4]thiazin-6-yl). xvii) According to a third main variant of this invention, the compounds of formula I as defined in one of embodiments i) to x) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that A represents a phenyl group which is mono substituted in position 4 by a (C1-C4)alkyl group, or a phenyl group which is disubstituted in positions 3 and 4, wherein each of the two substituents is independently selected from the group consisting of (C1-C4)alkyl and halogen. xviii) According to a subvariant of said third main variant of this invention, the compounds of formula I as defined in embodiment xvii) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that A represents a phenyl group which is mono substituted in position 4 by a (C1-C4)alkyl group (preferably by methyl or ethyl, and notably by ethyl). xix) According to another subvariant of said third main variant of this invention, the compounds of formula I as defined in embodiment xvii) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that A represents a phenyl group which is disubstituted in positions 3 and 4, wherein each of the two substituents is independently selected from the group consisting of (C]-C4)alkyl and halogen. xx) Preferably, the compounds of formula I as defined in embodiment xix) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that A represents a phenyl group which is substituted in position 3 by (C1-C4)alkyl (preferably methyl) and in position 4 by halogen (preferably fluorine). xxi) Besides, the compounds of formula I as defined in one of embodiments i) to x) above or their salts (among which the pharmaceutically acceptable salts will be preferred) wherein A represents 3-oxo-3,4,4a,8a-tetrahydro-2//-pyrido[3,2-6][l,4]thiazin-6-yl, 3-oxo- 3,4,4a,8a-tetrahydro-2//-pyrido[3,2-6][l,4]oxazin-6-yI, 3-f]uoro-4-methyl-phenyl, 4-ethyl-phenyl or 2-(2,5-difluoro-phenyl)-vinyl (notably the compounds of general formula I wherein A represents 3-oxo-3,4,4a,8a-tetrahydro-2//-pyrido[3,2-6][l,4]thiazin-6-yI, 3-oxo-3,4,4a,8a-tetrahydro-2//-pyrido[3,2-f)][l,4]oxazin-6-yl or 2-(2,5-difluoro-phenyl)-vinyl, and especially the compounds of general formula I wherein A represents 3-oxo-3,4,4a,8a-tetrahydro-2if-pyrido[3,2-6][l,4]thiazin-6-yl or 3-oxo-3,4,4a,8a-tetrahydro-2//-pyrido[3,2-fe][l,4]oxazin-6-yl) will be particularly preferred. xxii) According to a particular embodiment of this invention, the compounds of formula I as defined in one of embodiments i) to xxi) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that the two non-hydrogen substituents in positions 2 and 5 of the tetrahydropyran ring are trans configured. xxiii) According to a preferred variant of above embodiment xxii), the compounds of formula I as defined in embodiment xxii) or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that they possess the following stereochemistry: \\ // % f--.,. NH—CH2—A la In other words, the compounds of formula I according to embodiment xxii) wherein the carbon atom bearing the NH2 group has an (5) absolute configuration are especially preferred. xxiv) According to another variant of above embodiment xxii), the compounds of formula I as defined in embodiment xxii) or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that they possess the following stereochemistry: lb xxv) Particularly preferred are the following compounds of formula I as defined in embodiment i) or ii): - {(5i?,65)-6-[(ii?)-l-araino-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}-[3-(£)-(2,5-difluoro-phenyl)-allyl]-amine; - {(37?,6S)-6-[(iS)-l-amino-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}-[3-(£')-(2,5-difluoro-phenyl)-allyl]-amine; - {(5/?,(55)-6-[(7i?)-l-amino-2-(6-fIuoro-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}-[(£)-3-(2,5-difluoro-phenyl)-allyl]-amine; - {(5;?,65')-6-[(i5')-l-amino-2-(6-fluoro-quinolin-4-yI)-ethyl]-tetrahydro-pyran-3-yI}-[(£)-3-(2,5-difluoro-phenyl)-allyl]-amine; -6-({(5,6S)-6-[(i/?)-l-amino-2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4//-pyrido[3,2-6][l,4]thiazin-3-one; -6-({(5i?,65)-6-[(i5)-l-amino-2-(6-methoxy-quinolJn-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4//-pyrido[3,2-fe][l,4]thiazin-3-one; - {(5/?,65)-6-[(7)-l-araino-2-(6-methoxy-quinoIin-4-yI)-ethyl]-tetrahydro-pyran-3-yl}- [3-(£:)-(2,5-difluoro-phenyl)-allyl]-amine; - {(5/?,65)-6-[(iS)-l-aiiimo-2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}-[3-{£')-(2,5-difluoro-phenyl)-allyl]-amine; - 6-({(3/?,6S)-6-[(i7?)-1-ainino-2-(6-methoxy-[ 1,5]naphthyridin-4-yl)-ethyI]-tetrahydro-pyran-3-ylamino}-methyl)-4//-pyrido[3,2-6][l,4]thiazin-3-one; -6-({(3/?,65)-6-[(i5)-l-amino-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4//-pyrido[3,2-i>][l,4]thiazin-3-one; -6-({(5i?,65)-6-[(i/?)-l-amino-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4//-pyrido[3,2-fe][l,4]oxazin-3-one; -6-({(5i?,6S)-6-[(i5)-l-amino-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyI]-tetrahydro-pyran-3-yIamino}-methyl)-4J-pyrido[3,2-6][l,4]oxazin-3-one; - 8-[(2i?)-2-amino-2-{5-[(£')-3-(2,5-difluoro-phenyl)-allylamino]-tetrahydro-pyran-2-yl}-ethyl]-2-methoxy-quinoline-5-carboxylic acid methyl ester; - 8-[(25)-2-amino-2-{5-[(£')-3-(2,5-difIuoro-phenyI)-allyIainino]-tetrahydro-pyran-2-yI}-ethyI]-2-methoxy-quinoline-5-carboxylic acid methyl ester; - 8-((S)-2-amino-2-{(25,5/?)-5-[(£')-3-(2,5-difluoro-phenyl)-allylamino]-tetrahydro-pyran-2-yl}-ethyI)-2-methoxy-quinolin-5-yl]-methanol; -[8-((;?)-2-amino-2-{(2S,5/?)-5-[(£:)-3-(2,5-difluoro-phenyl)-allylaraino]-tetrahydro-pyran-2-yl}-ethyl)-2-methoxy-quinolin-5-yl]-methanol; - 6-({(5,(55)-6-[(iy?)-l-amino-2-(3-fluoro-6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro- pyran-3-ylamino}-methyl)-4//-pyrido[3,2-fe][l,4]thiazin-3-one; -6-({(5i?,65)-6-[(7S)-l-amino-2-(3-fluoro-6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro- pyran-3-ylamino}-niethy])-4-pyrido[3,2-i'][l,4]thiazin-3-one; -6-({(3/?,6S)-6-[(i/?)-l-amino-2-(3-fluoro-6-methoxy-quinolin-4-yI)-ethyl]-tetrahydro- pyran-3-ylamino}-methyl)-4/f-pyrido[3,2-6][l,4]oxazin-3-one; -6-({(3;?,(55)-6-[(i5)-l-amino-2-(3-fluoro-6-methoxy-quinoIin-4-yl)-ethyl]-tetrahydro- pyran-3-ylamino}-methyl)-4//-pyrido[3,2-6][l,4]oxazin-3-one; -6-({(37?,6S)-6-[(i;?)-l-amino-2-(3-fluoro-6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]- tetrahydro-pyran-3-ylamino}-methyl)-4i/-pyridot3,2-fe][l,4]thiazin-3-one; -6-({(5i?,6S)-6-[(i5')-l-amino-2-(3-fluoro-6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]- tetrahydro-pyran-3-ylamino}-methyl)-4//-pyrido[3,2-fc][l,4]thiazin-3-one; -6-({(37?,6S)-6-[(i/?)-l-amino-2-(3-fluoro-6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]- tetrahydro-pyran-3-ylamino}-methyl)-4//-pyrido[3,2-6][l,4]oxazin-3-one; -6-({(5/?,65)-6-[(i5)-l-amino-2-(3-f]uoro-6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4//-pyrido[3,2-fo][l,4]oxazin-3-one; - {(3R,6S)-6-[(lS)-1 -amino-2-(6-methoxy-[ 1,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}-(4-ethyl-benzyl)-amine; - {(5/?,(55)-6-[(i5)-l-amino-2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4//-benzo[l,4]oxazin-3-one; -6-({(5/?,65')-6-[(i5')-l-amino-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4i/-pyrido[3,2-6][l,4]oxazin-3-one; -6-({(5,(55')-6-[(iS')-l-amino-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethylj-tetrahydro-pyran-3-yl}-(3-fluoro-4-methyl-benzyl)-amine; - {(J/?,6S)-6-[(iS)-l-amino-2-(6-methoxy-[ 1,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran- 3-ylamino}-methyl)-4//-benzo[l,4]oxazin-3-one; -6-({(5S,(5/?)-6-[(i;?)-l-amino-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4//-pyrido[3,2-6][l,4]thiazin-3-one; -6-({(55,6/?)-6-[(i5)-l-amino-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4//-pyrido[3,2-6][l,4]thiazin-3-one; -6-({(5/?,6S)-6-[(ii?)-l-amino-2-(7-fluoro-2-methoxy-quinolin-8-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4i/-pyrido[3,2-6][l,4]oxazin-3-one; -6-({(5i?,6S)-6-[(i5)-l-amino-2-(7-fluoro-2-methoxy-quinolin-8-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-raethyl)-4//-pyrido[3,2-6][l,4]oxazin-3-one; -6-({(5/?,65)-6-[(i7?)-l-amino-2-(7-fluoro-2-methoxy-quinolin-8-yl)-ethyI]-tetrahydro-pyran-3-ylamino}-methyl)-4//-pyrido[3,2-6][l,4]thiazin-3-one; -6-({(57?,6S)-6-[(i5)-l-amino-2-(7-fluoro-2-methoxy-quinolin-8-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4//-pyrido[3,2-6][l,4]thiazin-3-one; -6-({(3;?,65)-6-[(;/?)-l-amino-2-(3-fluoro-6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4//-benzo[l,4]oxazin-3-one; -6-({(3;?,65)-6-[(iS)-l-ainino-2-(3-fluoro-6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4-benzo[l,4]oxazin-3'One; and the salts (in particular pharmaceutically acceptable salts) thereof, whereby the first 31 compounds in the list above (counted from the top of the list) and their salts (in particular their pharmaceutically acceptable salts) constitute a particular sub-embodiment. xxvi) Furthermore, the following compounds of formula I as defined in embodiment i) or ii) are particularly preferred: - {(5/?,65)-6-[l-amino-2-(6-methoxy-[l,5]naphthyridin-4-yI)-ethyl]-tetrahydro-pyran-3-yl}-[3-(£)-(2,5-difluoro-phenyl)-allyl]-amine; - {(5/?,65)-6-[(i5)-l-amino-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}-[3-(£)-(2,5-difluoro-phenyl)-allyl]-amine; - {(5/?,65)-6-[l-amino-2-(6-fluoro-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}-[(£')-3-(2,5-difluoro-phenyl)-allyl]-amine; - 6-({(37?,65)-6-[l-amino-2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-fe][l,4)thiazin-3-one; - {(i7f,65)-6-[l-amino-2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}-[3-(£')-(2,5-difluoro-phenyl)-allyl]-amine; -6-({(5/?,65)-6-[l-amino-2-(6-raethoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino } -methyl)-4//-pyrido[3,2-6] [1,4] thiazin-3-one; -6-({(5/?,65)-6-[l-amino-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino } -methyl)-4//-pyrido[3,2-i)] [1,4] oxazin-3-one; -6-({(i;?,65)-6-[(i5)-l-amino-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4//-pyrido[3,2-6][l,4]thiazin-3-one; -8-[2-amino-2-{5-[(£')-3-(2,5-difluoro-phenyl)-allylamino]-tetrahydro-pyran-2-yl}-ethyl]-2-methoxy-quinoline-5-carboxylic acid methyl ester; -8-((5)'2-amino-2-{(25,5/?)-5-[(£')-3-(2,5-difluoro-phenyl)-allylamino]-tetrahydro-pyran-2-yl}-ethyl)-2-methoxy-quinolin-5-yl]-methanol; -[8-((/?)-2-amino-2-{(25,5/?)-5-[(£:)-3-(2,5-difluoro-phenyl)-allylamino]-tetrahydro-pyran-2-yl}-ethyl)-2-methoxy-quinolin-5-yl]-methanol; -6-({(5/?,65)-6-[l-amino-2-(3-fluoro-6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4//-pyrido[3,2-fc][l,4]thiazin-3-one; - 6-({(5/?,65)-6-[l-amino-2-(3-fluoro-6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl>4//-pyrido[3,2-6][l,4]oxazin-3-one; - 6-({(3R,6S)-6-[ 1 -amino-2-(3-fluoro-6-methoxy-[ 1,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4//-pyrido[3,2-6][l,4]thiazin-3-one; -6-({(3i?,65)-6-[l-amino-2-(3-fluoro-6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4i/-pyrido[3,2-6][l,4]oxazin-3-one; - {(3i?,65)-6-[(i5)-l-amino-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}-(4-ethyl-benzyl)-aniine; - {(5/?,(5S)-6-[(i5)-l-amino-2-(6-methoxy-quinolin-4-yl)-ethyI]-tetrahydro-pyran-3-y lamino }-me thyl)-4/f-benzo [ 1,4] oxazin-3-one; -6-({(5/?,65)-6-[(i5')-l-amino-2-(6-methoxy-[l,5]naphthyridin-4-yI)-ethyI]-tetrahydro-pyran-3-ylamino}-methyl)-4//-pyrido[3,2-6][l,4]oxazin-3-one; -6-({(3i?,6S)-6-[(iS)-l-amino-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-yI}-(3-fluoro-4-methyl-benzyI)-amine; - {(37?,(55)-6-[(75)-l-amino-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran- 3-ylamino}-methyl)-4//-benzo[l,4]oxazin-3-one; -6-({(55,6/?)-6-[l-amino-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino} -methyl)-4//-pyrido[3,2-&] [ 1,4] thiazin-3-one; - 6-({(37?,65')-6-[l-amino-2-(7-fluoro-2-methoxy-quinolin-8-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4//-pyrido[3,2-fe][l,4]oxazin-3-one; - 6-({(J/?,65')-6-[l-amino-2-(7-fluoro-2-methoxy-quinolin-8-yl)-ethyl]-tetrahydro-pyran-3-ylaiiiino}-methyl)-4//-pyrido[3,2-fc][l,4]thiazin-3-one; -6-({(3i?,65')-6-[(i5)-l-ainino-2-(7-fluoro-2-methoxy-quinolin-8-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4/r-pyrido[3,2-6][l,4]oxazin-3-one; - 6-({(3R,6S)-6-[l-amino-2-(3-fluoro-6-methoxy-[ 1,5]naphthyridin-4-yl)-ethyl]-tetrahydro- pyran-3-ylamino}-methyl)-4//-benzo[l,4]oxazin-3-one; -6-({(5/?,65)-6-[(i5)-l-amino-2-(3-fluoro-6-methoxy-[l,5]naphthyridin-4-yI)-ethyI]-tetrahydro-pyran-3-y!amino}-methyl)-4H-pyrido[3,2-i>][l,4]oxazin-3-one; and the salts (in particular pharmaceutically acceptable salts) thereof, whereby the first 21 compounds in the list above (counted from the top of the list) and their salts (in particular their pharmaceutically acceptable salts) constitute a particular sub-embodiment. Compounds of formula I are suitable for the use as chemotherapeutic active compounds in human and veterinary medicine and as substances for preserving inorganic and organic materials in particular all types of organic materials for example polymers, lubricants, paints, fibres, leather, paper and wood. These compounds according to the invention are particularly active against bacteria and bacteria-like organisms. They are therefore particularly suitable in human and veterinary medicine for the prophylaxis and chemotherapy of local and systemic infections caused by these pathogens as well as disorders related to bacterial infections comprising pneumonia, otitis media, sinusitis, bronchitis, tonsillitis, and mastoiditis related to infection by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis. Staphylococcus aureus, Enterococcus faecalis, E. faecium, E. casseliflavus, S. epidermidis, S. haemolyticus, or Peptostreptococcus spp.; pharyngitis, rheumatic fever, and glomerulonephritis related to infection by Streptococcus pyogenes, Groups C and G streptococci, Corynebacterium diphtheriae, or Actinobacillus haemolyticum; respiratory tract infections related to infection by Mycoplasma pneumoniae, Legionella pneumophila. Streptococcus pneumoniae, Haemophilus influenzae, or Chlamydia pneumoniae; blood and tissue infections, including endocarditis and osteomyelitis, caused by 5. aureus, S. haemolyticus, E. faecalis, E. faecium, E. durans, including strains resistant to known antibacterials such as, but not limited to, beta-lactams, vancomycin, aminoglycosides, quinolones, chloramphenicol, tetracyclines and macrolides; uncomplicated skin and soft tissue infections and abscesses, and puerperal fever related to infection by Staphylococcus aureus, coagulase-negative staphylococci (i.e., S. epidermidis, S. haemolyticus, etc.), Streptococcus pyogenes, Streptococcus agalactiae. Streptococcal groups C-F (minute colony streptococci), viridans streptococci, Corynebacterium minutissimum, Clostridium spp., or Bartonella henselae; uncomplicated acute urinary tract infections related to infection by Staphylococcus aureus, coagulase-negative staphylococcal species, or Enterococcus spp.; urethritis and cervicitis; sexually transmitted diseases related to infection by Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum, or Neiserria gonorrheae; toxin diseases related to infection by S. aureus (food poisoning and toxic shock syndrome), or Groups A, B, and C streptococci; ulcers related to infection by Helicobacter pylori; systemic febrile syndromes related to infection by Borrelia recurrentis; Lyme disease related to infection by Borrelia burgdorferi; conjunctivitis, keratitis, and dacrocystitis related to infection by Chlamydia trachomatis, Neisseria gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes, H. influenzae, or Listeria spp.; disseminated Mycobacterium avium complex (MAC) disease related to infection by Mycobacterium avium, or Mycobacterium intracellulare; infections caused by Mycobacterium tuberculosis, M. leprae, M. paratuberculosis, M. kansasii, or M. chelonei; gastroenteritis related to infection by Campylobacter jejuni; intestinal protozoa related to infection by Cryptosporidium spp.; odontogenic infection related to infection by viridans streptococci; persistent cough related to infection by Bordetella pertussis; gas gangrene related to infection by Clostridium perfringens or Bacteroides spp.; and atherosclerosis or cardiovascular disease related to infection by Helicobacter pylori or Chlamydia pneumoniae. Compounds of formula I according to the present invention are further useful for the preparation of a medicament for the treatment of infections that are mediated by bacteria such as E. coli, Klebsiella pneumoniae and other Enterobacteriaceae, Acinetobacter spp., Stenothrophomonas maltophilia, Neisseria meningitidis, Bacillus cereus. Bacillus anthracis, Corynebacterium spp., Propionibacterium acnes and bacteroide spp. Compounds of formula I according to the present invention are further useful to treat protozoal infections caused by Plasmodium malaria, Plasmodium falciparum. Toxoplasma gondii, Pneumocystis carinii, Trypanosoma brucei and Leishmania spp. The present list of pathogens is to be interpreted merely as examples and in no way as limiting. One aspect of this invention therefore relates to the use of a compound of fomula I according to this invention, or of a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or treatment of a bacterial infection and in particular a bacterial infection caused by one of the bacteria mentioned in the four preceding paragraphs. According to a particularly preferred embodiment of this invention, the compounds of formula I, or the pharmaceutically acceptable salts thereof, can be used for the manufacture of a medicament for the prevention or treatment of a bacterial infection caused by Pseudomonas aeruginosa or A. baumannii. As well as in humans, bacterial infections can also be treated using compounds of formula I (or pharmaceutically acceptable salts thereof) in other species like pigs, ruminants, horses, dogs, cats and poultry. The present invention also relates to pharmacologically acceptable salts and to compositions and formulations of compounds of formula I. Any reference to a compound of formula I is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient. The term "pharmaceutically acceptable salts" refers to non-toxic, inorganic or organic acid and/or base addition salts. Reference can be made to "Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217. A pharmaceutical composition according to the present invention contains at least one compound of formula I (or a pharmaceutically acceptable salt thereof) as the active agent and optionally carriers and/or diluents and/or adjuvants, and may also contain additional known antibiotics. The compounds of formula I and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral or parenteral administration. The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkinsj) by bringing the described compounds of formula I or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants. Another aspect of the invention concerns a method for the prevention or the treatment of a bacterial infection in a patient comprising the administration to said patient of a pharmaceutically active amount of a derivative according to formula I or a pharmaceutically acceptable salt thereof. Besides, any preferences indicated for the compounds of formula I (whether for the compounds themselves, salts thereof, compositions containing the compounds or salts thereof, uses of the compounds or salts thereof, etc.) apply mutatis mutandis to compounds of formula ICE- Moreover, the compounds of formula I may also be used for cleaning purposes, e.g. to remove pathogenic microbes and bacteria from surgical instruments or to make a room or an area aseptic. For such purposes, the compounds of formula I could be contained in a solution or in a spray formulation. The compounds of formula I can be manufactured in accordance with the present invention using the procedures described hereafter. PREPARATION OF COMPOUNDS OF FORMULA I Abbreviations: The following abbreviations are used throughout the specification and the examples: Ac acetyl AcOH acetic acid AD-mix a l,4-bi5(dihydroquinine)phthalazine, K3Fe(CN)6, K2CO3 and K2OSO4.2H2O AD-mix p l,4-6i5(dihydroquinidine)phthalazine, K3Fe(CN)6, K2CO3 and K2OSO4.2H2O Alloc allyloxycarbonyl app. apparent aq. aqueous 9-BBN 9-borabicycIo[3.3.1]nonane BINAP 2,2'-Wj-(diphenylphosphino)-l,r-binaphthalene br. broad Boc ?ert-butoxycarbonyl «-BuLi rt-butyllithium f-Bu tert-hutyl Cbz benzyloxycarbonyl CC column chromatography over silica gel DEAD diethyl azodicarboxylate 1,2-DCE 1,2-dichloroethane DCM dichloromethane DIAD diisppropyl azodicarboxylate DIB AH diisobutylaluminium hydride DIPA A'A-diisopropylamine DIPEA A-diisopropylethyl amine DMA? 4-dimethylaminopyridine 1,2-DME 1,2-dimethoxyethane DMF /-dimethylformamide DMSO dimethylsulfoxide DPPA diphenyl phosphoryl azide EA ethyl acetate ESI Electron Spray lonisation eq. equivalent ether diethyl ether Et ethyl EtOH ethanol Hex hexane Hept heptane HV high vacuum conditions KHMDS potassium hexamethyldisilazide LC Liquid Chromatography LDA lithium diisopropylamide LiHMDS lithium hexamethyldisilazide Me methyl MeCN acetonitrile MeOH methanol MS Mass Spectroscopy Ms methanesulfonyl (mesyl) NBS 7-bromosuccinimide NMO //-methyl-morpholine iV-oxide ore. organic Pd/C palladium on carbon Pd(0H)2/C palladium dihydroxide on carbon Ph phenyl i-?r i50-propyl Pyr pyridine quant. quantitative rac. racemic rt room temperature sat. saturated SiOj silica gel TEA triethylamine TEMPO 2,2,6,6-tetramethyl-l-piperidinyloxy Tf trifluoromethanesulfonyl (triflyl) TFA trifluoroacetic acid THF tetrahydrofuran TMSCHN2 trimethylsilyldiazomethane tR retention time Ts pcra-toluenesulfonyl General reaction techniques: Part 1.:. .?.niine .protection: 1.1. Amines are usually protected as carbamates such as Alloc, Cbz or Boc. They are obtained by reacting the amine with allyl or benzyl chloroformate or di fez-f-butyl dicarbonate in presence of a base such as NaOH, TEA, DMA? or imidazole. 1.2. They can also be protected asiV-benzyl derivatives by reaction with benzyl bromide or chloride in presence of a base such as sodium carbonate or TEA. Alternatively, iV-benzyl derivatives can be obtained through reductive amination in presence of benzaldehyde (see section 7. below). 1.3. They can also be protected as A-acetyl derivative through reaction with acetyl chloride in presence of a base such as sodium carbonate or TEA or with acetic acid anhydride in presence of sodium acetate. 1.4. Amines can furthermore be protected as sulphonamides by their reaction with 2-nitro-or 4-nitro-phenylsulphonyl chloride in a solvent such as DCM or THF in presence of a base such as TEA or NaOH between -10°C and 40''C. 1.5. Further strategies to introduce other amine protecting groups have been described in Protecting Groups in Organic Synthesis, 3'" Ed (1999), 494-653; T.W. Greene, P.G.M. Wuts; (Publisher: John Wiley and Sons, Inc., New York, N.Y.). Part 2;. amine .deprgtectipn.: 2.1. The benzyl carbamates are deprotected by hydrogenolysis over a noble catalyst (e.g. Pd/C). The Boc group is removed under acidic conditions such as HCI in an org. solvent such as EA, or TFA neat or diluted in a solvent such DCM. The Alloc group is removed in presence of tetrakis(triphenylphosphine)palladium(0) in presence of an allyl cation scavenger such as morpholine, dimedone or tributyltin hydride between CC and 50°C in a solvent such as THF. 2.2. The A-benzyl protected amines are deprotected by hydrogenolysis over a noble catalyst (e.g. Pd(0H)2). 2.3. The A-acetyl protecting group is removed under basic conditions such as NajCOs, LiOH or NaOH in aq. MeOH or THF, or under acidic conditions such as aq. HCI in THF. 2.4. The 2- or 4-nitro-phenylsuIphonamides can be deprotected by using thiophenol in DMF in presence of a base such as K2CO3 (see Tetrahedron Lett. (1995), 36, 6373) 2.5. Further general methods to remove amine protecting groups have been described in Protecting Groups in Organic Synthesis, 3"* Ed (1999), 494-653; T.W. Greene, P.G.M. Wuts; (Publisher: John Wiley and Sons, Inc., New York, N.Y.). Pajt. 3;. oxidation, of.an.ajcohgl.inlo.a The alcohols can be transformed into their corresponding ketones through oxidation under Swern (see D. Swern et al., J. Org. Chem. (1978), 43, 2480-2482), Dess Martin (see D.B. Dess and J.C. Martin,/. Org. Chem. (1983), 48,4155) or Ley (using tetrapropylammonium perruthenate see Synthesis (1994), 7, 639-66) conditions, respectively. Pari. .4:. .nitro .group, .reduction; Typical reducing agents which can be used for such reaction are: 4.1, an alkali metal hydride such as LAH or NaBR2 in presence of C0CI2 or NiCli, or a metal such as iron or zinc in acidic medium (HCl or AcOH); or 4.2. hydrogen over Raney nickel or hydrogen or ammonium formate over a noble metal catalyst such as palladium on charcoal or platinum oxide. Further reagents such as aluminium amalgam or ferrous sulphate may also be used. Part. .5;. .Mits.unp.bu reaction: The alcohol is reacted with different nucleophiles such as phthalimide, DPPA or hydrazoic acid, generated from NaNs in acidic medium, in presence of PPha and DEAD or DIAD in a solvent such as THF, DMF, DCM or 1,2-DME between -20''C and eCC as reviewed by 0. Mitsunobu, in Synthesis (1981), 1. In the particular case of basic amines, the reaction is performed with the corresponding 2- or 4-nitro-phenylsulfonamides; the free amine is subsequently liberated as described in paragraph 2.4 above. The reaction might also be performed using a polymer-supported PPhs. Part6i.mesyI.atej.tosylateprJ. The alcohol is reacted with MsCl, TfCl or TsCl in presence of a base such as TEA in a dry aprotic solvent such as Pyr, THF or DCM between -SOC and 50'C. In the case of the triflate or mesylate, Tf20 or MS2O can also be used. Part..7;.reducti.v.e.amination: The reaction between the amine and the aldehyde or ketone is performed in a solvent system allowing the removal of the formed water through physical or chemical means (e.g. distillation of the solvent-water azeotrope or presence of drying agents such as molecular sieves, MgS04 or Na2S04). Such solvent is typically toluene, Hex, THF, DCM or 1,2-DCE or mixture of solvents such as 1,2-DCE/MeOH. The reaction can be catalyzed by traces of acid (usually AcOH). The intermediate imine is reduced with a suitable reducing agent (e.g. NaBH4, NaBHCNs, or NaBH(0Ac)3 or through hydrogenation over a noble catalyst such as Pd/C The reaction is carried out between -10°C and llCC, preferably between 0°C and eO'C. The reaction can also be carried out in one pot. It can also be performed in protic solvents such as MeOH or water in presence of a picoline-borane complex {Tetrahedron (2004), 60, 7899-7906). PajL8;..nitroaldolj.eacti.on.aMei™ The reaction between the aldehyde and the nitro derivative is performed in a solvent such as DCM or THF between 0°C and SCC is presence of a basic catalyst such as ammonium acetate, TBAF or sodium methylate (Tetrahedron. Lett. (1996), 37, 987). In a second step, the intermediate nitroaldol compound is transformed into its corresponding nitroalkene derivative by elimination of water or after transformation of the alcohol into its corresponding chloride by reaction with thionyl chloride or into its corresponding mesylate followed by treatment with a base such as sodium methylate. Further details can be found in Tetrahedron (2001), 915-945. Part 9;. Curti.us.reaction:. The reaction between the carboxylic acid and DPPA is performed in an inert solvent such as toluene between SCC and llCC. The resulting isocyanate is trapped in situ with an alcohol such as benzyl, allyl or rerr-butyl alcohol affording the corresponding Cbz, Alloc or Boc carbamates. Alternatively, the isocyanate can be hydrolyzed with water, affording the corresponding primary amine. Further detailed on this reaction can be obtained in T. Shioiri, Compendium of Organic Synthesis (1991), 6, 795-828. PaxLiO;..Pxidatipnof.aIcohoI.sjntoaci Alcohols can be directly oxydized into their corresponding acids by a variety of methods as described in Comprehensive Organic Transformations. A guide to Functionnal Group Preparations; 2nd Edition, R. C. Larock, Wiley-VC; New York, Chichester, Weinheim, Brisbane, Singapore, Toronto (1999), Section nitriles, carboxylic acids and derivatives p. 1646-1648. Among them, [bis(acetoxy)iodo]benzene in presence of TEMPO, the Jones reagents (Cr03/H2S04), NaI04 in presence of RuCl., KMn04 or pyridine HzCR2Oj are frequently used. General preparation methods: Prep.aration.of.cpmp.oundsof fom The compounds of formula I can be manufactured in accordance with the present invention by a) deprotecting, thanks to one of the methods described in part 2 of the section "General reaction techniques", a compound of formula II W, /)—CH,—CH ( ) N—CH2—A \ NH V I II wherein R\ R2 U, V, W and A are as in formula I and 1. R"* represents an amino protecting group such as COOR2', COR1, SO2R1* or benzyl, wherein R2' is terr-butyl, allyl or benzyl, R" is (C1-C4)alkyl and R2 represents 2-nitro-phenyl or 4-nitro-phenyl, and R2 represents hydrogen (such compounds of formula II being referred to hereafter as "compounds of formula Ila"); or 2. R2 represents hydrogen and R1* represents an amino protecting group such as COOR1, COR2, S02R2 or benzyl, wherein R" is tert-butyl, allyl or benzyl, R1 is (C]-C4)alkyl and R2 represents 2-nitro-phenyl or 4-nitro-phenyl (such compounds of formula II being referred to hereafter as "compounds of formula lib"); or also 3. R" represents an amino protecting group such as COOR1', COR1', SOaR" or benzyl, wherein R2" is tert-hutyl, allyl or benzyl, R1 is (C1-C4)alkyl and R" represents 2-nitro-phenyl or 4-nitro-phenyl, and R" represents an amino protecting group such as COOR2 COR2, SO2R2 or benzyl, wherein R1 is rerr-butyl, allyl or benzyl, R2 is (C1-C4)alkyl and R2 represents 2-nitro-phenyl or 4-nitro-phenyl (such compounds of formula II being referred to hereafter as "compounds of formula lie"); or b) reacting a compound of formula III r< W. /) CH,—C ( ) N—CHa—A III wherein R1, R2 U, V, W and A are as in formula I and R" is hydrogen or an amino protecting group as defined in paragraph a)2 above, with ammonium formate (which reaction is then preferably carried out using the conditions described in part 3 of the section "General reaction techniques") or ammonium acetate, hydroxylamine, alkyl or benzylhydroxylamine in presence of a hydride reagent such as LiAlFU or sodium cyanoborohydride, and, if applicable, removing the protecting group using one of the methods described in part 2 of the section "General reaction techniques"; or c) reducing a compound of formula IV W h—CHg—CH ( ) N—CHz—A ( NOa IV wherein R\ R2 U, V, W and A are as in formula I and R2 is hydrogen or an amino protecting group as defined in paragraph a)2 above following one of the methods described in part 4 of the section "General reaction techniques"; and, if applicable, removing the protecting group using one of the methods described in part 2 of the section "General reaction techniques"; or d) reducing a compound of formula V W CH=rT ( ) N—CH2—A \-\ NO, R2 V wherein R\ R\ U, V, W and A are as in formula I and R2 is hydrogen or an amino protecting group as defined in paragraph a)2 above, following one of the methods described in paragraph 4.1 of part 4 of the section "General reaction techniques", and, if applicable, removing the protecting group using one of the methods described in part 2 of the section "General reaction techniques"; or e) reacting a compound of formula VI R1 W h—CH2—CH ( ) N—CHj—A ( OH R2 VI wherein R\ R2, U, V, W and A are as in formula I and R1* is hydrogen or an amino protecting group as defined in paragraph a)2 above with sodium azide or phthalimide and subsequently transforming the azide into an amine through either reaction with PPh3 in presence of water or hydrogenolysis, or transforming the phthalimide into the corresponding amine through reaction with hydrazine, methyl hydrazine or an alkyl amine such as 3-A-dimethylaminopropylamine respectively, the reaction being performed either under Mitsunobu condition as described in part 5 of the section "General reaction techniques" or after transformation of the alcohol function of compounds of formula VII into a mesylate, triflate or tosylate as described in part 6 of the section "General reaction techniques", and, if applicable, removing the amino protecting group using methods described in part 2 of the section "General reaction techniques" (whereby the protecting group R1' might also be removed during the reaction - for example, when R"* is Cbz, it will be removed if a hydrogenolysis step is used); or f) reacting a compound of formula VII W, /)—CHg—CH ( ) NHa VII wherein R1, R2 U, V and W are as in formula I and R2 is an amino protecting group as defined in paragraph a)l above with a compound of formula VIII ACHO VIII wherein A is as in formula I under reductive amination conditions as described in part 7 of the section "General reaction techniques", and, if still present, removing the amino protecting group R"' using methods described in part 2 of the section "General reaction techniques"; or g) transforming a compound of formula Ilesi W, /)—CHo—CH ( ) N—CHz—A \_/ I vV V NH Ilest wherein U represents N, V represents CH, W represents CR", R" represents alkoxycarbonyl, R2 represents H, R1 and A are as in formula I and R1' and R"* are as defined in paragraphs a)l, a)2 or a)3 above into its corresponding hydroxymethyl derivative by reduction with an hydride reagent such as DIBAH or LiAlH4 and subsequent removal of the protecting groups using methods described in part 2 of the "General reaction techniques". Concerning variant d) of the above process, it should be noted that, as an alternative, compounds of formula V can be reduced to their corresponding saturated nitro derivatives of formula IV by reduction of the double bond using NaBH* in aq. THF as described in Tetrahedron Lett. (2003), 7345 and can be further converted into compounds of formula I by reduction of the nitro derivative following one of the methods described in paragraph 4.1 of part 4 of the section "General reaction techniques". The compounds of formula I obtained according to the abovementioned general preparation methods may then, if desired, be converted into their salts, and notably into their pharmaceutically acceptable salts. Compounds of formula I with controlled stereochemistry at the carbon bearing the free amine group are obtained through separation of the two diasteromers by crystallisation (with a chiral acid such as camphor sulfonic acid), by separation of the diastereomeric mixture on a column on SiOz. The compounds can also be obtained either from compounds of formula I-l or II-l described later on wherein the stereochemistry at the carbon bearing the hydroxyl group is controlled, as described in variant e) of the above process or through enantioselective reduction of a compound of formula III or its corresponding oximes or imines using for example chiral boron reagents as reviewed in Chem. Rev. (1993), 93, 763. Compounds of formula I with controlled stereochemistry at the carbons at positions 2 and 5 of the tetrahydropyranyl ring can be obtained through separation of the two diasteromers by crystallisation (with a chiral acid such as camphor sulfonic acid) or by separation of the diastereomeric mixture on a column on SiOi. The compounds can also be obtained either from glucal for compounds of formula la or from (S)-2-fe/-Nbutoxycarbonyl-hex-5-enoic acid methyl ester for compounds of formula lb as described in WO 2006/032466. Pr.epara.Up.n .of the y arious .synthetic .in.te.rmediates: Preparation of the compounds of formula 11 In Scheme 1, R1, U, V, W, R2 and A have the same meaning as in formula I, R2 is as described in formula Ila and PG is an amino protecting group such as Cbz or Boc. The compounds of formula Ila can be obtained (Scheme 1) through oxidation of the compounds of formula I-l (see WO 2006/032466 and part 3 of the section "General reaction techniques"), reductive aminatlon of the ketones of formula 1-2 with ammonium formate or an alternative thereof (as described in paragraph b) of the subsection "Preparation of compounds of formula I"), protection of the amine function (see part 1 of the section "General reaction techniques"; the nature of R"* is chosen in such as manner that the protecting group PG can be selectively removed, e.g. Boc vs. Cbz), removal of the protecting group PG of compounds of formula 1-3 to afford compounds of formula VII and finally either reductive animation with an aldehyde of formula VIII or substitution with a halogenide of formula ACH2Hal wherein Hal is a halogen such as bromine or iodide. Alternatively, the compounds of formula 1-3 can be obtained either by substitution of the mesylate, tosylate or triflate derived from the compounds of formula I-l followed by reaction with sodium azide, or by reaction with hydrazoic acid or DPPA under Mitsunobu conditions (see part 5 of the section "General reaction techniques"), followed by reduction of the intermediate azido derivative into an amine by e.g. hydrogenolysis over a noble metal catalyst or by using PPhs in presence of water, and final protection of the primary amino group. In Scheme 2, R\ R", U, V, W and A have the same meaning as in formula I, R"* is as described in formula lie, PG is an amino protecting group such as Cbz or Boc. The compounds of formula lib and lie can be obtained from the alcohol derivatives of formula II-1 (see WO 2006/032466) by protection of the primary amino group (see part 1 of the section "General reaction techniques"). The resulting alcohol of formula VI can be oxidized into the corresponding ketone of formula Hi (see part 3 of the section "General reaction techniques") and reacted under reductive amination conditions (see part 7 of the section "General reaction techniques") either with ammonium acetate or an alternative thereof as described in section b) to give the compounds of formula lib or with benzyl or diphenylmethyl amine to give the compounds of formula lie. Alternatively, the compounds of formula III can be obtained by hydratation of the ethynylic compounds of formula II-2 with HgO (see WO 2006/032466). In Scheme 3, R\ R2, U, V, W and A have the same meaning as in formula I and PG is an amino protecting group such as Cbz or Boc. The compounds of formula lib can also be obtained through nitro aldol reaction. The alcohol of formula III-l (see WO 2006/032466) can be transformed into the corresponding nitro derivative after transformation of the alcohol into its corresponding mesylate, triflate or tosylate and iodide (see part 6 of the section "General reaction techniques") which can subsequently be reacted with sodium nitrite in a polar solvent such as THF, DMSO or DMF between 20''C and SCC in presence of a base such as TEA or urea. The nitro derivative of formula III-2 can then be reacted with the aldehyde of formula III-3 (see part 8 of the section "General reaction techniques"). The Boc protecting group can then be removed (see paragraph 2.1 of part 2 of the section "General reaction techniques") and the resulting amine of formula III-5 can be reacted with a halogenide of formula ACHaHal wherein Hal is an halogen such as bromine or iodide, after which the secondary amine function of the compound of formula III-6 can be protected with an amino protecting group (see parts 7 and 1 of the section "General reaction techniques"). Finally the nitro group of the compound of formula V is reduced into the corresponding amine to afford the compound of formula lib (see part 4 of the section "General reaction techniques"). The compounds of formula lie can also be obtained by Curtius degradation of the ester of formula IV-5 (see scheme 4). In Scheme 4, R1, R", U, V, W, X and A have the same meaning as in formula I, R" is as described in formula lie, R1* represents halogen such as bromine, PG is an amino protecting group such as Cbz or Boc. Thus the alcohol derivative of formula IV-1 (see WO 2006/032466) can be oxidised into the corresponding acid (see part 10 of the section "General reaction techniques") and protected as a methyl ester after reaction with diazomethane or a diazomethane surrogate such as TMSCHN2. The ester can be treated with a strong base such as LDA or LiHMDS between -78°C and -SO'C and reacted with the halogenide of formula IV-3. The resulting Boc protecting group in the ester of formula IV-4 is removed and the amine is subjected to a reductive amination with an aldehyde of formula VIII. Finally the protecting group PG is installed on affording compounds of formula IV-5. The ester is hydrolysed into its corresponding acid using a base such as NaOH or LiOH and the acid is subjected to a Curtius degradation (see part 9 of the section "General reaction techniques") affording the compound of formula lie. Preparation ofchiral alcohols of formula I-l or II-l The chiral alcohols of formula I-l or II-l required to obtain the compounds of formula I wherein the carbon atom bearing the NH2 group has an (5) absolute configuration can be obtained by cw-dihydroxylation of the corresponding ethylenic compounds with AD-mix a, followed by hydrogenolysis of the corresponding cyclic carbonate (as described in WO 2006/032466). If instead an {R) absolute configuration is desired, then AD-mix P would be used in place of AD-mix a. Preparation of the compounds of formula II-2 The compounds of formula II-2 can be obtained from the corresponding ethynylic derivatives of formula IX (see WO 2006/032466) after removal of the Boc protecting group, reductive amination with the aldehyde of formula VIII and protection of the secondary amine. Preparation of the compounds of formula IV The compounds of formula IV can be obtained by reduction of the compounds of formula V with a hydride reagent such as NaBRj in a solvent such as EtOH. Preparation of the starting quinoline and [l,5]-naphthyridine derivatives The required starting quinoline and [l,5]-naphthyridine derivatives of formula 111-3 are either commercially available or can be prepared following literature procedures (see WO 2006/032466). In the particular case wherein U = V= CH, W = N, R1 = OMe and R2 = F, the corresponding derivative of formula III-3 can be obtained by lithiation of 3-fluoro-6-methoxyquinoline prepared according to WO 02/40474 between ~78°C and -30''C and quenching with DMF. The required starting quinoline and [l,5]-naphthyridine derivatives of formula IV-3 can be prepared by reduction of the aldehydes of formula III-3 with a hydride reagent such as NaBH4 in a solvent such as THF or MeOH and subsequent reaction with a trihalogenephosphine such as PCI3 or PBrj in a solvent such as DMF between 0°C and 60''C. Particular embodiments of the invention are described in the following Examples, which serve to illustrate the invention in more detail without limiting its scope in any way. EXAMPLES In the following section, unless stated, the "usual aq. work-up" means that after extraction of the aq. layer with an appropriate solvent, the combined org. layers are washed with brine, dried over Na2S04, filtered and concentrated to dryness. Preparation A: 6-fluoro-quinoline-4-carbaldehyde: A.i. 6-fluoro-quinolin-4'Ol: To a mixture of 4-fluoro-amline (25.0 g, 224.9 mmol) in EtOH (170 mL) were added successively Meldrum's acid (35.69 g, 247.6 mmol) and triethyl orthoformate (40.0 mL, 240.4 mmol). The reaction mixture was then refluxed for 2 h 30 min. The reaction mixture was cooled to 0°C and the solid was filtered and washed with cold EtOH. The solid was dried under HV to give 54.62 g of a yellow powder. To a boiling solution of diphenyl ether (230 g) was added the latter solid portion wise over 5 min. The reflux was maintained for further 3 min and the reaction mixture was allowed to stir at rt. After 30 min at rt, ether was added and the desired solid was filtered, thoroughly washed with ether and dried under HV to afford the title compound as a brown solid (11.11 g, 68.1 mmol). MS (ESI, m/z): 164.1 [M+H]. A.ii. 4-bromo-6-fluoro-quinoline: To a solution of intermediate A.i (20 g, 122.58 mmol) in DMF (130 mL), heated to eCC, was added phosphorous tribromide (13 mL, 1.15 eq.). The reaction was heated at 45''C for 45 min. After cooling to rt, the reaction was diluted with water (200 mL). Sat. NaiCOs was added until pH 10 was reached. The solid was formed was filtered off. The solid was taken up in EA (200 mL) and the solution was concentrated to dryness. The residue was chromatographed (EA) to afford the title bromide as a yellowish solid (22 g, 79% yield). 'H NMR (CDCI3) 5: 8.70 (d, J = 4.7 Hz, IH); 8.14 (m, IH); 7.96 (d, J = 4.7 Hz, IH); 7.81-7.73 (m, 2H). A.in. 6-fluorO'4-(E)-styryl-quinoline: To a hot (100 "C) solution of intermediate A.ii (18.5 g, 81.8 mmol), K2CO3 (14.7 g, 106 mmol), frfln5-2-phenylboronic acid (13.7 g, 90 mmol) in dioxane (320 mL) and water (80 mL) was added Pd(PPh3)4 (4.77 g, 5 mol%). The resulting mixture was stirred at lOO'C over night. After cooling, the reaction mixture was diluted with water (300 mL). The volatiles were removed in vacuo and the residue was taken up in EA (300 mL). The two layers were separated and the aq. layer was extracted one more with EA (300 mL). The combined org. layers were washed with brine, dried over MgS04, filtered and concentrated to dryness. The residue was chromatographed (EA-Hept 1:2) to afford the title compound as a yellow solid (17.79 g, 87% yield). 'H NMR (CDCI3) 5: 8.89 (d, J = 4.6 Hz, IH); 8.16 (dd, J = 9.5, 5.5 Hz, IH); 7.83 (dd, J = 2,7, 9.5 Hz, IH); 7.70-7.63 (m, 4H); 7.55-7.34 (m, 5H). A.iv. 6-fluoro-quinoline'4-carbaldehyde: To a mixture of intermediate A.iii (17.7 g, 71.3 mmol) in 2-methyl-2-propanol (300mL) and water (300 mL) were methanesulfonamide (7.46 g, 78.5 mmol, 1.1 eq.) and AD-mix (3 (100 g). The resulting mixture was stirred at room temperature for 48 h. Sodium bisulfite (107 g) was added portion wise. The two layers were separated and the aq. layer was extracted twice with EA (2 x 250 mL). The combined org. layers were washed with brine, dried over MgS04 and concentrated to dryness. The residue was taken up in acetone (400 mL) and warmed to 50°C. The resulting solution was treated with a solution of NaI04 (38 g, 178 mmol) in water (100 mL). After stirring for 30 min, the reaction mixture was diluted in water (200 mL) and the volatiles were removed in vacuo. The resulting solid was filtered off, thoroughly washed with water and dried under HV to afford the title aldehyde as a beige solid (10.05 g, 57.3 mmol). 'H NMR (CDCI3) 8: 10.41 (s, IH); 9.15 (d, J = 4.4 Hz, IH); 8.73 (dd, J = 10.2, 2.6 Hz, IH); 8.20 (dd, J = 9.1, 5,5 Hz, IH); 7.80 (d, J = 4.4 Hz, IH); 7.58 (m, IH). Preparations: (3i?,][l,4]oxaziii-3-one: Starting from intermediate 14.i (0.12 g, 0.285 mmol), the title compound was obtained as a white solid (0.073 g, 0.15 mmol) using the procedure of Example 7. The compound was obtained as a 1-1 mixture of epimers. MS (ESI, m/z): 483.5 [M+H*]. Example 16: {(5/?,][l,4]thiazin-3-one: 21.L [(lRS)-l-((2R,5S)'5-amino-tetrahydro-pyran-2-yl)-2'(6-methoxy-[l,5Jnaphthyridin-4-yl)-ethyl]'Carbamic acid tert-butyl ester: The title compound was obtained as a white foam (0.07 g, 0,17 mmol), starting from {(3S,6;?)-6-[(lS)-l'hydroxy-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}-carbamic acid rert-butyl ester (prepared as described in WO 2006/032466, 0,87 g, 2.15 mmol) and using sequentially the procedures of Example 2, steps 2.iv (Boc deprotection and Cbz formation, 72% yield), Example 1, steps l.i (oxidation, 36% yield) and l.ii (reductive amination, 48% yield) and Example 2, steps 2.vii (Boc formation, 80% yield) and 2.viii (hydrogenolysis, 78% yield). After each step, the crude material was purified by CC using an appropriate eluent, if necessary. The compound was obtained as an equinolar mixture of epimers. MS (ESI, m/z); 403.3 [M+H*]. 21.ii. 6-({(3S,6n)-6-[(lRS)-l-amino-2-(6-methoxy'[l,5]naphthyndin-4'yl)-ethylJ-tetrahydro-pyran-3-ylamino}-methyl)'4H-pyrido[3,2-b][l, 4]thiazin-3-one: Starting from intermediate 6.i (0.07 g, 0.174 mmol), the title compound was obtained as a beige solid (0,060 g, 0,12 mmol) using the procedures described in Example 4, step 4.ii and step 4.iii. After the reductive amination step, the intermediate NHBoc protected compound was purified by CC (DCM-MeOH 93-7 containing 0.7% aq. NH4OH) and an analytical sample was characterized using conditions reported in Example 6, step 6.i; the retention time of both epimers were respectively 19.7 and 29.5 min. The title compound was obtained as an equimolar mixture of epimers. MS (ESI, m/z): 481.4 [M+H]. Example 22: 6-({(5i?,d5)-6-[(i/?S)-l-amino-2-(7-fluoro-2-methoxy-quinoIin-8-yI)-ethyl]-tetrahydro-pyraii-3-ylainino}-methyl)-4W-pyrido[3,2-A][l,4]oxazin-3-one: 22, i. (7'fluoro-2-methoxy-quinolin-8-yl) -methanol: A suspension of 8-bromomethyI-7-fluoro-2-methoxy-quinoline (25 g, 92.56 mmol) in acetone (360 mL) and water (460 mL) was treated with NaHCOs (12.74 g, 151.64 mmol, 1.6 eq,). The mixture was heated to reflux overnight. After cooling, the volatiles were removed in vacuo and the residue was partitioned between EA (300 mL) and water (100 mL). The aq. layer was extracted once with EA (250 mL) and the combined org. layers were washed with brine, dried over Na2S04, filtered and concentrated to dryness. The residue was purified by CC (Hept-EA 3:1) to afford the title alcohol as a yellowish solid (14.04 g). 'H NMR (d6-DMS0) 5: 8.24 (d, J = 8.0 Hz, IH); 7.88 (dd, J = 6.4, 9.1 Hz, IH); 7.31 (t, J = 9.1 Hz, IH); 6.98 (d, J = 8.8 Hz, IH); 5.01 (dd, J = 2.1, 5.9 Hz, 2H); 4.86 (t, J = 5.9 Hz, IH); 4.02 (s, 3H). 22. a. 7-fluoro-2-methoxy-quinoline-8-carbaldehyde: To a solution of oxalyl chloride (17.2 mL, 203.28 mmol) in DCM (360 mL), cooled to -78''C, was added dropwise a solution of DMSO (17.3 mL) in DCM (150 mL) over 45 min. The mixture was stirred 15 min before a solution of intermediate 22.i (14.04 g, 67.76 mmol) in DCM (400 mL) was added dropwise over 2 h. The mixture was further stirred 1 h at this temperature. A solution of TEA (70.83 mL, 508.2 mmol, 7.5 eq) in DCM (150 mL) was added dropwise over 1 h. The mixture was stirred 30 min before warming gradually to rt. The reaction was quenched by adding a sat. NaHCOj solution (500 mL). The two layers were separated and the org. layer was dried over Na2S04, filtered and concentrated to dryness. The residue was dissolved in EA and was purified by CC (EA) affording the aldehyde as a yellowish solid (13.9 g, quant.). H NMR (d6-DMSO) 5: 11.12 (dd, J = 0.6, 1.5 Hz, IH); 8.35 (d, J = 8.8 Hz, IH); 8.25 (dd, J = 5.9, 9.1 Hz, IH); 7.42 (ddd, J = 0.6, 9.1,10.8 Hz, IH); 7.11 (d, J = 8.8 Hz, IH); 4.03 (s, 3H). MS (ESI, m/z): 206.1 [M+H]. 22.Hi. {3R,6S)'6-[(E)-2-(7-fluorO'2-methoxy-quinolin-8-yl)-vinyl]-tetrahydro-pyran-3-yl}-carbamic acid tert-butyl ester: A solution of LiHMDS (IM / THF, 62.8 mL, 1.7 eq.) was added dropwise over 40 min and at -78''C to a solution of preparation B (15.64 g, 36.94 mmol) in 1,2-DME (201 mL). The mixture was stirred 20 min at -78''C and intermediate 22.ii (7.58 g, 36.94 mmol) was added in one portion. After 1 h at the same temperature, the solution was warmed slowly to rt. At this point, water (220 mL) and EA (100 mL) were added. The two layers were decanted and the aq. layer was extracted twice (2 x 100 mL) with EA. The combined org. layers were washed with brine (100 mL), dried over Na2S04, filtered and concentrated to dryness. The residue was triturated in a EtjO-Hept (1:4) mixture affording the title (£)-alkene (12.33 g, 83% yield). MS (ESI, m/z): 403.2 [M+H]. 22.iv. [(lRS)-l-((2S,5R)'5-amino-tetrahydro-pyran-2-yl)-2-(7-fluoro-2-methoxy-quinolin-8-yl)-ethylJ-carbamic acid tert-butyl ester: Starting from intermediate 22.iii (12.32 g, 30.6 mmol), the title amine (1.73 g, 4.12 mmol) was obtained as a white foam using sequentially the procedures reported in Example 2, steps 2.i (asymmetric dihydroxylation using AD-mix a, 47% yield), 2.ii (carbonate formation, 99% yield), 2.iii (hydrogenolysis, 45% yield) and 2.iv (Boc deprotection and Cbz formation, 96% yield), Example 1, step l.ii (reductive amination, 75% yield) and Example 2, steps 2.vii (Boc formation, 96% yield) and 2.viii (hydrogenolysis, 95% yield). After each step, the crude material was purified by CC using an appropriate eluent, if necessary. The compound was recovered as a 3:2 mixture of epimers. MS (ESI, m/z): 420.2 [M+H*]. 22.V. 6-({(3R, 6S)-6-[(lRS)-l-amino-2'(7'fluoro'2-methoxy-quinoUn-8-yl)-ethylJ-tetrahydro-pyran-3'ylatnino}-methyl)-4H-pyrido[3,2-b][l,4]oxazin'3-one: Starting from intermediate 22.iv (0.15 g, 0.358 mmol) and 3-oxo-3,4-dihydro-2//-pyrido[3,2-6][l,4]oxazine-6-carbaldehyde (0.063 g, 1.0 eq,), the title compound was obtained as an off-white solid (0.137 g, 0.26 mmol) using the procedures of Example 4, steps 4.ii and 4.iii. After the reductive amination step, the compound was purified by CC (DCM-MeOH 93:7 containing 0.7% aq. NH4OH). MS (ESI, m/z): 482.2 [M+H']. Example 23: 6-({(3i?,6-t(i7?)-l-amino-2-(3-fluoro-6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4//-benzo[l,4]oxazin-3-one; and -6-({(3/?,(5S)-6-[(i5)-l-amino-2-(3-fluoro-6-methoxy-[l,5]naphthyridin-4-yl)-ethy]]-tetrahydro-pyran-3-ylamino}-methyl)-4//-benzo[l,4]oxa2in-3-one; or a salt of such a compound. 10. A compound according to claim 9, which is selected from the following compounds: - {(3/?,65)-6-[(i/?)-l-amino-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}-[3-(£)-(2,5-difluoro-phenyl)-allyl]-amine; - {(ii?,6S')-6-[(i5)-l-amino-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}-[3-(£)-(2,5-difluoro-phenyl)-allyl]-amine; -{(3i?,6S)-6-[(i/?)-l-amino-2-(6-fluoro-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}-[(£')-3-(2,5-difluoro-phenyl)-allyI]-amine; -{(5,65)-6-[(iS)-l-amino-2-(6-fluoro-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}-[(£')-3-(2,5-difluoro-phenyl)-allyl]-amine; -6-({(37?,65')-6-[(i/?)-l-amino-2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4//-pyrido[3,2-i][l,4]thiazin-3-one; -6-({(J,65')-6-[(i5)-l-amino-2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4//-pyrido[3,2-6][l,4]thia2in-3-one; - {(5/?,(5S)-6-[(i)-l-amino-2-(6-methoxy-quinolin-4-yl).ethyl]-tetrahydro-pyran-3-yl}-[3-(£)-(2,5-difluoro-phenyl)-aUyl]-amine; - {(3/?,65)-6-[(i5)-l-aroino-2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}-[3-(£)-(2,5-difluoro-phenyl)-allyl]-amine; -6-({(3;?,65)-6-[(i/?)-l-amino-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4//-pyrido[3,2-6][l,4]thiazin-3-one; -6-({(J7f,(55)-6-[(i5)-l-amino-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro- pyran-3-ylamino}-methyl)-4//-pyrido[3,2-6][l,4]thiazin-3-one; -6-({(3/?,65)-6-[(7/?)-l-amino-2-(6-raethoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro- pyran-3-ylamino}-methyl)-4//-pyrido[3,2-6][l,4]oxazin-3-one; -6-({(3/?,65)-6-[(i5')-l-amino-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro- pyran-3-ylamino}-methyl)-4/r-pyrido[3,2-6][l,4]oxazin-3-one; -8-[(2i?)-2-amino-2-{5-[(£)-3-(2,5-difluoro-phenyl)-allylainino]-tetrahydro-pyran-2-yl}- ethyl]-2-methoxy-quinoline-5-carboxylic acid methyl ester; - 8-[(2S)-2-amino-2-{5-[(£)-3-(2,5-difluoro-phenyl)-allylamino]-tetrahydro-pyran-2-yl}- ethyl]-2-methoxy-quinoline-5-carboxylic acid methyl ester; -8-((5)-2-amino-2-{(2S',5;?)-5-[(£:)-3-(2,5-difluoro-phenyl)-allylamino]-tetrahydro-pyran-2-yI}-ethyl)-2-methoxy-quinolin-5-yI]-methanol; -[8-((/?)-2-amino-2-{(25,5i?)-5-[(£)-3-(2,5-difluoro-phenyl)-allylamino]-tetrahydro-pyran-2-yl}-ethyl)-2-methoxy-quinolin-5-yl]-methanol; -6-({(3i?,65')-6-[(i/?)-l-amino-2-(3-fluoro-6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4i/-pyrido[3,2-6][l,4]thiazin-3-one; -6-({(5/?,65)-6-[(i5')-l-amino-2-(3-fluoro-6-methoxy-quinolin-4-yI)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4//-pyrido[3,2-&][l,4]thiazin-3-one; -6-({(3J?,65)-6-[(i/?)-l-amino-2-(3-fluoro-6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)'4//-pyrido[3,2-6][l,4]oxazin'3-one; -6-({(3i?,65)-6-[(iS')-l-amino-2-(3-fluoro-6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4/f-pyrido[3,2-6][l,4]oxazin-3-one; -6-({(J/?,65')-6-[(i/?)-l-amino-2-(3-fluoro-6-methoxy-[l,5]naphthyridin-4-yI)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4//-pyrido[3,2-fc][l,4]thiazin-3-one; -6-({(3i?,65)-6-[(i5)-l-amino-2-(3-fluoro-6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4//-pyrido[3,2-6][l,4]thiazin-3-one; -6-({(3;?,65)-6-[(i/?)-l-amino-2-(3-fluoro-6-methoxy-[l,5]naphthyridin-4-yl)-ethyI]-tetrahydro-pyran-3-yIamino}-methyl)-4//-pyrido[3,2-6][l,4]oxazin-3-one; -6-({(3/?,<55)-6-[(i5)-l-amino-2-(3-fluoro-6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4//-pyrido[3,2-6][l,4]oxazxn-3-one; - {(3,<55')-6-[(i5)-l-amino-2-(6-methoxy-[ 1,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran- 3-yl}-(4-ethyI-benzyl)-amine; - {(ii?,65')-6-[(75)-l-amino-2-(6-methoxy-quinolin-4-yI)-ethyl]-tetrahydro-pyran- 3-ylamino}-methyI)-4//-benzo[l,4]oxazin-3-one; -6-({(3;?,65)-6-[(i5)-l-amino-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4//-pyndo[3,2-6][l,4]oxazin-3-one; -6-({(i;?,6S)-6-[(75)-l-amino-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}-(3-fluoro-4-methyl-benzyl)-amine; - {(5i?,65)-6-[(75')-l-amino-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran- 3 -ylamino } -methyl)-4//-benzo[ 1,4] oxazin-3-one; -6-({(i5,6/?)-6-[(i/?)-l-amino-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4//-pyrido[3,2-6][l,4]thia2in-3-one; and -6-({(55',6/?)-6-[(;5)-l-amino-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4//-pyrido[3,2-6][l,4]thiazin-3-one; or a salt of such a compound. 11. As a medicament, a compound of formula I as defined in one of claims 1 to 10 or a pharmaceutical!y acceptable salt thereof. 12. A pharmaceutical composition containing, as active principle, a compound of formula I as defined in one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient. 13. Use of a compound of formula I as defined in one of claims 1 to 10, or of a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or treatment of a bacterial infection. 14. A compound of formula I as defined in one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for the prevention or treatment of a bacterial infection.

Documents

Application Documents

# Name Date
1 abs 0158-chenp-2010 abstract 08-01-2010 1.jpg 2010-01-08
2 abs 0158-chenp-2010 abstract 08-01-2010.jpg 2010-01-08
3 0158-chenp-2010 form-5 08-01-2010.pdf 2010-01-08
4 0158-chenp-2010 form-3 08-01-2010.pdf 2010-01-08
5 0158-chenp-2010 form-1 08-01-2010.pdf 2010-01-08
6 0158-chenp-2010 description(complete) 08-01-2010.pdf 2010-01-08
7 0158-chenp-2010 claims 08-01-2010.pdf 2010-01-08
8 0158-chenp-2010 power of attorney 08-01-2010.pdf 2010-01-08
9 0158-chenp-2010 pct 08-01-2010.pdf 2010-01-08
10 0158-chenp-2010 form-2 08-01-2010.pdf 2010-01-08
11 0158-chenp-2010 correspondence others 08-01-2010.pdf 2010-01-08
12 0158-chenp-2010 abstract 08-01-2010.pdf 2010-01-08
13 158-CHENP-2010 FORM-18 13-05-2011.pdf 2011-05-13
14 158-CHENP-2010 CORRESPONDENCE OTHERS 13-05-2011.pdf 2011-05-13
15 158-CHENP-2010 FORM-3 17-10-2014.pdf 2014-10-17
16 158-CHENP-2010 CORRESPONDENCE OTHERS 17-10-2014.pdf 2014-10-17
17 158-CHENP-2010-Form 3-220915.pdf 2015-11-30
18 158-CHENP-2010-Correspondence-220915.pdf 2015-11-30
19 158-CHENP-2010-Form 3-080316.pdf 2016-03-15
20 158-CHENP-2010-Correspondence-080316.pdf 2016-03-15
21 Form 3 [06-09-2016(online)].pdf 2016-09-06
22 158-CHENP-2010-FER.pdf 2016-12-20
23 Form 3 [08-03-2017(online)].pdf 2017-03-08
24 Petition Under Rule 137 [23-05-2017(online)].pdf_48.pdf 2017-05-23
25 Petition Under Rule 137 [23-05-2017(online)].pdf 2017-05-23
26 Other Document [23-05-2017(online)].pdf 2017-05-23
27 Form 3 [23-05-2017(online)].pdf 2017-05-23
28 Form 26 [23-05-2017(online)].pdf 2017-05-23
29 Examination Report Reply Recieved [23-05-2017(online)].pdf 2017-05-23
30 Description(Complete) [23-05-2017(online)].pdf_64.pdf 2017-05-23
31 Description(Complete) [23-05-2017(online)].pdf 2017-05-23
32 Claims [23-05-2017(online)].pdf 2017-05-23
33 Abstract [23-05-2017(online)].pdf 2017-05-23
34 Correspondence by Agent_Notarized US Assignment_24-05-2017.pdf 2017-05-24
35 158-CHENP-2010-FORM 3 [11-09-2017(online)].pdf 2017-09-11
36 158-CHENP-2010-HearingNoticeLetter.pdf 2017-09-15
37 158-CHENP-2010-Correspondence to notify the Controller (Mandatory) [04-10-2017(online)].pdf 2017-10-04
38 158-CHENP-2010-Written submissions and relevant documents (MANDATORY) [27-10-2017(online)].pdf 2017-10-27
39 158-CHENP-2010-Retyped Pages under Rule 14(1) (MANDATORY) [27-10-2017(online)].pdf 2017-10-27
40 158-CHENP-2010-2. Marked Copy under Rule 14(2) (MANDATORY) [27-10-2017(online)].pdf 2017-10-27
41 Correspondence by Agent_Affidavit_02-11-2017.pdf 2017-11-02
42 Marked Up Claims_Granted 289438_10-11-2017.pdf 2017-11-10
43 Description_Granted 289438_10-11-2017.pdf 2017-11-10
44 Claims_Granted 289438_10-11-2017.pdf 2017-11-10
45 Abstract_Granted 289438_10-11-2017.pdf 2017-11-10
46 158-CHENP-2010-PatentCertificate10-11-2017.pdf 2017-11-10
47 158-CHENP-2010-IntimationOfGrant10-11-2017.pdf 2017-11-10
48 158-CHENP-2010-PA [18-11-2017(online)].pdf 2017-11-18
49 158-CHENP-2010-ASSIGNMENT DOCUMENTS [18-11-2017(online)].pdf 2017-11-18
50 158-CHENP-2010-8(i)-Substitution-Change Of Applicant - Form 6 [18-11-2017(online)].pdf 2017-11-18
51 158-CHENP-2010-RELEVANT DOCUMENTS [12-03-2018(online)].pdf 2018-03-12
52 158-CHENP-2010-RELEVANT DOCUMENTS [27-02-2019(online)].pdf 2019-02-27

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1 NewMicrosoftWordDocument_05-12-2016.pdf

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