WO2006032466A2 - New bicyclic antibiotics - Google Patents

New bicyclic antibiotics Download PDF

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Publication number
WO2006032466A2
WO2006032466A2 PCT/EP2005/010154 EP2005010154W WO2006032466A2 WO 2006032466 A2 WO2006032466 A2 WO 2006032466A2 EP 2005010154 W EP2005010154 W EP 2005010154W WO 2006032466 A2 WO2006032466 A2 WO 2006032466A2
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Prior art keywords
methoxy
pyran
tetrahydro
dihydro
quinolin
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PCT/EP2005/010154
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French (fr)
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WO2006032466A3 (en
Inventor
Christian Hubschwerlen
Jean-Philippe Surivet
Cornelia Zumbrunn Acklin
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Actelion Pharmaceuticals Ltd
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Priority to CA002580621A priority Critical patent/CA2580621A1/en
Priority to EP05784860A priority patent/EP1799676A2/en
Priority to JP2007532823A priority patent/JP4887297B2/en
Publication of WO2006032466A2 publication Critical patent/WO2006032466A2/en
Publication of WO2006032466A3 publication Critical patent/WO2006032466A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention concerns novel antibiotics, pharmaceutical antibacterial compositions containing them and the use thereof in the manufacture of a medicament for the treatment of infections (e.g. bacterial infection).
  • infections e.g. bacterial infection
  • 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.
  • Enterobacteriacea are cephalosporin and quinolone resistant; - P. aeruginosa are ⁇ -lactam and quinolone resistant.
  • 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.
  • a new type of quinoline or naphthyridine derivatives having antibacterial activity and therefore useful for treating infections in mammals, particularly in humans, have been reported.
  • WO 99/37635, WO 00/21948, WO 00/21952, WO 00/43383, WO 03/101138, WO 01/025227, WO 02/040474 and WO 2004/011454 disclose quinoline, naphthyridine and quinazoline derivatives containing a 4-methylpiperidinyl spacer.
  • WO 00/78748, WO 02/50040 and WO 02/050061 disclose quinoline and naphthyridine derivatives containing a piperazinyl spacer.
  • WO 01/07432, WO 01/07433, WO 02/08224, WO 02/056882, WO 03/064421, WO 03/064431, WO 2004/02490 and WO 2004/058144 disclose quinoline, quinoxaline and naphthyridine derivatives containing a 4-aminopiperidinyl spacer.
  • WO 04/035569 discloses quinoline and naphthyridine derivatives containing a 3-aminomethylpiperidinyl spacer.
  • WO 2004/002992, WO 03/087098, WO 2004/014361 and WO 2004/035569 disclose quinoline, quinoxaline and naphthyridine derivatives containing a 4-aminocyclohexyl spacer.
  • novel bicyclic derivatives are useful antimicrobial agents and effective against a variety of multi-drug resistant bacteria.
  • the present invention relates to novel bicyclic derivatives of the formula
  • R 1 represents alkyl, alkoxy, haloalkoxy, halogen or cyano; one or two of U, V, W and X represent(s) N, the remaining represent CH, or, in the case of U, V and/or W, may also represent CR a and, in the case of X, may also represent CR b ; R a represents halogen; R > b . represents halogen or alkoxy;
  • D represents alkyl, aryl or heteroaryl
  • M is selected from the group consisting of M 1 , M 2 , M 3 and M 4 :
  • B 1 and B 2 each represent independently from each other N or CH; when A 1 represents OCH 2 , B 1 represents CH; n is 1; or n is also O when B 1 is CH; and p is 1; or p is also O when B 2 is CH;
  • R 2 represents hydrogen, alkyl, hydroxyalkyl, alkylcarbonyloxyalkyl, carbamoyloxyalkyl, carboxyalkyl or carbamoylalkyl;
  • R 3 and R 4 each independently represent hydrogen, hydroxy or alkylcarbonyloxy; or R 3 and R 4 together represent a bridged dimethylmethylenedioxy chain attached to the carbons bearing R 3 and R 4 ;
  • R 5 represents hydrogen, alkyl or hydroxyalkyl
  • the dotted line represents a single bond or, when R 3 and R 4 represent hydrogen, also a double bond;
  • a 7 represents NHCO 5 CH 2 CH 2 or OCH 2 ;
  • a 8 represents CH 2 ;
  • R 6 represents hydrogen or alkyl.
  • the compounds of formula I may be compounds of formula IC E
  • R 1 represents alkyl, alkoxy, haloalkoxy, halogen or cyano; one or two of U, V, W and X represent(s) N, the remaining represent CH, or, for one of U, V,
  • W or X may also represent CR a ;
  • R a represents halogen
  • D represents an alkyl radical, a phenyl radical optionally substituted one or twice by substituents independently selected from the halogen atoms or a heteroaryl radical
  • M is selected from the group consisting of M 1 , M 2 , M 3 and M 4 :
  • B 1 and B 2 each represent independently from each other N or CH; when A 1 represents OCH 2 , B 1 represents CH; n is 1; or n is also O when B 1 is CH; and. p is 1; or p is also O when B 2 is CH;
  • R 2 represents hydrogen or hydroxyalkyl
  • R 3 and R 4 each independently represent hydrogen or hydroxy; or R 3 and R 4 together represent a bridged dimethylmethylenedioxy chain attached to the carbons bearing R 3 and R 4 ;
  • R 5 represents hydrogen; and the dotted line represents a single bond or, when R 3 and R 4 represent hydrogen, also a double bond;
  • a 5 represents NHCO(CH 2 ) m , NHCOCH 2 O or O(CH 2 ) q ; m is 0, 1 or 2; q is 1, 2 or 3 and
  • a 7 represents NHCO, CH 2 CH 2 or OCH 2 ;
  • a 8 represents CH 2 ; and
  • R 6 represents hydrogen.
  • the compounds of formula I may also be compounds of formula IC EP 2
  • R 1 represents alkyl, alkoxy, haloalkoxy, halogen or cyano
  • one or two of U, V, W and X represent(s) N, the remaining represent CH, or, in case of U, V and/or W, may also represent CR a and, in the case of X, may also represent CR b
  • R a represents halogen
  • R b represents halogen or alkoxy
  • D represents alkyl, phenyl or heteroaryl
  • M is selected from the group consisting of M 1 , M 2 , M 3 and M 4 : wherein
  • B 1 and B 2 each represent independently from each other N or CH; when A 1 represents OCH 2 , B 1 represents CH; n is 1; or n is also O when B 1 is CH; and p is 1 ; or p is also O when B 2 is CH;
  • R 2 represents hydrogen or hydroxyalkyl
  • R 3 and R 4 each independently represent hydrogen or hydroxy; or R 3 and R 4 together represent a bridged dimethylmethylenedioxy chain attached to the carbons bearing R 3 and R 4 ;
  • R 5 represents hydrogen; and the dotted line represents a single bond or, when R 3 and R 4 represent hydrogen, also a double bond;
  • a 5 represents NHCO(CH 2 ) m , NHCOCH 2 O or O(CH 2 ) q ; m is 0, 1 or 2; q is 1, 2 or 3 and
  • a 7 represents NHCO, CH 2 CH 2 or OCH 2 ;
  • a 8 represents CH 2 ; and
  • R 6 represents hydrogen.
  • Another aspect of this invention relates to compounds of formula Ip 2
  • R 1 represents alkyl, alkoxy, haloalkoxy, halogen or cyano; one or two of U, V, W and X represent(s) N, the remaining represent CH, or, in case of U, V and/or W, may also represent CR a and, in the case of X, may also represent CR b ; R a represents halogen;
  • R b represents halogen or alkoxy
  • D represents alkyl, aryl or heteroaryl
  • M is selected from the group consisting of M 1 , M 2 , M 3 and M 4 : wherein
  • B 1 and B 2 each represent independently from each other N or CH; when A 1 represents OCH 2 , B 1 represents CH; n is 1; or n is also O when B 1 is CH; and p is 1 ; or p is also O when B 2 is CH;
  • R 2 represents hydrogen, alkyl, hydroxyalkyl, alkylcarbonyloxyalkyl, carbamoyloxyalkyl, carboxyalkyl or carbamoylalkyl;
  • R 3 and R 4 each independently represent hydrogen, hydroxy or alkylcarbonyloxy; or R 3 and R 4 together represent a bridged dimethylmethylenedioxy chain attached to the carbons bearing R 3 and R 4 ;
  • R 5 represents hydrogen, alkyl or hydroxyalkyl; and the dotted line represents a single bond or, when R 3 and R 4 represent hydrogen, also a double bond;
  • a 7 represents NHCO, CH 2 CH 2 or OCH 2 ;
  • a 8 represents CH 2 ;
  • R 6 represents hydrogen or alkyl.
  • a further aspect of this invention relates to compounds of formula Ip 1
  • R 1 represents alkyl, alkoxy, halogen or cyano
  • one or two of U, V, W and X represent(s) N, the remaining represents CH, or, in case of U and/or X, also CR
  • R represents alkoxy or halogen
  • D represents alkyl, aryl or heteroaryl
  • M is one of the spacers M 1 , M 2 and M 3 : wherein
  • B 1 and B 2 each represent independently from each other N or CH; when A 1 represents OCH 2 , B 1 represents CH; n is the integer 1; or n is also O when B 1 is CH; and p is the integer 1; or p is also O when B 2 is CH;
  • R 2 represents hydrogen, alkyl, hydroxyalkyl, alkylcarbonyloxyalkyl, carbamoyloxyalkyl, carboxyalkyl or carbamoylalkyl;
  • R 3 and R 4 each independently represent hydrogen, hydroxy or alkylcarbonyloxy;
  • R 5 represents hydrogen or alkyl; and the dotted line represents a single bond or, when R 3 and R 4 represent hydrogen, also a double bond;
  • a further emtoodiment of the bicyclic derivatives of the above formula I 5 I CE or Ip 1 relates to their prodrugs, their tautomers, their optically pure enantiomers, mixtures of enantiomers, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixture of diastereoisomeric racemates, meso forms, pharmaceutically acceptable salts, solvent complexes and morphological forms thereof.
  • Particularly preferred are the optically pure enantiomers, optically pure diastereoisomers, meso forms, pharmaceutically acceptable salts, solvent complexes and morphological forms.
  • alkyl refers to a saturated straight or branched chain alkyl group, containing from one to ten, preferably one to six, in particular one to four carbon atoms, for example methyl, ethyl, propyl, iso-propyl, butyl, ⁇ -butyl, .sec-butyl, tert-bxxtyl, w-pentyl, iso- pentyl, re-hexyl, 2,2-dimethylbutyl, w-octyl.
  • Any alkyl group as defined herein may be substituted with one, two or more substituents, for example F, Cl, Br, I 5 NH 2 , OH, SH, COOH or NO 2 .
  • substituents for example F, Cl, Br, I 5 NH 2 , OH, SH, COOH or NO 2 .
  • substituted alkyl groups are trifluoromethyl, trifluoroethyl, hydroxyrnethyl, hydroxyethyl, carboxymethyl and carboxyethyl.
  • Alkyl groups may also be substituted by alkylcarbonyloxy, such as in acetoxymethyl, acetoxyethyl, propionyloxymethyl or propionyloxyethyl; by carbamoyloxy, such as in carbamoyloxymethyl or carbamoyloxyethyl; or by carbamoyl, such as in carbamoylmethyl or carbamoylethyl.
  • alkyl groups combined to form alkylcarbonyloxy are exemplified e. g. as acetoxy or propionyloxy.
  • alkoxy is an "alkyl-O" group, where "alkyl” has the above significance. Examples for substituted alkoxy groups are trifluoromethoxy and trifluoroethoxy.
  • halogen refers to fluorine, chlorine, bromine or iodine, preferably to fluorine or chlorine.
  • aryl refers to an aromatic cyclic group with one, two or three rings, having five to 14 carbon ring-atoms preferably from five or six to ten carbon ring-atoms, for example phenyl or naphthyl groups.
  • Any aryl group as defined herein may be substituted with one, two or more substituents, for example F, Cl, Br, I, OH, NH 2 , SH, N3, NO 2 , alkyl groups such as methyl or ethyl, perfluoroalkyl groups such as trifluoromethyl or trifluoroethyl, alkoxy groups such as methoxy, amino groups such as methylamino or dimethylamino, or cyano.
  • substituents for example F, Cl, Br, I, OH, NH 2 , SH, N3, NO 2 , alkyl groups such as methyl or ethyl, perfluoroalkyl groups such as trifluoromethyl or trifluoroethyl, alkoxy groups such as methoxy, amino groups such as methylamino or dimethylamino, or cyano.
  • 4-fluoro-phenyl 4-chloro-phenyl, 4-methoxy-phenyl, 4-methyl-phenyl, 4-trifluoromethyl-phenyl, 4-trifluoromethoxy- phenyl, 2,4-difluoro-phenyl, 2,4-dichloro-phenyl, 2,4-dimethoxy-phenyl, 2,4-dimethyl- phenyl, 2,4-ditrifluoromethyl-phenyl and 2,4-ditrifluoromethoxy-phenyl.
  • heteroaryl refers to an aryl group as defined herein where one, two or more ring-carbon atoms are replaced by an oxygen, nitrogen or sulphur atom, for example pyridyl, imidazolyl, pyrazolyl, quinolinyl, isoquinolinyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl and pyridazinyl groups.
  • heteroaryl also covers bicyclic structures such as benzo[l,3]dioxol-5-yl, 2,3-dihydro- benzo [ 1 ,4]dioxin-6-yl, 4H-benzo [ 1 ,4]oxazin-3 -one-6-yl, 4 ⁇ -benzo [ 1 ,4]thiazin-3 -one-6-yl, 3-oxo-3,4-dihydro-2H-benzo[l,4]thiazin-6-yl, lH-pyrido[2,3-b][l,4]thiazin-2-one-7-yl, 2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-yl, 2,3-dihydro-[l,4]dioxino[2,3-Z>]pyridin-7-yl, 4H-pyrido[3,2- ⁇ ][l,4]oxazin-3-
  • Any heteroaryl group as defined herein may be substituted with one, two or more substituents, for example F, Cl, Br, I, OH, NH 2 , SH, N 3 , NO 2 , alkyl groups such as methyl or ethyl, perfluoroalkyl groups such as trifluoromethyl or trifluoroethyl, alkoxy groups such as methoxy, amino groups such as methylamino or dimethylamino, or cyano.
  • the present invention also relates to pro-drags that are composed of a compound of formula I P i having a free carboxylic acid and at least one pharmacologically acceptable protective group that will be cleaved off under physiological conditions.
  • prodrugs have been reviewed by Beaumont, Kevin; Webster, Robert; Gardner, Iain; Dack, Kevin in Current Drug Metabolism (2003), 4(6), 461-485.
  • promoities are alkoxy-, aralkyloxy-, 0CH(R a )0C0R b (e.g. pivaloyloxymethyloxy), OCH(R a )OR b , 2-alkyl-, 2-aryl- or 2-aralkyl-oxycarbonyl-2-alkylidene-ethoxy group, 5-alkyl[l,3]dioxol- 2-one-4-yl-methoxy, dialkylamino-alkyloxy or acyloxy as defined herein, e.g.
  • R a and R b are hydrogen, C 1 -C O alkyl, C 2 -C O alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 heteroalkyl, C 2 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, alkylaryl, alkylheteroaryl, heteroalkylcycloalkyl, heteroalkylheteroaryl, aryl, heteroaryl, heterocycloalkylaryl or heterocycloalkylheteroaryl.
  • a free hydroxy group is present on a compound of Formula I, it can be protected as a prodrug of the type sulfate (OSO 3 H), phosphate (OPO 3 H 2 ), oxymethylene phosphate (OCH 2 OPO 3 H 2 ), succinate (OCOCH 2 CH 2 COOH), or ester of naturally occurring amino acids or a derivative thereof
  • alkyl refers to a saturated straight or branched chain alkyl group, containing from one to ten, preferably one to six, and in particular one to four carbon atoms.
  • Representative examples of alkyl groi ⁇ ps include, but are not limited to, methyl, ethyl, propyl, iso-propyl, ⁇ -butyl, wo-butyl, .sec-butyl, tert-butyl, w-pentyl, wo-pentyl, w-hexyl,
  • (Ci-C x )alkyl (x being an integer) refers to a straight or branched chain alkyl group containing 1 to x carbon atoms.
  • alkoxy refers to a saturated straight or branched chain alkoxy group, containing from one to ten, preferably one to six, and in particular one to four carbon atoms.
  • alleoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, /so-propoxy, r ⁇ -bixtoxy, wo-butoxy, sec-butoxy, tert-butoxy or n- hexyloxy.
  • (Ci-C x )alkoxy refers to a straight or branched chain alkoxy group containing 1 to x carbon atoms.
  • (Ci-C 6 )alkoxy-(Ci-C6)alkyl refers to a (CrC6)allcyl group as previously defined itself substituted with a (Ci-C ⁇ )alkoxy group as previously defined.
  • haloalkoxy refers to a saturated straight or branched chain alkoxy group, containing from one to six and preferably one to four carbon atoms, in which at least one hydrogen atom (and possibly all) has been replaced by a halogen atom.
  • Representative examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy o ⁇ difluoromethoxy.
  • (Ci-C x )haloalkoxy (x being an integer) refers to a straight of branched chain haloalkoxy group containing 1 to x carbon a.toms.
  • hydroxyalkyl refers to a saturated straight or branched chain alkyl group substituted once by hydroxy and containing from one to six, and in particular one to four, carbon atoms.
  • alkylcarbonyloxyalkyl refers to an alkylcarbonyloxyalkyl wherein each alk> ⁇ l group is independently a saturated straight or branched cha_in alkyl group containing from one to six, and in particular one to four, carbon atoms.
  • carbamoyloxyalkyl refers to a carbamoyloxyaltcyl wherein the alkyl group is a saturated straight or branched chain alkyl group containing from one to six, and in particular one to four, carbon atoms.
  • carboxyalkyl refers to a carboxyalkyl wherein the alkyl group is a saturat&d straight or branched chain alkyl group containing from one to six, and in particular one to four, carbon atoms.
  • carbamoylalkyl refers to a carbamoylalkyl wherein the alkyl group is a saturated straight or branched chain alkyl group containing from one to six, and in particular one to four, carbon atoms.
  • alkylcarbonyloxy refers to an alkylcarbonyloxy wherein the alkyl group is a saturated straight or branched chain alkyl group containing from one to six, and in particular one to four, carbon atoms.
  • alkoxycarbonylalkyl refers to an alkoxycarbotvylalkyl wherein the alkyl group is a saturated straight or branched chain alkyl group corttaining from one to six, and in particular one to four, carbon atoms and the alkoxy gxoup is a saturated straight or branched chain alkoxy group, containing from one to six, and in particular one to four carbon atoms.
  • halogen refers to fluorine, chlorine, bromine or iodine, preferably to fluorine or chlorine.
  • cycloalkyl used alone or in combination, refers to a saturated cyclic hydrocarbon moiety containing 3 to 7 carbon atoms.
  • (C y -C z )cycloalkyl used alone or in combination, refers to a saturated cyclic hydrocarbon moiety containing y to z carbon atoms.
  • Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl and cyclohexyl.
  • cycloalkylalkyl refers to an alkyl group as previously defined itself substituted by a cycloalkyl group as previously defined.
  • Representative examples of cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl and cyclohexylmethyl.
  • (C 2 -C6)alkenyl refers to a straight or branched hydrocarbon chain containing 2 to 6 carbon atoms with at least one carbon-carbon double bond.
  • alkenyl include, but are not limited to, ethenyl, 2-propenyl, 3-butenyl, 4-pentenyl or 5-hexenyl.
  • aryl used alone or in combination, refers to an aromatic cyclic group with one, two or three rings, having five to 14 carbon ring-atoms preferably from five or six to ten carbon ring-atoms, for example phenyl or naphthyl groups. Any aryl group as defined herein may be substituted with one, two or more substituents, each of which is independently selected from the group consisting of halogen, alkyl, alkoxy, trifluoromethyl and trifluoromethoxy.
  • aryl examples include phenyl, naphtyl, 4-fluoro-phenyl, 4-chloro-phenyl, 4-methoxy-phenyl, 4-methyl-phenyl, 4-trifluoromethyl- phenyl, 4-trifluoromethoxy-phenyl, 2,4-difluoro-phenyl, 2,4-dichloro-phenyl, 2,4- dimethoxy-phenyl, 2,4-dimethyl-phenyl, 2,4-ditrifluoromethyl-phenyl and 2,4-ditrifluoromethoxy-phenyl.
  • heteroaryl refers to an aryl group as defined herein where one, two or more ring-carbon atoms are replaced by an oxygen, nitrogen or sulphur atom, for example pyridyl, imidazolyl, pyrazolyl, quinolinyl, isoquinolinyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl and pyridazinyl groups.
  • heteroaryl also covers bicyclic structures selected from the group consisting of benzo[l,3]dioxol-5-yl, 2,3-dihydro-benzo[l,4]dioxin-6-yl, 2,3-dihydro-
  • Any heteroaryl group as defined herein may be substituted with one, two or more substituents on its aromatic ring(s), said substituents being from the group consisting of halogen, alkyl and alkoxy; preferably, any heteroaryl group as defined herein may be substituted with one halogen substituent.
  • heteroaryl groups include, but are not limited to, benzo[l,3]dioxol-5-yl, 2,3-dihydro-benzo[l,4]dioxin-6-yl, 2,3-dihydro-[l,4]dioxino[2,3-6]pyridin-6-yl, 2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-yl, 3-oxo-3,4-dihydro-2H-benzo[l,4]thiazin-6-yl, 7-fluoro-3-oxo-3,4-dihydro- 2H-benzo[l,4]thiazin-6-yl, 3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-6-yl,
  • the two bonds linking the cyclohexyl ring to the radicals A 5 and A 6 are represented by two bold lines (and not by wedged bonds that would then depict an absolute stereochemistry), this means that the two bonds are in a cis configuration relatively to said cyclohexyl ring (i.e. the radicals A 5 and A 6 are either both above the median plan of the cyclohexyl ring or both under said median plan).
  • the radical R 1 will be alkyl, alkoxy, haloalkoxy or cyano. More preferably, the radical R 1 will be (Ci-C3)alkyl, (Ci-C 3 )alkoxy, (Ci-C 2 )haloalkoxy or cyano (in particular methyl, methoxy or cyano, and notably methoxy or cyano).
  • D will be aryl or heteroaryl, notably phenyl (which may optionally be substituted once or twice by substituents independently selected from halogen, methyl and methoxy) or heteroaryl. More preferably, D will be phenyl substituted once or twice by substituents independently selected from halogen atoms (especially 2,5-difluorophenyl) or heteroaryl. In particular, D will be heteroaryl.
  • radical R a will preferably be fluorine.
  • radical R b will be fluorine.
  • U, V, W and X will be such that one or two of U, V, W and X represent(s) N and the remaining represent CH.
  • U, V, W and X will be such that one or two of U, V, W and X represent(s) N, one of U, V, W and X represents CF and the remaining represent(s) CH.
  • R 1 is preferably (Ci-C3)alkyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy or cyano, and in particular methyl, methoxy or cyano.
  • R 1 is preferably (Ci-C3)alkyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy or cyano, and in particular methyl, methoxy or cyano.
  • Preferred embodiments of D for the compounds of formula I, ICE, Ip 2 , ICEP2 or I P i are (C 1 -C 9 ) linear alkyl, phenyl, benzofuran-3-yl, thiazol-2-yl or heteroaryl of the formula
  • P is a ring selected from
  • Q is O or S; K, Y and Z are each independently N or CR 3 ; and
  • R 3 is hydrogen or halogen (and in particular hydrogen or fluorine).
  • D will be a heteroaryl of the formula
  • P is a ring selected from
  • Q is O or S; K, Y and Z are each independently N or CR 3 ; and
  • R 3 is hydrogen or halogen (and in particular hydrogen or fluorine).
  • D for the compounds of formula I, I C E, hi, IC E P2 or I P i are: ⁇ 2,3-dihydro-benzo[l,4]dioxin-6-yl; ⁇ 4H-benzo[ 1 ,4]oxazin-3-one-6-yl;
  • the spacer M of the compounds of foxmula I, I C E, Ip2 > I C EP2 or Ipi will be the spacer M 1 .
  • preferred embodiments are the follo ⁇ ving three structures (the group of which will be called M 11 ):
  • a 11 represents NHCO, OCH 2 , CH(OH)CH 2 or CH 2 CH 2 ;
  • a 21 represents CH 2 , CO, CH(OH) or CH(OCONH 2 );
  • Particularly preferred spacers M 1 are the following:
  • Preferred compounds of formula I having the spacer M 1 are the following:
  • the compounds of formula I having the spacer M 1 will be selected from the first 48 compounds mentioned in the list hereabove.
  • the following compounds of formula I having the spacer M ! are preferred:
  • the spacer M of the compounds of formula I, ICE, Ip 2 , I C EP2 or Ipi will be the spacer M 2 .
  • Preferred compounds of formula I wherein M is M" are those wherein at least one of the following further characteristics is present:
  • a 3 representing OCH 2 , NHCO, CH 2 CH 2 , CH CH, COCH 2 , CH(OH)CH 2 or CH 2 CH(OH), or also, provided U is N, CH(OH)CH(OH);
  • a 4 representing CH 2 or CO, or also, provided D is a non-annelated aryl or heteroaryl group, CH 2 CH CH or CH 2 CONH;
  • ⁇ ⁇ R 2 representing hydrogen, alkyl or hydroxyalkyl
  • ⁇ * R 5 representing hydrogen, alkyl or hydroxyethyl
  • More preferred compounds of formula I wherein M is M 2 are those wherein at least one of the following further characteristics is present:
  • ⁇ R 2 representing hydrogen or hydroxyalkyl (and preferably hydrogen or hydroxyethyl); ⁇ R 3 and R 4 each independently representing hydrogen or hydroxy; ⁇ R 5 representing hydrogen or hydroxyethyl;
  • Particularly preferred compounds of formula I wherein M is M 2 are those wherein at least one of the following further characteristics is present:
  • ⁇ A 3 representing CH(OH)CH 2 or CH 2 CH(OH), or also, provided U is N, CH(OH)CH(OH); ⁇ A 4 representing CH 2 or CO;
  • spacer M 2 its stereochemistry will preferably be the following (called M 21 hereafter):
  • M 211 the stereochemistry of M 2 will preferably be the following (called M 211 hereafter):
  • Preferred spacers M 2 are the following:
  • spacers M 2 are also preferred.
  • spacers M 2 are the spacers M 221 , M 222 , M 223 , M 224 and M 225 represented below:
  • Preferred compounds of formula I having the spacer M 2 are the following: • (2,3-dihydro-benzo[l,4]dioxin-6-ylrnethyl)-[(3i? s ,6iS)-6-(6-rnethoxy-quinolin- 4-yloxymethyl)-3,6-dihydro-2H-pyran-3-yl]-amine;
  • the compounds of formula I having the spacer M 2 will be selected from the first 134 compounds mentioned in the list hereabove (and even more preferably from, the first 24 compounds mentioned in the list hereabove).
  • spacers M 3 wherein B 6 represents CH the relative stereochemistry is preferably the following (called M 31 hereafter):
  • spacers M 3 wherein B 6 represents CH the relative stereochemistry is more preferably the following (called M 311 hereafter):
  • Preferred spacers M 3 are the following:
  • Preferred compounds of the fo ⁇ nula I having the spacer M 3 are the following:
  • the compounds of formula I having the spacer M 3 will be selected from the first 28 compounds mentioned in the list hereabove.
  • ICE, IP2, I C EP2 or Ipi will be the spacer M 4 .
  • Preferred spacers M 4 are the following:
  • Preferred compounds of formula I having the spacer M 4 are the following:
  • Compounds of formula I are suitable for the use as ohemotherapeutic 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, pa-ints, 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. casselflcrvus, S. epidermidis, S.
  • haemolyticvcs or Peptostreptococcus spp.
  • pharyngitis rheumatic fever, and glomerulonephritis related to infection by Streptococcus pyogenes, Groups C and G streptococci, Corynebaterium 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 includecding endocarditis and osteomyelitis, caused by S. aureus, S. haemolyticus, E.
  • E. faecalis E. faec ⁇ ium
  • E. durans including strains resistant to known antibac-terials 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, coa-gulase-negative staphylococci (i.es., S. epidermidis, S.
  • known antibac-terials 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, coa-gulase-negative staphylococci (
  • Streptococcus pyogenes Streptococcus agalaetiae, Streptococcal groups C-F (minute colony streptococci), viridans streptococci, Corynehacterium 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 ti-achomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum, or Neiserria gonorrheae; toxin diseases related to infection by S.
  • aureus food poisoning and toxic shock syndrome
  • 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.
  • MAC Mycobacterium avium complex
  • 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.
  • 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.
  • bacterial infections can also be treated in other species like pigs, ruminants, horses, dogs, cats and poultry.
  • the present invention also relates to pharmacologically acceptable salts, or solvates and hydrates, respectively, and to compositions and formulations of compounds of formula I.
  • pharmacologically acceptable salts of sufficiently basic compounds of formula I are selected from the group consisting of salts of physiologically acceptable mineral acids like hydrochloric, hydrobromic, sulfuric and phosphoric acid; or salts of organic acids like methanesulfonic, p-toluenesulfonic, lactic, acetic, trifluoroacetic, citric, succinic, fumaric, maleic and salicylic acid.
  • a sufficiently acidic compound of formula I may form alkali or earth alkaline metal salts, for example sodium, potassium, lithium, calcium or magnesium salts; ammonium salts; or organic base salts, for example methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, meglumin, piperidine, morpholine, tris-(2-hydroxyethyl)amine, lysine or arginine salts.
  • Compounds of formula I may be solvated, especially hydrated. The hydratation can occur during the process of production or as a consequence of the hygroscopic nature of the initially water free compounds of formula I.
  • the 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 present invention also relates to pro-drugs that are composed of a compound of formula I or I C E having at least one pharmacologically acceptable protective group that will be cleaved off under physiological conditions.
  • prodrugs have been reviewed by Beaumont, Kevin; Webster, Robert; Gardner, Iain; Dack, Kevin in Current Drug Metabolism (2003), 4(6), 461-485.
  • promoities are, in case the compound of formula I or I CE contains a free carboxylic acid, alkoxy- (e.g. ethoxy), phenalkyloxy- (e.g. benzyloxy), OCH(R a )OCOR b (e.g. pivaloyloxymethyloxy), OCH(R a )OCO 2 R b ⁇ e.g.
  • therapeutically useful agents that contain compounds of formula I, their solvates, salts or formulations are also comprised in the scope of the present invention.
  • compounds of formula I will be administered by using the known and acceptable modes known in the art, either alone or in combination with any other therapeutic agent.
  • Such therapeutically useful agents can be administered by one of the following routes: ora.1, e.g. as tablets, dragee, coated tablets, pills, semisolids, soft or hard capsules, for example soft and hard gelatine capsules, aqueous or oily solutions, emulsions, suspensions or syrups, parenteral including intravenous, intramuscular and subcutaneous injection, e.g.
  • transdermal delivery system such as a plaster containing the active ingredient, topical or intranasal.
  • TDS transdermal delivery system
  • the substance of the present invention can also be used to impregnate or coated devices that are foreseen for implantation like catheters or artificial joints.
  • the pharmaceutically useful agents may also contain additives for conservation, stabilisation, e.g. UV stabilizers, emulsif ⁇ ers, sweetener, aromatisers, salts to change the osmotic pressure, buffers, coating additives and antioxidants.
  • Another aspect of the invention concerns a method for the treatment of disease comprising the administration to the patient of a pharmaceutically active amount of a derivative according to formula I.
  • 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 Ip 2 , compounds of formula ICE, compounds of formula ICEP2 and compounds of formula Ip 1 .
  • the compounds of formula I or I CE 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.
  • the compounds of formula I or I CE could be conta-ined in a solution or in a spray formulation.
  • the compounds of formula I (including tihe compounds of formula I CE or Ip 1 ) can be manufactured in accordance with the present invention by
  • R 1 , U, V, W, X and D are as before and A 0 M 0 is one of the spacers M 1 , M 2 , M 3 and M 4 , in which A 0 is A 1 , A 3 , A 5 or A 7 , respectively, functionally modified, as well as the reactive group L 1 , to connect the two moieties of formulas II and III, and M 0 is one of the spacers M 1 , M 2 , M 3 and M 4 diminished by A 1 , A 3 , A 5 or A 7 , respectively, and M 1 , M 2 , M 3 , M 4 , A 1 , A 3 , A 5 and A 7 are as before, or
  • L 2 is a reactive group yielding the group A 2 , A 4 , A 6 , A 8 , A 2 diminished by ISfH or A 6 diminished by CH 2 NH, respectively, and A ! -A 8 , B 1 , R 1 , R 3 , R 4 , R 5 , R 6 ,U, V, W, X, D, n and o are as before,
  • the compounds of formula I P i can be manufactured in accordance with the present invention by
  • R 1 , U, V, W, X and D are as before and A 0 M 0 is one of the spacers M 1 , M 2 and M 3 , in which A 0 is A 1 , A 3 or A 5 , respectively, functionally modified, as well as the reactive group L 1 , to connect the two moieties of formulas II and III, and M 0 is one of the spacers M 1 , M 2 and M 3 diminished by A 1 , A 3 or A 5 , respectively, and M 1 , M 2 , M 3 , A 1 , A 3 and A 5 are as before, or
  • L 2 is a reactive group yielding the group A 2 , A 4 , A 6 , A 2 diminished by NH or A 6 diminished by CH 2 NH, respectively, and A ! -A 6 , B 1 , R 1 , R 3 , R 4 , R 5 , U, V, W, X, D, n and o are as before,
  • quinoline, [l,5]-naphthyridine, quinazoline and quinoxaline derivatives of formula II are prepared following literature procedures.
  • 4-hydroxycarboxylic acid ester derivative with subsequent hydrolysis to acid, followed by thermal decomposition in inert solvents (J.T. Adams, J. Am. Chem. Soc. (1946), 68, 1317).
  • M 02 is the group M 011 wherein B 1 is CHC 5 M 012 wherein B 1 is CH, or M 013 , M 014 , M 015 or M 016 , wherein A 0 is HOOC(CH 2 ) t and t is 0, 1 or 2 and E is a protecting group; the other symbols have their above meanings.
  • Compounds of formula I can for example be obtained from an amine 1-1 and an acid 1-2.
  • a 4-h.ydroxy-[l,5]-naphthyridine, a 4-hydroxyquinazoline, a 5-hydroxy quinoxaline or a 4-hydroxy quinoline derivative can be converted into the corresponding chloro derivative by heating in phosphorous oxychloride between 40 0 C and 100 0 C neat or in an inert solvent like dichloroethane, or to the corresponding 4-trifluoromethanesulphonyloxy derivative by reaction with trifluoromethanesulphonic anhydride, in the presence of an organic base between -4O°C and 80 0 C in an aprotic solvent like DCM or THF (K. Ritter, Synthesis (1993), 735).
  • 4-amino-[l,5]-naphthyridine, 4-aminoxyquinazoline, 5-amino quinoxaline or 4-amino quinoline derivatives can be obtained by reaction of the corresponding 4- trifluoromethanesulphonyloxy derivatives with ammonia in a solvent like DCM or THF, or with R-propylamine hydrochloride in pyridine between -20 0 C and 100 0 C (R. Radinov, Synthesis (1986), 886).
  • 4-aminoxyquinazoline can also be obtained from its 4-chloro analogue by reaction with ammonia under the same conditions.
  • Carboxylic acids 1-2 may be prepared by Jones' oxidation of the corresponding alcohols using chromium acid and sulphuric acid in water/methanol between 40 0 C and HO 0 C (E. R. H. Jones et al, J. Chem. Soc. (1946), 39).
  • Other oxidising agents may be used for this transformation such as sodium periodate catalysed by ruthenium trichloride (G. F. Tutwiler et al, J. Med. Chem. (1987), 30, 1094), or potassium permanganate (D. E. Reedich et al, J. Org. C/zem. (1985), 50, 3535.
  • Derivatives 1-3 can be obtained by reacting the 4-amino derivative 1-1 with a carboxylic acid derivative 1-2, in the presence of an activating agent such as DCC, 1- (dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (EDC) or 1-hydroxybenzotriazole (HOBT) or HATU (G. Benz in Comprehensive Organic Synthesis, B.M. Trost, I. Fleming, Eds; Pergamon Press: New York (1991), vol. 6, p. 381) between -2O°C and 60 0 C in an dry aprotic solvent like DCM acetonitrile or DMF.
  • the carboxylic acid can be activated by conversion into its corresponding acid chloride by reaction with oxalyl chloride or thionyl chloride neat or in a solvent like DCM between -20° and 6O 0 C.
  • protecting group (E) such as Boc or Cbz on a nitrogen atom in 1-3 is carried out under standard acidic conditions to give the corresponding free amine.
  • the Cbz group can be removed under catalytic hydrogenation over palladium on charcoal.
  • protecting groups to mask reactive functionality is wellknown to those of skill in the art, and other protecting groups are listed in reference book such as PJ. Kocienski 'Protecting Groups', Thieme (1994).
  • the amine is then reacted with an (hetero)aryl aldehyde and a suitable reducing agent to provide the homologue 1-4.
  • the intermediate imine may be formed in a variety of protic or aprotic solvents such as DMF, N,N-dimethylacetamide, 1,2-DCE, MeOH, MeCN, in presence or not of a drying agent such as molecular sieves.
  • the imine is reduced subsequently or simultaneously with a suitable reagent such a NaBH 4 , sodium triacetoxyborohydride or sodium cyanoborohydride (R.O. and N4.K. Hutchins Comprehensive Organic Synthesis, B.M. Trost, I. Fleming, Eds; Pergamon Press: New York (1991), vol. 8, p. 25-78).
  • the amine may also be homologated to give product 1-4 by nucleophilic displacement of a suitable alkyl (hetero)aryl halide, mesylate or tosylate between -20 0 C and 100 0 C in a dry aprotic solvent like DCM, MeCN, DMF or THF in presence of a base such as K 2 CO 3 or DIPEA.
  • a suitable alkyl (hetero)aryl halide mesylate or tosylate between -20 0 C and 100 0 C in a dry aprotic solvent like DCM, MeCN, DMF or THF in presence of a base such as K 2 CO 3 or DIPEA.
  • M 03 is one of the group M 011 to M 016 , wherein A 1 , A 3 , A 5 and A 7 are H 2 NC(O)(CH 2 ) U , u is 0, 1 or 2 and E is a protecting group; the other symbols have their above meanings.
  • the intermediate 1-3 can also be obtained from a 4-trifluoromethanesulfonate derivative II-l and an amide derivative II-2.
  • These amide derivatives are obtained from a suitable carboxylic acid 1-2 3 which is converted into an activated form using, for example, EDC and HOBt, SOCl 2 or NHS and DCC between -20°C and 6O 0 C in a dry aprotic solvent like DCM, ethyl acetate or THF, and the activated acid is subsequently reacted with aqueous ammonium hydroxide or gaseous ammonia, to afford amide II-2 in an appropriate solvent such as THF or DCM between -2O 0 C and 60 0 C.
  • the amide II-2 and the 4-trifluoromethanesulphonate II-l are coupled under palladiuin-catalyzed Buchwald-Hartwig conditions (J. Am. Chem. Soc. (1996), 118, 10333) or copper-catalyzed conditions (J. Am. Chem. Soc. (2002), 124, 7421) to afford the derivative 1-3.
  • Various palladium sources and ligands may be used, as well as a variety of solvents, including for example dioxane, toluene.
  • M 04 is the group M 011 wherein B 1 is CH, M 012 wherein B 1 is CH or MI 013 to M 016 , wherein A 1 , A 3 , A 5 and A 7 are HO(CH 2 ) V , v is 1, Z or 3 and the other symbols have their above meanings.
  • the compounds of formula I can also be obtained by coupling, for example, a substituted 4-hydroxy quinoline, 8-hydroxy quinoline 4-hydroxy-[l,5]- naphthyridine, 4-hydroxy-[l,3]-quinazoline or 5-hyclroxy quinoxaline IH-I and an alcohol derivative III-2.
  • the coupling reaction between HI-I and III-2 may be achieved under Mitsunobu conditions (as reviewed in O. Mitsunob> ⁇ , Synthesis 1981, 1).
  • an alcohol ⁇ i-2 and a 4-hydroxy derivative III-l are reacted to form ether ⁇ i-3 in ftie presence of diethyl or diisopropyl azodicarboxylate and triphenylphosphine.
  • the reaction may be performed in a wide range of solvents such as N,N-dimethylformamide, THF, DCM and at a wide range of temperature (between -78°C and 50°CO.
  • An alternate route to HI-3 may require the activation of the alcohol III-2 as for example a tosylate, a triflate or a mesylate by treatment with tosyl chloride, trifluoromethanesulphonic anhydride or mesyl chloride respectively in the presence of an organic base such as triethylamine between -40 0 C and 6O 0 C in a dry aprotic solvent like DCM, acetonitrile or THF.
  • alcohol III-2 reacts with the anion of the 4-hydroxy derivative, generated with a mineral base such as sodium hydride or potassium carbonate or an organic base such, as lithium hexamethyldisilazide, to generate III-3 between -20 0 C and 60 0 C.
  • derivative III-3 can be obtained by reaction of a 4-halogeno quinazoline derivative with an alcohol derivative in presence of a strong base like alkali alkoxide like sodium or potassium, methylate, metal hydride like NaH, DBU or DBN between -20 0 C and 60 0 C in a dry aprotic solvent like DMF, MeCN or THF.
  • a strong base like alkali alkoxide like sodium or potassium, methylate, metal hydride like NaH, DBU or DBN between -20 0 C and 60 0 C in a dry aprotic solvent like DMF, MeCN or THF.
  • the protecting group is removed and th_e free amine is reacted with an alkyl (hetero)aryl halide in presence of a base or with an (hetero)aryl aldehyde in presence of a reducing reagent as previously described .
  • M 05 is the spacer M 1 diminished by A 1 a.xid A 2 and B 1 is N. The remaining symbols are as above.
  • Compounds of the formula I can also be obtained from a 4-oxiranyl derivative IV-I and an amine derivative IV-2.
  • the racemic epoxides IV-I may be prepared from the corresponding 4-carboxaldehydes using trimethylsulfonium iodide in presence of a base (G.A. Epling and aL . J Het. Chem. (1987), 24, 853), or by epoxidation of a 4-vinyl derivatives using an peroxyacid derivative such as MCPBA as an oxidizing reagent between -20 0 C and 60 0 C in an aprotic dry solvent like DCM or THF (Somersekar Rao, A. in Comjprehensive Organic Synthesis, B. MI.
  • the vinyl derivatives can be obtained from the corresponding aldehyde by a Wittig olefination reaction using triphenylmethylene phosphorane (for example generated by treatment of methyl triphenylphosphonium bromide with M-BuLi in THF at -78 0 C) or by reaction of the triflate II- 1 with a vinyl tributyl stannnane under Stille coupling reaction conditions.
  • triphenylmethylene phosphorane for example generated by treatment of methyl triphenylphosphonium bromide with M-BuLi in THF at -78 0 C
  • reaction of the triflate II- 1 with a vinyl tributyl stannnane under Stille coupling reaction conditions.
  • the corresponding chiral epoxides may be obtained using asymmetric catalytic dihydroxylation (AD-mixtures) followed by the chiral diol closure as reviewed by K.B. Sharp less et al. Chem. Rev. (1994), 94, 2483.
  • the optical purity is generally ranging between 10 and 98%, and may be further enhanced by recrystallisation. By such a method, both enantiomers are equally available.
  • the reaction of the bicyclic amine FV-2 and the epoxide IV-I may take place in various solvents such as ethanol, N,N-dimethylformamide, at a temperature generally ranging between O 0 C and 80 0 C. The reaction is helped by the addition of lithium perchlorate.
  • the protecting group of IV-3 is removed and the free amine is reacted with an alkyl (hetero)aryl halide in presence of a base such as DIPEA or K 2 CO3 in a solvent such as MeCN, DMF or EtOH at a temperature ranging between 0 0 C and 100 0 C.
  • a base such as DIPEA or K 2 CO3
  • a solvent such as MeCN, DMF or EtOH
  • the free amine may also be reacted with an (hetero)aryl aldehyde in presence of a reducing reagent as previously described.
  • M 06 is the group M ou wherein B 1 is CH, M 012 wherein B 1 is CH or M 013 to M 016 , wherein A 1 , A 3 , A 5 and A 7 are HC ⁇ C, L is OSO 2 CF 3 or a halogen atom and E is a protecting group; the other symbols have their above meanings.
  • Compounds of formula I can also be obtained from compound II-l (Scheme 5)
  • Intermediate V-2 may be obtained from derivative II-l and a terminal alkyne derivative V-I.
  • alkyne derivatives V-I are generally obtained from a suitable alcohol III-2 (see Scheme 3) which is converted first into an aldehyde using for example the Moffat-Swern (see Synthesis 1981, 165), or the Dess-Martin periodinane (see J. Am. Chem. Soc. (1991), 113, 7277) oxidation protocols.
  • the aldehyde is converted into the corresponding alkyne using either the Corey-Fuchs protocol (formation of the gem-dibromide then treatment with r ⁇ -BuLi) as described in Tetrahedron Letters (1972), 3769 or using dimethyl-2-oxopropylphosphonate diazo derivative (so called Ohira's reagent, Synth. Com.
  • alkyne V-I and the 4-trifluoromethanesulfonate II-l are coupled under Sonogashira conditions using catalytic amount of a palladium salt, an organic base such as triethylamine and a catalytic amount of a copper derivative (usually copper iodide) in a solvent such a DMF between 2O 0 C to 100 0 C (see Sonogashira, K. in Metal-Catalyzed Reactions, Diedrich, F., Stang, P.
  • the 4-trifluoromethanesulfonate II-l can be replaced by a halogeno (e.g. chloro) derivative II-l.
  • the resulting alkyne V-2 is hydrogenated to the alkane V-3 using catalytic system such as palladium on charcoal or platinum oxide in a solvent like EtOH or EA in presence of hydrogen.
  • catalytic system such as palladium on charcoal or platinum oxide in a solvent like EtOH or EA in presence of hydrogen.
  • Other methods may also be suitable as reviewed by Siegel, S. et al in Comprehensive Organic Synthesis, B. M. Trost, I. Fleming, Eds; Pergamon Press: New York (1991), vol. 8, p. 417-488.
  • the alkane V-3 is further transformed into the compounds V- 4 using procedures previously described.
  • M 07 is the group M 013 , wherein A 1 is RSO 2 CH 2 and E is a protecting group; R may be l-phenyl-lH-tetrazol-5-yl or benzothiazol-2-yl and the other symbols have their above meanings.
  • Compounds of formula I can also be obtained from compound VI-I (Scheme 6).
  • Intermediate VI-3 may be obtained as an (£)-isomer from an aldehyde derivative VI-I and a sulfone VI-2.
  • the sulfone is generated from the corresponding sulphide via an oxidation reaction.
  • a wide range of oxidizing agent may be used to perform such a reaction, such as MCPBA in a solvent such as DCM, oxone ® in a solvent such as a.q. MeOH (see Tetrahedron Letters (1981), 22, 1287), or aq. hydrogen peroxide in presence of ammonium heptamolybdate tetrahydrate in EtOH (see J. Org. Chem.
  • the sulphide is obtained from a suitable alcohol III-2 (Scheme 3) via a Mitsunobu coupling (as reviewed in O. Mitsunobu Synthesis (1981), 1) with l-phenyl-lH-tetrazole-5-thiol in the presence of diethyl azodicarboxylate or DIAD and PPh 3 .
  • the reaction may be performed in a wide range of solvents such as DMF, T ⁇ F or DCM and within a wide range of temperatures (between -78°C and 50 0 C).
  • An alternate route to form the intermediate sulphide requires the activation of the alcohol III-2 as for example a tosylate, a triflate or a mesylate by treatment with tosyl chloride, trifluoromethanesulphonic anhydride or mesyl chloride respectively in the presence of an organic base such as TEA between -40 0 C and 6O 0 C in a dry aprotic solvent like DCM, acetonitrile or T ⁇ F.
  • alcohol ⁇ i-2 reacts with sodium iodide or potassium iodide in acetone at a temperature ranging between O 0 C and 65 0 C, to form the corresponding iodide.
  • the latter serves as an alkylating agent of the l-phenyl-lH-tetrazole-5-thiol.
  • the alkylation reaction is performed in presence of an inorganic base such as KO ⁇ or NaOH in a solvent such as EtOH at a temperature ranging between -20 0 C and 70 0 C.
  • the sulfone VI-2 and the aldehyde VI-I are coupled in presence of a base such as potassium- or lithium-hexamethyldisilazide in a solvent such as 1,2-dimethoxyethane, DMF or toluene as reviewed by Blakemore, P.R in J.Chem.Soc, Perkin Trans. 1 (2002), 2563-2585.
  • the (£)-alkene VI-3 is transformed into the corresponding chiral czs-diol derivative by treatment with AD mixtures in presence of methanesulfonamide in a water/2-methy-2-propanol mixture as described in Chem. Rev. (1994), 94, 2483.
  • the sense of induction relies on the chiral ligand contained in the mixture, either a dihydroquinine-based ligand in AD-mix ⁇ or a dihydroquinidine-based ligand in AD-mix ⁇ .
  • the chiral cis-diol VI-4 is further transformed into the chiral compounds VI-5 using procedures previously described.
  • An alternate route to obtain (£)-alkene VI-3 may be to couple a 4-trifluoromethanesulfonate derivative II-l (Scheme 2) with an organostannane deriving from a terminal alkyne derivative V-I (see Scheme 5). Indeed, the hydrostannation reaction of an alkyne derivative
  • V-I using tributyl tin hydride and a catalytic amount of either a palladium salt or a molybdenum complex generates an E:Z mixture of the vinylstannane intermediate as described in J. Org. Chem. (1990), 55, 1857.
  • the vinylstannane is reacted with a 4- trifluoromethanesulfonate derivative II-l under Stille coupling conditions (as described in J.
  • Typical reaction conditions involve a palladium salt such as tetrakis(triphenylphosphine) palladium or dichloro bis(triphenylphophine) palladium, lithium chloride and a radical inhibitor such as 2,6-dimethyl-4-methyl phenol in a solvent such as DMF or dioxane at a temperature ranging between 0 0 C and 100 0 C, more preferably at a temperature ranging between 20 0 C and 8O 0 C.
  • a solvent such as DMF or dioxane
  • the previously mentioned chiral czs-diol VI-4 may be transformed in the corresponding cyclic carbonate VII-I, by treatment with either phosgene, diphosgene or triphosgene in presence of an organic base such as TEA or pyridine or carbonyldimidazole in an inert solvent such as DCM or THF at a temperature ranging between -78°C and 5O 0 C, more conveniently at a temperature ranging betrween 0°C and 20 0 C.
  • the cyclic carbonate V ⁇ -1 is subsequently transformed to the homobenzylic alcohol VII-2 by hydrogenolysis using catalytic system such as palladium on cha.rcoal in presence of hydrogen in a solvent such as EA.
  • the intermediate VII-2 is further transformed into the compounds VII-3 using procedures previously described.
  • M 08 is the group M 011 wherein B 1 is CH, M° 12 wherein B 1 is CH or M 013 to M 016 , wherein A 1 is HCO(CH 2 ) W , w is 1, 2 or 3 and E is a protecting group; the other symbols have their above meanings.
  • the benzylic alcohol VIII-2 may be obtained by addition of an organometallic derivative of aromatic H-I onto an aldehyde VIII-I.
  • the aldehyde VTII-I is obtained from a suitable alcohol III-2 by a homologation reaction. Oxidation of the alcohol ⁇ i-2 into its corresponding aldehyde may be performed using one of the aforementioned oxidation methods.
  • the resulting aldehyde is further converted to the corresponding alkene using the phosphorane generated from methyltriphenylphosphonium bromide and a base like «-BuLi or potassium tert-buto ⁇ de in a solvent such as THF at a temperature between -80 0 C and 0°C (see Org.
  • the terminal alkene is subsequently transformed into the primary alcohol via an hydroboration reaction using either BH 3 -dimethylsulfide complex, or 9-borabicyclo[3.3.1]nonane (9-BBN) (for a review see Smith, K.; Pelter, A. G. Comprehensive Organic Synthesis, B. M. Trost, I. Fleming, Eds; Pergamon Press: New York (1991), vol. 8, p. 703-731) followed by oxidative workup with aq. NaOH and 30% H 2 O 2 (see also Pelter, A.; Smith, K. G. Comprehensive Organic Synthesis, B.M. Trost, I.
  • an alkyllithium such as H-BuLi
  • a palladium salt an inorganic base such as K2CO3 or Na 2 COs
  • the corresponding alkene may be directly transformed into the aldehyde VI-I by ozonolysis (O 3 stream then quenching with either dimethylsulfide or PPh 3 ) or via a periodic cleavage of the intermediate diol using sodium periodate in aq. acetone.
  • the diol is obtained using a catalytic amount of osmium tetroxide in the presence a co-oxidant such as NMO in aq. solvent such as acetone-water or DCM-water (see Cha, J.K. Chem. Rev. (1995), 95, 1761-1795).
  • R c represents CH 2 OH, COOR e or CONH 2 ;
  • R e represents hydrogen or alkyl
  • R d represents hydrogen or a nitrogen protecting group.
  • Nitrogen protecting groups R d are preferably allyloxycarbonyl, if-butyloxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyl or acetyl.
  • the intermediates of formula VI can be converted into the end products of formula I by reaction with the compounds of formula II in analogy to the reaction between the compounds of formulas II and III; any nitrogen protecting group R d is subsequently split off as described above to yield starting compounds of formula IV.
  • the piperidine nitrogen of compound IX-I is protected with a protecting group PG (Cbz or BOC).
  • PG Cbz or BOC
  • the carboxylic acid function is reduced into its corresponding aJcohol by reduction with borane in THF in an organic solvent such as THF or dioxane between -20° and 50 0 C to yield the compound IX-2.
  • the alcohol is further transformed into the corresponding aldehyde IX-3 using Dess-Martin periodinane or Moffat-Swern protocols, protected as a silyl or THP ether using TBDMSCl in presence of an organic base such as TEA or pyridine in a solvent such as DCM or THF, or dihydropyran in an aprotic solvent such as DCM, THF or ether between -40° and +40 0 C, or directly used in coupling with compounds OI-l (see Scheme 3) wherein L 1 is OH or Cl.
  • the 5-methylester function is hydrolysed in pxesence of an alkali hydroxide such as NaOH, LiOH or KOH in a water/THF mixture between 0° and 40 0 C.
  • the resulting acids are subjected to a Curtius degradation in presence of diphenylphosphoryl azide in t-butanol in presence of an organic base such as TEA between 60° artd 140 0 C to give the intermediate t-butyl carbamate followed by acidic treatment with TFA or an inorganic acid such as HCl in an organic solvent such as THF or DCM to liberate the amine IX-5, IX-6 and IX-7.
  • the intermediate aldehyde IX-3 is reacted with dimethyl acetylmeth>dphosphonate, ⁇ -toluenesulfonyl azide and MeOH in presence of an inorganic base such as K 2 CO 3 in a polar solvent such as acetonitrile between 0 and 50 0 C to give the intermediate alkzyne derivative IX-4, which is subsequently subjected to coupling under Sonogashira conditions.
  • Example 1 (2,3-dihydro-[l,4]dioxino[2,3-6]pyridin-6-ylmethyl)- [(l ⁇ ,5 ⁇ ,6 ⁇ )-6-(6-methoxy-[l,5]naphth7ridin-4-yloxymethyI)-bicyclo[3.1.0]lmex-3-yl]- amine:
  • Example 3 -7-fl «oro-6- ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-[6-(6-methoxy-[l,5]nap hthyridin-4-yloxymethyl)- bicyclo[3.1.0]hex-3-ylamino]-methyl ⁇ -4H-benzo[l,4]thiazin-3-one:
  • Example 5 6- ⁇ [(l a,5a,6 ⁇ )- 6-(6-methoxy-[l,5]naphthyridin-4-yloxymethyl)- bicyclo [3.1.0] hex-3-ylamino] -methyl ⁇ -4H-benzo [1 ,4] thiazin-3-one :
  • Example 8 (1 a,3 ⁇ ,5a,6 ⁇ )-3-[(3-oxo-3,4-dihydro-2i ⁇ -pyrido [3 ,2-b] [1 ,4]thiazin- 6-ylmethyl)-amino]-bicyclo[3.1.0]hexane-6-carboxylic acid (6-methoxy- [1 ,5] naphthyridin-4-yl)-amide :
  • Example 10 l-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-2-[(l a,5a,6 ⁇ )-6-(6-methoxy- quinazolin-4-yloxymethyl)-3-aza-bicyclo[3.1.0]hex-3-yI]-ethanone:
  • Example 12 r ⁇ c-carbamic acid l-(2,3-dihydro-benzo[l,4]dioxin-6-yl> 2-[(l ⁇ ,5 ⁇ ,6 ⁇ )-6-(6-methoxy-quinazolin-4-yloxymethyl)-3-aza-bicyclo[3.1.0]hex-3-yI]- ethyl ester:
  • Example 13 4- ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-3-a ⁇ a- bicyclo[3.1.0]hex-6-ylmethoxy ⁇ -6-methoxy-quinoline:
  • Example 14 4- ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl] -3-aza- bicy do [3.1.0] hex-6-ylmethoxy ⁇ -6-methoxy-quinazoline:
  • Example 15 8- ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-3-aza- bicy clo [3.1.0] hex-6-y lmethoxy ⁇ -2-methoxy- [1 ,5] naphthy ridine :
  • Example 16 l-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-2-[(l ⁇ ,5o ⁇ 6 ⁇ )-6-(6-methoxy- [l,5]naplithyridin-4-yloxymethyl)-3-aza-bicyclo[3.1.0]hex-3-yl]-etha.iione;
  • Example 17 / • ⁇ c-l-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-2-[(l ⁇ ,5 ⁇ ,6> ⁇ )-6-(6-methoxy- [l,5]naphthyridin-4-yloxymethyl)-3-aza-bicyclo[3.1.0]hex-3-yI]-etha-iiol:
  • Example 18 r ⁇ c-carbamic acid l-(2,3-dihydro-benzo[l,4]dioxin-6-yI)- 2-[(l «,5 ⁇ ,6c ⁇ )-6-(6-methoxy-[l,5]naphthyridin-4-yIoxymethyl)-3-aza bicyclo[3.1.0]hex- 3-yl]-ethyl ester:
  • Example 19 r «c-(l ⁇ ,5 ⁇ ,6 ⁇ )-4- ⁇ 3-[2-(2,3-dihydro-be ⁇ zo>[l,4]dioxin-6-yl)-ethyl]-3-aza- bicyclo ⁇ .l.OJhex- ⁇ -ylmethoxyJ-quinoIine- ⁇ -carbonitrile:
  • Example 20 3-chIoro-4- ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-3-[2-(2,3-dihydro-benzo [l,4]dioxin-6-yl)-ethyl]- 3-aza-bicycIo [3.1.0] hex-6-ylmethoxy ⁇ -6-methoxy-quinoline :
  • Example 22 rac-2- [(I a,5 ⁇ ,6 ⁇ )-6-(3-chlo ro-6-methoxy-quinolin-4-yloxy m «thy l)-3-aza- bicyclo[3.1.0]hex-3-yl]-l-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethanol:
  • Example 23 r ⁇ c-carbamic acid 2-[(l «,5a,6a)-6-(3-chloro-6-methoxy-q»iiiiolin-
  • Example 24 6- ⁇ 2-[(l ⁇ ,5 ⁇ ,6 ⁇ )-6-(3-chIoro-6-methoxy-quinolin-4-yloxymetImyI)-3-aza- bicycIo[3.1.0]hex-3-yI]-l-hydroxy-ethyl ⁇ -4J ⁇ -benzo[l,4]oxazin-3-one:
  • Example 25 5- ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yI)-ethyl]-3-aza- bicyclo [3.1.0] hex-6-ylmethoxy ⁇ -3-methoxy-quinoline:
  • Example 26 6- ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-2-[6-(3-methoxy-quinolin-5-yloxymethyl)-3-aza- bicycIoIS.l.Ojhex-S-y ⁇ -acetylJ ⁇ H-benzoll j ⁇ oxazin-S-one:
  • Example 27 6- ⁇ l-b ⁇ droxy-2-[(l ⁇ ,5 ⁇ ,6 ⁇ )-6-(3-methoxy-quinolin-5-yloxymethyI)-3-aza- bicyclo[3.1.0]hex-3-yl]-ethyl ⁇ -4H-benzo[l,4]oxazin-3-one:
  • This compound was prepared from intermediate 28. i (0.776 g) and trifluoro-methanesulfonic acid 6-methoxy-[l,5]naphthyridin-4-yl ester (0.92 g) by the method of Example 28, step 28.ii.
  • step 13 the title compound (0.037 g) was obtained from intermediate 30. ⁇ i (0.086 g). MS (ESI, m/z): 480.3 [M+H + ].
  • Example 31 (1 ⁇ ,5 ⁇ ,6 ⁇ )-3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-3-aza- bicyclo[3.1.0]hexane-6-carboxylic acid (3-methoxy-quinoxalin-5-yl)-amide:
  • step 13 the title compound (0.035 g) was obtained from intermediate 31 -ii (0.078 g). MS (ESI, m/z): 447.6 [M+H + ].
  • Example 32 3- [(I ⁇ ,5 a,6 ⁇ )-2-(2,3-dihydro-benzo [1 ,4] dioxin-6-yl)-2-oxo-ethyl] — 3-aza- bicyclo[3.1.0]hexane-6-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-am ⁇ de:
  • Example 33 rac-3-[(l ⁇ ,5 ⁇ ,6 ⁇ )-2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-2-l ⁇ ydroxy-ethyl]- 3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid (6-methoxy- [1 ,5] naphthy rid fn-4-yl)-amide:
  • Example 35 rac-(l ⁇ ,5 ⁇ ,6 ⁇ )-6-( ⁇ 3-[2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-3-aza- bicyclo[3.1.0]hex-6-ylamino ⁇ -m ⁇ ethyI)-4 J fir-pyrido[3,2-6][l,4]thiazin-3-one :
  • Example 36 rac- ⁇ ⁇ ,5 ⁇ ,6 ⁇ )-6-( ⁇ 3-[2-hydroxy-2-(6- methoxy-quinolin-4-yl)-ethyl]-3-aza- bicyclo [3.1.0] hex-6-y lamino ⁇ -methyl)-4H-benzo [1 ,4] oxazin-3-one :
  • Example 37 r ⁇ c-(l ⁇ ,5 ⁇ ,6 ⁇ )-2- ⁇ 6-[(2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-ylme ⁇ :hyl)- amino]-3-aza-bicycIo[3.1.0]hex-3-yl ⁇ -l-(6-methoxy- «juinoIin-4-yl)-ethanol:
  • Example 38 r ⁇ c-2- ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-6-[(2,3-dihydro-beiizo[l,4]dioxin-6-ylmethyI)-ainino]- 3-aza-bicyclo[3.1.0]hex-3-yl ⁇ -l-(6-methoxy-quinolin-4-yl)-ethanol:
  • Example 39 r ⁇ c-2- ⁇ (l « ⁇ 5flr,6 ⁇ )-6-[(2,3-dihydro-benzo[l,4]dlioxiii-6-yImethyl)-amino]- 3-aza-bicycIo[3.1.0]hex-3-yl ⁇ -l-(6-methoxy-[l,5]naphthyrid ⁇ n-4-yI)-ethanol:
  • step 35.iii the title compound (0.055 g) was obtained from intermediate 39.iii (0.059 g) as a yellow gum. MS (ESI, m/z): 449.5 [M+H + ].
  • Example 40 r ⁇ c-6-( ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-3-[2-hydroxy-2-(6-methoxy-[l,5]naphthyridin-4-3 r l)- ethyl] -3-aza-bicycIo [3.1.0] hex-6-y lamino ⁇ -methyl)-4//-benzo [1,4] thiazin-3-one :
  • step 35.iii the title compound (0.049 g) was obtained from intermediate 39.iii (0.059 g) as a yellow foam.
  • Example 41 r ⁇ c-2- ⁇ (l a,5a,6 «)-6-[(2,3-dihydro-[l,4]dioxino[2,3-A]pyridin-6-ylmethyl)- amino]-3-aza-bicyclo [3.1.0] hex-3-yl ⁇ -l-(6-methoxy- [1,5] naphthyridin-4-yl)-ethanc»l :
  • the heterogenous mixture was heated at 60 0 C for 30 min.
  • the solids were filtered off and water (20 ml) was added to the filtrate.
  • the volatiles were removed under reduced pressure and the residue was extracted twice with EA (2 x 150 ml).
  • the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • the residue was purified by chromatography (EA-Hex 1-1 then 2-1) to afford the title compound (1.6 g) as a beige solid.
  • Example 43 rac-2- ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-6-[(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-6-ylmethyl)- amino]-3-aza-bicyclo[3.1.0]hex-3-yl ⁇ -l-(3-methoxy-quinolin-5-yl)-ethanol:
  • Example 44 r ⁇ c-6-( ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-3-[2-hydroxy-2-(3-methoxy-quinolin-5-yl)-et;hyl]-3-aza- bicyclo [3.1.0] hex-6-ylamino ⁇ -methy l)-4H-py r ido [3,2-6] [1 ,4] thiazin-3-one :
  • Example 45 r ⁇ c-6-( ⁇ (l «,5 ⁇ ,6 ⁇ )-3-[2-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-3-aza- bicyclo [3.1.0] hex-6-yla ⁇ riino ⁇ -methyl)-4H-benzo [1 ,4] thiazin-3-one :
  • the enantiomeric excess was measured by chiral HPLC on Chiralcel OD (detection at 254 nm) using a THF-Hex mixture (3-7). The major enantiomer eluted after 13.0 min and the minor one after 14.1 min (column Chiralcel OD 4.6 x250 mm, 10 ⁇ m; flow 0.8 ml/min; eluent: 95% Hex and 5% EtOH with 0.1% diethanolamine).
  • Example 48 (2JR!-2- ⁇ (l ⁇ ,5 ⁇ ,6Qr)-6-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-ainino]- S-aza-bicyclop.l.Olhex-S-ylJ-l-CS-methoxy-quinolin-S-ylJ-ethanol:
  • Example 50 6-methoxy-4- ⁇ 3-[l-(fr ⁇ «s-3-phenyI-a!lyI)-piperidin-3-yI]-propoxy ⁇ - quinoline:
  • Example 52 r ⁇ c-3-[l-(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-piperidin-3-yl]- JV-(6-methoxy-[l,5]naphthyridin-4-yl)-propioiiamide:
  • Example 54 r ⁇ c-iV-(6-methoxy-[l,5]naphthyridin-4-yl)-3- ⁇ l-[2-(thiopheii-2-ylsulfanyl)- ethyl]-piperidin-3-yl ⁇ -propionamide:
  • Example 56 r ⁇ c-iV-(6-metlioxy-[l,5]naphthyridin-4-yl)-3-[l-(3-oxo-3,4-dihydro- 2H-pyrido[3,2-6][l,4]thiazin-6-yImethyl)-piperidin-3-yl]-propionami ⁇ ie:
  • Example 57 /- ⁇ c-3-[l-(2,3-c ⁇ ihydro-[l,4]dioxino[2,3-c]pyridin-7-ylinethyl)-piperidin- 3-y 1] -iV-(6-methoxy- [1 ,5] nap hthy ridin-4-y l)-propionamide :

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Abstract

The invention relates to novel antibiotics of formula (I) wherein R1 represents alkyl, alkoxy, haloalkoxy, halogen or cyano; one or two of U, V, W and X represent(s) N, the remaining represent CH, or, in case of U, V and/or W, may also represent CRa and, in the case of X, may also represent CRb; Ra represents halogen; Rb represents halogen or alkoxy; M is a linking chain containing a non-aromatic cyclic or heterocyclic group, and D represents alkyl, aryl or heteroaryl.

Description

Actelion 64A/TI1
New bicyclic antibiotics
The present invention concerns novel antibiotics, pharmaceutical antibacterial compositions containing them and the use thereof in the manufacture of a medicament for the treatment of infections (e.g. bacterial infection). 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 micro-organisms 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. artificial joints-related infections, 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 β-lactam, quinolone and now even to vancomycin;
- S. pneumoniae is becoming resistant to penicillin, quinolone and even to new macrolides;
- Enteroccocci are quinolone and vancomycin resistant and β-lactams are inefficacious against these strains;
- Enterobacteriacea are cephalosporin and quinolone resistant; - P. aeruginosa are β-lactam and quinolone resistant.
Further 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.
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. A new type of quinoline or naphthyridine derivatives having antibacterial activity and therefore useful for treating infections in mammals, particularly in humans, have been reported.
WO 99/37635, WO 00/21948, WO 00/21952, WO 00/43383, WO 03/101138, WO 01/025227, WO 02/040474 and WO 2004/011454 disclose quinoline, naphthyridine and quinazoline derivatives containing a 4-methylpiperidinyl spacer.
WO 00/78748, WO 02/50040 and WO 02/050061 disclose quinoline and naphthyridine derivatives containing a piperazinyl spacer.
WO 01/07432, WO 01/07433, WO 02/08224, WO 02/056882, WO 03/064421, WO 03/064431, WO 2004/02490 and WO 2004/058144 disclose quinoline, quinoxaline and naphthyridine derivatives containing a 4-aminopiperidinyl spacer.
WO 04/035569 discloses quinoline and naphthyridine derivatives containing a 3-aminomethylpiperidinyl spacer.
WO 2004/002992, WO 03/087098, WO 2004/014361 and WO 2004/035569 disclose quinoline, quinoxaline and naphthyridine derivatives containing a 4-aminocyclohexyl spacer.
It has now been found that certain novel bicyclic derivatives are useful antimicrobial agents and effective against a variety of multi-drug resistant bacteria. Thus, the present invention relates to novel bicyclic derivatives of the formula
Figure imgf000003_0001
wherein R1 represents alkyl, alkoxy, haloalkoxy, halogen or cyano; one or two of U, V, W and X represent(s) N, the remaining represent CH, or, in the case of U, V and/or W, may also represent CRa and, in the case of X, may also represent CRb; Ra represents halogen; R > b . represents halogen or alkoxy;
D represents alkyl, aryl or heteroaryl;
M is selected from the group consisting of M1, M2, M3 and M4:
Figure imgf000004_0001
wherein A1 represents NHCO, OCH2, CH2CH2, CH=CH or CH(OH)CH2;
A2 represents NHCH2, NHCO, NHCH2CONH, NHCH2CH=CH, CH2CH2, CH2CO, COCH2, CH2CH(OH) or CEt2CH(OCONH2);
B1 and B2 each represent independently from each other N or CH; when A1 represents OCH2, B1 represents CH; n is 1; or n is also O when B1 is CH; and p is 1; or p is also O when B2 is CH;
Figure imgf000004_0002
wherein
A3 represents :NHC0, CH2CH2, CH=CH, COCH2, CH(OH)CH2, CH2CH(OH),
CH(OH)CH(OH) or OCH2; A4 represents CH2, CO, CH2CH=CH, COCH=CH or CH2CONH;
R2 represents hydrogen, alkyl, hydroxyalkyl, alkylcarbonyloxyalkyl, carbamoyloxyalkyl, carboxyalkyl or carbamoylalkyl;
R3 and R4 each independently represent hydrogen, hydroxy or alkylcarbonyloxy; or R3 and R4 together represent a bridged dimethylmethylenedioxy chain attached to the carbons bearing R3 and R4;
R5 represents hydrogen, alkyl or hydroxyalkyl; and - A -
the dotted line represents a single bond or, when R3 and R4 represent hydrogen, also a double bond;
Figure imgf000005_0001
wherein
A5 represents CH2CH2, CH=CH, COCH2, CH(OH)CH2, NHC0(CH2)m, NHCOCH2O, NHCOOCH2 or 0(CH2)q; m is 0, 1 or 2; q is 1, 2 or 3 and B6 represents N and A6 represents CH2, CH2CH2, CH2CH=CH or CH2CH2S; or
B6 represents CH and A6 represents CH2NHCH2, CH2NHCH2CONH or CH2NHCH2CH=CH;
_ 2 .
Figure imgf000005_0002
wherein
A7 represents NHCO5 CH2CH2 or OCH2;
A8 represents CH2; and
R6 represents hydrogen or alkyl.
In particular, the compounds of formula I may be compounds of formula ICE
Figure imgf000005_0003
wherein R1 represents alkyl, alkoxy, haloalkoxy, halogen or cyano; one or two of U, V, W and X represent(s) N, the remaining represent CH, or, for one of U, V,
W or X, may also represent CRa;
Ra represents halogen; D represents an alkyl radical, a phenyl radical optionally substituted one or twice by substituents independently selected from the halogen atoms or a heteroaryl radical; M is selected from the group consisting of M1, M2, M3 and M4:
Figure imgf000006_0001
wherein A1 represents NHCO, OCH2, CH2CH2, CH=CH or CH(OH)CH2;
A2 represents NHCH2, NHCO, NΗCH2CONH, NHCH2CH=CH, CH2CH2, CH2CO, CH2CH(OH) or CH2CH(OCONH2);
B1 and B2 each represent independently from each other N or CH; when A1 represents OCH2, B1 represents CH; n is 1; or n is also O when B1 is CH; and. p is 1; or p is also O when B2 is CH;
Figure imgf000006_0002
wherein
A3 represents NHCO, CH2CH2, CH=CH, COCH2, CH(OH)CH2, CH2CH(OH),
CH(OH)CH(OH) or OCH2; A4 represents CH2, CO, CH2CH=CH, C OCH=CH or CH2CONH;
R2 represents hydrogen or hydroxyalkyl;
R3 and R4 each independently represent hydrogen or hydroxy; or R3 and R4 together represent a bridged dimethylmethylenedioxy chain attached to the carbons bearing R3 and R4;
R5 represents hydrogen; and the dotted line represents a single bond or, when R3 and R4 represent hydrogen, also a double bond;
Figure imgf000007_0001
wherein
A5 represents NHCO(CH2)m, NHCOCH2O or O(CH2)q; m is 0, 1 or 2; q is 1, 2 or 3 and
B6 represents N and A6 represents CH2, CH2CH2, CH2CH=CH or CH2CH2S; or
B6 represents CH and A6 represents CH2NHCH2 or CH2NHCH2CH=CH;
Figure imgf000007_0002
wherein
A7 represents NHCO, CH2CH2 or OCH2; A8 represents CH2; and R6 represents hydrogen.
The compounds of formula I may also be compounds of formula ICEP2
Figure imgf000007_0003
wherein R1 represents alkyl, alkoxy, haloalkoxy, halogen or cyano; one or two of U, V, W and X represent(s) N, the remaining represent CH, or, in case of U, V and/or W, may also represent CRa and, in the case of X, may also represent CRb; Ra represents halogen; Rb represents halogen or alkoxy; D represents alkyl, phenyl or heteroaryl; M is selected from the group consisting of M1, M2, M3 and M4:
Figure imgf000008_0001
wherein
A1 represents NHCO, OCH2, CH2CH2, CH=CH or CH(OH)CH2;
A2 represents NHCH2, NHCO, NHCH2CONH, NHCH2CH=CH, CH2CH2, CH2CO,
CH2CH(OH) or CH2CH(OCONH2);
B1 and B2 each represent independently from each other N or CH; when A1 represents OCH2, B1 represents CH; n is 1; or n is also O when B1 is CH; and p is 1 ; or p is also O when B2 is CH;
Figure imgf000008_0002
wherein A3 represents NHCO, CH2CH2, CH=CH, COCH2, CH(OH)CH2, CH2CH(OH),
CH(OH)CH(OH) or OCH2;
A4 represents CH2, CO, CH2CH=CH or CH2CONH;
R2 represents hydrogen or hydroxyalkyl;
R3 and R4 each independently represent hydrogen or hydroxy; or R3 and R4 together represent a bridged dimethylmethylenedioxy chain attached to the carbons bearing R3 and R4;
R5 represents hydrogen; and the dotted line represents a single bond or, when R3 and R4 represent hydrogen, also a double bond;
_5 _
M3 — A 6
Figure imgf000008_0003
wherein
A5 represents NHCO(CH2)m, NHCOCH2O or O(CH2)q; m is 0, 1 or 2; q is 1, 2 or 3 and
B6 represents N and A6 represents CH2, CH2CH2, CH2CH=CH or CH2CH2S; or
B6 represents CH and A6 represents CH2NHCH2 or CH2NHCH2CH=CH;
wherein
A7 represents NHCO, CH2CH2 or OCH2; A8 represents CH2; and R6 represents hydrogen.
Another aspect of this invention relates to compounds of formula Ip2
Figure imgf000009_0002
wherein R1 represents alkyl, alkoxy, haloalkoxy, halogen or cyano; one or two of U, V, W and X represent(s) N, the remaining represent CH, or, in case of U, V and/or W, may also represent CRa and, in the case of X, may also represent CRb; Ra represents halogen;
Rb represents halogen or alkoxy;
D represents alkyl, aryl or heteroaryl;
M is selected from the group consisting of M1, M2, M3 and M4:
Figure imgf000010_0001
wherein
A1 represents NHCO, OCH2, CH2CH2, CH=CH or CH(OH)CH2;
A2 represents NHCH2, NHCO, NHCH2CONH, NHCH2CH=CH, CH2CH2, CH2CO, COCH2,
CH2CH(OH) or CH2CH(OCONH2);
B1 and B2 each represent independently from each other N or CH; when A1 represents OCH2, B1 represents CH; n is 1; or n is also O when B1 is CH; and p is 1 ; or p is also O when B2 is CH;
Figure imgf000010_0002
wherein A3 represents NHCO, CH2CH2, CH=CH, COCH2, CH(OH)CH2, CH2CH(OH),
CH(OH)CH(OH) or OCH2;
A4 represents CH2, CO, CH2CH=CH or CH2CONH;
R2 represents hydrogen, alkyl, hydroxyalkyl, alkylcarbonyloxyalkyl, carbamoyloxyalkyl, carboxyalkyl or carbamoylalkyl; R3 and R4 each independently represent hydrogen, hydroxy or alkylcarbonyloxy; or R3 and R4 together represent a bridged dimethylmethylenedioxy chain attached to the carbons bearing R3 and R4;
R5 represents hydrogen, alkyl or hydroxyalkyl; and the dotted line represents a single bond or, when R3 and R4 represent hydrogen, also a double bond;
Figure imgf000011_0001
wherein
A5 represents CH2CH2, CH=CH, COCH2, CH(OH)CH2, NHCO(CH2)m, NHCOCH2O,
NHCOOCH2 or O(CH2)q; m is 0, 1 or 2; q is 1, 2 or 3 and
B6 represents N and A6 represents CH2, CH2CH2, CH2CH=CH or CH2CH2S; or
B6 represents CH and A6 represents CH2NHCH2, CH2NHCH2CONH or CH2NHCH2CH=CH;
-
Figure imgf000011_0002
wherein
A7 represents NHCO, CH2CH2 or OCH2; A8 represents CH2; and
R6 represents hydrogen or alkyl.
A further aspect of this invention relates to compounds of formula Ip1
Figure imgf000011_0003
wherein R1 represents alkyl, alkoxy, halogen or cyano; one or two of U, V, W and X represent(s) N, the remaining represents CH, or, in case of U and/or X, also CR; R represents alkoxy or halogen; D represents alkyl, aryl or heteroaryl; M is one of the spacers M1, M2 and M3:
Figure imgf000012_0001
wherein
A1 represents NHCO, OCH2, CH2CH2, CH=CH or CH(OH)CH2;
A2 represents NHCH2, NHCH2CONH, NHCH2CH=CH, CH2CH2, CH2CO, CH2CH(OH) or
CH2CH(OCONH2);
B1 and B2 each represent independently from each other N or CH; when A1 represents OCH2, B1 represents CH; n is the integer 1; or n is also O when B1 is CH; and p is the integer 1; or p is also O when B2 is CH;
Figure imgf000012_0002
wherein A3 represents NHCO, CH2CH2, CH=CH, COCH2, CH(OH)CH2, CH(OH)CH(OH) or OCH2;
A4 represents CH2, CH2CH=CH or CH2CONH;
R2 represents hydrogen, alkyl, hydroxyalkyl, alkylcarbonyloxyalkyl, carbamoyloxyalkyl, carboxyalkyl or carbamoylalkyl;
R3 and R4 each independently represent hydrogen, hydroxy or alkylcarbonyloxy; R5 represents hydrogen or alkyl; and the dotted line represents a single bond or, when R3 and R4 represent hydrogen, also a double bond;
M° 3 — A6-§-
Figure imgf000012_0003
wherein
A5 represents CH2CH2, CH=CH, COCH2, CH(OH)CH2, NHCO(CH2)m, NHCOCH2O, NHCOOCH2 or O(CH2)q; m is an integer between 0 and 2; q is an integer between 1 and 3 and
B6 represents 1ST and A6 represents CH2, CH2CH2, CH2CH=CH or CH2CH2S; or
B6 represents CH and A6 represents CH2NHCH2, CH2NHCH2CONH or CH2NHCH2CH=CH.
A further emtoodiment of the bicyclic derivatives of the above formula I5 ICE or Ip1 relates to their prodrugs, their tautomers, their optically pure enantiomers, mixtures of enantiomers, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixture of diastereoisomeric racemates, meso forms, pharmaceutically acceptable salts, solvent complexes and morphological forms thereof. Particularly preferred are the optically pure enantiomers, optically pure diastereoisomers, meso forms, pharmaceutically acceptable salts, solvent complexes and morphological forms.
The following paragraphs provide definitions of the various chemical moieties for the compounds of formula Ip1 and are intended to apply to those compounds unless an otherwise expressly set out definition provides a broader definition:
♦♦♦ The terra "alkyl" refers to a saturated straight or branched chain alkyl group, containing from one to ten, preferably one to six, in particular one to four carbon atoms, for example methyl, ethyl, propyl, iso-propyl, butyl, ώσ-butyl, .sec-butyl, tert-bxxtyl, w-pentyl, iso- pentyl, re-hexyl, 2,2-dimethylbutyl, w-octyl. Any alkyl group as defined herein may be substituted with one, two or more substituents, for example F, Cl, Br, I5 NH2, OH, SH, COOH or NO2. Examples for substituted alkyl groups are trifluoromethyl, trifluoroethyl, hydroxyrnethyl, hydroxyethyl, carboxymethyl and carboxyethyl. Alkyl groups may also be substituted by alkylcarbonyloxy, such as in acetoxymethyl, acetoxyethyl, propionyloxymethyl or propionyloxyethyl; by carbamoyloxy, such as in carbamoyloxymethyl or carbamoyloxyethyl; or by carbamoyl, such as in carbamoylmethyl or carbamoylethyl.
♦♦♦ Alkyl groups combined to form alkylcarbonyloxy are exemplified e. g. as acetoxy or propionyloxy. ❖ The term "alkoxy" is an "alkyl-O" group, where "alkyl" has the above significance. Examples for substituted alkoxy groups are trifluoromethoxy and trifluoroethoxy.
❖ The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably to fluorine or chlorine. ❖ The term "aryl" refers to an aromatic cyclic group with one, two or three rings, having five to 14 carbon ring-atoms preferably from five or six to ten carbon ring-atoms, for example phenyl or naphthyl groups. Any aryl group as defined herein may be substituted with one, two or more substituents, for example F, Cl, Br, I, OH, NH2, SH, N3, NO2, alkyl groups such as methyl or ethyl, perfluoroalkyl groups such as trifluoromethyl or trifluoroethyl, alkoxy groups such as methoxy, amino groups such as methylamino or dimethylamino, or cyano. Specific examples are 4-fluoro-phenyl, 4-chloro-phenyl, 4-methoxy-phenyl, 4-methyl-phenyl, 4-trifluoromethyl-phenyl, 4-trifluoromethoxy- phenyl, 2,4-difluoro-phenyl, 2,4-dichloro-phenyl, 2,4-dimethoxy-phenyl, 2,4-dimethyl- phenyl, 2,4-ditrifluoromethyl-phenyl and 2,4-ditrifluoromethoxy-phenyl. ❖ The term "heteroaryl" refers to an aryl group as defined herein where one, two or more ring-carbon atoms are replaced by an oxygen, nitrogen or sulphur atom, for example pyridyl, imidazolyl, pyrazolyl, quinolinyl, isoquinolinyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl and pyridazinyl groups. The term "heteroaryl" also covers bicyclic structures such as benzo[l,3]dioxol-5-yl, 2,3-dihydro- benzo [ 1 ,4]dioxin-6-yl, 4H-benzo [ 1 ,4]oxazin-3 -one-6-yl, 4Η-benzo [ 1 ,4]thiazin-3 -one-6-yl, 3-oxo-3,4-dihydro-2H-benzo[l,4]thiazin-6-yl, lH-pyrido[2,3-b][l,4]thiazin-2-one-7-yl, 2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-yl, 2,3-dihydro-[l,4]dioxino[2,3-Z>]pyridin-7-yl, 4H-pyrido[3,2-δ][l,4]oxazin-3-one-6-yl, 3,4-dihydro-2H-pyrido[3,2-δ]thiazin-6-yl, 3-oxo-3,4-dihydro-2H-pyrido[3 ,2-Z>]thiazin-6-yl, 3,4-dihydro-lH-quinolin-2-one-7-yl,
3,4-dihydro-lH-quinoxalin-2-one-7-yl, 2-oxo-3,4-dihydro-lH-[l,8]naphtyridin-6-yl,
6,7-dihydro-[l,4]dioxino[2,3-d]pyrimidin-2-yl, 2-oxo-2,3-dihydro- lH-pyrido[3,4-Z»][l,4]oxazin-7-yl, 2-oxo-2,3-dihydro-lH-pyrido[2,3-Z>][l,4]oxazin-7-yl, benzo[l,2,5]thiadiazol-5-yl, benzofuran-3-yl and 7-fluoro-4H-benzo[l,4]thiazin-3-one- 6-yl. Any heteroaryl group as defined herein may be substituted with one, two or more substituents, for example F, Cl, Br, I, OH, NH2, SH, N3, NO2, alkyl groups such as methyl or ethyl, perfluoroalkyl groups such as trifluoromethyl or trifluoroethyl, alkoxy groups such as methoxy, amino groups such as methylamino or dimethylamino, or cyano. ❖ The present invention also relates to pro-drags that are composed of a compound of formula IPi having a free carboxylic acid and at least one pharmacologically acceptable protective group that will be cleaved off under physiological conditions. Such prodrugs have been reviewed by Beaumont, Kevin; Webster, Robert; Gardner, Iain; Dack, Kevin in Current Drug Metabolism (2003), 4(6), 461-485. Examples of such promoities are alkoxy-, aralkyloxy-, 0CH(Ra)0C0Rb (e.g. pivaloyloxymethyloxy), OCH(Ra)ORb, 2-alkyl-, 2-aryl- or 2-aralkyl-oxycarbonyl-2-alkylidene-ethoxy group, 5-alkyl[l,3]dioxol- 2-one-4-yl-methoxy, dialkylamino-alkyloxy or acyloxy as defined herein, e.g. ethoxy, benzyloxy, acetyl or acetyloxy wherein Ra and Rb are hydrogen, C1-CO alkyl, C2-CO alkenyl, C2-C6 alkynyl, C2-C6 heteroalkyl, C2-C6 cycloalkyl, C2-C6 heterocycloalkyl, alkylaryl, alkylheteroaryl, heteroalkylcycloalkyl, heteroalkylheteroaryl, aryl, heteroaryl, heterocycloalkylaryl or heterocycloalkylheteroaryl. Furthermore, if a free hydroxy group is present on a compound of Formula I, it can be protected as a prodrug of the type sulfate (OSO3H), phosphate (OPO3H2), oxymethylene phosphate (OCH2OPO3H2), succinate (OCOCH2CH2COOH), or ester of naturally occurring amino acids or a derivative thereof
(e.g. dimethylaminoglycine).
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 (except for the compounds of formula Ipi that have their own definitions), unless an otherwise expressly set out definition provides a broader or narrower definition:
❖ The term "alkyl" refers to a saturated straight or branched chain alkyl group, containing from one to ten, preferably one to six, and in particular one to four carbon atoms. Representative examples of alkyl groiαps include, but are not limited to, methyl, ethyl, propyl, iso-propyl, π-butyl, wo-butyl, .sec-butyl, tert-butyl, w-pentyl, wo-pentyl, w-hexyl,
2,2-dimethylbutyl, rc-heptyl or w-octyl. The term "(Ci-Cx)alkyl" (x being an integer) refers to a straight or branched chain alkyl group containing 1 to x carbon atoms.
❖ The term "alkoxy" refers to a saturated straight or branched chain alkoxy group, containing from one to ten, preferably one to six, and in particular one to four carbon atoms. Representative examples of alleoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, /so-propoxy, rø-bixtoxy, wo-butoxy, sec-butoxy, tert-butoxy or n- hexyloxy. The term "(Ci-Cx)alkoxy" refers to a straight or branched chain alkoxy group containing 1 to x carbon atoms.
❖ The term (Ci-C6)alkoxy-(Ci-C6)alkyl refers to a (CrC6)allcyl group as previously defined itself substituted with a (Ci-Cό)alkoxy group as previously defined. ♦♦♦ The term "haloalkoxy" refers to a saturated straight or branched chain alkoxy group, containing from one to six and preferably one to four carbon atoms, in which at least one hydrogen atom (and possibly all) has been replaced by a halogen atom. Representative examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy oτ difluoromethoxy. The term "(Ci-Cx)haloalkoxy" (x being an integer) refers to a straight of branched chain haloalkoxy group containing 1 to x carbon a.toms.
❖ The term "hydroxyalkyl" refers to a saturated straight or branched chain alkyl group substituted once by hydroxy and containing from one to six, and in particular one to four, carbon atoms.
❖ The term "alkylcarbonyloxyalkyl" refers to an alkylcarbonyloxyalkyl wherein each alk>^l group is independently a saturated straight or branched cha_in alkyl group containing from one to six, and in particular one to four, carbon atoms.
♦♦♦ The term "carbamoyloxyalkyl" refers to a carbamoyloxyaltcyl wherein the alkyl group is a saturated straight or branched chain alkyl group containing from one to six, and in particular one to four, carbon atoms. ♦> The term "carboxyalkyl" refers to a carboxyalkyl wherein the alkyl group is a saturat&d straight or branched chain alkyl group containing from one to six, and in particular one to four, carbon atoms.
♦♦♦ The term "carbamoylalkyl" refers to a carbamoylalkyl wherein the alkyl group is a saturated straight or branched chain alkyl group containing from one to six, and in particular one to four, carbon atoms.
❖ The term "alkylcarbonyloxy" refers to an alkylcarbonyloxy wherein the alkyl group is a saturated straight or branched chain alkyl group containing from one to six, and in particular one to four, carbon atoms.
❖ The term "alkoxycarbonylalkyl" refers to an alkoxycarbotvylalkyl wherein the alkyl group is a saturated straight or branched chain alkyl group corttaining from one to six, and in particular one to four, carbon atoms and the alkoxy gxoup is a saturated straight or branched chain alkoxy group, containing from one to six, and in particular one to four carbon atoms.
❖ The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably to fluorine or chlorine. ❖ The term "cycloalkyl", used alone or in combination, refers to a saturated cyclic hydrocarbon moiety containing 3 to 7 carbon atoms. The term "(Cy-Cz)cycloalkyl", used alone or in combination, refers to a saturated cyclic hydrocarbon moiety containing y to z carbon atoms. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl and cyclohexyl. ♦♦♦ The term "cycloalkylalkyl", used alone or in combination, refers to an alkyl group as previously defined itself substituted by a cycloalkyl group as previously defined. Representative examples of cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl and cyclohexylmethyl.
❖ The term "(C2-C6)alkenyl" refers to a straight or branched hydrocarbon chain containing 2 to 6 carbon atoms with at least one carbon-carbon double bond. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 3-butenyl, 4-pentenyl or 5-hexenyl.
♦♦♦ The term "aryl", used alone or in combination, refers to an aromatic cyclic group with one, two or three rings, having five to 14 carbon ring-atoms preferably from five or six to ten carbon ring-atoms, for example phenyl or naphthyl groups. Any aryl group as defined herein may be substituted with one, two or more substituents, each of which is independently selected from the group consisting of halogen, alkyl, alkoxy, trifluoromethyl and trifluoromethoxy. Specific examples of aryl are phenyl, naphtyl, 4-fluoro-phenyl, 4-chloro-phenyl, 4-methoxy-phenyl, 4-methyl-phenyl, 4-trifluoromethyl- phenyl, 4-trifluoromethoxy-phenyl, 2,4-difluoro-phenyl, 2,4-dichloro-phenyl, 2,4- dimethoxy-phenyl, 2,4-dimethyl-phenyl, 2,4-ditrifluoromethyl-phenyl and 2,4-ditrifluoromethoxy-phenyl.
♦♦♦ The term "heteroaryl" refers to an aryl group as defined herein where one, two or more ring-carbon atoms are replaced by an oxygen, nitrogen or sulphur atom, for example pyridyl, imidazolyl, pyrazolyl, quinolinyl, isoquinolinyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl and pyridazinyl groups. The term "heteroaryl" also covers bicyclic structures selected from the group consisting of benzo[l,3]dioxol-5-yl, 2,3-dihydro-benzo[l,4]dioxin-6-yl, 2,3-dihydro-
[1,4] dioxino [2, 3 -Z>]pyridin-6-y 1, 2,3 -dihydro-[ 1 ,4] dioxino[2,3 -c]pyridin-7-y 1, 3 -oxo- 3,4-dihydro-2H-benzo[l,4]thiazin-6-yl, 3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-6-yl, 3-oxo-3,4-dihydro-2H-pyrido[3,2-£][l,4]thiazin-6-yl, 3-oxo-3,4-dihydro-
2H-pyrido[3,2-έ][l,4]oxazin-6-yl, 2-oxo-2,3-dihydro-lH-pyrido[3,4-έ][l,4]oxazine-7-yl, 2-oxo-3,4-dihydro-lH-quinolin-7-yl, benzo[l,2,5]thiadiazol-5-yl, chroman-7-yl and benzofuran-3-yl. Any heteroaryl group as defined herein may be substituted with one, two or more substituents on its aromatic ring(s), said substituents being from the group consisting of halogen, alkyl and alkoxy; preferably, any heteroaryl group as defined herein may be substituted with one halogen substituent. Hence, exemples of heteroaryl groups include, but are not limited to, benzo[l,3]dioxol-5-yl, 2,3-dihydro-benzo[l,4]dioxin-6-yl, 2,3-dihydro-[l,4]dioxino[2,3-6]pyridin-6-yl, 2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-yl, 3-oxo-3,4-dihydro-2H-benzo[l,4]thiazin-6-yl, 7-fluoro-3-oxo-3,4-dihydro- 2H-benzo[l,4]thiazin-6-yl, 3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-6-yl,
3-oxo-3,4-dihydro-2H-pyrido[3,2-Z>][l,4]thiazin-6-yl, 3-oxo-3,4-dihydro-
2H-pyrido[3,2-ό][l,4]oxazin-6-yl, 2-oxo-2,3-dihydro-lH-pyrido[3,4-6][l,4]oxazine-7-yl, 2-oxo-3,4-dihydro-lH-quinolin-7-yl, benzo[l,2,5]thiadiazol-5-yl, thiophen-2-yl, thiazol- 2-yl, 2,2-dimethyl-chroman-7-yl and benzofuran-3-yl. ❖ When in the formula
Figure imgf000018_0001
M represents the radical
Figure imgf000019_0001
this means specifically that the radical A3 is attached to the
Figure imgf000019_0002
group whereas the radical A4 is attached to the D group.
This is applicable mutatis mutandis to all other variants of the M radical (i.e. M1, M3 and M4) and to all radicals that make M radicals (e.g. A3 and A4). As a further example, in the substructure M2, if it is stated that A4 represents CH2CONH, it is thereby meant that the CH2 part of the CH2CONH radical is attached to the nitrogen bearing the radical R5 and that the CONH part of the CH2CONH is attached to the D group. In other words, the left part of a radical is always attached to the right part of the radical that is next to the left. ❖ When in a rest
Figure imgf000019_0003
the two bonds linking the cyclohexyl ring to the radicals A5 and A6 are represented by two bold lines (and not by wedged bonds that would then depict an absolute stereochemistry), this means that the two bonds are in a cis configuration relatively to said cyclohexyl ring (i.e. the radicals A5 and A6 are either both above the median plan of the cyclohexyl ring or both under said median plan).
This is applicable mutatis mutandis to all other cyclohexyl, pyrane or piperidine ring representations of compounds of formula I or ICE-
Compounds of formula I, ICEJ IP2> ICEP2 or IP1 carrying a double bond in Ai -Ae are present as ZIE (cis/trans) isomer mixtures or as Z (cis) or E (trans) isomers. Preferred are the E (trans) isomers.
Preferably, the radical R1 will be alkyl, alkoxy, haloalkoxy or cyano. More preferably, the radical R1 will be (Ci-C3)alkyl, (Ci-C3)alkoxy, (Ci-C2)haloalkoxy or cyano (in particular methyl, methoxy or cyano, and notably methoxy or cyano).
Preferably also, D will be aryl or heteroaryl, notably phenyl (which may optionally be substituted once or twice by substituents independently selected from halogen, methyl and methoxy) or heteroaryl. More preferably, D will be phenyl substituted once or twice by substituents independently selected from halogen atoms (especially 2,5-difluorophenyl) or heteroaryl. In particular, D will be heteroaryl.
Besides, the radical Ra will preferably be fluorine. Preferably also, the radical Rb will be fluorine.
Preferably, U, V, W and X will be such that one or two of U, V, W and X represent(s) N and the remaining represent CH. According to another preferred embodiment, U, V, W and X will be such that one or two of U, V, W and X represent(s) N, one of U, V, W and X represents CF and the remaining represent(s) CH.
Preferred combinations for the symbols U, V, W and X in the compounds of formula I, ICE or Ipi are evident from the following particular structures:
"XTUVV.
Figure imgf000021_0002
Figure imgf000021_0001
wherein R1 is preferably (Ci-C3)alkyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy or cyano, and in particular methyl, methoxy or cyano.
Other preferred combinations for the symbols U, V, W and X in the compounds of formula I, ICE or Ip1 are evident from the following particular structures:
Figure imgf000021_0003
wherein R1 is preferably (Ci-C3)alkyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy or cyano, and in particular methyl, methoxy or cyano. Preferred embodiments of D for the compounds of formula I, ICE, Ip2, ICEP2 or IPi are (C1-C9) linear alkyl, phenyl, benzofuran-3-yl, thiazol-2-yl or heteroaryl of the formula
Figure imgf000022_0001
wherein P is a ring selected from
Figure imgf000022_0002
Q is O or S; K, Y and Z are each independently N or CR3; and
R3 is hydrogen or halogen (and in particular hydrogen or fluorine).
More preferably, D will be a heteroaryl of the formula
Figure imgf000022_0003
wherein P is a ring selected from
Figure imgf000022_0004
Q is O or S; K, Y and Z are each independently N or CR3; and
R3 is hydrogen or halogen (and in particular hydrogen or fluorine).
Particularly preferred embodiments of D for the compounds of formula Ip1 are:
❖ 2,3-dihydro-benzo[l,4]dioxin-6-yl;
❖ benzo[l,3]dioxol-5-yl; ❖ 4H-benzo[l,4]oxazin-3-one-6-yl; ❖ 4H-benzo[l ,4]thiazin-3-one-6-yl;
❖ 7-fluoro-4H-benzo[l,4] thiazin -3-one-6-yl;
❖ 2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-yl;
❖ 2,3-dihydro[l,4]dioxino[2,3-Z>]pyridin-6-yl; ❖ 3-oxo-3,4-dihydro-2H-pyrido[3,2-6][l,4]thiazin-6-yl;
❖ 2-oxo-lH-pyrido[2,3-b][l,4]thiazin-7-yl; and
❖ benzo[l,2,5]thiadiazol-5-yl.
Particularly preferred embodiments of D for the compounds of formula I, ICE, hi, ICEP2 or IPi are: ❖ 2,3-dihydro-benzo[l,4]dioxin-6-yl; ♦♦♦ 4H-benzo[ 1 ,4]oxazin-3-one-6-yl;
❖ 4H-benzo[l,4]thiazin-3-one-6-yl;
❖ 7-fluoro-4H-benzo[l,4] thiazin -3-one-6-yl;
❖ 2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-yl; ❖ 2,3-dihydro[l,4]dioxino[2,3-ό]pyridin-6-yl;
❖ 3-oxo-3,4-dihydro-2H-pyrido[3,2-Z>][l,4]thiazin-6-yl;
❖ benzo[l,2,5]thiadiazol-5-yl.
According to a first variant of the invention, the spacer M of the compounds of foxmula I, ICE, Ip2> ICEP2 or Ipiwill be the spacer M1.
For the spacer M1, preferred embodiments are the folloΛving three structures (the group of which will be called M11):
Figure imgf000024_0001
OH 3
- ■I§—- HC — CH2-N y→ S-A.--I- M ,11
wherein
11
A11 represents NHCO, OCH2, CH(OH)CH2 or CH2CH2; A21 represents CH2, CO, CH(OH) or CH(OCONH2); A22 represents CH2, CO, CH2CONH or CH2CH=CH.
Particularly preferred spacers M1 are the following:
Figure imgf000025_0001
Other preferred spacers M1 are the following:
Figure imgf000025_0002
Preferred compounds of formula I having the spacer M1 are the following:
• (2,3-dihydro-[l,4]dioxino[2,3-Z)]pyridin-6-ylmethyl)-[(lo;,5ci;,6α)-6-(6-methoxy- [l,5]naphthyridin-4-yloxymethyl)-bicyclo[3.1.0]hex-3-yl]-amine;
• (2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-[(lo;,5α,6α)-6-(6-methoxy-[l,5]naphthyridm- 4-yloxymethyl)-bicyclo[3.1.0]hex-3-yl] -amine;
• 7-fluoro-6-{(l a,5a,6Q;)-[6-(6-methoxy-[l,5]naphthyridin-4-yloxymethyl)- bicyclo[3.1.0]hex-3-ylamino]-methyl}-4H-benzo[l,4]thiazin-3-one;
• 6- { [( 1 a, 5 a, 6 α)-6-(6-methoxy- [ 1 , 5]naphthyridin-4-yloxymethy l)-bicyclo [3.1.0]hex- 3 -ylamino] -methyl } -4H-benzo [1,4] oxazin-3 -one; • 6-{[(l ofjSαjβorJ-ό-Cβ-methoxy-tljSJnaphthyridin^-yloxymethy^-bicyclop.1.0]hex- 3 -ylamino] -methyl } -4H-benzo [ 1 ,4]thiazin-3 -one;
• (l«,3Jfi,5α,6o:)-{3-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]- bicyclo[3.1.0]hexane-6-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide;
• ( 1 a,3β, 5 a, 6 α)-3 - [(3 -oxo-3 ,4-dihydro-2H-benzo [1,4] oxazin-6-ylmethy l)-amino] - bicyclo[3.1.0]hexane-6-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide;
• (1 a,3β,5 a,6a)-3-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-o][l,4]thiazin-6-ylmethyl)-amino]- bicyclo[3.1.0]hexane-6-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide;
• (lα,3y0,5α;,6cι;)-3-[(7-fluoro-3-oxo-3,4-dihydro-2H-benzo[l,4]thiazin-6-ylmethyl)-amino]- bicyclo[3.1.0]hexane-6-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide; • l-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-2-[(l α,5α,6α)-6-(6-methoxy-quinazolin- 4-yloxymethyl)-3-aza-bicyclo[3.1.0]hex-3-yl]-ethanone;
• rac-l-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-2-[(lα,5or,6α)-6-(6-methoxy-quinazolin- 4-yloxymethyl)-3-aza-bicyclo[3.1.0]hex-3-yl]-ethanol;
• rac-carbamic acid l-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-2-[(l«,5«,6a>)-6-(6-methoxy- quinazolin-4-yloxymethyl)-3-aza-bicyclo[3.1.0]hex-3-yl] -ethyl ester;
• 4-{(la,5a,6cc)-3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-3-aza-bicyclo[3.1.0]hex- 6-ylmethoxy}-6-methoxy-quinoline;
• 4-{(la,5a,6o;)-3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-3-aza-bicyclo[3.1.0]hex- 6-ylmethoxy}-6-methoxy-quinazoline; • 8-{(lα,5«,6α)-3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-3-aza-bicyclo[3.1.0]hex- 6-ylmethoxy}-2-methoxy-[l,5]naphthyridine; • l-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-2-[(l(2,5c!;,6α)-6-(6-methoxy-[l,5]naphthyridin- 4-yloxymethyl)-3-aza-bicyclo[3.1.0]hex-3-yl]-ethanone;
• røc-l-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-2-[(lα,5α,6α)-6-(6-methoxy- [l,5]naphthyridin-4-yloxymethyl)-3-aza-bicyclo[3.1.0]hex-3-yl]-ethanol; • røc-carbamic acid l-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-2-[(lcøα,6α)-6-(6-methoxy- [ 1 , 5]naphthyridin-4-yloxymethy l)-3 -aza bicyclo [3.1.0]hex-3 -yl] -ethyl ester;
• rαc-(l α,5α,6α)-4-{3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-3-aza- bicyclo[3.1.0]hex-6-ylmethoxy}-quinoline-6-carbonitrile;
• 3-chloro-4-{(l«,5Q;,6α)-3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-3-aza- bicyclo[3.1.0]hex-6-ylmethoxy} -6-methoxy-quinoline;
• rac-A- { ( 1 a, 5 a, 6 α)-3 -[2-hydroxy-2-(3 -oxo-3 ,4-dihydro-2H-benzo [1,4] oxazin-6-y l)-ethyl] - 3-aza-bicyclo[3.1.0]hex-6-ylmethoxy}-quinoline-6-carbonitrile;
• rac-2-[(l«,5a,6a)-6-(3-chloro-6-methoxy-quinolin-4-yloxymethyl)-3-aza- bicyclo[3.1.0]hex-3-yl]-l-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethanol; • røc-carbamic acid 2-[(lα,5α,6α)-6-(3-chloro-6-methoxy-quinolin-4-yloxymethyl)-3-aza- bicyclo[3.1.0]hex-3-yl]-l-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl ester;
• 6-{2-[(l a,5 or,6α)-6-(3-chloro-6-methoxy-quinolin-4-yloxymethyl)-3-aza- bicyclo[3.1.0]hex-3-yl]-l-hydroxy-ethyl}-4H-benzo[l,4]oxazin-3-one;
• 5-{(lor,5o;,6a:)-3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-3-aza-bicyclo[3.1.0]hex- 6-ylmethoxy } -3 -methoxy-quinoline;
• 6-{(lα,5or,6α)-2-[6-(3-methoxy-quinolin-5-yloxymethyl)-3-aza-bicyclo[3.1.0]hex-3-yl]- acetyl } -4H-benzo [ 1 ,4]oxazin-3 -one;
• 6-{ l-hydroxy-2-[(l «,5α,6o:)-6-(3-methoxy-quinolin-5-yloxymethyl)-3-aza- bicyclo[3.1.0]hex-3-yl]-ethyl}-4H-benzo[l,4]oxazin-3-one; • (lα,5α,6α)-3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-3-aza-bicyclo[3.1.0]hexane- 6-carboxylic acid (2-cyano-quinolin-8-yl)-amide;
• (lα,5α,6α)-3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-3-aza-bicyclo[3.1.0]hexane- 6-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide;
• (1 a,5 α,6«)-3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-3-aza-bicyclo[3.1.0]hexane- 6-carboxylic acid (3-chloro-6-methoxy-quinolin-4-yl)-amide;
• (lα,5or,6Q;)-3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-3-aza-bicyclo[3.1.0]hexane- 6-carboxylic acid (3-methoxy-quinoxalin-5-yl)-amide; • 3-[(lα,5α,6α)-2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-2-oxo-ethyl]-3-aza- bicyclo[3.1.0]hexane-6-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide;
• røc-3-[(l a,5 «,6or)-2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-2-hydroxy-ethyl]-3-aza- bicyclo[3.1.0]hexane-6-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide; • røc-4-{(l ff,5o;,6a)-3-[2-hydroxy-2-(3-oxo-3,4-dihydro-2H-benzo[l,4]thiazin-6-yl)-ethyl]- 3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide;
• rαc-(l cc,5α,6α)-6-({3-[2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-3-aza- bicyclo[3.1.0]hex-6-ylamino}-methyl)-4H-pyrido[3,2-ό][l,4]thiazin-3-one;
• rac-(l a,5 α,6α)-6-({3-[2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-3-aza- bicyclo [3.1.0]hex-6-ylamino } -methyl)-4H-benzo [1,4] oxazin-3 -one;
• rαc-(l α,5α,6α)-2-{6-[(2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-3-aza- bicyclo[3.1.0]hex-3-yl}-l-(6-methoxy-quinolin-4-yl)-ethanol;
• rαc^-KlαjS^βoO-ό-^jS-dihydro-benzofl^Jdioxin-ό-ylmethy^-aminoJ-S-aza- bicyclo [3.1.0]hex-3 -yl} - 1 -(6-methoxy-quinolin-4-yl)-ethanol; • rac-2-{{\ cs,5a,6a)-6-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmetliyl)-amino]-3-aza- bicyclo[3.1.0]hex-3-yl}-l-(6-methoxy-[l,5]naphthyridin-4-yl)-ethanol;
• rαc-6-({(lor,5o;,6α)-3-[2-hydroxy-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-3-aza- bicyclo[3.1.0]hex-6-ylamino}-methyl)-4H-benzo[l,4]thiazin-3-one;
• rac-2-{{\ a,5 α,6α)-6-[(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin~6-ylmethyl)-amino]-3-aza- bicyclo[3.1.0]hex-3-yl}-l-(6-methoxy-[l,5]naphthyridin-4-yl)-ethanol;
• røc-6-({(l a,5 α,6α)-3-[2-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-3-aza- bicyclo [3.1.0]hex-6-ylamino } -methyl)-4H-benzo [1,4] oxazin-3 -one;
• rαc-2-{(lα,5α,6α)-6-[(2,3-dihydro-[l,4]dioxino[2,3-ό]pyridin-6-ylmethyl)-amino]-3-aza- bicyclo[3.1.0]hex-3-yl}-l-(3-methoxy-quinolin-5-yl)-ethanol; • rac-6-({(l α,5o;,6α)-3-[2-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-3-aza- bicyclo [3.1.0]hex-6-ylamino } -methyl)-4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one;
• rac-6-( { ( 1 a, 5 a, 6 a)-3 -[2-hydroxy-2-(3 -methoxy-quinolin-5-yl)-ethyl] -3 -aza- bicyclo [3.1.0]hex-6-ylamino } -methyl)-4H-benzo [ 1 ,4]thiazin-3 -one;
• rac-2-{(lα,5ci;,6α)-6-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-3-aza- bicyclo[3.1.0]hex-3-yl}-l-(3-methoxy-quinolin-5-yl)-ethanol;
• 6-({(lα;,5«,6Q;)-3-[(2i?)-2-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-3-aza- bicyclo [3.1.0]hex-6-ylamino } -methyl)-4H-benzo [ 1 ,4]thiazin-3 -one; • (2K)-2- { ( 1 a, 5 a, 6 ct)-6-[(2,3 -dihydro-benzo [1,4] dioxin-6-ylmethyl)-amino] -3 -aza- bicyclo[3.1.0]hex-3-yl} - 1 -(3-methoxy-quinolin-5-yl)-ethanol;
• 3-oxo-3,4-dihydro-2H-pyrido[3,2-Z>][l,4]thiazine-6-carboxylic acid {(lα,5α,6<2)-3-[(2i?)-2-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-3-aza- bicyclo[3.1.0]hex-6-yl}-amide;
• 6-({(l a,5 α,6c^-3-[(2i?)-2-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-3-aza- bicyclo[3.1.0]hex-6-ylamino}-methyl)-4Η-benzo[l,4]oxazin-3-one;
• rac-2-{(l a,5 α,6α)-3-[2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-3-aza- bicyclo[3.1.0]hex-6-ylamino}-N-thiazol-2-yl-acetamide; • rαc-(lα,5α,6α)-2-{6-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-3-aza- bicyclo[3.1.0]hex-3-yl}-l-(3-methoxy-quinoxalin-5-yl)-ethanol;
• røc-(l a,5 α,6α)-6-({3-[2-hydroxy-2-(3-methoxy-quinoxalin-5-yl)-ethyl]-3-aza- bicyclo[3.1.0]hex-6-ylamino} -methyl)-4H-benzo[ 1 ,4]thiazin-3-one;
• røc-(l a,5 «,6«)-6-({3-[2-hydroxy-2-(3-methoxy-quinoxalin-5-yl)-ethyl]-3-aza- bicyclo [3.1.0]hex-6-ylamino } -methyl)-4H-benzo [1,4] oxazin-3 -one;
• rαc-(l α,5α,6α)-2-{6-[(benzo[l,2,5]thiadiazol-5-ylmethyl)-amino]-3-aza- bicyclo[3.1.0]hex-3-yl}-l-(3-methoxy-quinoxalin-5-yl)-ethanol;
• rαc-(l a,5 α,6o;)-6-({3-[2-hydroxy-2-(3-methoxy-quinoxalin-5-yl)-ethyl]-3-aza- bicyclo [3.1.0]hex-6-y lamino } -methyl)-4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one ; • rac-( la,5a,6ά)-2-{6- [(benzofuran-2-ylmethyl)-amino] -3 -aza-bicyclo [3.1.0]hex-3 -yl } - 1 - (3 -methoxy-quinoxalin-5 -yl)-ethanol;
• rac-{ 1 a, 5 a,6 a)- 1 -(3 -methoxy-quinoxalin-5-yl)-2- [6-(3 -pheny l-allylamino)-3 -aza- bicyclo [3.1.0]hex-3 -yl] -ethanol;
• TOC-(I a,5 α,6«)-2-{6-[(2,2-dimethyl-chronian-7-ylmethyl)-amino]-3-aza- bicyclo[3.1.0]hex-3-yl} - 1 -(3-methoxy-quinoxalin-5-yl)-ethanol;
• 6-{2-[(lα,5 a,6 «)-6-(6-methoxy-quinazolin-4-yloxymethyl)-3 -aza-bicyclo [3.1.0]hexi- 3-yl]-acetyl} -4H-benzo[l ,4]thiazin-3-one;
• 6-{ l-hydroxy-2-[(l a,5a,6«)-6-(6-methoxy-quinazolin-4-yloxymethyl)-3-aza- bicyclo[3.1.0]hex-3-yl]-ethyl}-4H-benzo[l,4]thiazin-3-one.
More preferably, the compounds of formula I having the spacer M1 will be selected from the first 48 compounds mentioned in the list hereabove. In particular, the following compounds of formula I having the spacer M! are preferred:
• 2-{rαc-(lα,5α,6α)-6-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-3-aza- bicyclo[3.1.0]hex-3-yl}-l-(3-methoxy-quinoxalin-5-yl)-ethanol;
• rac-{ 1 α, 5 α,6α)-6-( { 3 -[2-hydroxy-2-(3 -methoxy-quinoxalin-5 -yl)-ethy 1] -3 -aza- bicyclo[3.1.0]hex-6-ylamino}-methyl)-4H-benzo[l,4]oxazin-3-one;
• rαc-ClαjSαjό^-ό-dS-p-hydroxy^-CS-methoxy-quinoxalin-S-y^-ethylJ-S-aza- bicyclo[3.1.0]hex-6-ylamino}-methyl)-4H-benzo[l,4]thiazin-3-one;
• rac-{ lα,5α,6α)-6-({3- [2-hydroxy-2-(3 -methoxy-quinoxalin-5 -y l)-ethyl] -3 -aza- bicyclo [3.1.0]hex-6-y lamino } -methyl)-4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one .
According to a second variant of the invention, the spacer M of the compounds of formula I, ICE, Ip2, ICEP2 or Ipiwill be the spacer M2.
Preferred compounds of formula I wherein M is M" are those wherein at least one of the following further characteristics is present:
• A3 representing OCH2, NHCO, CH2CH2, CH=CH, COCH2, CH(OH)CH2 or CH2CH(OH), or also, provided U is N, CH(OH)CH(OH);
«$» A4 representing CH2 or CO, or also, provided D is a non-annelated aryl or heteroaryl group, CH2CH=CH or CH2CONH;
<♦ R2 representing hydrogen, alkyl or hydroxyalkyl; <* R5 representing hydrogen, alkyl or hydroxyethyl.
More preferred compounds of formula I wherein M is M2 are those wherein at least one of the following further characteristics is present:
<* A3 representing NHCO, CH2CH2, CH=CH, CH(OH)CH2 or CH2CH(OH), or also, provided U is N, CH(OH)CH(OH);
❖ A4 representing CH2 or CO, or also, provided D is a non-annelated aryl or heteroaryl group, CH2CH=CH or CH2CONH;
❖ R2 representing hydrogen or hydroxyalkyl (and preferably hydrogen or hydroxyethyl); ♦♦♦ R3 and R4 each independently representing hydrogen or hydroxy; ❖ R5 representing hydrogen or hydroxyethyl;
♦♦♦ the dotted line of M2 representing a single bond.
Particularly preferred compounds of formula I wherein M is M2 are those wherein at least one of the following further characteristics is present:
❖ A3 representing CH(OH)CH2 or CH2CH(OH), or also, provided U is N, CH(OH)CH(OH); ❖ A4 representing CH2 or CO;
❖ R2 representing hydrogen;
♦♦♦ each of R3 and R4 representing hydrogen;
❖ R5 representing hydrogen;
❖ the dotted line of M2 representing a single bond.
Besides, among the compounds of formula I wherein M is M2, those wherein the substituents A3 and N(R5)-A4 have the trans stereochemistry are preferred (in particular when each of R2, R3 and R4 is hydrogen).
With regard to the spacer M2, its stereochemistry will preferably be the following (called M21 hereafter):
Figure imgf000031_0001
In particular, when one of R2, R3 and R4 is not hydrogen, the stereochemistry of M2 will preferably be the following (called M211 hereafter):
Figure imgf000032_0001
Preferred spacers M2 are the following:
Figure imgf000032_0002
Also preferred are the following spacers M2:
Figure imgf000032_0003
Figure imgf000033_0001
Other preferred spacers M2 are the spacers M221, M222, M223, M224 and M225 represented below:
-
Figure imgf000033_0002
and in particular the spacers M ■2215
Figure imgf000033_0003
a, nd M /f2"23.
Preferred compounds of formula I having the spacer M2 are the following: • (2,3-dihydro-benzo[l,4]dioxin-6-ylrnethyl)-[(3i?s,6iS)-6-(6-rnethoxy-quinolin- 4-yloxymethyl)-3,6-dihydro-2H-pyran-3-yl]-amine;
• (2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-[(3Λ=>65)-6-(6-methoxy-quinolin- 4-yloxymethyl)-tetrahydro-pyran-3-yl]-amine;
• (2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-ylmetliyl)-[(3i?,65)-6-(6-methoxy-quino>lin- 4-yloxymethyl)-tetrahydro-pyran-3 -yl] -amine ;
• 6-{[(3i?,65)-6-(6-methoxy-quinolin-4-yloxymettaLyl)-tetrahydro-pyran-3-ylamino]- methyl} -4H-benzo [1,4] oxazin-3 -one ;
• (2,3-dihydro-benzo [ 1 ,4]dioxin-6-ylmethyl)-[(3i?36<S)-6-(6-methoxy-[ 1 , 5]naphthyridin- 4-yloxymethyl)-tetrahydro-pyran-3-yl]-amine; • 6-{[(3i?,6/S)-6-(6-methoxy-[l,5]naphthyridin-4->^loxymethyl)-tetrahydro-pyran- 3 -y lamino] -methyl } -4H-benzo [1,4] oxazin-3 -one ; • 6-{[(3i?,65)-6-(6-methoxy-quinolin-4-yloxymethyl)-tetrahydro-pyran-3-ylamino]- methyl}-4H-benzo[l,4]thiazin-3-one;
• 6-{[(3R,65)-6-(6-methoxy-[l,5]naphthyridin-4-yloxymethyl)-tetrahydro-pyran- 3 -y lamino] -methyl } -4H-benzo [ 1 ,4]thiazin-3 -one; • 6-{[(3i?,65)-6-(6-methoxy-[l,5]naphthyridin-4-yloxymethyl)-tetrahydro-pyran- 3-ylamino]-methyl}-4H-pyrido[3,2-έ][l,4]thiazin-3-one;
• [(3R, 65)-6-(6-methoxy- [ 1 , 5]naphthyridin-4-yloxymethyl)-tetrahy dro-pyran-3 -y 1] - (3-phenyl-allyl)-amine;
• benzofuran-2-ylmethyl-[(3i?,61S)-6-(6-methoxy-[l,5]naphthyriciin-4-yloxymethyl)- tetrahydro-pyran-3-yl]-amine;
• (25',5i?)-5-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino] -tetrahydro-pyran- 2-carboxylic acid (2-methyl-quinolin-8-yl)-amide;
• S-IS-CCS-oxo-S^-dihydro^H-pyrido^^-όltl^lthiazin-ό-ylmethy^-aminol-tetrahydro- pyran-2-ylmethoxy}-quinoline-2-carbonitrile; • (25r,5i?)-5-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino] -tetrahydro-pyran- 2-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide;
• (2iSf,5i?)-5-[(2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-tetrahydro-pyran- 2-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide;
• (25r,5i?)5-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-έ][l,4]thiazin-6-ylmethyl)-amino]- tetrahydro-pyran-2-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide;
• (25r,5/?)-5-[(2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-ylmethy"l)-amino]-tetrahydro-pyran- 2-carboxylic acid (2-cyano-quinolin-8-yl)-amide;
• (25f,5i?)-5-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino] -tetrahydro-pyran- 2-carboxylic acid (2-cyano-quinolin-8-yl)-amide; • (25',5i?)-5-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-ό][l,4]thiazin-S-ylmethyl)-amino]- tetrahydro-pyran-2-carboxylic acid (2-cyano-quinolin-8-yl)-amide;
• (25',5i?)-5-[(3-oxo-3,4-dihydro-2H-benzo[l,4]thiazin-6-ylmettιyl)-amino]-tetrahydro- pyran-2-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide;
• (26',5i?)-5-[(2,3-dihydro-[l,4]dioxino[2,3-έ]pyridin-6-ylmethχl)-aniino]-tetrahydro-pyran- 2-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide;
• 2-[(2i?,3i?,6,S)-3-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-6-(6-methoxy- quinolin-4-yloxymethyl)-tetrahydro-pyran-2-yl]-ethanol; • 6-{[(2i?,3i?,6lS)-2-(2-hydroxy-ethyl)-6-(6-methoxy-quinolin-4-yloxymethyl)-tetrahydro- pyran-3-ylamino]-methyl} -4H-benzo[ 1 ,4]thiazin-3-one;
• 6-{[(2/?,3i?,6.S)-2-(2-hydroxy-ethyl)-6-(6-methoxy-quinolin-4-yloxymethyl)-tetrahydro- pyran-3 -y lamino] -methyl} -4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one; • 6-{[(3i?,65)-6-(3-methoxy-quinolin-5-yloxymethyl)-tetrahydro-pyran-3-ylamino]- methyl}-4H-pyrido[3,2-έ][l,4]thiazin-3-one;
• 6-{[(3/?,6iS)-6-(3-methoxy-quinolin-5-yloxymethyl)-tetrahydro-pyran-3-ylamino]- methy 1 } -4H-benzo [ 1 ,4]thiazin-3 -one;
• benzo[l,3]dioxol-5-ylmethyl-[(3i?,6.S)-6-(3-methoxy-quinolin-5-yloxymethyl)-tetrahydro- pyran-3-yl]-amine;
• (2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-[(3i?,6S)-6-(3-methoxy-quinolin- 5-yloxymethyl)-tetrahydro-pyran-3-yl]-amine;
• 6-{[(3i?,65)-6-(3-methoxy-quinolin-5-yloxymethyl)-tetrahydro-pyran-3-ylamino]- methy 1 } -4H-benzo [1,4] oxazin-3 -one ; • (2,3-dihydro-[l,4]dioxino[2,3-ό]pyridin-6-ylmethyl)-[(3i?,6ιS)-6-(3-methoxy-quinolin- 5 -yloxymethyl)-tetrahydro-pyran-3 -yl] -amine;
• (2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)-[(3i?,65}-6-(3-methoxy-quinolin- 5 -y loxymethyl)-tetrahydro-pyran-3 -yl] -amine;
• 7-fluoro-6-{[(3i?,61S)-6-(3-methoxy-quinolin-5-yloxymethyl)-tetrahydro-pyran- 3-ylamino]-methyl}-4H-benzo[l,4]thiazin-3-one;
• benzofuran-2-ylmethyl-[(3i?,65)-6-(3-methoxy-quinolin-5-yloxymethyl)-tetrahydro- pyran-3 -y 1] -amine;
• [(3R, 6S)-6-(3 -methoxy-quinolin-5 -y loxymethyl)-tetrahydro-pyran-3 -yl] -(3 -pheny 1-ally I)- amine; • benzo[l,2,5]thiadiazol-5-ylmethyl-[(3i?,65)-6-(3-methoxy-qumolm-5-yloxymethyl)- tetrahydro-pyran-3 -yl] -amine;
• (3i?,6<S)-heptyl-[6-(3-methoxy-quinolin-5-yloxymethyl)-tetrahydro-pyran-3-yl]-amine;
• 2-[(3i?,65)-6-(3-methoxy-quinolin-5-yloxymethyl)-tetrahydro-pyran-3-ylamino]- 7V-thiazol-2-yl-acetamide; • (2,3 -dihydro-benzo [1,4] dioxin-6-ylmethyl)- [(3R,6S)-6-(3 -methoxy-quinoxalin- 5-yloxymethyl)-tetrahydro-pyran-3-yl]-amine;
• 6- { [(3R,6S)-6-(3 -methoxy-quinoxalin-5 -yloxymethyl)-tetrahydro-pyran-3 -ylamino] - methyl}-4H-pyrido[3,2-Z>][l,4]thiazin-3-one; • (2,3-dihydro-benzo[ 1 ,4]dioxin-6-ylmethyl)-[(3i?,65)-6-(6-trifluoromethoxy-quinolin- 4-yloxymethyl)-tetrahydro-pyran-3-yl]-amine;
• 6-{[(3i?,65)-6-(6-trifluoromethoxy-quinolin-4-yloxymethyl)-tetrahydro-pyran-3-ylamino]- methyl}-4H-pyrido[3,2-b][l,4]thiazin-3-one; • 8-{(25',5i?)-5-[(3-oxo-3,4-dihydro-2H-benzo[l,4]thiazin-6-ylmethyl)-amino]-tetrahydro- pyran-2-ylmethoxy}-quinoline-2-carbonitrile;
• 6-{[(3i?,6iS)-6-(6-methoxy-quinolin-4-yloxymethyl)-tetrahydro-pyran-3-ylamino]- methyl}-4H-pyrido[3,2-δ][l,4]thiazin-3-one;
• 6-{[(3i?,65)-6-(2-methoxy-quinolin-8-yloxymethyl)-tetrahydro-pyran-3-ylamino]- methyl } -4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one;
• 6-{[(3i?,65)-6-(6-methoxy-quinazolin-4-yloxymethyl)-tetrahydro-pyran-3-ylamino]- methyl}-4H-pyrido[3,2-έ][l,4]thiazin-3-one;
• 6- { [(3i?,6S)-6-(8-fluoro-6-methoxy-quinolin-4-yloxymethyl)-tetrahydro-pyran- 3 -ylamino] -methyl } -4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one; • 6-{[(3i?,6.S)-6-(8-fluoro-6-methoxy-quinolin-4-yloxymethyl)-tetrahydro-pyran- 3 -ylamino] -methyl } -4H-pyrido [3,2-b] [ 1 ,4] oxazin-3 -one;
• 6-{(3i?,65)-[6-(6-methoxy-quinazolin-4-yloxymethyl)-3,6-dihydro-2H-pyran-3-ylamino]- methyl } -4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one;
• 6-{[(3i?,65)-6-(6-difluoromethoxy-quinolin-4-yloxymethyl)-tetrahydro-pyran-3-ylamino]- methyl} -4H-pyrido[3,2-ό] [l,4]thiazin-3-one;
• 6- { (3R,6S)- [6-(3 -methoxy-quinoxalin-5 -yloxymethyl)-tetrahydro-pyran-3 -ylamino] - methyl}-4H-pyrido[3,2-έ][l,4]oxazin-3-one;
• 6-{(3i?,6,S)-[6-(3-methoxy-quinoxalin-5-yloxymethyl)-tetrahydro-pyran-3-ylamino]- methyl}-4H-benzo[l,4]oxazin-3-one; • 6-{(3i?,65)-[6-(3-methoxy-quinoxalin-5-yloxymethyl)-tetrahydro-pyran-3-ylamino]- methyl } -4H-benzo [ 1 ,4]thiazin-3 -one;
• 3-oxo-3,4-dihydro-2H-pyrido[3,2-δ][l,4]thiazine-6-carboxylic acid (3i?J6.S)-[6-(3-methoxy-quinoxalin-5-yloxymethyl)-tetrahydro-pyran-3-yl]-amide;
• 3-oxo-3,4-dihydro-2H-pyrido[3,2-ό][l,4]thiazine-6-carboxylic acid (3i?,65)-[6-(2-methoxy-quinolin-8-yloxymethyl)-tetrahydro-pyran-3-yl]-amide;
• 4-{(2,S',5i?)-5-[(2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-tetrahydro- pyran-2-ylmethoxy}-quinoline-6-carbonitrile; • 4-{(25',5i?)-5-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-tetrahydro-pyran- 2-ylmethoxy}-quinoline-6-carbonitrile;
• 4-{(25',5i?)-5-[(3-oxo-3,4-dihydro-2H-benzo[l,4]thiazin-6-ylmethyl)-amino]-tetrahydro- pyran-2-ylmethoxy}-quinoline-6-carbonitrile; • 3-oxo-3,4-dihydro-2H-pyrido[3,2-ό][l,4]thiazine-6-carboxylic acid QR, 6S)- £6-(6-cyano- quinolin-4-yloxymethyl)-tetrahydro-pyran-3-yl]-amide;
• 3-0X0-3 ,4-dihydro-2H-pyrido [3 ,2-b] [ 1 ,4]thiazine-6-carboxylic acid (4JR,75)-[4-(6-methoxy-quinolin-4-yloxymethyl)-c/5-(4iiS',5itS)-2J2-dimethyL-tetrahydro- [1,3] dioxolo [4, 5 -c]pyran-7-yl] -amide; • 6-{(4i?,75)-[4-(6-methoxy-quinolin-4-yloxymethyl)-(4JS',55)-2,2-dimethyl-tetrahydro- [l,3]dioxolo[4,5-c]pyran-7-ylamino]-methyl}-4H-pyrido[3,2-ό][l,4]thiazin-3-one;
• 6-{(4JR,75)-([4-(6-methoxy-quinolin-4-yloxymethyl)-(4JR,5i?)-2,2-dimethyl-tetrahydro- [l,3]dioxolo[4,5-c]pyran-7-ylamino]-methyl}-4H-pyrido[3,2-δ][l,4]thiazin-3-one;
• 6-{(3>S',4JS',5JSr,6i?)-[4,5-dihydroxy-6-(6-methoxy-quinolin-4-yloxymethyl)-tetrahydro- pyran-3 -y lamino] -methyl} -4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one ;
• 6-{(3ιSl,4i?,5i?,6i?)-[4,5-dihydroxy-6-(6-methoxy-quinolin-4-yloxymethyl)-tetrahydro- pyran-3-ylamino]-methyl}-4H-pyrido[3,2-έ][l,4]thiazin-3-one;
• 8-{(25',5i?)-5-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-Z>][l,4]oxazin-6-ylmethyl)-amino]- tetrahydro-pyran-2-ylmethoxy}-quinoline-2-carbonitrile; • 6-{[(35',6i?)-6-(6-methoxy-quinazolin-4-yloxymethyl)-tetrahydro-pyran-3-ylamino]- methyl} -4H-pyrido[3 ,2-b] [ 1 ,4]thiazin-3-one;
• (2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-[(35',6i?)-6-(3-methoxy-quinolin- 5 -yloxymethyl)-tetrahydro-pyran-3 -yl] -amine;
• 6-{[(35',6i?)-6-(3-methoxy-quinolin-5-yloxymethyl)-tetrahydro-pyran-3-ylamino]- methyl}-4H-pyrido[3,2-δ][l,4]oxazin-3-one;
• 6-{[(3iSr,6i?)-6-(3-methoxy-quinolin-5-yloxymethyl)-tetrahydro-pyran-3-ylarnino]- methyl}-4H-pyrido[3,2-Z>][l,4]thiazin-3-one;
• 6-({(3i?,6Λ)-6-[2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran- 3 -y lamino } -methyl)-4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one; • 3-oxo-3,4-dihydro-2H-pyrido[3,2-έ][l,4]thiazine-6-carboxylic acid
{(3i?,6i?)-6-[2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}-amide;
• 6-({(3i?,6i?)-(6-[2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran- 3 -y lamino } -methyl)-4H-pyrido [3 ,2-b] [ 1 ,4]oxazin-3 -one; • 6-((3i?,6i?)-{6-[2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran- 3-ylamino} -methyl)-4H-benzo[ 1 ,4]thiazin-3-one;
• 6-({(3i?,6i?)-6-[2-(6-methoxy-quinazolin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}- methy l)-4H-pyrido [3 ,2-6] [ 1 ,4]thiazin-3 -one; • 6-((3i?, 6R)- { 6-[2-(6-methoxy-quinazolin-4-yl)-ethyl] -tetrahydro-pyran-3 -ylamino } - methyl)-4H-benzo[l,4]thiazin-3-one;
• 6-( { (3R, 6S)-6-E- [2-(3 -methoxy-quinolin-5 -yl)-vinyl] -tetrahydro-pyran-3 -ylamino } - methyl)-4H-pyrido[3,2-Z>][l,4]thiazin-3-one;
• 6-({(3i?,6i?)-6-[2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)- 4H-pyrido[3 ,2-b] [ 1 ,4]thiazin-3 -one;
• 3-0X0-3 ,4-dihydro-2H-pyrido[3,2-έ][l,4]thiazine-6-carboxylic acid (3i?,6i?)-{6-[2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro-pyran-3-yl}-amide;
• 6-((3i?,6i?)-{6-[2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)- 4H-pyrido[3,2-έ][l,4]oxazin-3-one; • 6-((3i?,6i?)-{6-[2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)- 4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one;
• (3i?,6i?)-6-({6-[2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)- 4H-benzo[ 1 ,4]thiazin-3 -one;
• 6-((3i?,6i?)-{6-[2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)- 4H-benzo[l,4]oxazin-3-one;
• 6-({3i?,6JS)-6-[(li?,2JR)-l,2-dihydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro- pyran-3 -ylamino } -methyl)-4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3-one;
• 3 -oxo-3 ,4-dihydro-2H-pyrido [3 ,2-b] [ 1 ,4]thiazine-6-carboxylic acid {(3i?,6S)-6-[(li?,2i?)-l,2-dihydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro-pyran- 3-yl} -amide;
• 6-({(3i?,61S)-6-[(li?,2i?)-l,2-dihydroxy-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]- tetrahydro-pyran-3 -ylamino} -methyl)-4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one;
• 3 -oxo-3 ,4-dihydro-2H-pyrido [3 ,2-b] [ 1 ,4]thiazine-6-carboxylic acid {(3i?,65)-6-[(li?,2/?)-l,2-dihydroxy-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]- tetrahydro-pyran-3-yl} -amide;
• (3i?,6,S)-6-({6-[(lJR,2i?)-l,2-dihydroxy-2-(2-methoxy-quinolin-8-yl)-ethyl]-tetrahydro- pyran-3 -ylamino } -methyl)-4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one; • 3-oxo-3,4-dihydro-2H-pyrido[3,2-δ][l,4]thiazine-6-carboxylic acid {(3i?,6»S)-6-[(li?,2i?)-l,2-dihydroxy-2-(2-methoxy-quinolin-8-yl)-ethyl]-tetrahydro-p>^ran- 3-yl} -amide;
• (3i?,65)-6-({6-[(li?,2i?)-l,2-dihydroxy-2-(3-methoxy-quinoxalin-5-yl)-ethyl]-tetrahyciro- pyran-3-ylamino}-methyl)-4H-pyrido[3,2-έ][l,4]thiazin-3~one;
• 6-( { (3R,6S)-6-[( IS,2S)~ 1 ,2-dihydroxy-2-(6-methoxy-[ 1 ,5]naphthyridin-4-yl)-ethyl] - tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-ό][l,4]thiazin-3-one;
• 3-oxo-3,4-dihydro-2H-pyrido[3,2-έ][l,4]thiazine-6-carboxylic acid (3i?,65)-{6-[(li?,2i?)-l,2-dihydroxy-2-(3-methoxy-quinoxalin-5-yl)-ethyl] tetrahydro- pyran-3-yl} -amide;
• 6-( { (3R,6S)-6-[( 1 R,2R)- 1 ,2-dihydroxy-2-(3 -methoxy-quinoxalin-5-yl)ethyl] -tetrahydaro- pyran-3 -ylamino} -methyl)-4H-pyrido [3 ,2-b] [ 1 ,4]oxazin-3-one;
• 8-((lJR,2i?)-l,2-dihydroxy-2-{(21S',5i?)-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-Z>][l,4]thia3in- 6-ylmethyl)-amino]-tetrahydro-pyran-2-yl}-ethyl)-quinoline-2-carbonitrile; • 3-oxo-3,4-dihydro-2H-pyrido[3,2-Z)][l,4]thiazine-6-carboxylic acid
{(3i?,61S)-6-[(li?,2i?)-2-(2-cyano-quinolin-8-yl)-l,2-dihydroxy-ethyl]-tetrahydro-pyra3i- 3-yl}-amide;
• 8-((li?,2i?)-l,2-dihydroxy-2-{(25,5JR)-5-[(3-oxo-3,4-dihydro- 2H-pyrido[3,2-έ][l,4]oxazin-6-ylmethyl)-amino]-tetrahydro-pyran-2-yl}-ethyl)- quinoline-2-carbonitrile;
• 6-((3i?,65)-{6-[trαrø-(lΛS',2iiS)-l,2-dihydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]- tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-έ][l,4]thiazin-3-one;
• 6-((3i?,6,S)-{6-[(li?,2i?)-l,2-diliydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro- pyran-3-ylamino}-methyl)-4H-pyrido[3,2-ό][l,4]thiazin-3-one; • 6-((3i?,65)-{6-[(15',2i?)-l,2-dihydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydrc>- pyran-3 -ylamino } -methy l)-4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one;
• (li?5)-l-{(2>S',5i?)-5-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-tetrahydro-pyran- 2-yl}-2-(6-methoxy-quinolin-4-yl)-ethanol;
• 6-({(3i?,65)-6-[(li?5)-l-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyraJi- 3 -ylamino } -methy l)-4H-pyrido [ 1 ,4]thiazin-3 -one;
• 3-oxo-3,4-dihydro-2H-pyrido[3,2-έ][l,4]thiazine-6-carboxylic acid {(3i?,65)-6-[(li?5)-l-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}- amide; • 6-({(3i?,65)-6-[(15)-l-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran- 3-ylamino} -methyl)-4iJ-pyrido[3,2-Z>] [ 1 ,4]thiazin-3-one;
• 6-((3i?, 65)-{6-[l-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran- 3 -ylamino } -methyl)-4i/-py rido [3 ,2-b] [ 1 ,4] oxazin-3 -one; • 7-((3i?,65)-{6-[(l,S)-l-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran- 3 -ylamino } -methyl)- lH-pyrido [3 ,4-b] [ 1 ,4] oxazin-2-one;
• 3-oxo-3,4-dihydro-2H-pyrido[3,2-Z>][l,4]thiazine-6-carboxylic acid
(3R,6S)-{ 6-[( 1 S)- 1 -hydroxy -2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3 -yl} - amide; • 6-({(3i?,65)-6-[(li?)-l-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran- 3-ylamino} -methyl)-4H-pyrido[ 1 ,4]thiazin-3-one;
• 6-({(3i?,65)-6-[(li?5)-l-hydroxy-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro- pyran-3-ylamino} -methyl)-4H-pyrido[3,2-έ] [ 1 ,4]thiazin-3-one;
• S-oxo-S^-dihydro^H-pyrido^^-έlCl^lthiazine-β-carboxylic acid (3i?,65)- {6-[(7<S)-l-hydroxy-2-(6-m.ethoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}- amide;
• (3i?,6JS)-6-({6-[(15)-l-hydroxy-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro- pyran-3 -ylamino } -methyl)-4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one;
• 6-((3R, 6.S)-{6-[(15)-l-hydroxy-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro- pyran-3 -ylamino} -methyl)-4H-pyrido [3 ,2-b] [ 1 ,4]oxazin-3 -one;
• (S^β^-Cβ-dβ-CCl^^^-l.S-dihydroxy^-Cό-methoxy-tl^lnaphthyridin^-yO-ethyl]- tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-b][l,4]thiazin-3-one;
• 6-((3i?,6,S)-{6-[(15)-l-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro-pyran- 3 -ylamino } -methy l)-4H-py rido [3 ,2-b] [ 1 ,4]oxazin-3 -one; • 6-((3R, ό^-lβ-CCl^-l-hydroxy^-CS-methoxy-quinolin-S-y^-ethyll-tetrahydro-pyran- 3 -ylamino } -methyl)-4ϋT-py rido [3 ,2-b] [ 1 ,4]thiazin-3 -one;
• (i5)-l-((2.S',5JR)-5-heptylainino-tetrahydro-pyran-2-yl)-2-(6-methoxy-quinolin-4-yl)- ethanol;
• 6-((37?,65)-{6-[(2i?)-2-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro-pyran- 3-ylamino}-methyl)-4H-pyrido[3,2-Z)][l,4]thiazin-3-one;
• 6-((3i?,65)-{6-[(25)-2-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro-pyran- 3-ylamino}-methyl)-4H-pyrido[3,2-έ][l,4]thiazin-3-one; • S-oxo-S^-dihydro^H-pyridoP^-^tl^thiazme-ό-carboxylic acid (3R,6S)-{6-[(2RS)-2- hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro-pyran-3-yl} -amide;
• 6-((3i?,65)-{6-frα«5-[2-(3-fluoro-6-methoxy-[l,5]naphthyridin-4-yl)-vinyl]-tetrahydro- pyran-3-ylamino}-methyl)-4J!y-pyrido[3,2-ό][l,4]thiazin-3-one; • ό-CS^ό^-lό-tCl^Z^^-CS-fluoro-ό-methoxy-tljSlnaphthyridin^-yO-l^-dihydroxy- ethyl] -tetrahydro-pyran-3 -y lamino } -methyl)-4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one;
• 6-({6-[2-(8-fluoro-6-methoxy-quinolin-4-yl)-vinyl]-tetrahydro-pyran-3-ylamino}- methyl)-4H-pyrido[3,2-&][l,4]thiazin-3-one;
• 6-((3i?, 6iS)-{6-[2-(8-fluoro-6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran- 3 -ylamino} -methyl)-4H-pyrido [3,2-Z>] [ 1 ,4]thiazin-3 -one;
• 6-((3i?,65)-{6-[(li?,2i?)-2-(8-fluoro-6-methoxy-quinolin-4-yl)-l,2-dihydroxy-ethyl]- tetrahydro-pyran-3 -ylamino }- -methyl)-4H-pyrido[3 ,2-b] [ 1 ,4]thiazin-3 -one;
• 6-((3i?,65)-{6-[(li?,2i?)-2-(8-fluoro-6-methoxy-quinolin-4-yl)-l,2-dihydroxy-ethyl]- tetrahydro-pyran-3 -ylamino }- -methy l)-4H-pyrido [3 ,2-b] [ 1 ,4]oxazin-3 -one ; • 6-(3i?,65)-{6-[(li?,2i?)-2-(3-fluoro-6-methoxy-[l,5]naphthyridin.-4-yl)-l,2-dihydroxy- ethyl] -tetrahydro-pyran-3 -ylamino } -methy l)-4H-pyrido [3 ,2-b] [ 1 ,4] oxazin-3 -one;
• (35',6i?)-6-({6-[(l1Sr,25)-l,2-dihydroxy-2-(6-methoxy-[l,5]naphth.yridin-4-yl)-ethyl]- tetrahydro-pyran-3-ylamino)--methyl)-4H-pyrido[3,2-έ][l,4]oxazin-3-one;
• (35r,6i?)-(6-({6-[(li?,2JR)-l,2-dihydroxy-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]- tetrahydro-pyran-3 -ylamino }- -methy l)-4H-pyrido [3 ,2-b] [ 1 ,4]thia~zin-3 -one;
• (3^,6JR)-6-({6-[(li?,2i?)-l,2-dihydroxy-2-(6-methoxy-[l,5]naphtliyridin-4-yl)-ethyl]- tetrahydro-pyran-3-ylamino)--methyl)-4H-pyrido[3,2-Z>][l,4]oxazin-3-one;
• (3θ',6i?)-6-({(6-[(li?)-l-hydroxy-2-(6-methoxy-[l55]naphthyridin-4-yl)-ethyl]-tetrahydro- pyran-3-ylamino}-methyl)-4JH-pyrido[3,2-έ][l,4]thiazin-3-one; • (35',6i?)-6-({6-[(li?)-l-hydroxy-2-(6-methoxy-[l,5]naphthyridiiι-4-yl)-ethyl]-tetrahydro- pyran-3 -ylamino } -methyl)-4--H-pyrido[3 ,2-b] [ 1 ,4]oxazin-3-one;
• (3»S',6JR)-6-({(6-[(15)-l-hydroxy-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro- pyran-3-ylamino}-methyl)-4_H-pyrido[3,2-Z)][l,4]thiazin-3-one;
• 6-({(3i?,65)-6-[(15',21S)-l,2-dihydroxy-2-(3-methoxy-quinoxalin-5-yl)-ethyl]-tetrahydro- pyran-3 -ylamino } -methy l)-4iϊ-pyrido [3,2-Z)][1 ,4]thiazin-3 -one;
• 6-({ (3S,6R)-6-[( 1R,2R)- 1 ,2-dihydroxy-2-(3 -methoxy-quinoxaliix-5 -yl)-ethyl] -tetrahydro- pyran-3-ylamino}-methyl)-4--H-pyrido[3,2-έ][l,4]thiazin-3-one; • 6-({(3i?,61S)-6-[(15)-2-(8-fluoro-6-methoxy-quinolin-4-yl)-l-hydroxy-ethyl]-tetrahydro- pyran-3 -ylamino } -methyl)-4H-pyrido[3 ,2-b] [ 1 ,4]thiazin-3 -one;
• 6- { [6-(6-fluoro-quinolin~4-y loxymethyl)-tetrah>^dro-pyran-3 -ylamino] -methyl } - 4H-pyrido[3,2-Z>][l,4]thiazin-3-one; • 6-{[(3R,6S)-6-(6, 8-difluoro-quinolin-4-yloxymethyl)-tetrahydro-pyran-3 -ylamino] - methyl}-4H-pyrido[3,2-ό][l,4]thiazin-3-one;
• 3-oxo-3,4-dihydro-2H-pyrido[3,2-ό][l,4]oxazinLe-6-carboxylic acid (3i?,61S)-{6-[(15)-l-hydroxy-2-(3-methoxy-qumolin-5-yl)-ethyl]-tetrahydro-pyran-3-yl}- amide; • (15)-l-{(2,S',5i?)-5-trαrø-[3-(2,5-difluoro-phenyl)-allylamino]-tetrahydro-pyran-2->^l}- 2-(6-methoxy-quinolin-4-yl)-ethanol;
• 6-({(3i?,65)-6-[(2ΛS)-2-hydroxy-2-(6-methoxy- [l,5]naphthyridin-4-yl)-ethyl]-tetra,hydro- pyran-3 -ylamino } -methyl)-4H-pyrido [3 ,2-h] [ 1 , «4]thiazin~3 -one ;
• 3-oxo-3,4-dihydro-2H-pyrido[3,2-ό][l,4]thiazirαe-6-carboxylic acid {(3i?,6,S)-6-[(2ΛS)-2-liydroxy-2-(6-methoxy-[l, 5]naphthyridin-4-yl)-ethyl]-tetrahydro- pyran-3 -y 1 } -amide ;
• 2-{(2ιS',5i?)-5-[ϊrα«5-3-(2,5-difluoro-phenyl)-all^lamino]-tetrahydro-pyran-2-yl}- l-(6-methoxy-[l,5]naphthyridin-4-yl)-ethanol;
• trαrø-3-(2,5-difluoro-phenyl)-N-{(3i?,61S)-6-[(2J?1S)-2-hydroxy-2-(6-methoxy- [l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran_-3-yl}-acrylamide;
• trαm-3-(2,5-difluoro-phenyl)-Ν-{(3i?,61S)-6-[(lJ5)-l-hydroxy-2-(6-methoxy-quinolin- 4-yl)-ethyl]-tetrahydro-pyran-3-yl} -acrylamide z,
• (li?,25)-l-{(25',5/?)-5-[frα«5-3-(2,5-difluoro-plienyl)-allylamino]-tetrahydro-pyraα-2-yl}- 2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethane-l ,2-diol; • 3-oxo-3,4-dihydro-2H-pyrido[3,2-Z>][l,4]thiazine-6-carboxylic acid
{(3i?,65)-6-[(15',2JR)-2-(3-fluoro-6-methoxy-[l, 5]naphthyridin-4-yl)-l,2-dihydroxy-ethyl]- tetrahydro-pyran-3-yl}-amide;
• 3-oxo-3,4-dihydro-2H-pyrido[3,2-ό][l,4]oxazine-6-carboxylic acid {(3i?,65)-6-[(15',2i?)-2-(3-fluoro-6-methoxy-[U 5]naphth-yridin-4-yl)-l,2-dihydroxiy- ethyl]-tetrahydro-pyran-3-yl}amide;
• (3,4-dichloro-benzyl)-{6-[2-(8-fluoro-6-methos:y-quinolin-4-yl)-etliyl]-tetrahydro-pyran- 3-yl} -amine; • 3-oxo-3,4-dihydro-2H-pyrido [3 ,2-b] [ 1 ,4]thiazine-6-carboxylic acid ^R^^ό^-ό-^l.S'^^-l^-dihydroxy^-Cό-methoxy-Cl^lnaphthyπdin^-yO-ethyL]- 2-(2-hydroxy-ethyl)-tetrahydro-pyran-3-yl]-amide;
• 3 -oxo-3 ,4-dihydro-2H-pyrido[3 ,2-b] [ 1 ,4]thiazine-6-carboxylic acid (2JR,3i?,6i?)-{2-(2-hydroxy-ethyl)-6-[2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]- tetrahydro-pyran-3-yl} -amide;
• 6-((2i?,3i?,6i?)-{2-(2-hydroxy-ethyl)-6-[2-(6-methoxy-[l,5]naphthyridin-4-yl)-eth>^l]- tetrahydro-pyran-3 -ylamino} -methyl)-4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one;
• ^orø-3-(2,5-difluoro-phenyl)-N-{(2i?,3i?,6i?)-2-(2-hydroxy-ethyl)-6-[2-(6-methθ)C3'- [1 , 5]naphthyridin-4-yl)-ethyl] -tetrahydro-pyran-3 -yl} -acrylamide ;
• rrα«5-3-(2,5-difluoro-phenyl)-N-{(2i?,3i?,6i?)-6-[2-(6-methoxy-quinolin-4-yl)-ethτ-l]- tetrahydro-pyran-3-yl}-acrylamide;
• 6-({(3i?,65)-6-[(2i?)-2-(3-fluoro-6-methoxy-quinolin-4-yl)-2-hydroxy-ethyl]-tetrah-Lydro- pyran-3 -ylamino } -methyl)-4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one; • 6-({(3i?,65)-6-[(25)-2-(3-fluoro-6-methoxy-quinolin-4-yl)-2-hydroxy-ethyl]-tetrahLydro- pyran-3 -ylamino } -methy l)-4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one;
• N-(2,5-difluoro-phenyl)-2-{(3i?,6JR)-6-[2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrah>^dro- pyran-3-ylamino}-acetamide.
More preferably, the compounds of formula I having the spacer M2 will be selected from the first 134 compounds mentioned in the list hereabove (and even more preferably from, the first 24 compounds mentioned in the list hereabove).
In particular, the following compounds of formula I having the spacer M2 are preferred:
• (2ΛS)-{(25',5i?)-5-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-tetrahydro-pyran- 2-yl} - 1 -(6-methoxy-quinolin-4-yl)-ethanol; • (2ΛS)-2-{(25',5i?)-{5-[(2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]- tetrahydro-pyran-2-yl} - 1 -(6-methoxy-quinolin-4-yl)-ethanol;
• (2i?5)-2-{(2)S,5i?)-{5-[(2,3-dihydro-[l,4]dioxino[2,3-έ]pyridin-6-ylmethyl)-ammo]- tetrahydro-pyran-2-yl} - 1 -(6-methoxy-quinolin-4-yl)-ethanol;
• 6-({(3i?,65)-6-[(2i?5)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-p3'ran- 3-ylamino} -methyl)-4H-benzo[l,4]oxazin-3-one;
• 6-({(3i?,6.S}-6-[(2itS)-6-[2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran- 3 -ylamino } -methy l)-4H-benzo [ 1 ,4]thiazin-3 -one; • 6-({(3i?,65)-6-[(2i?5)- [2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran- 3-ylamino} -methyl)-4H-pyrido[3,2-b] [1 ,4]thiazin-3-one;
• (2ΛS)-{(25',5i?)-5-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-tetrahydro-pyran- 2-yl}-l-(3-methoxy-quinolin-5-yl)-ethanol; • (2ΛS)-2-{(25',5i?)-{5-[(2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)-aniino]- tetrahydro-pyran-2-yl}-l-(3-methoxy-quinolin-5-yl)-ethanol;
• (2ΛS)-2-{(25',5i?)-{5-[(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-6-ylmethyl)-amino]- tetrahydro-pyran-2-yl}-l-(3-methoxy-quinolin-5-yl)-ethanol;
• 6-({(3i?,65)-6-[(2ΛS)-2-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro-pyran- 3-ylamino} -methyl)-4H-benzo[l ,4]oxazin-3-one;
• 6-({(3i?,65)-6-[(2i?S)-6-[2-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro-pyran- 3-ylamino}-methyl)-4H-benzo[l,4]thiazin-3-one;
• 6-({(3i?,65)-6-[(2ΛS)-[2-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro-pyran- 3 -ylamino } -methy l)-4H-pyrido [3,2-Z?][l ,4]thiazin-3 -one; • (2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-{(3i?,65)-6-[2-(6-methoxy-quinolin-4-yl)- ethy 1] -tetrahy dro-pyran-3 -y 1 } -amine ;
• (2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)-{(3i?, 65)-6-[2-(6-niethoxy-quinolin- 4-yl)-ethyl]-tetrahydro-pyran-3-yl}-amine;
• (2,3-dihydro-[l,4]dioxino[2,3-δ]pyridin-6-ylmethyl)-{(3i?,65)-6-[2-(6-methoxy-quinolin- 4-yl)-ethyl]-tetrahydro-pyran-3-yl} -amine;
• 6-({(3i?,65)-6-[2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)- 4H-benzo[l,4]oxazin-3-one;
• 6-( { (3i?,65)-6-[2-(6-methoxy-quinolin-4-yl)-ethyl] -tetrahy dro-pyran-3 -ylamino } -methy I)- 4H-benzo [ 1 ,4]thiazin-3-one; • 6-({(3i?,65)-6-[2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino} -methyl)- 4H-pyrido[3,2-ό][l,4]thiazin-3-one;
• (2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-{(3i?,65)-6-[2-(3-methoxy-quinolin-5-yl)- ethyl]-tetrahydro-pyran-3-yl}-amine;
• (2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)-{(3i?,65)-6-[2-(3-methoxy-quinolin- 5~yl)-ethyl]-tetrahydro-pyran-3-yl}-amine;
• (2,3-dihydro-[l,4]dioxino[2,3-ό]pyridin-6-ylmethyl)-{(3i?,6,S)-6-[2-(3-methoxy-quinolin- 5-yl)-ethyl]-tetrahydro-pyran-3-yl}-amine; • 6-({(3i?,6iS)-6-[2-(3-methoxy-quinolyin-5-yl)-ethyl]-tetrahydro-pyran-3-ylamino}- methyl)-4H-benzo[l,4]oxazin-3-one;
• 6-({(3i?, 65)-6-[2-(3-methoxy-quinolyin-5-yl)-ethyl]-tetrahydro-pyran-3-ylamino}- methyl)-4H-benzo[ 1 ,4]thiazin-3-one; • 6-({(3R, 65)-6-[2-(3-methoxy-quinolyin-5-yl)-ethyl]-tetrahydro-pyran-3-ylamino}- methyl)-4H-pyrido[3,2-Z>][l,4]thiazin-3-one;
• (2- { (IS, 5R)-5 -[(2,3 -dihydro-benzo [1,4] dioxin-6-ylmethy l)-amino] -tetrahydro-pyran- 2-yl} - 1 -(6-methoxy-quinolin-4-yl)-ethane- 1 ,2-diol;
• 2-{(2S, 5i?)-{5-[(2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-tetrahydro- pyran-2-yl} - 1 -(6-methoxy-quinolin-4-yl)-ethane- 1 ,2-diol;
• 2-{(25',5i?)-{5-[(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-6-ylmethyl)-amino]-tetrahydro- pyran-2-yl}-l-(6-methoxy-quinolin-4-yl)-ethane-l,2-diol;
• 6-({(3i?,6iS)-6-[l,2-dihydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran- 3-ylamino}-methyl)-4H-benzo[l,4]oxazin-3-one; • 6-({(3i?,65)-6-[l,2-dihydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran- 3 -ylamino } -methy l)-4H-benzo [ 1 ,4]thiazin-3 -one;
• 6-({(3i?,65)-6-[l,2-dihydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran- 3 -ylamino } -methy l)-4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one;
• 2-{(25',5i?)-5-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-tetrahydro-pyran-2-yl}- l-(3-methoxy-quinolin-5-yl)-ethane-l,2-diol;
• 2-{(25',5i?)-{5-[(2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-tetrahydro- pyran-2-yl} - 1 -(3-methoxy-quinolin-5-yl)-ethane- 1,2-diol;
• 2-{(25',5i?)-{5-[(2,3-dihydro-[l,4]dioxino[2,3-&]pyridin-6-ylmethyl)-amino]-tetrahydro- pyran-2-yl } - 1 -(3 -methoxy-quinolin-5-yl)-ethane- 1 ,2-diol; • 6-({(3i?,65)-6-[l,2-dihydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro-pyran- 3 -ylamino } -methy l)-4H-benzo [1,4] oxazin-3 -one;
• 6-({(3i?,65)-6-[l,2-dihydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro-pyran- 3 -ylamino } -methy l)-4H-benzo [ 1 ,4]thiazin-3 -one;
• 6-({(3R,6S)-6-[l ,2-dihydroxy-2-(3 -methoxy-quinolin-5 -yl)-ethy 1] -tetrahy dro-pyran- 3-ylamino}-methyl)-4H-pyrido[3,2-Z)][l,4]thiazin-3-one;
• 6-({(3i?,65)-6-[l,2-dihydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro-pyran- 3 -ylamino } -methy l)-4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one; • (2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-{(3i?,65)-£'-6-[2-(6-methoxy-quinolin-4-yl)- vinyl]-tetrahydro-pyran-3-yl}-amine;
• (2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-ylniethyl)-{(3i?,65)-£1-6-[2-(6-metho>cy- [l,5]naphthyridin-4-yl)-vinyl]-tetrahydro-pyran-3-yl}-amine; • (2,3-dihydro-[l ,4]dioxino[2,3-Z>]pyridin-6-ylmethyl)-{(3i?,6θ)-£-6-[2-(6-methoxy- [l,5]naphthyridin-4-yl)-vinyl]-tetrahydro-pyran-3-yl}-amine;
• 6-({(3i?,65)-£'-6-[2-(6-methoxy-quinolin-4-yl)-vinyl]-tetrahydro-pyran-3-ylamino}- methyl)-4H-benzo [ 1 ,4]oxazin-3 -one;
• 6-({(3i?,65)-£'-6-[2-(6-methoxy-quinolin-4-yl)-vinyl]-tetrahydro-pyran-3-ylamino}- methyl)-4H-benzo [ 1 ,4]thiazin-3 -one;
• 6-({(3i?,65)-£'-6-[2-(6-methoxy-quinolin-4-yl)-vinyl]-tetrahydro-pyran-3-ylamino}- methyl)-4H-pyrido[3,2-έ] [ 1 ,4]thiazin-3-one;
• (2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-{(3i?,65)-£-6-[2-(3-methoxy-quinol in-5-yl)- vinyl]-tetrahydro-pyran-3-yl}-amine; • (2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)-{(3i?, 6S)-£-6-[2-(3-metho>xy- quinolyin-5-yl)-vinyl]-tetrahydro-pyran-3-yl}-amine;
• (2,3-dihydro-[l,4]dioxino[2,3-δ]pyridin-6-ylmethyl)-{(3i?,65)-£-6-[2-(3-methoxy- quinolyin-5 -yl)-vinyl] -tetrahydro-pyran-3 -yl } -amine;
• 6-({(3i?, 65)-£'-6-[2-(3-methoxy-quinolin-5-yl)-vinyl]-tetrahydro-pyran-3-ylaniino} - methyl)-4H-benzo[l ,4]oxazin-3-one;
• 6-( { (3R,6S)-E-6-[2-(3 -methoxy-quinolin-5 -yl)-vinyl] -tetrahydro-pyran-3 -ylamioo } - methyl)-4H-benzo [ 1 ,4]thiazin-3 -one;
• 6-( { (3R, 6S)-E-6-[2-(3 -methoxy-quinolin-5 -y l)-viny 1] -tetrahydro-pyran-3 -ylamino } - methyl)-4H-pyrido[3,2-έ][l,4]thiazin-3-one; • (2i?,3JR,6i?)-{3-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-6-[2-(6-met]ioxy- quinolin-4-yl)-ethyl]-tetrahydro-pyran-2-yl} -acetic acid;
• (2i?,3i?,6i?)-{3-[(2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]- 6-[2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran-2-yl}-acetic acid;
• (2i?,3i?,6i?)-{3-[(2,3-dihydro-[l,4]dioxino[2,3-δ]pyridin-6-ylmethyl)-amino]- 6-[2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran-2-yl} -acetic acid;
• (2i?,3i?,6i?)-{6-[2-(6-methoxy-quinolin-4-yl)-ethyl]-3-[(3-oxo-3,4-dihydro- 2H-benzo[l,4]oxazin-6-ylmethyl)-amino]-tetrahydro-pyran-2-yl}-acetic acid; • (2i?,3i?,6i?)-{6-[2-(6-methoxy-quinolin-4-yl)-ethyl]-3-[(3-oxo-3,4-dihydro- 2H-benzo[l,4]thiazin-6-ylmethyl)-amino]-tetrahydro-pyran-2-yl}-acetic acid;
• (2i?,3i?,6i?)-{6-[2-(6-methoxy-quinolin-4-yl)-ethyl]-3-[(3-oxo-3,4-dihydro- 2H-pyrido[3,2-ό][l,4]thiazin-6-ylmethyl)-amino]-tetrahydro-pyran-2-yl}-acetic acid; • (2i?,3i?,6i?)-{3-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-6-[2-(3-methoxy- quinolin-5-yl)-ethyl]-tetrahydro-pyran-2-yl}-acetic acid;
• (2i?,3i?,6JR)-{3-[(2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]- 6-[2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro-pyran-2-yl}-acetic acid;
• (2JR,3i?,6i?)-{3-[(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-6-ylmethyl)-amino]- 6-[2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro-pyran-2-yl}-acetic acid;
• (2i?,3i?,6i?)-{6-[2-(3-methoxy-quinolin-5-yl)-ethyl]-3-[(3-oxo-3,4-dihydro- 2H-benzo[ 1 ,4] oxazin-6-ylmethyl)-amino] -tetrahydro-pyran-2-yl } -acetic acid;
• (2i?,3i?,6i?)-{6-[2-(3-methoxy-quinolin-5-yl)-ethyl]-3-[(3-oxo-3,4-dihydro- 2H-benzo[l,4]thiazin-6-ylmethyl)-amino]-tetrahydro-pyran-2-yl}-acetic acid; • (2i?,3i?,6i?)-{6-[2-(3-methoxy-quinolin-5-yl)-ethyl]-3-[(3-oxo-3,4-dihydro-
2H-pyrido [3 ,2-b] [ 1 ,4]thiazin-6-y lmethyl)-amino] -tetrahydro-pyran-2-yl} -acetic acid;
• 2-[(3i?,6,S)-6-(6-methoxy-quinolin-4-yloxymetliyl)-tetrahydro-pyran-3-ylamino]- N-thiazol-2-yl-acetamide.
According to a third variant of the invention, the spacer M of the compounds of formula I, ICE=> Ip2, ICEP2 or Ip1WiIl be the spacer M3.
With regard to spacers M3 wherein B6 represents CH, the relative stereochemistry is preferably the following (called M31 hereafter):
M 31
Figure imgf000047_0001
With regard to spacers M3 wherein B6 represents CH, the relative stereochemistry is more preferably the following (called M311 hereafter):
Figure imgf000048_0001
Preferred spacers M3 are the following:
Figure imgf000048_0002
Figure imgf000048_0003
Figure imgf000048_0004
Even more preferred spacers M3 are the following:
Figure imgf000049_0001
Preferred compounds of the foπnula I having the spacer M3 are the following:
• rac-A- { 3 -[ 1 -(2, 3 -dihydro -benzo [1,4] dioxin-6-y lmethyl)-piperidin-3 -y 1] -propoxy } - 6-methoxy-quinoline; • 6-methoxy-4-{3-[l-(trα/7Λ-3-phenyl-allyl)-piperidin-3-yl]-propoxy}-quinoline;
• 4-[3-(l-benzofuran-2-ylmethyl-piperidin-3-yl)-propoxy]-6-methoxy-quinoline;
• rac-3-[ 1 -(2,3-dihydro-benzo[ 1 ,4]dioxin-6-ylmethyl)-piperidin-3-yl]-N-(6-methoxy- [ 1 ,5]naphthyridin-4-yl)-propionamide;
• røc-N-(6-methoxy-[ 1 , 5]naphthyridin-4-y l)-3 - [ 1 -(3 -phenyl-ally l)-piper idin-3 -y 1] - propionamide;
• rac-N-(6-methoxy-[ 1 , 5]naphthyridin-4-yl)-3 - { 1 - [2-(thiophen-2-ylsulf anyl)-ethyl] - piperidin-3 -yl } -propionamide;
• rαc-N-(6-methoxy-[l,5]n.aphthyridin-4-yl)-3-[l-(3-oxo-3,4-dihydro-2iy-benzo[l,4]oxazin- 6-ylmethyl)-piperidin-3-yl]-propionamide; • rαc-N-(6-methoxy-[l,5]αaphthyridin-4-yl)-3-[l-(3-oxo-3,4-dihydro-
2H-pyrido[3,2-Z>][l,4]thiazin-6-ylmethyl)-piperidin-3-yl]-propionamide;
• rac-3 - [ 1 -(2,3 -dihydro-[ 1 , 4] dioxino [2,3 -c]pyridin-7-y lmethy l)-piperid in-3 -y 1] - N-(6-methoxy-[l,5]naphthyridin-4-yl)-propionamide;
• rac-3-{l-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-piρeridin-3-yl}-N-(6-methoxy- [l,5]naphthyridin-4-yl)-propionamide;
• røc-N-(2-cyano-quinolin-8-yl)-3-[l-(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-piperidin- 3 -y 1] -propionamide; • rac-N-(2-cyano-quinolin-8-yl)-3-[/7-αw-l-(3-phenyl-allyl)-piperidin-3-yl]-propionamide;
• rac-N-(2-cyano-quinolin-8-yl)-3-[ 1 -(3-oxo-3,4-dihydro-2H-benzo[l ,4]thiaziα- 6-ylmethyl)-piperidin-3-yl]-propionamide;
• rac-2-[ 1 -(2,3-dihydro-benzo[l ,4]dioxin-6-ylmethyl)-piperidin-3-yloxy]-N-(6— methoxy- [l,5]naphthyridin-4-yl)-acetamide ;
• (2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-[3-(6-methoxy-quinolin-4-yloxytnethyl)- cyclohexylmethyl]-amine;
• (2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-[(li?,3iS)-3-(6-methoxy-quinolin- 4-yloxymethyl)-cyclohexylmethyl]-amine; • rαc-3-{[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-methyl}- cyclohexanecarboxylic acid (2-methyl-quinolin-8-yl)-amide;
• rac-3-[/rø/ω-(3-phenyl-allylamino)-methyl]-cyclohexanecarboxylic acid (2-inethyl- quinolin-8-yl)-amide;
• rac-3 - { [(2,3 -dihydro-benzo [1,4] d ioxin-6-y lmethy l)-amino] -methyl } - cyclohexanecarboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide;
• rac-3 - { [(3 -oxo-3 ,4-dihydro-2H-benzo [1,4] oxazin-6-y lmethy l)-amino] -methy 1 } - cyclohexanecarboxylic acid (6-methoxy-[ 1 ,5]naphthyridin-4-yl)-amide;
• cώ-3-{[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-methyl}- cyclohexanecarboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide; • c/5-3-{[(3-oxo-3,4-dihydro-2/f-benzo[l,4]thiazin-6-ylmethyl)-amino]-methyl}- cyclohexanecarboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide;
• cω-3-{[(2,3-dihydro-[l,4]dioxino[2,3-ό]pyridin-6-ylmethyl)-amino]-methyl} - cyclohexanecarboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide;
• cω-3-{[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-methyl}- cyclohexanecarboxylic acid (2-cyano-quinolin-8-yl)-amide;
• cw-3-{[(3-oxo-3,4-dihydro-2H-benzo[l,4]thiazin-6-ylmethyl)-amino]-methyl}- cyclohexanecarboxylic acid (2-cyano-quinolin-8-yl)-amide;
• cw-3-{[(benzo[l,2,5]thiadiazol-5-ylmethyl)-amino]-methyl}-cyclohexanecarboxylic acid (2-cyano-quinolin-8-yl)-amide; • ci5-3-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]thiazin-6-ylmethyl)-amino] -methyl}- cyclohexanecarboxylic acid (2-cyano-quinolin-8-yl)-amide;
• cw-3-[(trα«5-3-phenyl-allylamino)-methyl]-cyclohexanecarboxylic acid (2-c^ano- quinolin-8-yl)-amide; • cis-3 - { [(3 -oxo-3 ,4-dihydro-2H-pyrido [3 ,2-b] [ 1 ,4-]thiazin-6-y lmethyl)-amino] -methyl } - cyclohexanecarboxylic acid (6-methoxy-[l ,5]naphthyridin-4-yl)-amide;
• 3 - { [(3 -oxo-3 ,4-dihydro-2H-pyrido [3 ,2-b] [ 1 ,4] ox:azin-6-y lmethy l)-amino] -methyl } - cyclohexanecarboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide.
More preferably, the compounds of formula I having the spacer M3 will be selected from the first 28 compounds mentioned in the list hereabove.
According to a fourth variant of the invention, the spacer M of the compounds of formula I,
ICE, IP2, ICEP2 or Ipiwill be the spacer M4.
Among the compounds of formula I wherein M is IM4, those wherein the substituents A7 and N(R6)-A8 have the trans stereochemistry are preferred.
Preferred spacers M4 are the following:
Figure imgf000051_0001
Preferred compounds of formula I having the spacer M4 are the following:
• rαc-ϊrα«5-(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-[6-(6-methoxy-quinolin- 4-yloxymethyl)-piperidin-3-yl]-amine; • rac-trans-6-{ [6-(6-methoxy-quinazolin-4-yloxymethyl)-piperidin-3-ylamino]-niethιy 1} - 4H-pyrido[3,2-Z>][l,4]thiazin-3-one;
• rαc-trα«5-(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-[6-(6-methoxy-quinazolin- 4-yloxymethyl)-piperidin-3 -yl] -amine ;
• rac-rrαrø-{2-(6-methoxy-quinazolin-4-yloxymethyl)-5-[(3-oxo-3,4-dihydro- 2H-pyrido[3,2-έ][l,4]thiazin-6-ylmethyl)-ammo]-piperidin-l-yl}-acetic acid tert-\>Mty\ ester;
• rac-frα»5-{2-(6-methoxy-quinazolin-4-yloxymethyl)-5-[(3-oxo-3,4-dihydro- 2H-pyrido [3 ,2-b] [ 1 ,4]thiazin-6-y lmethy l)-amino] -piperidin- 1 -yl} -acetic acid;
• rαc-frαrø-6-({6-[2-(6-methoxy-[l,5]naphthyridln-4-yl)-ethyl]-piperidin-3-ylamino }- methyl)-4H-pyrido[3,2-5][l,4]thiazin-3-one; • røc-trørø-5-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-&][ l,4]thiazin-6-ylmethyl)-amino]- piperidine-2-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide;
• rαc-/rα«5-5-[(3-oxo-3,4-dihydro-2H-benzo[l,4]thia.zin-6-ylmethyl)-amino]-piperidine— 2-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-3/l)-amide; • rac-tr««5-5-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-piperidine-2-carboxylic acid (6-methoxy-[ 1 , 5]naphthyridin-4-yl)-amide.
Compounds of formula I are suitable for the use as ohemotherapeutic 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, pa-ints, 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. casselflcrvus, S. epidermidis, S. haemolyticvcs, or Peptostreptococcus spp.; pharyngitis, rheumatic fever, and glomerulonephritis related to infection by Streptococcus pyogenes, Groups C and G streptococci, Corynebaterium 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, inclucding endocarditis and osteomyelitis, caused by S. aureus, S. haemolyticus, E. faecalis, E. faec÷ium, E. durans, including strains resistant to known antibac-terials 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, coa-gulase-negative staphylococci (i.es., S. epidermidis, S. haemolyticus, etc.), Streptococcus pyogenes, Streptococcus agalaetiae, Streptococcal groups C-F (minute colony streptococci), viridans streptococci, Corynehacterium 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 ti-achomatis, 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 intracellular; 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.
As well as in humans, bacterial infections can also be treated in other species like pigs, ruminants, horses, dogs, cats and poultry.
The present invention also relates to pharmacologically acceptable salts, or solvates and hydrates, respectively, and to compositions and formulations of compounds of formula I. Examples of pharmacologically acceptable salts of sufficiently basic compounds of formula I are selected from the group consisting of salts of physiologically acceptable mineral acids like hydrochloric, hydrobromic, sulfuric and phosphoric acid; or salts of organic acids like methanesulfonic, p-toluenesulfonic, lactic, acetic, trifluoroacetic, citric, succinic, fumaric, maleic and salicylic acid. Further, a sufficiently acidic compound of formula I may form alkali or earth alkaline metal salts, for example sodium, potassium, lithium, calcium or magnesium salts; ammonium salts; or organic base salts, for example methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, meglumin, piperidine, morpholine, tris-(2-hydroxyethyl)amine, lysine or arginine salts. Compounds of formula I may be solvated, especially hydrated. The hydratation can occur during the process of production or as a consequence of the hygroscopic nature of the initially water free compounds of formula I.
The 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 present invention also relates to pro-drugs that are composed of a compound of formula I or ICE having at least one pharmacologically acceptable protective group that will be cleaved off under physiological conditions. Such prodrugs have been reviewed by Beaumont, Kevin; Webster, Robert; Gardner, Iain; Dack, Kevin in Current Drug Metabolism (2003), 4(6), 461-485. Examples of such promoities are, in case the compound of formula I or ICE contains a free carboxylic acid, alkoxy- (e.g. ethoxy), phenalkyloxy- (e.g. benzyloxy), OCH(Ra)OCORb (e.g. pivaloyloxymethyloxy), OCH(Ra)OCO2Rb {e.g.
[[(l-methylethoxy)carbonyl]oxy]ethyl ester; proxetil), OCH(Ra)ORb, 2-alkyl-, 2-cycloalkyl-, or 2-cycloalkylalkyl-oxycarbonyl-2-alkylidene-ethoxy groups, 5-alkyl[l,3]dioxol-2-one-4yl- methyloxy, dialkylamino-alkoxy or acyloxy wherein Ra is hydrogen or (Ci-C4)alkyl and Rb is hydrogen, (Ci-C6)alkyl, (C2-C6)alkenyl, (CrC6)alkoxy-(Ci-C6)alkyl,
(Ci-C6)haloalkoxy-(CrC6)alkyl, (C3-Ce)cycloalkyl or (C3-C6)cycloalkylmethyl. Furthermore, if a free hydroxy group is present on a compound of formula I or ICE> it can be protected as a prodrug of the type sulfate (OSO3H), phosphate (OPO3H2), oxymethylene phosphate (OCH2OPO3H2), succinate (OCOCH2CH2COOH), ester of dimethylaminoglycine or of a naturally occurring amino acid, or as an inorganic salt of one of the latter. As mentioned above, therapeutically useful agents that contain compounds of formula I, their solvates, salts or formulations are also comprised in the scope of the present invention. In general, compounds of formula I will be administered by using the known and acceptable modes known in the art, either alone or in combination with any other therapeutic agent. Such therapeutically useful agents can be administered by one of the following routes: ora.1, e.g. as tablets, dragee, coated tablets, pills, semisolids, soft or hard capsules, for example soft and hard gelatine capsules, aqueous or oily solutions, emulsions, suspensions or syrups, parenteral including intravenous, intramuscular and subcutaneous injection, e.g. as an injectable solution or suspension, rectal as suppositories, by inhalation or insufflation, e.g. as a powder formulation, as microcrystal or as a spray (e.g. liquid aerosol), transdermal, for example via an transdermal delivery system (TDS) such as a plaster containing the active ingredient, topical or intranasal. The substance of the present invention can also be used to impregnate or coated devices that are foreseen for implantation like catheters or artificial joints.. The pharmaceutically useful agents may also contain additives for conservation, stabilisation, e.g. UV stabilizers, emulsifϊers, sweetener, aromatisers, salts to change the osmotic pressure, buffers, coating additives and antioxidants.
Another aspect of the invention concerns a method for the treatment of disease comprising the administration to the patient of a pharmaceutically active amount of a derivative according to formula I.
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 Ip2, compounds of formula ICE, compounds of formula ICEP2 and compounds of formula Ip1.
Moreover, the compounds of formula I or ICE 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 or ICE could be conta-ined in a solution or in a spray formulation. PREPARATION OF COMPOUNDS OF FORMULA I
Abbreviations:
The following abbreviations are used throughout the specification and the examples;
AcOH acetic acid
AD-mix α l,4-όώ(dihydroquinine)phthalazine, KsFe(CN)6, K2COs and
K2OsO4.2H2O
AD-mix β l,4-έzχdihydroquinidine)phthalazine, KsFe(CN)6, K2COs and
K2OsO4.2H2O aq. aqueous atm atmosphere
BINAP 2,2'-Z>ώ-(diphenylphosphino)-l,r-binaphthaline
BOC2O di-tert-bυty\ dicarbonate
Cbz benzyloxycarbonyl d day(s)
DCC dicyclohexyl carbodiimide
1,2-DCE 1 ,2-dichloroethane
DBU l,8-diazabicyclo[5.4.0]undec-7-ene
DBN l,5-diazabicyclo[4.3.0]non-ene
DCM dichloromethane
(DHQD)2PHAL l,4-έώ(dihydroquinidine)phthalazine
DIAD diisopropyl azo dicarboxylate
DIBAH diisobutylaluminium hydride
DIPEA N,N-diisopropylethylamine
DMAP 4-dimethylaminopyridine
1,2-DME 1 ,2-dimethoxyethane
DMF N,N-dimethylformamide
DMSO dimethylsulfoxide DMPU l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidone
DPPA diphenylphosphorylazide
EA ethyl acetate
ESI electron spray ionisation
Ether or Et2O diethyl ether
EtOH ethanol h hour(s)
HATU <9-(7-azabenzotriazol- 1 -yl)-N,N,N',N -tetramethyluroniαm hexafluorophosphate
Hex hexane
HMPA hexamethylphosphoramide
HV high vacuum conditions
LC liquid chromatography
LDA lithium diisopropylamide
LG leaving group
LiHMDS lithium hexamethyldisilane
MeOH methanol min minute(s)
MCPBA metø-chloroperbenzoic acid
MeCN acetonitrile
MS mass spectroscopy
MsCl methanesulfonyl chloride
NBS N-bromosuccinimide
NHS N-hydroxysuccinimide
R-BuLi M-butyl lithium
NMO 4-methylmorpholine-N-oxide org. organic
PPh3 triphenylphosphine
PTSA σora-toluene sulfonic acid quant. quantitative rac racemic
Rf retention factor rt room temperature
TBAF tetrabutylammonium fluoride
TBDMSCl tert-butyldimethylsilyl chloride
TEA triethyl amine
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
TLC over SiO2 thin layer chromatography over silica gel wt% weight percent
General preparation methods:
The compounds of formula I (including tihe compounds of formula ICE or Ip1) can be manufactured in accordance with the present invention by
a) reacting a compound of the general formula II
Figure imgf000058_0001
with a compound of the general formula III
A0M0D III
wherein R1, U, V, W, X and D are as before and A0M0 is one of the spacers M1, M2, M3 and M4, in which A0 is A1, A3, A5 or A7, respectively, functionally modified, as well as the reactive group L1, to connect the two moieties of formulas II and III, and M0 is one of the spacers M1, M2, M3 and M4 diminished by A1, A3, A5 or A7, respectively, and M1, M2, M3, M4, A1, A3, A5 and A7 are as before, or
b) reacting a compound of the general formula IV:
Figure imgf000059_0001
IV wherein M is
Figure imgf000059_0002
M01
Figure imgf000059_0003
with a compound of the general formula V:
L2D V
wherein L2 is a reactive group yielding the group A2, A4, A6, A8, A2 diminished by ISfH or A6 diminished by CH2NH, respectively, and A!-A8, B1, R1, R3, R4, R5, R6,U, V, W, X, D, n and o are as before,
and where required, transforming groups A1 -A8 into other such groups,
and, if desired, may be converted into their pharmaceutically acceptable salts. In particular, the compounds of formula IPi can be manufactured in accordance with the present invention by
a) reacting a compound of the general formula II
Figure imgf000060_0001
II
with a compound of the general formula III
A0M0D III
wherein R1, U, V, W, X and D are as before and A0M0 is one of the spacers M1, M2 and M3, in which A0 is A1, A3 or A5, respectively, functionally modified, as well as the reactive group L1, to connect the two moieties of formulas II and III, and M0 is one of the spacers M1, M2 and M3 diminished by A1, A3 or A5, respectively, and M1, M2, M3, A1, A3 and A5 are as before, or
b) reacting a compound of the general formula IV:
M01— H
Figure imgf000060_0002
wherein M01 is
Figure imgf000061_0001
M ,1011 M 012
Figure imgf000061_0002
N .T0130 M ,0' 14 IVI ,'015
with a compound of the general formula V:
L2D V
wherein L2 is a reactive group yielding the group A2, A4, A6, A2 diminished by NH or A6 diminished by CH2NH, respectively, and A!-A6, B1, R1, R3, R4, R5, U, V, W, X, D, n and o are as before,
and where required, transforming groups A*-A6 into other such groups,
and, if desired, may be converted into their pharmaceutically acceptable salts.
In process alternative a) preferred reactive groups L1 and A0 and resulting connections A1, A3, A5 and/or A7, as the case may be, are evident from the following Table 1 :
Table 1
Figure imgf000062_0001
Figure imgf000063_0001
In process alternative b) preferred reactive groups L2 and resulting connections A2, NR5A4, A6 and/or NR6A8, as the case may be, are evident from the following Table 2:
Table 2
Figure imgf000063_0002
Figure imgf000064_0001
halogen Ts= tosyl
The required quinoline, [l,5]-naphthyridine, quinazoline and quinoxaline derivatives of formula II are prepared following literature procedures. For example, 4-hydroxy-[l,5]- naphthyridines (L= OH, U= W= N and V= X= CH) and 4-hydroxy quinolines (L= OH, W= N and U= V= X= CH) can be prepared from the corresponding aminopyridines or anilines by reaction with diethyl ethoxymethylene malonate to produce the 4-hydroxycarboxylic acid ester derivative with subsequent hydrolysis to acid, followed by thermal decomposition in inert solvents (J.T. Adams, J. Am. Chem. Soc. (1946), 68, 1317). Others routes to such derivatives uses the condensation of substituted aminopyridines or anilines with 2,2-dimethyl- [l,3]dioxane-dione and triethylorthoformate followed by heating of the resulting 2,2-dimethyl-5-[(arylamino)methylidene]-l,3-dioxane-4,6-dione intermediate in refluxing diphenyl ether. Quinazolines (L= OH, Cl, NH2, W= ZX= N and U= V= CH) may be prepared by standard routes as described by T.A. Williamson in Heterocyclic Compounds (1957), 6, 324. 3-substituted quinoxalin-5-ol (L= OH, U= V= TS[ and X= W= CH) can be prepared as described by Y. Abe et al. in J. Med. Chem. 1998, 41, 4062.
The compounds of formula I can be prepared by different routes as illustrated in Schemes 1-8 below (reference is made to Tables 1 and 2 above):
n
Figure imgf000065_0001
I-l 1-3 0D
Figure imgf000065_0002
1-4
Scheme 1
In Scheme 1, M02 is the group M011 wherein B1 is CHC5 M012 wherein B1 is CH, or M013, M014, M015 or M016, wherein A0 is HOOC(CH2)t and t is 0, 1 or 2 and E is a protecting group; the other symbols have their above meanings. Compounds of formula I can for example be obtained from an amine 1-1 and an acid 1-2. Thus, a 4-h.ydroxy-[l,5]-naphthyridine, a 4-hydroxyquinazoline, a 5-hydroxy quinoxaline or a 4-hydroxy quinoline derivative can be converted into the corresponding chloro derivative by heating in phosphorous oxychloride between 400C and 1000C neat or in an inert solvent like dichloroethane, or to the corresponding 4-trifluoromethanesulphonyloxy derivative by reaction with trifluoromethanesulphonic anhydride, in the presence of an organic base between -4O°C and 800C in an aprotic solvent like DCM or THF (K. Ritter, Synthesis (1993), 735). 4-amino-[l,5]-naphthyridine, 4-aminoxyquinazoline, 5-amino quinoxaline or 4-amino quinoline derivatives can be obtained by reaction of the corresponding 4- trifluoromethanesulphonyloxy derivatives with ammonia in a solvent like DCM or THF, or with R-propylamine hydrochloride in pyridine between -200C and 1000C (R. Radinov, Synthesis (1986), 886). 4-aminoxyquinazoline can also be obtained from its 4-chloro analogue by reaction with ammonia under the same conditions.
Carboxylic acids 1-2 may be prepared by Jones' oxidation of the corresponding alcohols using chromium acid and sulphuric acid in water/methanol between 400C and HO0C (E. R. H. Jones et al, J. Chem. Soc. (1946), 39). Other oxidising agents may be used for this transformation such as sodium periodate catalysed by ruthenium trichloride (G. F. Tutwiler et al, J. Med. Chem. (1987), 30, 1094), or potassium permanganate (D. E. Reedich et al, J. Org. C/zem. (1985), 50, 3535.
Derivatives 1-3 can be obtained by reacting the 4-amino derivative 1-1 with a carboxylic acid derivative 1-2, in the presence of an activating agent such as DCC, 1- (dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (EDC) or 1-hydroxybenzotriazole (HOBT) or HATU (G. Benz in Comprehensive Organic Synthesis, B.M. Trost, I. Fleming, Eds; Pergamon Press: New York (1991), vol. 6, p. 381) between -2O°C and 600C in an dry aprotic solvent like DCM acetonitrile or DMF. Alternatively, the carboxylic acid can be activated by conversion into its corresponding acid chloride by reaction with oxalyl chloride or thionyl chloride neat or in a solvent like DCM between -20° and 6O0C.
Removal of the protecting group (E) such as Boc or Cbz on a nitrogen atom in 1-3 is carried out under standard acidic conditions to give the corresponding free amine. Alternatively the Cbz group can be removed under catalytic hydrogenation over palladium on charcoal. The use of protecting groups to mask reactive functionality is wellknown to those of skill in the art, and other protecting groups are listed in reference book such as PJ. Kocienski 'Protecting Groups', Thieme (1994). The amine is then reacted with an (hetero)aryl aldehyde and a suitable reducing agent to provide the homologue 1-4. The intermediate imine may be formed in a variety of protic or aprotic solvents such as DMF, N,N-dimethylacetamide, 1,2-DCE, MeOH, MeCN, in presence or not of a drying agent such as molecular sieves. The imine is reduced subsequently or simultaneously with a suitable reagent such a NaBH4, sodium triacetoxyborohydride or sodium cyanoborohydride (R.O. and N4.K. Hutchins Comprehensive Organic Synthesis, B.M. Trost, I. Fleming, Eds; Pergamon Press: New York (1991), vol. 8, p. 25-78). Alternatively, the amine may also be homologated to give product 1-4 by nucleophilic displacement of a suitable alkyl (hetero)aryl halide, mesylate or tosylate between -200C and 1000C in a dry aprotic solvent like DCM, MeCN, DMF or THF in presence of a base such as K2CO3 or DIPEA.
Figure imgf000067_0001
L= OTf, halogen
0D
Figure imgf000067_0002
1-4
Scheme 2
In Scheme 2, M03 is one of the group M011 to M016, wherein A1, A3, A5 and A7 are H2NC(O)(CH2)U, u is 0, 1 or 2 and E is a protecting group; the other symbols have their above meanings.
As illustrated in Scheme 2, the intermediate 1-3 can also be obtained from a 4-trifluoromethanesulfonate derivative II-l and an amide derivative II-2. These amide derivatives are obtained from a suitable carboxylic acid 1-23 which is converted into an activated form using, for example, EDC and HOBt, SOCl2 or NHS and DCC between -20°C and 6O0C in a dry aprotic solvent like DCM, ethyl acetate or THF, and the activated acid is subsequently reacted with aqueous ammonium hydroxide or gaseous ammonia, to afford amide II-2 in an appropriate solvent such as THF or DCM between -2O0C and 600C. The amide II-2 and the 4-trifluoromethanesulphonate II-l are coupled under palladiuin-catalyzed Buchwald-Hartwig conditions (J. Am. Chem. Soc. (1996), 118, 10333) or copper-catalyzed conditions (J. Am. Chem. Soc. (2002), 124, 7421) to afford the derivative 1-3. Various palladium sources and ligands may be used, as well as a variety of solvents, including for example dioxane, toluene. Other partners of Formula H-I, such as iodo (L= I), bromo (L=Br) or chloro (L= Cl) may be used in the metal-catalysed coupling reaction.
Figure imgf000068_0001
III-4
Scheme 3
In Scheme 3, M04 is the group M011 wherein B1 is CH, M012 wherein B1 is CH or MI013 to M016, wherein A1, A3, A5 and A7 are HO(CH2)V, v is 1, Z or 3 and the other symbols have their above meanings.
As shown in Scheme 3, the compounds of formula I can also be obtained by coupling, for example, a substituted 4-hydroxy quinoline, 8-hydroxy quinoline 4-hydroxy-[l,5]- naphthyridine, 4-hydroxy-[l,3]-quinazoline or 5-hyclroxy quinoxaline IH-I and an alcohol derivative III-2. The coupling reaction between HI-I and III-2 may be achieved under Mitsunobu conditions (as reviewed in O. Mitsunob>υ, Synthesis 1981, 1). For example, an alcohol πi-2 and a 4-hydroxy derivative III-l are reacted to form ether πi-3 in ftie presence of diethyl or diisopropyl azodicarboxylate and triphenylphosphine. The reaction may be performed in a wide range of solvents such as N,N-dimethylformamide, THF, DCM and at a wide range of temperature (between -78°C and 50°CO. An alternate route to HI-3 may require the activation of the alcohol III-2 as for example a tosylate, a triflate or a mesylate by treatment with tosyl chloride, trifluoromethanesulphonic anhydride or mesyl chloride respectively in the presence of an organic base such as triethylamine between -400C and 6O0C in a dry aprotic solvent like DCM, acetonitrile or THF. Once activated, alcohol III-2 reacts with the anion of the 4-hydroxy derivative, generated with a mineral base such as sodium hydride or potassium carbonate or an organic base such, as lithium hexamethyldisilazide, to generate III-3 between -200C and 600C. Alternatively, derivative III-3 can be obtained by reaction of a 4-halogeno quinazoline derivative with an alcohol derivative in presence of a strong base like alkali alkoxide like sodium or potassium, methylate, metal hydride like NaH, DBU or DBN between -200C and 600C in a dry aprotic solvent like DMF, MeCN or THF. Io a subsequent step, the protecting group is removed and th_e free amine is reacted with an alkyl (hetero)aryl halide in presence of a base or with an (hetero)aryl aldehyde in presence of a reducing reagent as previously described .
Figure imgf000069_0001
IV-4
Scheme 4
In Scheme 4, M05 is the spacer M1 diminished by A1 a.xid A2 and B1 is N. The remaining symbols are as above.
Compounds of the formula I can also be obtained from a 4-oxiranyl derivative IV-I and an amine derivative IV-2. The racemic epoxides IV-I may be prepared from the corresponding 4-carboxaldehydes using trimethylsulfonium iodide in presence of a base (G.A. Epling and aL . J Het. Chem. (1987), 24, 853), or by epoxidation of a 4-vinyl derivatives using an peroxyacid derivative such as MCPBA as an oxidizing reagent between -200C and 600C in an aprotic dry solvent like DCM or THF (Somersekar Rao, A. in Comjprehensive Organic Synthesis, B. MI. Trost, I. Fleming, Eds; Pergamon Press: INfew York (1991), vol. 7, p. 357). The vinyl derivatives can be obtained from the corresponding aldehyde by a Wittig olefination reaction using triphenylmethylene phosphorane (for example generated by treatment of methyl triphenylphosphonium bromide with M-BuLi in THF at -780C) or by reaction of the triflate II- 1 with a vinyl tributyl stannnane under Stille coupling reaction conditions. The corresponding chiral epoxides may be obtained using asymmetric catalytic dihydroxylation (AD-mixtures) followed by the chiral diol closure as reviewed by K.B. Sharp less et al. Chem. Rev. (1994), 94, 2483. The optical purity is generally ranging between 10 and 98%, and may be further enhanced by recrystallisation. By such a method, both enantiomers are equally available. The reaction of the bicyclic amine FV-2 and the epoxide IV-I may take place in various solvents such as ethanol, N,N-dimethylformamide, at a temperature generally ranging between O0C and 800C. The reaction is helped by the addition of lithium perchlorate. In a further step, the protecting group of IV-3 is removed and the free amine is reacted with an alkyl (hetero)aryl halide in presence of a base such as DIPEA or K2CO3 in a solvent such as MeCN, DMF or EtOH at a temperature ranging between 00C and 1000C. The free amine may also be reacted with an (hetero)aryl aldehyde in presence of a reducing reagent as previously described.
Figure imgf000070_0001
V-3 V-4
Scheme 5
In Scheme 5, M06 is the group Mou wherein B1 is CH, M012 wherein B1 is CH or M013 to M016, wherein A1, A3, A5 and A7 are HC≡C, L is OSO2CF3 or a halogen atom and E is a protecting group; the other symbols have their above meanings. Compounds of formula I can also be obtained from compound II-l (Scheme 5) Intermediate V-2 may be obtained from derivative II-l and a terminal alkyne derivative V-I. These alkyne derivatives V-I are generally obtained from a suitable alcohol III-2 (see Scheme 3) which is converted first into an aldehyde using for example the Moffat-Swern (see Synthesis 1981, 165), or the Dess-Martin periodinane (see J. Am. Chem. Soc. (1991), 113, 7277) oxidation protocols. The aldehyde is converted into the corresponding alkyne using either the Corey-Fuchs protocol (formation of the gem-dibromide then treatment with rø-BuLi) as described in Tetrahedron Letters (1972), 3769 or using dimethyl-2-oxopropylphosphonate diazo derivative (so called Ohira's reagent, Synth. Com. (1989), 19, 561) or dimethyldiazomethylphosphonate as described in Synlett (2003), 59 and Synlett (1996), 521. The alkyne V-I and the 4-trifluoromethanesulfonate II-l are coupled under Sonogashira conditions using catalytic amount of a palladium salt, an organic base such as triethylamine and a catalytic amount of a copper derivative (usually copper iodide) in a solvent such a DMF between 2O0C to 1000C (see Sonogashira, K. in Metal-Catalyzed Reactions, Diedrich, F., Stang, P. J., Eds; Wiley-VCH: New York 1998); alternatively, for example when U = V = CH and W = X = N, the 4-trifluoromethanesulfonate II-l can be replaced by a halogeno (e.g. chloro) derivative II-l. The resulting alkyne V-2 is hydrogenated to the alkane V-3 using catalytic system such as palladium on charcoal or platinum oxide in a solvent like EtOH or EA in presence of hydrogen. Other methods may also be suitable as reviewed by Siegel, S. et al in Comprehensive Organic Synthesis, B. M. Trost, I. Fleming, Eds; Pergamon Press: New York (1991), vol. 8, p. 417-488. The alkane V-3 is further transformed into the compounds V- 4 using procedures previously described.
Figure imgf000072_0001
VI-4 VI-5
Scheme 6
In Scheme 6, M07 is the group M013, wherein A1 is RSO2CH2 and E is a protecting group; R may be l-phenyl-lH-tetrazol-5-yl or benzothiazol-2-yl and the other symbols have their above meanings.
Compounds of formula I can also be obtained from compound VI-I (Scheme 6). Intermediate VI-3 may be obtained as an (£)-isomer from an aldehyde derivative VI-I and a sulfone VI-2. The sulfone is generated from the corresponding sulphide via an oxidation reaction. A wide range of oxidizing agent may be used to perform such a reaction, such as MCPBA in a solvent such as DCM, oxone® in a solvent such as a.q. MeOH (see Tetrahedron Letters (1981), 22, 1287), or aq. hydrogen peroxide in presence of ammonium heptamolybdate tetrahydrate in EtOH (see J. Org. Chem. (1963), 28, 1140). The sulphide is obtained from a suitable alcohol III-2 (Scheme 3) via a Mitsunobu coupling (as reviewed in O. Mitsunobu Synthesis (1981), 1) with l-phenyl-lH-tetrazole-5-thiol in the presence of diethyl azodicarboxylate or DIAD and PPh3. The reaction may be performed in a wide range of solvents such as DMF, TΗF or DCM and within a wide range of temperatures (between -78°C and 500C). An alternate route to form the intermediate sulphide requires the activation of the alcohol III-2 as for example a tosylate, a triflate or a mesylate by treatment with tosyl chloride, trifluoromethanesulphonic anhydride or mesyl chloride respectively in the presence of an organic base such as TEA between -400C and 6O0C in a dry aprotic solvent like DCM, acetonitrile or TΗF. Once activated, alcohol πi-2 reacts with sodium iodide or potassium iodide in acetone at a temperature ranging between O0C and 650C, to form the corresponding iodide. The latter serves as an alkylating agent of the l-phenyl-lH-tetrazole-5-thiol. The alkylation reaction is performed in presence of an inorganic base such as KOΗ or NaOH in a solvent such as EtOH at a temperature ranging between -200C and 700C.
The sulfone VI-2 and the aldehyde VI-I are coupled in presence of a base such as potassium- or lithium-hexamethyldisilazide in a solvent such as 1,2-dimethoxyethane, DMF or toluene as reviewed by Blakemore, P.R in J.Chem.Soc, Perkin Trans. 1 (2002), 2563-2585. The (£)-alkene VI-3 is transformed into the corresponding chiral czs-diol derivative by treatment with AD mixtures in presence of methanesulfonamide in a water/2-methy-2-propanol mixture as described in Chem. Rev. (1994), 94, 2483. The sense of induction relies on the chiral ligand contained in the mixture, either a dihydroquinine-based ligand in AD-mix α or a dihydroquinidine-based ligand in AD-mix β. The chiral cis-diol VI-4 is further transformed into the chiral compounds VI-5 using procedures previously described.
An alternate route to obtain (£)-alkene VI-3 may be to couple a 4-trifluoromethanesulfonate derivative II-l (Scheme 2) with an organostannane deriving from a terminal alkyne derivative V-I (see Scheme 5). Indeed, the hydrostannation reaction of an alkyne derivative
V-I using tributyl tin hydride and a catalytic amount of either a palladium salt or a molybdenum complex generates an E:Z mixture of the vinylstannane intermediate as described in J. Org. Chem. (1990), 55, 1857. The vinylstannane is reacted with a 4- trifluoromethanesulfonate derivative II-l under Stille coupling conditions (as described in J.
Am. Chem. Soc. (1987), 109, 5478). Typical reaction conditions involve a palladium salt such as tetrakis(triphenylphosphine) palladium or dichloro bis(triphenylphophine) palladium, lithium chloride and a radical inhibitor such as 2,6-dimethyl-4-methyl phenol in a solvent such as DMF or dioxane at a temperature ranging between 00C and 1000C, more preferably at a temperature ranging between 200C and 8O0C. As the reaction proceeds normally at a faster rate using (£)-vinylstannane, the resulting (E)-alkene VI-3 is usually obtained with a high isomeric purity.
Figure imgf000074_0001
VII-2 VII-3
Scheme 7
As illustrated in Scheme 7, the previously mentioned chiral czs-diol VI-4 may be transformed in the corresponding cyclic carbonate VII-I, by treatment with either phosgene, diphosgene or triphosgene in presence of an organic base such as TEA or pyridine or carbonyldimidazole in an inert solvent such as DCM or THF at a temperature ranging between -78°C and 5O0C, more conveniently at a temperature ranging betrween 0°C and 200C. The cyclic carbonate Vπ-1 is subsequently transformed to the homobenzylic alcohol VII-2 by hydrogenolysis using catalytic system such as palladium on cha.rcoal in presence of hydrogen in a solvent such as EA. The intermediate VII-2 is further transformed into the compounds VII-3 using procedures previously described.
Figure imgf000075_0001
VIEI-3
Scheme 8
In Scheme 8, M08 is the group M011 wherein B1 is CH, M°12 wherein B1 is CH or M013 to M016, wherein A1 is HCO(CH2)W, w is 1, 2 or 3 and E is a protecting group; the other symbols have their above meanings.
As illustrated in Scheme 8, the benzylic alcohol VIII-2 may be obtained by addition of an organometallic derivative of aromatic H-I onto an aldehyde VIII-I. The aldehyde VTII-I is obtained from a suitable alcohol III-2 by a homologation reaction. Oxidation of the alcohol πi-2 into its corresponding aldehyde may be performed using one of the aforementioned oxidation methods. The resulting aldehyde is further converted to the corresponding alkene using the phosphorane generated from methyltriphenylphosphonium bromide and a base like «-BuLi or potassium tert-buto^άde in a solvent such as THF at a temperature between -800C and 0°C (see Org. Synth. Coll. (1973), 5, 751). The terminal alkene is subsequently transformed into the primary alcohol via an hydroboration reaction using either BH3-dimethylsulfide complex, or 9-borabicyclo[3.3.1]nonane (9-BBN) (for a review see Smith, K.; Pelter, A. G. Comprehensive Organic Synthesis, B. M. Trost, I. Fleming, Eds; Pergamon Press: New York (1991), vol. 8, p. 703-731) followed by oxidative workup with aq. NaOH and 30% H2O2 (see also Pelter, A.; Smith, K. G. Comprehensive Organic Synthesis, B.M. Trost, I. Fleming, Eds; Pergamon Press: New York (1991), vol. 7, p. 593-611). The alcohol is finally oxidized to the aldehyde VIII-I as already described. Derivatives II-l (L1=Br) are treated with an alkylithiαm such as n-BuLi at a temperature ranging between -800C and — 300C to generate a lithio specie that undergoes nucleophilic addition on to the aldehyde VIII-I to from the benzylic alcohol VIII-2. The intermediate Vπi-2 is further transformed into the compounds VIII-3 using procedures previously described.
Aldehydes VI-I are prepared, following literature procedures or from the corresponding derivatives II-l (L1=Br) are after treatment with an alkyllithium such as H-BuLi at a temperature ranging between — 800C and -300C and subsequent quenching of the lithio specie with DMF as described in J. Org. Chem. (1980), 45, 1514.
An alternate route to generate aldehyde VI-I consists in reacting derivative II-l (L=OTf, Br or Cl) with traHs-phenylvinyl boronic acid under typical Miyaura-Suzuki coupling conditions (see SynthCommun. (1981), 11, 513) employing a palladium salt, an inorganic base such as K2CO3 or Na2COs, in an aq. solvent such as a dioxane-water mixture at a temperature ranging between 20° and 1000C. The corresponding alkene may be directly transformed into the aldehyde VI-I by ozonolysis (O3 stream then quenching with either dimethylsulfide or PPh3) or via a periodic cleavage of the intermediate diol using sodium periodate in aq. acetone. The diol is obtained using a catalytic amount of osmium tetroxide in the presence a co-oxidant such as NMO in aq. solvent such as acetone-water or DCM-water (see Cha, J.K. Chem. Rev. (1995), 95, 1761-1795).
However, the following compounds are novel intermediates useful in the manufacture of the bicyclic derivatives of formula I in accordance with the methods disclosed above, viz. such novel intermediates are of the general formula
Figure imgf000076_0001
VI
wherein Rc represents CH2OH, COORe or CONH2;
Re represents hydrogen or alkyl; and Rd represents hydrogen or a nitrogen protecting group. Nitrogen protecting groups Rd are preferably allyloxycarbonyl, if-butyloxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyl or acetyl.
The intermediates of formula VI can be converted into the end products of formula I by reaction with the compounds of formula II in analogy to the reaction between the compounds of formulas II and III; any nitrogen protecting group Rd is subsequently split off as described above to yield starting compounds of formula IV.
Processes involving the spacers M2, M3 and M4 proceed in quite analogous fashion to those involving spacer M1. The above Tables 1 and 2 give suitable coupling reactions for arriving at each and every compound of formula I.
The required bicyclic systems M1 involved in these reactions were prepared according to literature procedures described in Synlett (1996), 1097-99, or from procedures deriving from J. Chem. Soc Perkin Trans I (1994), 1891-92, and J Org. Chem. (1997), 62, 4601-09.
The required tetrahydropyran derivatives M2 involved in these reactions were prepared according to literature procedures described in Eur. J. Org. Chem. (2003), 2418-2427.
The required systems M3 involved in these reactions were prepared according to literature procedures described in J Med. Chem. (1998), 41, 2175-79.
The required systems M4 involved in these reactions were prepared starting from rac-trans- piperidine-2,5-dicarboxylic acid 5-methyl ester (J. Heterocycl. Chem. (1995), 32, 857) after the transformations set out in Scheme 9 hereafter.
Figure imgf000078_0001
111-4 V-4 (M0= W01β)
Scheme 9
The piperidine nitrogen of compound IX-I is protected with a protecting group PG (Cbz or BOC). The carboxylic acid function is reduced into its corresponding aJcohol by reduction with borane in THF in an organic solvent such as THF or dioxane between -20° and 500C to yield the compound IX-2. The alcohol is further transformed into the corresponding aldehyde IX-3 using Dess-Martin periodinane or Moffat-Swern protocols, protected as a silyl or THP ether using TBDMSCl in presence of an organic base such as TEA or pyridine in a solvent such as DCM or THF, or dihydropyran in an aprotic solvent such as DCM, THF or ether between -40° and +400C, or directly used in coupling with compounds OI-l (see Scheme 3) wherein L1 is OH or Cl. The 5-methylester function is hydrolysed in pxesence of an alkali hydroxide such as NaOH, LiOH or KOH in a water/THF mixture between 0° and 400C. The resulting acids are subjected to a Curtius degradation in presence of diphenylphosphoryl azide in t-butanol in presence of an organic base such as TEA between 60° artd 1400C to give the intermediate t-butyl carbamate followed by acidic treatment with TFA or an inorganic acid such as HCl in an organic solvent such as THF or DCM to liberate the amine IX-5, IX-6 and IX-7. The intermediate aldehyde IX-3 is reacted with dimethyl acetylmeth>dphosphonate, ^-toluenesulfonyl azide and MeOH in presence of an inorganic base such as K2CO3 in a polar solvent such as acetonitrile between 0 and 500C to give the intermediate alkzyne derivative IX-4, which is subsequently subjected to coupling under Sonogashira conditions. The intermediates IX-4, IX-5 and IX-6 are further processed to deliver compounds III-4 (M°=M016) and V-4 (M°=M016).
The following examples further illustrate the preparation of the pharmacologically active compounds of the invention but do not limit the scope thereof.
EXAMPLES
All temperatures are stated in 0C. All analytical and preparative HPLC investigations on non- chiral phases are performed using RP-C 18 based columns. Analytical HPLC investigations are performed on two different instruments with cycle-times of -2.5 min and -3.5 min respectively.
Example 1: (2,3-dihydro-[l,4]dioxino[2,3-6]pyridin-6-ylmethyl)- [(lα,5α,6α)-6-(6-methoxy-[l,5]naphth7ridin-4-yloxymethyI)-bicyclo[3.1.0]lmex-3-yl]- amine:
1.i. rac-(la,5a, 6a)-bicyclo[3.1.0]hex-2-en-6-yl-methanoh
To a solution of rac-(lα,5α,6α)- bicyclo[3.1.0]hex-2-ene-6-carbaldehyde (crude product obtained from bicyclo[2.2.1]hepta-2,5-diene (16 g) as described by M.E Jung et a in J. Org. Chem. (1997), 62, 4601-4609) in MeOH (300 ml) was added, at 0°C, sodium borohydride (13 g). The reaction was stirred at the same temperature for 1 h and watex (100 ml) was added. The volatiles were removed in vacuo and the residue was extracted twice with ether (2 x 300 ml). After drying over Na2SO4, and filtration, the solvent was removed in vacuo. The residue was purified over silica gel (EA-Hex 1-4 then 1-1) to afford the title compound as an oil (6.2 g).
1H NMR (CDCl3) δ: 5.91 (m, IH), 5.43 (m., IH), 3.53 (dd, J= 6.7, 11.3 Hz, IH); 3.42 (dd, J= 7.4, 11.3 Hz, IH); 2.61 (tdd, J= 1, 5, 15 Hz, IH); 2.39 (dd, J= 2, 17.8 Hz, IH); 1.80 (m, IH); 1.51 (m, 2H), 0.57 (m, IH). 1.ii. rac-(l a, 5 a, 6a)-(bicyclo[3.1.0]hex-2-en-6-ylmethoxy)-tert-butyl-dimethyl-silane:
To a solution of intermediate l.i (6.2 g) in DCM (250 ml) were added, at rt, DMAP (10.3 g) and tert-butylchlorodimethylsilane (8.5 g). The reaction was stirred at rt for 1 h, and the solvent was removed under reduced pressure. The residue was purified over silica gel (EA- Hex 1-4) to afford the title compound (10.2 g) as an oil.
1H NMR (CDCl3) δ: 5.90 (m, IH), 5.40 (m, IH); 3.56 (dd, J= 6, lO.8Hz, IH); 3.48 (dd, J= 6, 10.8 Hz5 IH); 2.51 (m, IH); 2.31 (m, IH); 1.75 (m, IH); 1.46 (m, IH); 0.9 (s, 9H); 0.07 (s, 6H).
1. iii. (Ia, 3 a, 5 a, 6a)- 6-(tert-butyl-dimethyl-silanyloxymethyl)-bicyc:lo[3.1.0]hexan-3-ok To an ice-cooled solution of intermediate l.ii (10.2 g) in THF (210 ml) was added borane.THF complex solution (IM in THF, 45 ml). The reaction was let under stirring at the same temperature for 11 h. After cooling down to 00C, EtOH (10 ml) was added followed by 3M aq. NaOH (90 ml) and 50% aq. hydrogen peroxide (80 ml). After stirring for 40 min at 00C, the reaction mixture was warmed to rt over 40 min. The two layers were separated. The aq. layer was extracted twice with EA (2 x 100 ml). The combined organic layers were washed with water (3 x 100 ml) and saturated sodium thiosulfate (100 ml). After washing with brine (100 ml), the organic phase was dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by chromatography (EA-Hex 1-4 then 1-2) to afford the title compound (6.2 g) as an oil. 1H NMR (CDCl3) δ: 4.01 (p, J= 7 Hz, IH); 3.39 (d, J= 6.3 Hz, 2H); 2.16 (dd, J= 6.3, 12.6 Hz, 2H); 1.66 (m, 2H); 1.56 (br s, IH); 1.19 (m, 2H); 0.9 (s, 9H); 0.74 (m, IH); 0.07 (s, 6H). 13C NMR (CDCl3) δ: 71.8, 65.9, 36.8, 25.9, 24.9, 20.4, 18.3, -4.3.
1.iv. (1 a, 3β, 5a, 6a)-(3-azido-bicyclo[3.1.0]hex-6-ylmethoxy)-tert-butyl-dimethyl-silane: To a solution of intermediate l.iii (5 g) in DCM (100 ml) cooled to 00C, were added successively TEA (5.8 ml) and then MsCl (1.91 ml). The reaction was stirred at the same temperature for 3 h. The reaction mixture was washed with diluted aq. saturated NaHCO3 (2 x 100 ml). The organic layer was dried over Na2SO4, filtered and concentrated to dryness. The residue was taken up in pentane (300 ml). The resulting solid was filtered off and the filtrate was concentrated in vacuo. This substance (6.5 g) was taken up in DMF (80 ml) and sodium azide (2.6 g) was added. The reaction mixture was heated at 8O0C overnight. After cooling, the reaction mixture was diluted with water (200 ml) and extracted with Hex (3 x 200 ml). The combined extracts were washed with brine, dried over Na2SC^, filtered and concentrated to dryness. The oily residue was further dried under high vacuum to give the title compound (4.9 g) as an oil. 1U NMR (CDCl3) δ: 4.12 (m, IH); 3.46 (d, J= 6Hz, 2H); 2.09 (m, 2H); 1.86 (dd, J= 1, 14.4 Hz, 2H); 1.25 (m, 2H); 1.19 (m, IH); 0.9 (s, 9H); 0.07 (s, 6H).
1.v. (1 a, 3β, 5 a, 6a)-[6-(tert-bιιtyl-dimethyl-silanyloxymethyl)-bicyclo [3.1. OJhex-3-ylJ- carbamic acid tert-butyl ester:
To a solution of intermediate l.iv (4.9 g) in THF (60 ml) and water (6 ml) was added PPh3 (9.6 g). The reaction mixture was heated at 600C for 2 h. After cooling to rt, IM NaOH
(40 ml) was added and BOC2O (4.36 g) was added. The reaction was stirred 3 h at rt and the volatiles were removed under reduced pressure. The residue was then extracted with EA (3 x
150 ml). The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was chromatographed (EA-Hex 1-19) to afford the title compound (5.2 g) as a white solid.
1H NMR (CDCl3) δ: 4.2 (br s, IH); 4.12 (m, IH); 3.46 (d, J= 6.3 HEz, 2H); 2.27 (m, 2H); 1.62 (m, 2H); 1.42 (s, 9H); 1.2 (m, 2H); 0.92 (s, 9H); 0.81 (m, IH); 0.05 (s, 6H).
1.vi. (1 a, 3β, 5 a, 6a)-(6-hydroxymethyl-bicyclo[3.1.0]hex-3-yl)-carbam ic acid tert-butyl ester:
To a solution of inteπnediate l.v (5.2 g) in THF (60 ml) was added a solution of TBAF (IM in THF, 20 ml). The reaction was stirred at rt for 3 h. The reaction mixture was then concentrated in vacuo. The residue was chromatographed (EA-Hex 1-1) to afford the title compound (3.3 g) as an oil.
1H NMR (CDCl3) δ: 4.2 (br s, IH); 4.12 (m, IH); 3.45 (d, J= 6 Hz, ZH); 2.29 (m, 2H); 1.62
(m, 2H); 1.42 (s, 9H); 1.25 (m, 2H); 0.93 (m, IH). MS (ESI, m/z): 228.3 [M+H+].
1.vii. (Ia, 5 a, 6a)-[6-(6-methoxy-[l, 5]naphthyridin-4-yloxymethyl)-bicyclo[3.1. OJhex-3-yl]- carbamic acid tert-butyl ester:
To a solution of intermediate l.vi (1 g), 6-methoxy-[l,5]naphthyridin-4-ol (0.775 g, prepared as described in WO 03/010138) and PPh3 (1.73 g) in THF (26 ml), was added dropwise DIAD (1.3 ml). The reaction mixture was stirred overnight at rt and concentrated to dryness. The residue Λvas purified over silica gel (DCM-MeOH 19-1) to afford the title compound (1.5 g) as a yellow foam.
MS (ESI, m/z): 386.5 [M+H+].
1.viii. (J a, 5 a, 6a)-6-(6-methoxy-[l, 5]naphthyridin-4-yloxymethyl)-bicyclo[3.1.0]hex- 3-ylamine:
A solution of intermediate l.vii (1.5 g) in TFA (7 ml) was stirred at rt for 30 min. The reaction was concentrated under HV and the residue was partitioned between 2N aq. NaOH (10 ml) and a DCM-MeOH mixture (9-1, 40 ml). The organic la^er was extracted twice more with the same mixture and the combined extracts were washed with brine and dried over Na2SO4. The residue was chromatographed over silica gel (DCME-MeOH 19-1 1% NH4OH) to afford the title compound (0.582 g) as a yellow oil. MS (ESI, m/z): 286.2 (MH+).
1.ix. (2, 3-dihydro-[l, 4]dioxino[2, 3-b]pyridin-6-ylmethyl)-[(l a, J a, 6a)-6-(6-methoxy- [1, 5]naphthyridin-4-yloxymethyl)-bicyclo[3.1. OJhex-3-ylJ -amine: To a solution of intermediate l.viii (0.085 g) in 1,2-DCE (6 ml) a.nd MeOH (2 ml) were added 3A molecular sieves (1.5 g) and 2,3-dihydro-[l,4]dioxino[2,3-Z>]pyridine-6-carbaldehyde (0.054 g, prepared as described in WO 2004/014361). The reaction was stirred at rt overnight. NaBH4 (0.1 g) was added and the reaction was stirred for 2 ti. The reaction mixture was filtered through Hydromatrix® (pretreated with aq. NaHCOs). The filtrate was concentrated in vacuo and the residue was chromatographed (DCM-MeOH 19- 1 1% aq. NH4OH) to afford the title compound (0.071 g) as a white solid.
1H NMR (CDCl3) δ: 8.58 (d, J= 5.2 Hz, IH); 8.15 (d, J= 9.0 Hz, IH); 7.12 (d, J= 7.9 Hz, IH); 7.1 1 (d, J= 9.0 Hz, IH); 6.89 (d, J= 5.2 Hz, IH); 6.83 (d, J= 7.9 Hz, IH); 4.43 (m, 2H); 4.24 (m, 2H); 4.13 (s, 3H); 4.06 (d, J= 6.8 Hz, 2H); 3.68 (s, 2H); 3.38 (m, IH); 2.18 (m, 2H); 1.86 (m, IH); 1.84 (br s, IH); 1.69 (dd, J= 3.0, 13.7 Hz, 2H); 1.26 (s, 2H). MS (ESI3 m/z): 435.3 [M+H+].
Example 2: (2,3-dihydro-benzo[l,4]dioxin-6-ylmethyI)-[(l a,5 α,6α)-6-(6-methoxy- [l,5]naphthyridin-4-yloxymethyI)-bicyclo[3.1.0]hex-3-yl]-amiiie:
This compound (0.072 g) was prepared from intermediate l.viii (0.100 g) and l,4-benzodioxan-6-carboxaldehyde (0.039 g) using the procedure of Example 1, step l.ix. MS (ESI, m/z): 434.5 [M+H+].
Example 3: -7-fl«oro-6-{(l α,5α,6α)-[6-(6-methoxy-[l,5]nap hthyridin-4-yloxymethyl)- bicyclo[3.1.0]hex-3-ylamino]-methyl}-4H-benzo[l,4]thiazin-3-one:
This compound (0.O99 g) was prepared from intermediate l.viii (0.100 g) and 7-fiuoro-3-oxo- 3,4-dihydro-2H-benzo[l,4]thiazine-6-carbaldehyde (0.081 g, prepared as described in WO 03/087098) using the procedure of Example 1, step l.ix. MS (ESI, m/z): 481 .5 [M+Η+].
Example 4: 6-{[(l α,5α,6α)-6-(6-methoxy-[l,5]naphthyridm-4-yloxymethyl)- bicyclo [3.1.0]hex-3-ylamino]-methyl}-4H-benzo [1,4] oxazin-3-one :
The title compound (0.081 g) was prepared from intermedia."te l.viii (0.100 g) and 3-oxo- 3,4-dihydro-2H-benzo[l,4]oxazine-6-carbaldehyde (0.068 g, prepared as described in WO 02/34754) using the procedure of Example 1, step l.ix.
1H NMR (CDCl3) δ: 8.63 (d, J= 5.2 Hz, IH); 8.21 (d, J= 9.O Hz, IH); 7.13 (d, J= 9.0 Hz, IH); 6.95 (d, J= 5.2 Hz, IH); 6.87 (m, 2H); 4.57 (s, 2H); 4.1 3 (s, 3H); 4.12 (d, J= 7.1 Hz, 2H); 3.58 (s, 2H); 3.40 (m, IH); 2.18 (m, 2H); 1.88 (m, IH); L .67 (dd, J= 2.6, 13.6 Hz, 2H); 1.51 (s, 2H); 1.7 (br s, IH). MS (ESI, m/z): 447.5 [M+H*].
Example 5: 6-{[(l a,5a,6ά)- 6-(6-methoxy-[l,5]naphthyridin-4-yloxymethyl)- bicyclo [3.1.0] hex-3-ylamino] -methyl}-4H-benzo [1 ,4] thiazin-3-one :
The title compound (0.051 g) was prepared from intermedia.te l.viii (0.085 g) and 3-oxo- 3,4-dihydro-2//-benzo[l,4]thiazine-6-carbaldehyde, using the procedure of Example 1, step l.ix. MS (ESI, m/z): 463.5 [M+H+].
Example 6: (lα,3>0,5α,6α)-{3-[(2,3-dihydro-benzo[l,4]dioxiii-6-ylmethyl)-amino]- bicyclo[3.1.0]hexane-6-carboxylic acid (6-methoxy-[l,5]naplithyridin-4-yl)-amide:
6.i. (1 a,3β,5a, 6a)—3-tert-butoxycarbonylamino-bicyclo[3.1, OJ/jex-6-carboxylic acid:
To an ice-chilled solution of intermediate l.vi (2.2 g) in DCM (22 ml), water (22 ml) and MeCN (22 ml) was added sodium periodate (9.5 g) and a solution of ruthenium trichloride (22 mg) in water (9 ml). The mixture was stirred at the same temperature for 4 h. The reaction mixture was diluted with EA- (100 ml). The solids were filtered off and MeOH (20 ml) was added to the filtrate. The resulting precipitate was removed by filtration. The filtrate was treated with a diluted solution of sodium hydrogenosulfite (10%, 35 ml) and the pH was adjusted to 2 by addition of IM aq. HCl. The organic layer was separated and the aq. layer was extracted with EA (2 x 100 ml). The combined extracts were washed with brine, dried over Na2SC^, and filtered. The filtrate was evaporated to dryness. The solid was triturated in Hex and filtered to yield the title compound (1.7 g) as a tan solid.
1H NMR (d6-DMSO) δ: 6.S (br s, IH); 3.91 (m, IH), 2.15 (rn, 2H); 1.68 (m, 4H); 1.5 (t, J= 2.9 Hz, IH); 1.37 (s, 9H). MS (ESI, m/z): 240.2.3 [M-HE+].
6.ii. (1 a, 3β, 5a, 6a)-[6-(6-me thoxy-[l, 5]naphthyridin-4-ylcarbctmoyl)-bicyclo[3.1. OJhex- 3-ylJ-carbanιic acid tert-butyl ester:
To a solution of intermediate 6.i (0.725 g), DIPEA (0.5 ml) and HATU (1.15 g) in DMF (6 ml) was added 6-methoxy-[l,5]naphthyridin-4-ylamine (0.525 g, prepared as described in WO 03/010138). The reaction was stirred at rt for 22h. The volatiles were removed under HV and the residue was chromatographed over silica gel (DCM-MeOH 19-1) to afford the title compound (0.65 g) as a yelloΛvish oil. MS (ESI, m/z): 399.7 [M+H+"].
6.iii. (1 a,3β,5a, 6a)~3-amino-bicyclo[3.1.0]hexane-6-carboxylic acid (6-methoxy- [1, 5]naphthyridin-4-yl) -amide :
A solution of intermediate 6.ii (0.65 g) in TFA (5 mL) was stirred at rt for 20 min. The reaction was concentrated under HV and the residue was partitioned between 2N NaOH (10 ml) and a DCM-MeOH (Θ-l, 40 ml). The organic layer was extracted twice more with the same mixture and the combined extracts were washed with brine and dried over Νa2Sθ4. The residue was evaporated under reduced pressure and chromatographed over silica gel (DCM- MeOH 19-1 1% NH4OH) to afford the title compound (0.27 g) as a colourless solid. MS (ESI, m/z): 299.3 [M+H"1"]. 6.iv. (1 a,3β,5a, 6a)-{3-[(2, 3-dihydro-ben∑ofl, 4]dioxin-6-ylmethyZ)-amino]- bicycloβ.1. OJhexane-6-carboxylic acid (6-methoxy-[l, 5]naphthyr-idin-4-yl)-amide:
To a solution of intermediate 6.iii (0.09 g) in 1,2-DCE (6 ml) and MeOH (2 ml) were added l,4-benzodioxan-6-carboxaldehyde (0.058 g) and powdered 3A molecular sieves (2 g). The resulting mixture was stirred at rt overnight. NaBH4 (0.1 g) was added and the mixture was stirred at rt for 1 h. The reaction mixture was filtered through a plug of Hydromatrix®, pretreated with NaHCO3 (6mL). The filtrate was concentrated in vacuo. The residue was chromatographed over silica gel (DCM-MeOH 19-1 1% concentrated NH4OH) to afford the title compound (0.12 g) as a foam. MS (ESI, m/z): 447.6 [M+H+].
Example 7: (^^^^^^-[(S-oxo-S^-dihydro^H-benzoIl^loxaziii-β-ylmethyl)- amino] -bicyclo [3.1.0] hexane-6-carboxylic acid (6-methoxy- [1,5] naphthy ridin-4-yl)- amide:
The title compound (0.071 g) was obtained from 3-oxo-3,4-dirrydro-2H-benzo[l,4]oxazine- 6-carbaldehyde (0.062 g) and intermediate 6.iii (0.090 g) by the method described in Example
6, step 6.iv.
1H NMR (d6- DMSO) δ: 10.68 (s, IH); 9.76 (s, IH); 8.64 (d, J= 5.2 Hz, IH); 8.37 (d,
J= 5.2 Hz, IH); 8.25 (d, J= 9.0 Hz, IH); 7.31 (d, J= 9.0 Hz, IH); 6.90 (m, 3H); 4.55 (s, 2H);
4.09 (s, 3H); 3.54 (s, 2H); 3.26 (m, IH); 2.63 (s, IH); 2.09 (m, 2H); 1.86 (s, br s, 2H); 1.73 (d, J= 15 Hz, IH).
MS (ESI, m/z): 460.4 [M+H+].
Example 8 : (1 a,3β,5a,6 α)-3-[(3-oxo-3,4-dihydro-2iϊ-pyrido [3 ,2-b] [1 ,4]thiazin- 6-ylmethyl)-amino]-bicyclo[3.1.0]hexane-6-carboxylic acid (6-methoxy- [1 ,5] naphthyridin-4-yl)-amide :
The title compound (0.025 g) was obtained from 3-oxo-3,4-dihydro- 2H-pyrido[3,2-&][l,4]thiazine-6-carbaldehyde (0.018 g, prepared as described in WO 2004/002992) and intermediate 6.iii (0.024 g) by the method described in Example 6, step 6.iv. MS (ESI5 m/z): 477.3 [M+Η+]. Example 9: (la,3>5,5fl^6a)-3-[(7-fluoro-3-oxo-3,4-dihydro-2H-benzo[l,4]thiaziri- 6-y lmethy l)-amino] -bicyclo [3.1.0] hexane-6-carboxy lie acid (6-methoxy- [ 1 ,5] naphthy ridin-4-yl)-amide :
The title compound (0.071 g) was obtained from 7-fluoro-3-oxo-3,-4-dihydro- 2H-benzo[l,4]thiazine-6-carbaldehyde (0.052 g) and intermediate ό.iii (0.062 g) by the method described in Example 6, step 6.iv. MS (ESI, m/z): 494.4 [M+Η+].
Example 10: l-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-2-[(l a,5a,6ά)-6-(6-methoxy- quinazolin-4-yloxymethyl)-3-aza-bicyclo[3.1.0]hex-3-yI]-ethanone:
10.i. (la,5a, 6a)-6-(6-methoxy-quinazolin-4-yloxyrnethyl)-3-aza-bicyclo[3.1. OJhex- 3-carboxylic acid benzyl ester:
To an ice-chilled solution of (l α,5α,6α)-6-riydroxymethyl-3-aza-bicyclo[3.1 .0]hexane- 3-carboxylic acid benzyl ester (2 g) (obtained as described by K.E. Brighty et aL in Synlett (1996), 1097-1099) in DMF (40 ml) was added NaH (60% dispersion in mineral oil, 0.357 g). After stirring for 15 min, 4-chloro-6-methoxy-quirxazoline (1.57 g) was added in one portion. The reaction was then stirred for 2 h at rt. Water (50 ml) was added and the reaction mixture was extracted with EA (2 x 100 ml). The combined organic layers were washed with brine and dried over Na2SO4. After filtration, the filtrate was concentrated to dryness. TThe residue was purified over silica gel (EA) to afford the title compound (3.1 g) as a foam. 1H NMR (CDCl3) δ: 8.68 (s, IH); 7.86 (d, J= 9. 1 Hz, IH); 7.48 (dd, J= 2.9, 9. 1 Hz, IH); 7.41 (d, J= 2.9 Hz, IH); 7.31 (m, 5H); 5.12 (s, 2H); 4.48 (m, 2H); 3.98 (s, 3H); 3.76 (dd, J= 11.8, 18.1 Hz, 2H); 3.49 (m, 2H); 1.70 (m, 2H); 1.32 (m, IH).
10. ii. 4- [(I ex, 5 a, 6a)-3-aza-bicyclo[3.1.0]hex-6-ylmethoxy]-6-methoxy-quinazoline :
To a solution of intermediate 10.i (3.05 g) in MeOH (100 ml) was added 20% Pd(OH)2 on charcoal (2 g). The reaction mixture was stirred under hydrogen atmosphere for 9>0 min. The catalyst was removed by filtration and the filtrate was concentrated to dryness to afford the title compound (2.31 g) as a white solid.
1H NMR (CDCl3) δ: 8.68 (s, IH); 7.86 (d, J= 9.1 Hz3 IH); 7.48 (dd, J= 2.9, 9.1 Hz, IH);
7.41 (d, J= 2.9 Hz, IH); 4.50 (d, J= 7.2 Hz, 2H); 3.98 (s, 3H); 3.10 (d, J= 11.4 Hz, 2H); 2.96 (br d, J= 11.4 Hz, 2H); 1.60 (m, 2H); 1.21 (try, IH). MS (ESI, m/z): 272.2 [M+H+]
10.iii. l-(2, 3-dihydro-benzo[l , 4]dioxin-6-yl)-2-[(l a, 5 a, 6a)-6-(6-methoxy-quinazolin- 4-yloxymethyl)-3-aza-bicyclo[3.1. OJhex-3-ylJ-ethanone:
To a solution of intermediate lO.ii (0.8 g) in DMF (6 ml) were added DIPEA (0.53 ml) and 2- chloro- l-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethanone (0.744 g). The reaction was heated at 7O0C for 3 h. The volatiles were removed under reduced pressure . The residue was chromatographed (DCM-MeOH 19-1) to afford the title compound (1.15 g) as a yellowish solid. MS (ESI, m/z): 448.6 [M+H+].
Example 11: rαc-l-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-2-[(lα,5α,6α)— 6-(6-methoxy- quinazolin-4-yloxymethyl)-3-aza-bicyclo[3.1.0]hex-3-yl]-ethanol:
To a solution of the compound of Example 10 (1.05 g) in MeOH (20 ml) was added at rt NaBH4. (0.25 g). The reaction was stirred for 2 h. Water (10 ml) was added and the volatiles were removed under reduced pressure. The residue was dissolved in EA and filtered through a plug of Hydromatrix® (pretreated with aq. NaHCOs). The filtrate was concentrated in vacuo and the residue was purified by chromatography (DCM-MeOH 9-1) to afford the title compound (0.78 g) as a yellowish foam. MS (ESI, m/z): 450.6 [M+H+].
Example 12: rαc-carbamic acid l-(2,3-dihydro-benzo[l,4]dioxin-6-yl> 2-[(lα,5α,6α)-6-(6-methoxy-quinazolin-4-yloxymethyl)-3-aza-bicyclo[3.1.0]hex-3-yI]- ethyl ester:
To a solution of the compound of Example 11 (0.53 g) in DCM (6 ml) was added at 00C, trichloroacetylisocyanate (0.18 ml). The reaction was stirred at the same temperature for 1 h. The volatiles were removed under reduced pressure and the residue was taken up in MeOH (6 ml). 2-methyl-2-propanol (6 ml) and THF (2 ml). Saturated aq. K2CO3 (3 ml) was added and the mixture was refluxed for 3 h. The volatiles were removed under reduced pressure and the residue was extracted with DCM-MeOH (9-1, 2 x 50 ml). The combined extracts were washed with brine and dried over Na2SO4. After filtration, the solvent was evaporated to dryness. The residue was chromatographed (DCM-MeOH 19-1, 1% concentrated aq. NH4OH) to afford the title compound (0.220 g) as a foam. MS (ESI, m/z): 493.4 [M+H+]
Example 13: 4-{(lα,5α,6α)-3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-3-aκa- bicyclo[3.1.0]hex-6-ylmethoxy}-6-methoxy-quinoline:
13.i. (Ia, 5 a, 6a)-6-(6-methoxy-quinolin-4-yloxymethyl)-3-aza-bicyclo[3.1. OJhexane— 3-carboxylic acid benzyl ester:
To a solution of (lα,5α,6α)-6-hydro:xymethyl-3-aza-bicyclo[3.1.0]hexane-3-carbo:xylic acid benzyl ester (1 g), 6-methoxy-quinolin-4-ol (0.85 g) and PPh3 (1.59 g) in THF (3 O ml) and DMF (2 ml) was added dropwise DIAD (1.2 ml). The reaction mixture was stirred at rt for 4 h. The reaction mixture was concentrated to dryness. The residue was diluted with 0.2NHCl (100 ml). The aq. layer was washed three times with ether (3 x 100 ml). The pH was then made basic using IMNaOH (20 ml). The aq. layer was extracted with EA (2 x 15O ml). The combined extracts were washed with brine and dried over Na2SO4. After filtration, tlie solvent was removed under reduced pressure and the residue was purified by chromatography (EA- MeOH 19-1) to afford the title compound (0.97 g) as a thick oil. 1H NMR (CDCl3) δ: 8.60 (d, J= 5.8 Hz, IH); 7.93 (d, J= 9.2 Hz, IH); 7.43 (d, T= 2.8 Hz, IH); 7.35 (m, 6H); 6.64 (d, J= 5.2 Hz, IH); 5.12 (s, 2H); 4.10 (d, J= 6.8 Hz, 2HC); 3.97 (s, 3H); 3.80 (dd, J= 10.8, 20.1 Hz, 2H); 3.52 (m, 2H); 1.70 (m, 2H); 1.32 (m, IH).
13.ii. 4-[(l a, 5(X16a)-3-aza-bicyclo[3. 1.0]hex-6-ylmethoxy]-6-methoxy-quinoline:
The title amine (0.63 g) was obtained from intermediate 13. i (0.97 g) using the xnethod of Example 10, step lO.ii.
1H NMR (CDCl3) δ: 8.60 (d, J= 5.2 Hz, IH); 7.93 (d, J= 9.2 Hz, IH); 7.46 (d, ^= 2.8 Hz, IH); 7.35 (dd, J= 2.8, 9.2 Hz, IH); 5.12 (s, 2H); 4.10 (d, J= 6.8 Hz, 2H); 3.9>7 (s, 3H); 3.16 (d, J= 11.4 Hz, 2H); 3.01 (d, J = 11.4 Hz, 2H), 20.1Hz, 2H); 3.52 (m, 2H); 2.18 (br s, IH); 1.70 (m, 2H); 1.32 (m, IH).
13.iii. Toluene -4-sulfonic acid 2-(2, 3 -dihydro-benzo[l,4]dioxin-6-yl)-ethyl ester.
To a solution of 2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethanol (3.55 g; prepared as described in EP 350309) in DCM (70 ml) were added at 00C, DMAP (4.2 g) and ^-toluene sulfonyl chloride (4.13 g). After stirring at this temperature for 20 min, the reaction mixture was warmed to rt. After 2 h, the reaction mixture was concentrated in vacuo and the residue partitioned between EA (150 mL) and a saturated solution of CuSO4 (50 mL). Tie organic layer was further washed with the same solution (4 x 50 ml) and brine (50 ml). After drying over Na2SO4 and filtration, the filtrate was evaporated to dryness.
1H NMR (CDCl3) δ: 7.73 (m, 2H); 7.31 (m, 2H); 6.74 (d, J= 8.1 Hz, IH); 6.59 (m, 2H); 4.23 (s, 4H); 4.16 (t, J= 7.1 Hz, 2H); 2.84 (t, J= 7.1 Hz, 2H); 2.45 (s, 3H).
13. rv. 4-{(la,5a,6a)-3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-3-aza- bicycloβ.1.0]hex-6-ylmethoxy}-6-methoxy-quinoline:
To a solution of intermediate 13. ii (0.4 g) in DMF (6 ml) were added DIPEA-. (0.53 ml) and intermediate 13.iii (0.535 g). The reaction was heated at 700C overnight. The volatiles were removed under reduced pressure and the residue was chromatographed (DCML-MeOH 19-1, 1% concentrated NH4OH) to afford the title compound (0.138 g) as a yellowish, solid. MS (ESI, m/z): 433.7 [MH-H+].
Example 14: 4-{(lα,5α,6α)-3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl] -3-aza- bicy do [3.1.0] hex-6-ylmethoxy}-6-methoxy-quinazoline:
The title compound (0.388 g) was obtained from intermediate 10. ii (0.4 g) using the method of Example 13, step 13. iv.
MS (ESI, m/z): 434.6 [M+H+].
Example 15 : 8-{(lα,5α,6α)-3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-3-aza- bicy clo [3.1.0] hex-6-y lmethoxy}-2-methoxy- [1 ,5] naphthy ridine :
15. i . (lcc,5a,6a)-6- (6-methoxy-[l, 5]naphthyridin-4-yloxymethyl)-3-aza- bicycloβ.1. OJhexane-3-carboxylic acid benzyl ester.
This compound (0.98 g) was obtained from 6-methoxy-[l,5]naphthyridin-4-ol (0.932 g) and (lor,5«,6α)-6-hydroxymethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester (1.1 g) using the method of Example 13, step 13. i. MS (ESI, m/z) : 406.5 [M+H+].
15.ii. 8-[(loc,5a,6a)-3-aza-bicyclo[3.1.0]hex-6-ylmethoxy]-2-methoxy-[l,5]nap>hthyridine:
This compound (0.68 g) was obtained from intermediate 15.i (0.98 g) using the method of Example 10, step lO.ii. 1U NMR (CDCl3) δ: 8.60 (d, J= 5.2 Hz, IH); 8.16 (d, J= 9.1 Hz, IH); 7.12 (d, J= 9.1 Hz, IH); 6.9O (d, J= 5.2 Hz, IH); 4.20 (d, J= 6.7 Hz, 2H); 4.13 (s, 3H); 3.13 (d, J= 11.4 Hz, 2H); 2.99 (d, J= 11.4 Hz, 2H); 2.08 (br s, IH); 1.64 (m, 2H); 1.31 (m, IK). MS (ESI, m/z): 272.6 [MH-H+]
15.Hi. 8- {(la, 5 a, 6a)-3-[2-(2, 3-dihydro-benzo[l, 4]dioxin-6-yl)-ethyl]-3-aza- bicyclo[3.1.0]hex-6-ylmethoxy}-2-methoxy-[l, 5]naphthyridine :
The title compound (0.103 g) was obtained from intermediate 15.ii (0.136 g) using the method of Example 13, step 13.iv.
1H NMR (CDCl3) δ: 8.60 (d, J= 5.2 Hz, IH); 8.16 (d, J= 9.0 Hz, IH); 7.11 (d, J= 9.0 Hz5 IH); 6.9O (d, J= 5.2 Hz, IH); 6.77 (d, J= 8.2 Hz, IH); 6.71 (d, J= 2.2 Hz, IH); 6.65 (dd, J= 2.2, 8.0 Hz, IH); 4.24 (s, 4H); 4.13 (overlapped d, J= 7.0 Hz, 2H); 4.12 (s, 3H); 3.21 (br d, J= 7.O Hz, 2H); 2.67 (br s, 4H); 2.43 (br d, J= 7.0 Hz, IH); 1.90 <br s, IH); 1.60 (br s, 2H). MS (ESI, m/z): 434.6 [M+H+].
Example 16 : l-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-2-[(lα,5o^6α)-6-(6-methoxy- [l,5]naplithyridin-4-yloxymethyl)-3-aza-bicyclo[3.1.0]hex-3-yl]-etha.iione;
The title compound (0.38 g) was obtained from intermediate 15. H (0.5 g) using the method of
Example 10, step 10. Hi.
MS (ESI, m/z): 448.6 [M+H+]
Example 17 : /•αc-l-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-2-[(lα,5α,6>α)-6-(6-methoxy- [l,5]naphthyridin-4-yloxymethyl)-3-aza-bicyclo[3.1.0]hex-3-yI]-etha-iiol:
The title compound (0.286 g) was obtained from the compound of Example 16 (0.37 g) using the method of Example 11. MS (ESI, m/z): 450.5 [MH-H+] Example 18: rαc-carbamic acid l-(2,3-dihydro-benzo[l,4]dioxin-6-yI)- 2-[(l«,5α,6cκ)-6-(6-methoxy-[l,5]naphthyridin-4-yIoxymethyl)-3-aza bicyclo[3.1.0]hex- 3-yl]-ethyl ester:
The title compound (0.045 g) was obtained from the compound of Example 17 (0.67 g) using the method of Example 12.
1H NMR (d6-DMS0) δ: 8.56 (d, J= 5.2 Hz, IH); 8.34 (br s, IH); 8.16 (d, J= 9.0 Hz, IH); 7.20 (d, J= 9.0 Hz, IH); 7.12 (d, J= 5.2 Hz, IH); 6.76 (m, 3H); 6.54 (br s, IH); 5.47 (m, IH); 4.19 (s, 4H); 4.10 (d, J= 6.4 Hz, 2H); 4.00 (s, 3H); 3.02 (br t, J= 9.0 Hz, 2H); 2.75 (m, IH); 2.58 (m, IH); 2.39 (m, 2H); 1.74 (br s, 2H); 1.34 (s, IH). MS (ESI, m/z): 493.4 [M+H+].
Example 19 : r«c-(lα,5α,6α)-4-{3-[2-(2,3-dihydro-beπzo>[l,4]dioxin-6-yl)-ethyl]-3-aza- bicycloβ.l.OJhex-δ-ylmethoxyJ-quinoIine-β-carbonitrile:
19. i. (la,5oc, 6a)-6-hydroxynιethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester: To a solution of (lα,5α,6α)-6-hydroxymethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester (2.8 g) in MeOH (100 ml) was added 20% Pd(OH)2 on charcoal (0.6 g). The reaction was stirred under hydrogen atmosphere for 1 h. 0.2iV aq. HCl (50 ml) was added and the reaction mixture was filtered. The volatiles were removed under reduced pressure and the residue was partitioned between dioxane (50 ml) and 3M aq. NaOH (15 ml). BOC2O (4 g) was added and the reaction was stirred for 1 h. The volatiles were removed under reduced pressure and the residue was extracted twice with EA (2 x 150 ml). The combined extracts were washed with brine and dried over Na2SO4. After filtration, the solvent was removed in vacuo and the residue was purified by chromatography (EA-Hex 2-1 then 1-0) to afford the title compound (2.4 g) as an oil. MS (ESI, m/z): 236.3 [M+Na].
19.ii. (Ia, 5 cz, 6a)-6-(6-cyano-quinolin-4-yloxymethyl)-3-aza-bicyclo[3.1. OJhexane- 3-carboxylic acid tert-butyl ester:
To a solution of intermediate 19.i (1 g), 6-cyano-quinolin-4— ol (0.8 g, prepared as described in WO 2004/002992) and PPh3 (1.59 g) in THF (28 mL) and DMF (2 ml) was added dropwise DIAD (1.4 ml). The reaction mixture was stirred at rt overnight and concentrated to dryness under reduced pressure. The residue was chromatographed (DCM-MeOH 19-1) to afford a yellow oil (1.06 g). MS (ESI, m/z): 366.2 [M+H+].
19.iii. 4-[(lα,5α,6α)-3-aza-bicyclo[3.1.0]hex-6-ylmethoxy]-quinoline-6-carbonitrile:
A solution of intermediate 19.ii (1.06 g) in TFA (6 ml) was stirred at rt for 36 h. The volatiles were removed under reduced pressure and the residue was taken up in saturated NaHCCh. The solids were filtered off and then dissolved in MeOH. The organic layer was concentrated to dryness and the residue was purified by chromatography (DCM-MeOH 19-1, 1% concentrated NH4OH) to afford the title compound (0.143 g). MS (ESI, m/z): 266.4 [M+H+]
19.iv. rac-(l a, 5 a, 6a)-4- {3-[2-(2, 3-dihydro-benzo[l, 4] dioxin-6-yiJ-ethyl] -3-aza- bicyclo[3.1.0]hex-6-ylmethoxy}-quinoline-6-carbonitrile\
The title compound (0.O52 g) was obtained by the method of Example 13, step 13.iv from intermediate 19.iii (0.1OO g) and intermediate 13.iii (0.152 g). MS (ESI, m/z): 428.4 [M+H+].
Example 20 : 3-chIoro-4-{(l α,5α,6α)-3-[2-(2,3-dihydro-benzo [l,4]dioxin-6-yl)-ethyl]- 3-aza-bicycIo [3.1.0] hex-6-ylmethoxy}-6-methoxy-quinoline :
20. i. (1 a, 5a, όaJ-ό-β-chloro-ό-methoxy-quinolin^-yloxymethylj-J-aza-bicyclop.1. OJhexane- 3-carboxylic acid tert-butyl ester:
The title compound (2.6 g) was obtained by the method of Example 1, step l.vii from 3-chloro-6-methoxy-quinolin-4-ol (1.65g, prepared as described in WO 02/40474) and intermediate 19.i (1.4 g). MS (ESI, m/z): 405.2 [MH-H+].
2O.ii. 4-[(l a,5 cc,6a)-3-aza-bicyclo[3.1.0]hex-6-ylmethoxy] S-chloro-ό-methoxy-quinoline:
This compound was prepared from (lα,5α,6α)-6-(3-chloro-6-methoxy-quinolin- 4-yloxymethyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (2.6 g) according to the method described for Example 19, step 19.iii to afford a yellow solid (1.4 g). MS (ESI, m/z): 305.4 [M+H+]. 2O.iii. 3-chloro-4-{(la,5a,6a)-3-[2-(2,3-ciihydro-benzo[l,4]dioxin-6-yl)-ethyJ]-3-aza- bicyclo[3.1.0]hex-6-ylmethoxy}-6-methoxy-quinoline:
The title compound (0.020 g) was obtained by the method of Example 13, step 13. iv from intermediate 2O.ii (0.200 g) and intermediate 13.iii (0.182 g). MS (ESI, m/z): 467.5 [M+H+]
Example 21: rαc-4-{(lα,5c^6α)-3-[2-hydroxy-2-(3-oxo-3,4-dihydro-
2H-benzo [1 ,4] oxazin-6-yl)-ethyl]-3-aza- t>icyclo [3.1.0] hex-6-ylmethoxy}-q»iinoline-
6-carbonitriIe:
To a solution of intermediate 19.iii (0.1 g) in DMF (3.5 ml) were added D3PEA (0.132 ml) and 2-chloro-l-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethanone (0.093 g). The reaction was heated at 700C for 1 h. The volatiles were removed under reduced pressure and the residue was taken up in MeOH (6 ml) and NaBO4 (0.03 g) was added at 00C. The reaction mixture was stirred for 1 h and concentrated to dryness. The residue was chromatographed (DCM-
MeOH 19-1 1% concentrated aq. ammonia) to afford the title compound- (0.082 g) as an orange solid.
MS (ESI, m/z): 457.5 [M+H+].
Example 22 : rac-2- [(I a,5 α,6 α)-6-(3-chlo ro-6-methoxy-quinolin-4-yloxy m «thy l)-3-aza- bicyclo[3.1.0]hex-3-yl]-l-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethanol:
According to the procedures described in Examples 10 and 11, the title compound (0.410 g) was obtained in two steps from intermediate 20. ii (0.5 g) as a foam. MS (ESI, m/z): 483.6 [IvH-H+].
Example 23 : rαc-carbamic acid 2-[(l«,5a,6a)-6-(3-chloro-6-methoxy-q»iiiiolin-
4-yloxymethyl)-3-aza-bicyclo[3.1.0]hex-3-yl]-l-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl ester:
This compound was prepared according to the method of Example 12 from the compound of Example 22 (0.35 g). A foam (0.290 g) was obtained. MS (ESI, m/z): 526.4 [IvH-H+]. Example 24: 6-{2-[(l α,5α,6α)-6-(3-chIoro-6-methoxy-quinolin-4-yloxymetImyI)-3-aza- bicycIo[3.1.0]hex-3-yI]-l-hydroxy-ethyl}-4JΪ-benzo[l,4]oxazin-3-one:
To a solution of intermediate 20. ii (0.483 g) in DMF (8 ml) was added 6-(2-chloro-acetyl)- 477-benzo[l,4]oxazin-3-one (0.375 g) and DIPEA (0.56 ml). The mixture was heated at 700C for 30 min. After the volatiles were removed, under reduced pressure, the residue was taken up in MeOH (15 ml) and NaBH4 (0.19 g) was added at rt. The reaction was then stirred for 30 min and the volatiles were removed under reduced pressure. The residue was purified over silica gel (DCM MeOH 19-1) to afford the title compound (0.380 g) as a yellowish foam. MS (ESI, m/z): 496.5 [M+H*].
Example 25 : 5-{(lα,5α,6α)-3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yI)-ethyl]-3-aza- bicyclo [3.1.0] hex-6-ylmethoxy}-3-methoxy-quinoline:
25. i . 3, 5-dibromoquinoline :
To concentrated H2SO4 (130 ml) was added dropwise at 00C, over 80 min, 3-bromoquinoline (50 g) at a rate allowing the internal temperature to be maintained between 0° and 100C. After trie addition was complete, NBS (48 g) was added portionwise and the reaction mixture was stirred at rt overnight. The reaction mixture was poured onto ice (2 1) and the xesulting solid was dissolved in DCM (600 ml). The aq. layer was further extracted with DClVI (600 ml) and the combined extracts were washed with liU/NaOH (300 ml) and concentrated in vacuo. The residue was dispersed in silica gel and the resulting dispersal was loaded on the top of a column and eluted with a DCM-Hex (1-1, 3 1) then DCM (3 1) and finally DCM-ether (1-1, 2 1). The title compound was recovered from the last fraction after evaporation to yield 40 g of a white solid.
1H NMR (CDCl3) δ: 8.94 (d, J= 2.2 Hz, IH); 8.73 (d, J= 2.2 Hz, IH); 8.08 Cd, J= 8.5 Hz, IH); 7.88 (d, J= 7.5 Hz, IH); 7.62 (dd, J= 7.5, 8.5 Hz, IH).
25. ii. 5-bromo-3-methoxyquinoline:
To a mixture of sodium methoxide (14.5 g) in DMPU (350 ml) heated at 1250C, was added in one portion 3, 5-dibromoquinoline (34.5 g). The reaction was then heated at the same temperature for 1 h. The reaction mixture was then cooled to rt and poured onto ice (300 g). After the ice melt, the solid was filtered off and dried under vacuum. Thte filtrate was extracted with ether (4 x 150 ml). The combined extracts were washed with biine and dried over Na2SO4. After filtration, the solvent was evaporated and the residue was purified oΛ^er silica gel (Hex-EA 4-1) to afford a material that was pooled with the solid. The material was dissolved in DCM and dried over Na2SO4. After filtration and evaporation, the solid was further dried under HV to afford the title compound (24.5 g) as a beige solid. 1H NMR (CDCl3) δ: 8.68 (d, J =2.8 Hz, IH); 8.03 (d, J= 8.3 Hz, IH); 7.80 (d, J= 7.5 IHz, IH); 7.72 (d, J= 2.8 Hz5 IH); 7.42 (dd, J= 7.5, 8.3 Hz, IH); 4.02 (s, 3H). MS (ESI, m/z): 239.7 [M+H+].
25.iii. 3-methoxy-5-(4, 4, 5, 5-tetramethyl-[l, 3, 2]dioxaborolan-2-yJ)-quinoline:
To a mixture of Z>/£(pinacolato)diboron (1.92 g), l,l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (0.5 g) and potassium acetate (1.9 g) Avas added a solution of intermediate 25.ii (1.5 g) in DMSO (45 ml). The resulting mixture ^vas stirred at 80°C overnight. After cooling, the reaction mixture was diluted with water (100 ml) and EA (100 ml). The two layers were decanted and the aq. layer was extracted twice with EA
(2 x 100 ml). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The brown residue was chromatographed (EA-Hex 1-4) to afford the title boronate as a white solid (1.3 g).
1U NMR (CDCl3) δ: 8.67 (d, J= 2.9 Hz, IH); 8.49 (d, J= 2.9 Hz, IH); 8.12 (m, 2H); 7.55 (m, IH); 3.97 (s, 3H); 1.42 (s, 12H). MS (ESI, m/z) : 285.8 [M+H"1"].
25. iv. 3-methoxy-quinolin-5-ol:
To an ice-chilled solution of intermediate 25. iii (1.35 g), in THF (35 ml) were added ?>k£ aq. NaOH (4.25 ml) and then 30% aq. hydrogen peroxide (2 ml). The reaction mixture was stLrred at the same temperature for 1 h. Water (50 ml) and 3N aq. HCl was added until the brright yellow colour vanished to leave a colourless reaction mixture (pH 6). The reaction mix-ture was then diluted Λvith EA (100 ml). The two layers were decanted and the aq. layer was extracted twice more (2 x 100 ml). The combined organic layers were washed with bzrine, dried over Na2SO-V, filtered and concentrated to dryness. The residue was triturated with Et2O and the solid was filtered to afford after drying the title compound (0.62 g). 1H NMR (d6-DMSO) δ: 10.34 (s, IH); 8.60 (d, J= 3.0 Hz, IH); 7.76 (d, J= 3.0 Hz, IH); 7.39 (m, 2H); 6.92 (dd, J= 1.4, 7.2 Hz, IH); 3.92 (s, 3H) MS (ESI, m/z): 175.8 [M +H+]. 25.v. (1 cx,5cc,6a)-6-(3-methoxy-quinolin-5-yloxymethyl)-3-aza-bicyclo[3.1. OJhexane- 3-carboxylic acid benzyl ester:
The title compound (0.7 g) was obtained as an oil using the method of Example 1, step l.vi i and starting from 3-methoxy-quinolin-5-ol (0.62 g) and intermediate 19.i (0.875 g). 1H NMR (CDCl3) δ: 8.69 (d, J= 3.0 Hz, IH); 7.81 (d, / = 3.0 Hz, IH); 7.67 (d, J= 8.4 HE, IH); 7.44 (dd, J= 7.6, 8.4 Hz, IH); 7.37 (m, 5H); 6.82 (d, J= 7.6 Hz, IH); 5.15 (s, 2H> ; 4.08 (dd, J= 4.8, 6.9 Hz, 2H); 4.00 (s, 3H); 3.83 (d, J= 10.9 Hz, IH); 3.77 (d, J= 10.9 Hz;, IH); 3.53 (m, 2H); 1.70 (m, 2H); 1.31 (m, IH). MS (ESI, m/z): 406.2 [M +H+].
25.vi. 5-/(1 a, 5 a, 6a)-3-aza-bicyclo[3.1.0]hex-6-ylmethoxyJ-3-methoxy-quinoline:
This compound (0.35 g) was obtained as a colourless oil starting from intermediate 25.^v (0.7 g) and using the method of Example 10, step 10. ii. MS (ESI, m/z): 271.3 [M +H+].
25.vii. 5-{(l a,5a, 6a)-3-[2-(2, 3-dihydro-benzo[l, 4]dioxirz-6-yl)-ethyl]-3-aza- bicyclo[3.1.0]hex-6-ylmethoxy}-3-methoxy-quinoline:
The title compound (0.094 g) was obtained as a colourless foam using the procedure described in Example 13, step 13. iv and starting from intermediate 25.vi (0.1 g) and intermediate 13. Hi (0.123 g).
1H NMR (d6-DMSO) δ: 8.65 (d, J= 3.0 Hz, IH); 7.77 (d, J= 3.0 Hz, IH); 7.53 (<d, J= 8.2 Hz, IH); 7.48 (dd, J= 7.6, 8.2 Hz, IH); 7.02 Cd5 J= 7.6 Hz, IH); 6.69 (m, 3IQ; 4.19 (s, 4H); 4.04 (d, J= 6.9 Hz, 2H); 3.95 (s, 3H); 2.89 Cm, 2H); 2.56 (m, 2H); 2.34 (m, 2IQ; 1.63 (m, 2H); 1.54 (m, 2H); 1.27 (m, IH). MS (ESI, m/z): 433.1[M +H+].
Example 26: 6-{(l α,5α,6α)-2-[6-(3-methoxy-quinolin-5-yloxymethyl)-3-aza- bicycIoIS.l.Ojhex-S-y^-acetylJ^H-benzollj^oxazin-S-one:
To a solution of intermediate 25.vi (0.125 g) in DMF (2 ml) were added DIPEA (0.17 ml) and 2-chloro-l-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethanone (0.104 g). The reaction mixture was heated at 70°C for 1 h and then diluted with water (30 ml). The solid was filtered off and dried under HV to afford the title compound (0.093 g) as a yellowish foam. MS (ESI, m/z): 460.5[M +H+]. Example 27 : 6-{l-b^droxy-2-[(lα,5α,6α)-6-(3-methoxy-quinolin-5-yloxymethyI)-3-aza- bicyclo[3.1.0]hex-3-yl]-ethyl}-4H-benzo[l,4]oxazin-3-one:
To a solution of the compound of Example 26 (0.083 g) in MeOH (3 ml) was added at rt NaBH4 (0.1 g). The reaction was stirred for 30 min and the volatiles were removed under reduced pressure. The residue was purified over silica gel (DCM MeOH 19-1) to afford the title compound (0.071 g) as a white foam. MS (ESI, m/z): 462.4 [M+H+].
Example 28 : (lα,5cκ,6α)-3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-3-aza- bicyclo[3.1.0]hexane-6-carboxylic acid (2-cyano-quinolin-8-yl)-amide:
28. i. (1 a, 5 cc, 6a)-6-carbamoyl-3-aza-bicyclo[3.1. OJhexane-3-carboxylic acid benzyl ester:
To a solution of {\ a, 5α,6α)-3-aza-bicyclo[3.1.0]hexane-3,6-dicarboxylic acid 3-benzyl ester (4.65 g) (obtained as described by K.E. Brighty et al. in Synlett (1996), 10^7-1099) in DCM (80 ml) were added DMF (0.6 ml) and oxalyl chloride (2.2 ml). The reaction was stirred at rt for 1 h, and the volatiles were removed under reduced pressure. The residue was then diluted with THF (80 ml) and DCM (10 ml) and concentrated aq. NH4OH (80 ml) was added quickly. After stirring at rt for 3 h, the volatiles were removed under reduced pressure and the residue was filtered off and thoroughly washed with water until neutral pH was reached. The solid was collected by filtration, and a recrystallisation from EA afforded the title compound (2.95 g) as a white solid. MS (ESI, m/z): 261.4 [M+H+] .
28. ii. (1 a, 5a, 6a)-6-(2-cyano-quinoHn-8-ylcarbamoyl)-3-aza-bicyclo[3.1. OJhexane- 3-carboxylic acid benzyl ester:
A mixture of intermediate 28. i (0.522 g), rac-2,2'-bis(diphenylphosphino)-l,r-binaphtyl (0.089 g), tris (dibenzylideneacetone) dipalladium(0)-chloroform complex (0.036 g) and cesium carbonate (0.8 g) was degassed. After 10 min, dioxane (25 ml) was added and the mixture was sonicated for 5 min. Trifluoro-methanesulfonic acid 2-cyano-quinolin-8-yl ester (0.602 g) (prepared as described in WO 03/010138) was added and the reaction was refluxed overnight. The reaction mixture was then filtered through celite (rinsed Λvith THF). After concentration to dryness, the residue was recrystallized from an EA-MeOH mixture to give the title compound (0.82 g) as a yellowish solid. MS (ESI, m/z): 413.2 [M+H+].
28. in. (1 a,5 a,6a)-3-aza-bicyclo[3.1.OJhexane-6-carboxylic acid (2-cyano-quinolin-8-yl)- amide:
A solution of intermediate 28. ii (0.275 g) in TFA (6 ml) was stirred at rt for 36 h. The volatiles were removed under reduced pressure and the residue was taken up in saturated NaHCO3. The solids were filtered off and then dissolved in MeOH. The organic layer was concentrated to dryness and the residue was purified by chromatography (DCM-MeOH 19-1, 1% concentrated aq. NH4OH) to afford the title compound (0.2 g) as a solid. MS (ESI, m/z): 279.5 [M+H+].
28.iv. (1 a,5a,6a)-3-[2-(2, 3-dihydro-benzo[l, 4]dioxin-6-yl)-ethyl]-3-aza- bicyclo[3.1. OJhexane-6-carboxylic acid (2-cyano-quinolin-8-yl)-amide:
The title compound (0.124 g) was obtained from intermediate 28.iii (0.143 g) by the method of Example 13, step 13. iv. MS (ESI5 m/z): 441.2 [M+H*].
Example 29: (lα,5α,6α)-3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-3-aza- bicyclo[3.1.0]hexane-6-carboxy!ic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide:
29. i. (la,5a,6a)-6-C6-methoxy-[l,5]naphthyridin-4-ylcarbamoyl)-3-aza- bicychβ.1. OJhexane-3-carboxylic acid benzyl ester:
This compound was prepared from intermediate 28. i (0.776 g) and trifluoro-methanesulfonic acid 6-methoxy-[l,5]naphthyridin-4-yl ester (0.92 g) by the method of Example 28, step 28.ii.
A white solid (0.98 g) was obtained.
1H NMR (d6-DMSO) δ: 10.06 (s, IH); 8.65 (d, J= 5.2 Hz, IH); 8.65 (d, J= 5.2 Hz, IH);
8.24 (d, J= 9.0 Hz, IH); 7.39 (m, 5H); 7.29 (d, J= 9.0 Hz, IH); 5.08 (s, 2H); 4.17 (s, 3H);
3.67 (m, 2H); 3.54 Cm, 2H); 2.36 (t, J= 3.3 Hz, IH); 2.15 (br s, IH). MS (ESI, m/z): 419.5 [M+H1"].
29. ii. (1 cc,5 a,6a)-3-aza-bicyclo[3.1. OJhexane-6-carboxylic acid (6-methoxy- [l,5]naphthyridin-4-yl)-amide:
To a solution of intermediate 29.i (0.98 g) in MeOH (30 ml) and THF (10 ml) was added palladium hydroxide (0.55 g). The reaction mixture was stirred under hydrogen atmosphere for 3 h. After filtration, the solvent was evaporated to dryness to give the title amine (0.56 g) as a white solid.
1H NMR (d6-DMSO) δ: 9.79 (s, IH); 8.64 (d, J= 5.2 Hz, IH); 8.40 (d, J= 5.2 Hz, IH); 8.26 (d, J= 9.0 Hz, IH); 7.30 (d, J= 9.0 Hz, IH); 4.15 (s, 3H); 3.01 (d, J= 11.3 Hz, 2H); 2.80 (D, J= 11.3 Hz, 2H); 2.46 (br s, IH); 2.14 (t, J= 3.0 Hz, IH); 1.98 (br s, 2H). MS (ESI5 m/z): 285.2 PVH-H+].
29.iii. (Ia, 5 a, 6a)-3-[2-(2, 3-dihydro-benzofl, 4]dioxin-6-yl)-ethyl]-3-aza- bicyclo[3.1.0]hexcme-<5-carboxyIic acid (6-methoxy-[l, 5]naphihyridin-4-yl)-ωm ide:
To a solution of intermediate 29.ii (0.029 g) in DMF (1 ml) were added DIPEA (0.035 ml) and toluene-4-sulfonic acid 2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl ester (0.037 g). The reaction mixture was stirred at 700C overnight and then concentrated to dryness. The residue was purified by preparative TLC eluted with DCM-MeOH 19-1 containing I^ concentrated NH4OH, to give a yellow gum (0.013 g). MS (ESI, m/z): 447.5 [M+H+].
Example 30: (lα,5α,6α)-3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyI]-3-aza- bicyclo[3.1.0]hexane-6-carboxylic acid (3-chIoro-6-methoxy-quinolin-4-yl)- amide:
3O.i. (1 a,5 (x,6a)-6-(3-chloro-6-methoxy-quinolin-4-ylcarbamoy])-3-aza- bicycloβ.1. OJhexane-3-carboxylic acid benzyl ester:
This compound was prepared by the method of Example 28, step 28. ii from 4-bromo- 3-chloro-6-methoxy-qvιinoline (0.545 g, prepared as described in WO 02/40474) and intermediate 28. i (0.522 g). A yellow solid (1.08 g) was obtained. MS (ESI, m/z): 452.4 [M+H+].
30. ii. (lα,5α,6α)-3-Aza-bicyclo[3.1.0]hexane-6-carboxylic acid (3-chloro-6-m_ethoxy- quinolin-4-yl)-amide This compound was prepared by the method of Example 28, step 28.iii from intermediate 30.i (1.05 g). A yellow solid (0.086 g) was obtained. MS (ESI, m/z): 318.6 [M-I-H+]. 3O.iϊi. (1 a,5 cc,6a)-3-[2-(2,3-dihydro-benzo[l ,4]dioxin-6-yl)-ethyl] -3-aza- bicycloβ.1. OJhexane-6-carboxylic acid (3-chloro-6-methoxy-quinolin-4-yl)-amide\
According to the procedure described in Example 13, step 13. iv, the title compound (0.037 g) was obtained from intermediate 30. ϊi (0.086 g). MS (ESI, m/z): 480.3 [M+H+].
Example 31 : (1 α,5α,6α)-3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-3-aza- bicyclo[3.1.0]hexane-6-carboxylic acid (3-methoxy-quinoxalin-5-yl)-amide:
31.i . (la,5a, 6a)-6-(3-methoxy-quinoxalin-5-ylcarbamoyl)-3-aza-bicyclo[3.1.0]hexcune-3- carboxylic acid benzyl ester: This compound was prepared by the method of Example 28, step 28. ii from, trifluoro- methanesulfonic acid 3-methoxy-quinoxalin-5-yl ester (0.550 g) (prepared as described in WO 2004/002992) and intermediate 28.i (0.463 g). A yellow solid (0.550 g) was obtained. MS (ESI, m/z): 419.5 [M+H+].
31.ii. (Ice, 5 a, 6a)-3-aza-bicyclo[3.1.0Jhexane-6-carboxylic acid (3-methoxy-quinoχ:alin-5-yl)- amide:
This compound was prepared by trie method of Example 10, step lO.ii from intermediate 31. i (0.55 g). A yellow solid (0.080 g) was obtained. MS (ESI, m/z): 285.4 [M+H+].
31.ϊii. (la,5a, 6a)-3-[2-(2, 3-dihydro-benzo[l, 4]dioxin-6-yl)-ethyl]-3-aza- bicyclo[3.1.0]hexane-6-carboxylic acid (3-meihoxy-quinoxalin-5-yl)-amide:
According to the procedure described in Example 13, step 13. iv, the title compound (0.035 g) was obtained from intermediate 31 -ii (0.078 g). MS (ESI, m/z): 447.6 [M+H+].
Example 32 : 3- [(I α,5 a,6 α)-2-(2,3-dihydro-benzo [1 ,4] dioxin-6-yl)-2-oxo-ethyl] — 3-aza- bicyclo[3.1.0]hexane-6-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amϊde:
The title compound (0.16 g) was prepared from intermediate 29. ii (0.2 g) according to the procedure described for Example 1 0, step lO.iii. 1H NMR (CDCl3) δ: 9.60 (s, IH); 8.68 (d, J= 5.2 Hz, IH); 8.51 (d, J= 5.2 Hz, IH); 8.24 (d, J= 9.0 Hz, IH); 7.52 (s, IH); 7. 51 (d, J- 7.6 Hz, IH); 7.18 (d, J= 9.0 Hz, IH); 6.93 (d, J= 7.6 Hz, IH); 4.34 (m, 4H), 4.19 (s, 3H); 4.07 (s, 2H); 3.51 (m, 2H); 2.81 Cm, 2H); 2.46 (br s, IH); 2.40 (br s, 2H). MS (ESI, m/z): 461.3 [M+H+].
Example 33: rac-3-[(l α,5α,6α)-2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-2-lιydroxy-ethyl]- 3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid (6-methoxy- [1 ,5] naphthy rid fn-4-yl)-amide:
The title compound (0.052 g) was prepared from the compound of Example 32 (0.1 g) according to the procedure described for Example 11. MS (ESI, m/z): 463.4 [M+H+].
Example 34: rflc-4-{(lα,5α,6α)-3-[2-hydroxy-2-(3-oxo-3,4-dihydro- 2H-benzo[l,4]thiazin-6-yl)-ethyl]-3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid (6-methoxy- [1 ,5] naphthy ridin-4-yl)-amide :
To a solution of intermediate 29. ii (0.2 g) in DMF (4 ml) were added DIPEA (0.35 ml) and 2-chloro-l-(2,3-dihydro-benzo[l,4]thiazin-6-yl)-ethanone (0.170 g). The reaction was heated at 700C for 1 h. The volatiles were removed under reduced pressure and the residue was taken up in MeOH (6 ml) and NaBH4 (0.2 g) was added at 00C. After stirring for 2 h, the reaction mixture was diluted with water (100 ml). The solid was filtered off and taken up in EA (50 ml). The insoluble material was filtered off and the filtrate was concentrated in dryness to afford the title compound (0.084 g) as a beige solid. MS (ESI, m/z): 492.4 [M+H+].
Example 35: rac-(l α,5α,6α)-6-({3-[2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-3-aza- bicyclo[3.1.0]hex-6-ylamino}-mιethyI)-4Jfir-pyrido[3,2-6][l,4]thiazin-3-one :
35. i. rac-(la,5a,6ay{3~[2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-S-aza.- bicycloβ.1.0]hex-6-yl}-carbamic acid tert-butyl ester.
To a solution of (lα,5α,6α)-(3-aza-bicyclo[3.1.0]hex-6-yl)-carbamic acid, tert-butyl ester (0.587 g, obtained as described by K.E. Brighty et al. in Synlett (1996), 1097-1099) and 6-methoxy-4-oxiranyl-quinoline (0.567 g, obtained from 6-methoxy-quinoline- 4-carbaldehyde as described in WO 2004/035569) in DMF (9 ml) were added K2CO3 (0.545 g) and lithium perchlorate (0.315 g). The reaction mixture was stirred a-t 800C overnight. The solids were filtered off and the filtrate concentrated to dryness. The residue was chromatographed (DCM-MeOH 19-1) to afford a yellow foam (0.724 g). 1H NMR (CDCl3) δ: 8.74 (d, J= 4.5 Hz, IH); 8.01 (s, IH); 7.57 (d, J= 4.5 Hz, IH); 7_35 (dd, J= 2.7, 9.2 Hz, IH); 7.18 (d, J= 2.7 Hz, IH); 5.33 (dd, J= 3.6, 9.4 Hz, IH); 4.71 (h>s, IH); 3.92 (s, 3H); 3.52 (d, J= 8.4 Hz, IH); 3.16 (d, J= 9.1 Hz, IH); 2.66 (m, 5H); 1.84 (bs, IH), 1.67 (m,lH), 1.59 (m, IH); 1.45 (s, 9H).
35. ii. rac-(l a,5 a,6a)-2-(6-amino-3-aza-bicyclo[3.1. 0]hex-3-yl)-l-(6-methoxy-quinolirz-4-yl)- ethanol; A solution of intermediate 35. i (0.724 g) in TFA (4 ml) was stirred at rt for 30 min. The solvent was removed under reduced pressure. The residue was basified with IN aq. NaOH solution and extracted with a mixture DCM-MeOHL 9-1 (5 x 20 ml). The combined organic layers were dried over MgSO4 and concentrated to dryness to afford a yellowisli foam (0.532 g). 1H ΝMR (CDCl3) δ: 8.76 (d, J =4.5 Hz, IH); 8.03 (d, J= 9.2 Hz, IH); 7.60 (dd, J= 0.66, 4.5 Hz, IH); 7.36 (dd, J= 2.7, 9.2 Hz, IH); 7.18 (d, J= 2.7 Hz, IH); 5. 32 (dd, J= 3.4, 10 Hz, IH); 3.93 (s, 3H); 3.40 (d, J= 8.5 Hz, IH); 3.05 (d, J=8.9 Hz, IH); 2.62 (m, 3H), 2.54 (dd, J= 3.8, 8.4 Hz, IH), 1.73 (bs, 3H), 1.43 (ddd, J= 1.9, 3.8, 9.9 HCz5 IH), 1.35 (ddd, J= 1.9, 3.8, 9.9 Hz, IH).
35.iii. rac-(la,5a,6a)-6-({3-[2-hydroxy-2-(6-methoχry-quinolin-4-yl)-ethylJ-3-aza- bicyclo[3.1.0]hex-6-ylamino}-methyl)-4H-pyrido[3,2-b] [1 , 4]thiazin-3-one:
To a solution of intermediate 35. H (0.1 g) in MeOH (2 ml) and DCM (5 ml) were added 3 A molecular sieves (1.5 g) and 3-oxo-3,4-dihydro-2/7-pyrido[3,2-δ][l,4]thiazme-6-carbaldehyde (0.058 g). The reaction mixture was stirred at rt overnight. NaBH4 (0.1 g) was added and the reaction was stirred for 2 h. The reaction mixture was filtered through Hydro imatrix® (pretreated with saturated NaHCO3). The filtrate was concentrated to dryness and the residue was chromatographed (DCM-MeOH 19-1, 1% concentrated NH4OH) to afford a white foam (0.070 g). 1H NMR (CDCl3) δ: 8.76 (d, J= 4.5 Hz, IH); 8.34 (br s, IH); 8.03 (d, J= 9.2 Hz, IH); 7.59 (m, 2H); 7.36 (dd, J= 2.7, 9.2 Hz, IH); 7.17 (d, J= 2.7 Hz, IH); 6.94 (d, J= 7.8 Hz, IH); 5.36 (bd, J= 8.2 Hz, IH); 3.93 (s, 3H); 3.85 (s, 2H); 3.49 (s, 2H); 3.40 (d, J= 8.5 Hz, IH); 3.06 (d, J= 8.6 Hz, IH); 2.63 (m, 5H), 1.73 (bs, 2H), 1.43 (m, IH), 1.35 (m, IH). MS (ESI, m/z): 478.3 [M+H+].
Example 36 : rac-{\ α,5α,6α)-6-({3-[2-hydroxy-2-(6- methoxy-quinolin-4-yl)-ethyl]-3-aza- bicyclo [3.1.0] hex-6-y lamino}-methyl)-4H-benzo [1 ,4] oxazin-3-one :
This was prepared by the method of Example 35 , step 35.iii from 3-oxo-3,4-dihydro- 2H-benzo[l,4]oxazine-6-carbaldehyde (0.064 g) and intermediate 35. ii (0.100 g) to afford a pale yellow foam (0.099 g). MS (ESI, m/z): 461.5 [M+Η+].
Example 37: rαc-(lα,5α,6α)-2-{6-[(2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-ylme^:hyl)- amino]-3-aza-bicycIo[3.1.0]hex-3-yl}-l-(6-methoxy-«juinoIin-4-yl)-ethanol:
This was prepared by the method of Example 35, step 35.iii from 2,3-Λihydro- [l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (prepared as described in WO 02/O56882, 0.024 g) and intermediate 35.ii (0.049 g) to afford a white foam (0.060 g). 1H NMR (CDCl3) δ: 8.76 (d, J= 4.5 Hz, IH); 8.13 (s, IH); 8.04 (d, J= 9.2 Hz, IH); 7.59 (d, J= 4.5 Hz, IH); 7.46 (dd, J= 2.7, 9.2 Hz, IH); 7. 18 (d, J= 2.7 Hz, IH); 6.79 O, IH); 5.33 (m, IH); 4.31 (m, 4H); 3.94 (s, 3H); 3.82 (s, 2H); 3.40 (d, J= 8.4 Hz, IH); 3.05 (d, J= 8.8 Hz, IH); 2.67 (m, 3H); 2.55 (m, 2H); 1.92 (br s, 2H); 1.58 (m, 2H). MS (ESI, mVz): 449.5 [M+H1"]
Example 38: rαc-2-{(lα,5α,6α)-6-[(2,3-dihydro-beiizo[l,4]dioxin-6-ylmethyI)-ainino]- 3-aza-bicyclo[3.1.0]hex-3-yl}-l-(6-methoxy-quinolin-4-yl)-ethanol:
According to the procedure described in Example 16, the title compound (0.025 g) was obtained from intermediate 35. ii (0.1 g) as a foam. MS (ESI, m/z): 448.5 [M+H+]. Example 39: røc-2-{(l «^5flr,6α)-6-[(2,3-dihydro-benzo[l,4]dlioxiii-6-yImethyl)-amino]- 3-aza-bicycIo[3.1.0]hex-3-yl}-l-(6-methoxy-[l,5]naphthyridϊn-4-yI)-ethanol:
39. i. 2-methoxy-8-oxiranyl-[l, 5]naphthyridine:
To an ice-chilled solution of 2-bromo-l-(6-methoxy-[L ,5]naphthyridin-4-yl)-ethanone (prepared as described in WO 02/056882, 5.2 g) in EtOH (75 rnL), was added NaBH4 (2.1 g). The reaction was stirred 1 h at this temperature and then 15 rnin at rt. The reaction mixture was partitioned between water and EA. The aq. layer was extracted twice with EA. The combined organic extracts were washed with brine and dried OΛ^er Na2SO4. After filtration and evaporation to dryness, the residue was taken up in MeOH (15 ml), and K2CO3 (2.6 g) was added. After stirring for 1 h, water (20 ml) was added and the volatiles were removed in vacuo. The residue was extracted with ether (2 x 50 ml) and the combined ethereal layers were dried over MgSO^, filtered and concentrated to dryness. The residue was purified over silica gel (Hex-EA 1-1) to afford the title epoxide (2.9 g). 1H NMR (d6-DMSO) δ: 8.77 (d, J= 4.5 Hz, IH); 8.31 (d, J= 9.5 Hz, IH), 7.39 (d, J= 4.5 Hz, IH); 7.29 Cd, J= 9.5 Hz, IH); 4.90 (dd, J= 2.5, 4.3 Hz, IH); 4.06 (s, 3H); 3.37 (dd, J= 4.3, 5.7 Hz, IH); 2.92 (dd, J= 2.5, 5.7 Hz, IH). MS (ESI, m/z): 203.3 [M+H+].
39. ii. rac-(l a, 5 ex, 6a)-{3-[2-hydroxy-2-(6-methoxy-[l, 5]naphthyridin-4-yl)-ethyl]-3-aza- bicycloβ.1.0]hex-6-yl}-carbamic acid tert-butyl ester. Starting from intermediate 39.i (0.35O g) and (lα,5α,6α>3-aza-bicyclo[3.1.0]hex-6-yl)- carbamic acid tert-butyl ester (0.360 g), the title compound (0.371 g) was prepared according to the procedure described in Example 35, step 35. i.
1H NMR (CDCl3) δ: 8.75 (d, J= 4.5 Hz, IH); 8.20 (d, J= 9.1 Hz, IH); 7.74 (d, J= 4.5 Hz, IH); 7.10 (d, J= 9.1 Hz, IH); 5.62 (dd, J= 3.2, 9.8 Hz, IH); 4.61 (bs, IH); 4.04 (s, 3H); 3.48 (m, IH); 3.16 (m, IH); 3.04 (dd, J= 3.5, 12.1 Hz, IH); 2.60 (m, 4H); 1.83 (bs, IH); 1.62 (m, IH); 1.58 (m, IH); 1.43 (s, 9H). MS (ESI, m/z): 401.6 [M+H+]. 39.iii. rac-(lα,5α,6α)-2-(6-ammo-3-aza-bicyclo[3.1.0]hex-3-yl)-l-(6-methoxy- [l,5]naphthyridin-4-yl)-ethanol:
Starting from intermediate 39. ii (0.370 g), the title amine (0.223 g) was obtained according to the procedure described in Example 35, step 35.ii. MS (ESI, m/z): 301.4 [M+H+].
39. iv. rac-2-{(l a, 5a, 6a)-6-[(2, 3-dihydro-benzofl, 4]dioxin-6-ylmethyl)-amino]-3-aza- bicyclo[3.1.0]hex-3-yl}-l-(6-methoxy-[l , 5]naphthyridin-4-yl)-ethanok
According to the procedure described in Example 35, step 35.iii, the title compound (0.055 g) was obtained from intermediate 39.iii (0.059 g) as a yellow gum. MS (ESI, m/z): 449.5 [M+H+].
Example 40: røc-6-({(l α,5α,6α)-3-[2-hydroxy-2-(6-methoxy-[l,5]naphthyridin-4-3rl)- ethyl] -3-aza-bicycIo [3.1.0] hex-6-y lamino}-methyl)-4//-benzo [1,4] thiazin-3-one :
According to the procedure described in Example 35, step 35.iii, the title compound (0.049 g) was obtained from intermediate 39.iii (0.059 g) as a yellow foam. MS (ESI, m/z): 478.3 [M+H+].
Example 41: rαc-2-{(l a,5a,6 «)-6-[(2,3-dihydro-[l,4]dioxino[2,3-A]pyridin-6-ylmethyl)- amino]-3-aza-bicyclo [3.1.0] hex-3-yl}-l-(6-methoxy- [1,5] naphthyridin-4-yl)-ethanc»l :
The title compound (0.067 g) was prepared from intermediate 39.iii (0.1O0 g) and 2,3-dihydro-[l,4]dioxino[2,3-&]pyridine-6-carbaldehyde (prepared as described in WO 2004/014361, 0.049 g) using the procedure of Example 35, step 35.iii.
1H NMR (CDCl3) δ: 8.75 (d, J= 4.3 Hz, IH); 8.20 (d, J= 9.1 Hz, IH), 7.72 (d, J= 4.3 Hz, IH); 7.14 (d, J= 7.9 Hz, IH); 7.10 (d, J= 9.1 Hz, IH); 6.82 (d, J= 7.9 Hz, IH); 5 .61 (dd, J= 3.2, 9.9 Hz, IH); 4.45 (m, 2H); 4.26 (m, 2H); 4.04 (s, 3H); 3.77 (s, 2H); 3.34 (d, J= 8.8 Hz, IH); 3.03 (m, 2H); 2.56 (m, 3H); 2.47 (m, IH); 1.88 (bs, 2H); 1.57 (m, IH); 1.50 (m, IH).
MS (ESI, m/z): 450.4 [M+H+]. Example 42: rαc-6-({(l α,5α,6α)-3-[2-hydroxy-2-(3-methoxy-quinolin-5-yI)-etlryl]-3-aza- bicyclo[3.1.0]hex-6-ylamino}-methyl)-4H-benzo[l,4]oxazin-3-one:
42. i. 3-methoxyquinoline-5-carbaldehyde:
To a solution of 5-bromo-3-methoxyquinoline (10 g) in THF (250 ml) cooled to — 78°C, was added H-BuLi (22 ml). After 15 min, a solution of DMF (10 ml) in ether (20 ml) was quickly added. The solution was stirred 15 min and EtOH (5 ml), followed by IMNaHSO4 (40 ml), was added. After warming to rt, the organic layer was diluted with EA (100 ml). The two layers were separated and the aq. layer was extracted once with EA (100 ml). The combined organic layers were washed with brine and concentrated to dryness. The residue was chromatographed (EA-Hex 1-2 then 1-1) to afford the title compound (4.75 g) as a yellowish solid.
1R NMR (CDCl3) δ: 10.32 (s, IH); 9.02 (d, J= 2.9 Hz, IH); 8.75 (d, J= 2.9 Hz, IH); 8.31 (d, J= 8.3 Hz, IH); 8.02 (d, J= 7.1 Hz, IH); 7.72 (dd, J= 7.1, 8.3 Hz, IH); 4.02 (s, 3HE). MS (ESI, m/z): 187.9 [M+H+]
42. ii. rac-3-methoxy-5-(oxiran-2-yl)quinoline:
To a solution of 3-methoxyquinoline-5-carbaldehyde (2.1 g) in MeCN (35 ml) were added successively water (20 drops), trimethylsulfonium iodide (2.4 g) and crushed KOH (4.5 g).
The heterogenous mixture was heated at 600C for 30 min. The solids were filtered off and water (20 ml) was added to the filtrate. The volatiles were removed under reduced pressure and the residue was extracted twice with EA (2 x 150 ml). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by chromatography (EA-Hex 1-1 then 2-1) to afford the title compound (1.6 g) as a beige solid.
1H NMR (CDCl3) δ: 8.72 (d, J= 2.9 Hz, IH); 8.02 (dd, J= 2, 7.2 Hz, IHQ; 7.68 (d, J= 2.9 Hz, IH); 7.51 (m, 2H); 4.40 (dd, J= 2.7, 3.7 Hz, IH); 4.00 (s, 3H); 3.31 C<ld, J= 3.7,
5.6 Hz, IH); 2.91 (dd, J= 2.7, 5.6 Hz, IH).
MS (ESI, m/z): 202.2 [M+H+] 42.iii. rac- {(la,5a, 6a)-3-[2-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-3-aza- bicyclo[3.1.0]hex-6-yl}-carbamic acid tert-biityl ester:
Starting from intermediate 42. ii (1.59 g) and (lα,5α,6α)-3-aza-bicyclo[3.1.0]hex-6-yl)- carbamic acid tert-bxityl ester (1.48 g), the title compound (1.60 g) was prepared according to the procedure described in Example 35, step 35. i. MS (ESI, m/z): 400.5 [M+H+].
42.iv. rac-2-[(la,5cx,6a)-6-amino-3-aza-bicyclo[3.1.0]hexan-3-yl]-l-(3-methoxyqviinolin- 5-yl)ethanol:
Starting from intermediate 42.iii (1.6 g), the title amine was obtained in 75% yield according to the procedure described in Example 35, step 35.ii. MS (ESI, m/z): 300.3 [M+H+].
42.v. rac-6-({(l a,5 cc, 6a)-3-[2-hydroxy-2-(3-methoxy-quinolm-5-yl)-ethyl]-3-aza- bicyclo[3.1.0]hex-6-ylamino}-methyl)-4H-benzo[l, 4]oxazin-3-one:
The title compound (0.082 g) was prepared from intermediate 42.iv (0.100 g) and 3-oxo-3,4- dihydro-2H-benzo[l,4]oxazine-6-carbaldehyde (0.065 g) using the procedure of Example 35, step 35.iii. MS (ESI, m/z): 461 .4 [M+H+].
Example 43: rac-2-{(l α,5α,6α)-6-[(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-6-ylmethyl)- amino]-3-aza-bicyclo[3.1.0]hex-3-yl}-l-(3-methoxy-quinolin-5-yl)-ethanol:
The title compound (0.086 g) was prepared from intermediate 42. iv (0. 100 g) and 2,3-dihydro-[l,4]dioxino[2,3-6]pyridine-6-carbaldehyde (0.061 g) using the procedure of Example 35, step 35.iii. MS (ESI, m/z): 449.5 [M+H+].
Example 44: rαc-6-({(l α,5α,6α)-3-[2-hydroxy-2-(3-methoxy-quinolin-5-yl)-et;hyl]-3-aza- bicyclo [3.1.0] hex-6-ylamino}-methy l)-4H-py r ido [3,2-6] [1 ,4] thiazin-3-one :
The title compound (0.032 g) was prepared from intermediate 42.iv (0.100 g) and 3-oxo-3,4- dihydro-2H-pyrido[3,2-Z>][l,4]thiazine-6-carbaldehyde (0.071 g) using the procedure of Example 35, step 35.iii. MS (ESI, m/z): 478.5 [M+H+].
Example 45: røc-6-({(l «,5α,6α)-3-[2-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-3-aza- bicyclo [3.1.0] hex-6-ylaπriino}-methyl)-4H-benzo [1 ,4] thiazin-3-one :
The title compound (0.072 g) was prepared from intermediate 42. iv (0.10O g) and 3-oxo- 3,4-dihydro-2H-benzo[l,4]thiazine-6-carbaldehyde (0.071 g) using the procedure of Example 35, step 35.iii. MS (ESI, m/z): 477.3 [M-+Η+].
Example 46: rαc-2-{(loc,5α,6α)-6-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]- 3-aza-bicycIo[3.1.0]hex-3-yl}-l-(3-methoxy-quinolin-5-yI)-ethanol:
The title compound (0.045 g) was prepared from intermediate 42. iv (O.lOO g) and 2,3-dihydro-benzo[l,4]dioxine-6-carbaldehyde (0.06 g) using the procedure of Example 35, step 35.iii. MS (ESI, m/z): 448.5 [M-+H+]
Example 47: 6-({(l cr,5cr,6α)-3-[(2iϊ)-2-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]- 3-aza-bicyclo[3.1.0]hex-6-ylamino}-methyl)-4H-benzo[l,4]thiazin-3-one:
47. i . 3-methoxy-5-vinyl-quinoline :
To a solution of triphenyl methyl phosphonium bromide (10 g) in TΗF (110 m.1) was added «-BuLi (2.5M, 2.6 ml) at -78°C. The mixture was stirred at the same temperature for 15 min and then 45 min at 00C. After cooling to -780C, a solution of 3-methos:y-quinoline- 5-carbaldehyde (4.0 g) in TΗF (15 ml+ 5 ml rinse) was quickly added. The resulting mixture was then stirred at rt for 90 min. The volatiles were removed under reduced pre ssure and the residue was loaded on a silica gel column and eluted (Ηex-EA 4-1 then 1-1) to a-fford the title compound (3.7 g) as an oil. MS (ESI, m/z): 463.4 [M-FH+].
47.ii. (lR)-l-(3-methoxy-quinolin-5-yl)-ethane-l,2-diol\
To an ice-chilled solution of intermediate 47. i (4.9 g) in 2-methyl-2-propanol (130 ml) and water (130 ml) was added AD mix β (38 g). The solution was stirred at this temperature overnight. Sodium metabisulfite (42 g) was added portion wise. After stirring further 30 min, the two layers were separated. The aq. layer was extracted twice with EA (2 x 2OO ml). The combined organic phases were washed with brine and dried over Na2SO4. After filtration and evaporation to dryness, the residue was purified over silica gel (EA-MeOH 19-1) to afford the title diol compound (5.2 g) as a white foam. MS (ESI, m/z): 220.5 [M+H+].
47.iii. (2R)-toluene-4-sulfonic acid 2-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl ester:
To a mixture of intermediate 47.ii (3.0 g) in DCM (65 ml) were added TEA (3.8 ml) and DMAP (1.67 g). The resulting mixture was then cooled to -78°C and /7-toluene sulfonyl chloride (2.60 g) was added in one portion. The reaction was then stored in a fridge at -30°C for 12 h. The solution was warmed up to rt and saturated NaHCO3 (50 ml) was added. The two layers were separated and the organic layer was evaporated to dryness. The residue was purified over silica gel (EA-Hex 1-2 then 2-1) to afford the title compound (3.1 g) as a white solid. MS (ESI, m/z): 374.6 [M+H*].
47.iv. 3-methoxy-5-[(2R)-oxiran-2-ylJquinoline:
To a solution of intermediate 47.iii (3.1 g) in MeOH (100 ml) was added K2CO3 (2 g). The reaction was stirred at rt for 1 h. Water (100 ml) was added and the volatiles were removed in vacuo. The residue was extracted three times with EA (3 x 100 ml). The combined extracts were washed with brine and dried over Na2SO4. After filtration and evaporation to dryness, the residue was chromatographed (EA.-Hex 1-1) to afford the title epoxide as a solid (1.6 g) of 96-98% enantiomeric excess.
The enantiomeric excess was measured by chiral HPLC on Chiralcel OD (detection at 254 nm) using a THF-Hex mixture (3-7). The major enantiomer eluted after 13.0 min and the minor one after 14.1 min (column Chiralcel OD 4.6 x250 mm, 10 μm; flow 0.8 ml/min; eluent: 95% Hex and 5% EtOH with 0.1% diethanolamine).
47.v. {(la,5a,6a)-3-[(2R)-2-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-3-aza- bicycloβ.1.0]hex-6-yl}-carbamic acid tert-butyl ester:
Starting from intermediate 47. iv (0.995 g) and (lα,5α,6α)-3-aza-bicyclo[3.1.0>]hex-6-yi)- carbamic acid tert-butyl ester (1.0 g), the title compound (1.36 g) was prepared according to the procedure described in Example 35, step 35. i. MS (ESI, m/z): 400.2 [M+H+]. 47.vi. (lR)-2-[(la,5a,6a)-6-aminG-3-aza-bicyclo[3.1.0Jhexan-3-yl]-l-f3-tnethoxyquinolin- 5-yl)ethanoh
Starting from intermediate 47.v (1 .36 g), the title amine was obtained in 98% yield according to the procedure described in Example 35, step 35. ii. MS (ESI, m/z): 300.3 [MH-H+].
47.vii. 6-({(l a, 5a, 6a)-3-[(2R)-2-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-3-a∑a- bicycloβ.1.0]hex-6-ylamino}-methyl)-4H-benzo[l, 4]thiazin-3-one\
The title compound (0.053 g) was prepared from intermediate 47.vi (0. 100 g) and 3-oxo-3,4- dihydro-2H-benzo[l,4]thiazine-6-carbaldehyde (0.071 g) using the procedure of Example 35, step 35.iii.
MS (ESI, m/z): 477.5 [M+Η+].
Example 48: (2JR!)-2-{(lα,5α,6Qr)-6-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-ainino]- S-aza-bicyclop.l.Olhex-S-ylJ-l-CS-methoxy-quinolin-S-ylJ-ethanol:
The title compound (0.08I g) was prepared from intermediate 47. vi (0.100 g) and 2,3- dihydro-benzo[l,4]dioxine-6-carbaldehyde (0.061 g) using the procedure of Example 35, step 35.iii. MS (ESI, m/z): 448.8 [M+H+].
Example 49: /•αc-4-{3-[l-(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyI)-piperidin-3-yI]- propoxy}-6-methoxy-quinoline:
49. i. rac-3-[3-(6-methoxy-quinoIin-4-yloxy)-propyl]-piperidine-l-carboxylic acid tert-butyl ester.
To a solution of rac-3-(3-hydroxy-propyl)-piperidine-l-carboxylic acid tert-butyl ester (1 g, prepared as described in WO 94/12181), 6-methoxy-quinolin-4-ol (1.55 g) and PPh3 (2.46 g) in THF (30 ml) was added DIAD (1.86 ml). The reaction mixture was stirred at rt for 4 h and then concentrated to dryness. Tfcie residue was diluted with 0.2N aq. ΗC1 (100 ml). The aq. layer was washed three times with ether (3 x 100 ml). The pH was then made basic using IM aq. NaOH (20 ml). The aq. layer was extracted with EA (2 x 150 ml). The combined extracts were washed with brine and dried over Na2SO4. After filtration, the solvent was evaporated and the residue was purified by chromatography (EA-MeOH 9-1) to afford the title compound (1.1 g) as an oil.
1H NMR (CDCl3) δ: 8.60 (d, J= 5.2 Hz, IH); 7.95 (d, J= 9.1 Hz, IH); 7.44 (d, J= 2.8 Hz, IH); 7.55 (dd, J= 2.8, 5.2 Hz, IH); 6.70 (d, J= 9.1 Hz, IH); 4.19 O, J= 6.5 Hz, IH); 3.94 (s, 3H); 3.93 (overlapped m, IH); 2.84 (m, IH); 2.60 (broad m, IH); 2.04 (s, J= 6.5 Hz, 2H); 1.96 (m, IH); 1.64-1.42 (m, 5H); 1.44 (s, 9H); 1.26 (m, IH).
49. ii. rac-6-methoxy-4-(3-piperidin-3-yl-propoxy)-quinoline:
To a solution of intermediate 49. i (1.1 g) in MeOH (10 mL) was added HCl (15 ml, 1.25N in MeOH). After stirring at rt for 5 In, the reaction mixture was concentrated to dryness, and the residue was taken up in water (1OO ml). The aq. layer was washed twice with EA (2 x 50 ml). Solid KOH (1 g) was added to reach pH 12. The aq. layer was extracted with EA (2x 100 ml) and the combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentrated to dryness, the residue was purified over silica gel (DCM-MeOH 19-1, 1% concentrated aq. NH4OH) to afford the title piperidine (0.81 g) as an oil. 1H NMR (CDCl3) δ: 8.60 (d, J= 5.2 Hz, IH); 7.93 (d, J= 9.1 Hz, IH); 7.44 (d, J= 2.8 Hz5 IH); 7.35 (dd, J= 2.8, 9.1 Hz, IH); 6.69 (d, J= 5.2 Hz, IH); 4.18 (t, J= 6.5 Hz, 2H); 3.93 (s, 3H); 3.13 (br d, J= 11.9 Hz, IH); 3.03 (br d, J= 11.9 Hz, IH); 2.54 (td, J= 2.9, 11.9 Hz5 IH); 2.31 (dd, J= 10.1, 11.9 Hz3 IH); 2.04-1.88 (m, 4H); 1.68 (rn, IH); 1.56-1.40 (m, 3H); 1.11 (m, IH).
49.iii. rac-4-{3-[l-(2, 3-dihydro-benzo[l, 4]dioxin-6-ylmethyl)-piperidin-3-yl]-propoxy}- 6-methoxy-quinoline :
To a solution of intermediate 49.ii (0.15 g) in 1,2-DCE (3 ml) were added successively 2,3-dihydro-benzo[l,4]dioxine-6-carbaldehyde (0.098 g) and sodium triacetoxyborohydride (0.137 g). The reaction was stirred overnight. The reaction mixture was diluted with DCM (15 ml) and washed once with saturated aq. NaHCO3 (10 ml). The organic layer was dried over Na2SO4, filtered and concentrated to dryness. The residue "was purified over silica gel (DCM-MeOH 9-1) to afford the title compound (0.165 g) as a thick oil. 1H NMR (CDCl3) δ: 8.60 (d, J= 5.2 Hz, IH); 7.93 (d, J= 9.1 Hz, IH); 7.44 (d, J= 2.8 Hz, IH); 7.35 (dd, J= 2.8, 9.1 Hz, IH); 6.89 (s, IH); 6.82 (app s, 2H); 6.69 (d, J= 5.2 Hz, IH); 4.23 (s, 4H); 4.17 (t, J= 6.5 Hz, 2H); 3.96 (s, 3H); 3.50 (m, 2H); 3.02 (m, 2H); 2.08-1.71 (m, 6H); 1.48 (m, 3H); 1.05 (m, 2H). MS (ESI, m/z): 449.6 [M+H+].
Example 50: 6-methoxy-4-{3-[l-(frα«s-3-phenyI-a!lyI)-piperidin-3-yI]-propoxy}- quinoline:
Starting from intermediate 49.ii (0.1 g) and trαrø'-cinnamaldehyde (0.053 ml), the title compound (0.105 g) was prepared as a white foam according to the procedure described in Example 49, step 49.iii. MS (ESI, m/z) : 449.6 [TvB-H+].
Example 51 : 4-[3-(l-benzofuran-2-ylmethyl-piperidin-3-yl)-propoxy]-6-methoxy- quinoline:
Starting from intermediate 49. ii (0.15 g) and benzofurari-2-carbaldehyde (0.072 ml), the title compound (0.183 g) was prepared as a white foam according to the procedure described in Example 49, step 49.iii. MS (ESI, m/z): 431.5 [MH-H+].
Example 52: rαc-3-[l-(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-piperidin-3-yl]- JV-(6-methoxy-[l,5]naphthyridin-4-yl)-propioiiamide:
52. i. rac-3-[2-(6-methoxy-[l,5]naphthyridin-4-ylcarbamoyl)-ethyl]-piperidine-l-carboxylic acid tert-butyl ester:
To a solution of 3-(2-carboxy-ethyl)-piperidine-l-carboxylic acid tert-butyl ester (0.525 g), DIPEA (0.338 ml) and HATU (0.776 g) in DMF (4 ml) was added 6-methoxy- [l,5]naphthyridin-4-ylamine (0.357 g). The reaction was stirred at rt for 22 h. DMF was removed under reduced pressure and the residue was purified by chromatography (DCM-MeOH 19-1) to afford the title compound (0.51 g) as an oil. MS (ESI, m/z): 415.3 [M+H+]
52. ii. rac-N-(6-methoxy-[l,5]naphthyridin-4-yl)-3-piperidin-3-yl-propionamide: The title piperidine (0.374 g) was obtained as an oil starting from intermediate 52.i (0.51 g), using the procedure described in Example 49, step 49.ii. MS (ESI, m/z): 315.4 [M+H+]. 52.iii. rac-3-[l-(2,3-dihydro-benzo[l,4]dioxin-6-ylnιethyl)-piperidin'3-yl]-N-(6-methoxy- [l,5]naphthyridin-4-yl)-propionamide:
Starting from intermediate 52.ii (0.1 g) and 2,3-dihydro-benzo[l,4]dloxine-6-carbaldehyde (0.057 g), the title compound (0.078 g) was prepared as a gum according to the procedure described in Example 49, step 49.iii). MS (ESI, m/z): 463.6 [M+H+].
Example 53: rαc-N-(6-methoxy-[l,5]naphthyridin-4-yl)-3-[l-(3-pheiiyI-allyl)-piperidin- 3-yI]-propionamide:
Starting from intermediate 52. ii (0.1 g) and trarø-cinnamaldehyde (0.05 ml), the title compound (0.025 g) was prepared as a gum according to the procedure described in Example 49, step 49.iii. MS (ESI, m/z): 431.6 [M+H+].
Example 54: rαc-iV-(6-methoxy-[l,5]naphthyridin-4-yl)-3-{l-[2-(thiopheii-2-ylsulfanyl)- ethyl]-piperidin-3-yl}-propionamide:
To a solution of intermediate 52.H (0.1 g) in DMF (4 ml) were added 2-(2-bromo- ethylsulfanyl)-thiophene (0.112 g) and DIPEA (0.15 ml). The reaction was heated at 7O0C for 2. h. The volatiles were removed under HV and the residue was purified over silica gel (DCM- IvIeOH 19-1, 1% concentrated aq. NH4OH) to afford the title compound (0.056 g) as a thick oil. MS (ESI, m/z): 457.6 [M+H4].
Example 55: rαc-iV-(6-methoxy-[l,5]naphthyridin-4-yl)-3-[l-(3-oxo>-3,4-dihydro- 2Jy-benzo[l,4]oxazin-6-ylmethyl)-piperidin-3-yI]-propionamide:
Starting from intermediate 52. ii (0.1 g) and 3-oxo-3,4-dihydro-2.£Z-benzo[l,4]oxazine-6- carbaldehyde (0.057 g), the title compound (0.026 g) was prepared as a, foam according to the procedure described in Example 49, step 49.iii. MS (ESI, m/z): 476.5 [M+H+]. Example 56: rαc-iV-(6-metlioxy-[l,5]naphthyridin-4-yl)-3-[l-(3-oxo-3,4-dihydro- 2H-pyrido[3,2-6][l,4]thiazin-6-yImethyl)-piperidin-3-yl]-propionami<ie:
Starting from intermediate 52. ii (0.1 g) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-έ][l,4]thiazine- 6-carbaldehyde (0.058 g), the title compound (0.038 g) was prepared as a foam according to the procedure described in Example 49, step 49.iii. MS (ESI, m/z): 493.1 [M+Η+] .
Example 57: /-αc-3-[l-(2,3-cϊihydro-[l,4]dioxino[2,3-c]pyridin-7-ylinethyl)-piperidin- 3-y 1] -iV-(6-methoxy- [1 ,5] nap hthy ridin-4-y l)-propionamide :
Starting from intermediate 52. ii (0.1 g) and 2,3-dihydro-[l,4]dio>cino[2,3-c]pyridine-7- carbaldehyde (0.057 g), the title compound (0.075 g) was prepared as a Λvhite foam according to the procedure described in Example 49, step 49.iii). MS (ESI3 m/z): 464.6 [M+H^].
Example 58: rαc-3-{l-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-piperidin-3-yl}- 7V-(6-methoxy- [1,5] naphthy r idin-4-yl)-propionamide :
Starting from intermediate 52. ii (0.077 g) and intermediate 13.iii (0.1 g), the title compound (0.034 g) was prepared as a yellow foam according to the procedure described in Example 54. MS (ESI, m/z): 477.5 [MfH+].
Example 59: /•flC-Λr-(2-cyano-quinolin-8-yl)-3-[l-(2,3-dihydro-benzo [l,4]dioxin- 6-ylmethyl)-piperidin-3-yl]-propionamide:
59. i. rac-3-(2-carbamoyl-ethyl)-piperidine-l-carboxylic acid tert-butyl ester:
To a solution of rαc-3-(2-carboxy-ethyl)-piperidine-l-carboxylic acid tert-buty\ ester (5 g) in EA (75 ml) were added NHS (2.14 g) and DCC (4.3 g). The reaction was stirred for 13 h at rt, whereupon the solids were filtered off and the filtrate concentrated to dryness. The residue was taken up in THF (200 ml) and gaseous NH3 was bubbled through tbie mixture for 10 min. The resulting slurry was stirred for 2 h. The solvent was evaporated and the residue directly subjected to chromatography over silica gel (DCM-MeOH 9-1) to a.fford the title amide (4.4 g) as a thick oil. 1H NMR (CDCl3) δ: 5.60 (br s, IH), 5.48 (br s, IH); 3.86 (m, 2H); 2.86 (m, IH); 2.58 (dd, J= 9.3, 13.1 Hz, IH); 2.28 (td, J= 1.2, 7.6 Hz, 2H); 1.84 (m, IHQ; 1.60 (m, 3H), 1.44 (overlapped m, 2H); 1.43 (s, 9H); 1.16 (m, IH). MS (ESI, m/z): 257.5 [M+H+].
59. ii. rac-3-[2-(2-cyano-quinolin-8-ylcarbamoyl)-ethyl]-piperidine-l-carboxylic acid tert-hutyl ester.
To a mixture of intermediate 59. i (1.02 g), cesium carbonate (1.6 g), rø^-BINAP (0.18O g) and tris(dibenzilideneacetone) dipalladium(0)-chloroform complex (0.O74 g) was added dioxane (41 ml). The mixture was sonicated 15 min and trifluoro-methanesulfonic acid 2- cyano-quinolin-8-yl ester (1.2 g) was added. The mixture was heated at 1000C overnight.
After filtration, the filtrate was concentrated to dryness and the residue was triturated in ether to afford the title amide (1.1 g) as a white solid.
1H NMR (d6-DMSO) δ: 10.07 (s. IH); 8.70 (partially overlapped dd, J = 2.7, 6.6 Hz, IH);
8.67 (d, J= 8.4 Hz, IH); 8.11 (d, J= 8.4 Hz, IH); 7.78 (m, 2H), 3.84 (br s9 IH); 3.75 (m, IH); 2.80 (ddd, J= 3.0, 11.1, 14.1 Hz, IH); 2.65 (t, J= 7.5 Hz, 2H); 1.84 (m, IH); 1.64-1.49 (m,
3H); 1.43-1.24 (overlapped m, 3H); 1.36 (s, 9H); 1.13 (m, IH).
MS (ESI, m/z): 409.4 IMfH+].
59.iii. rac-N-(2-cyano-quinolin-8-yl)-3-piperidin-3-yl-propionamide:
A solution of intermediate 59. ii (1.1 g) in TFA (5 ml) was stirred at rt for 10 min. After the solvent was evaporated, the residue was partitioned between 3N aq. NaOH (20 ml) and a
DCM-MeOH mixture (9-1, 50 ml). The aq. layer was extracted twice more and the combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness.
The residue was chromatographied (DCM-MeOH 9-1, 1% concentrated aq. NH4OH) to afford the title compound (0.720 g) as a yellowish foam. MS (ESI, m/z): 309.1 IMfH+].
59. iv. rac-N-(2-cyano-quinolin-8-yl)-3-[l-(2, 3-dihydro-benzo[l, 4]dioxin-6-ylmethyl)- piperidin-3-yl]-propionamide\
Starting from intermediate 59.iii (0.11 g) and 2,3-dihydro-benzo[l,4]dioxine-6-carbaldehyde (0.065 g), the title compound (0.073 g) was prepared as a white foam according to the procedure described in Example 49, step 49.iv. MS (ESI, m/z): 457.1 [M+rf"]. Example δO: /•ac-N-(2-cyano-quinolin-8-yl)-3-[frans-l-(3-phenyl-aUyl)-piperidin-3-yl]- propionamide:
Starting from intermediate 59.iii (0.11 g) and trørø-cinnamaldehyde (0.055 ml), the title compound (0.062 g) was prepared according to the procedure described in Example 49, step 5 49.iv.
MS (ESI, m/z): 425.5 [M+H*].
Example 61 : rac-N-(2-cyano-quinoIin-8-yl)-3-[l-(3-oxo-3,4-dihydro- 2/7-benzo [1,4] thiazin-6-yImethy I)-piperidin-3-y 1] -propionamide :
Starting from intermediate 59.iii (0.11 g) and 3-oxo-3,4-dihydro-2H-benzo[]l,4]thiazine-6- O carbaldehyde (0.076 g), the title compound (0.081 g) was prepared according to the procedure described in Example 49, step 49. iv. MS (ESI, m/z): 486.1 [M+Η+].
Example 62: rαc-2-[l-(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-piperidin-3-yloxy]- iV-(6-methoxy-[l,5]naphthyridin-4-yl)-acetamide:
5 62. i. rac-3-carboxymethoxy-piperidine-l-carboxylic acid benzyl ester:
A solution of rac-3-ter^butoxycarbonylmethoxy-piperidine-l-carboxylic acid benzyl ester (2.8 g, prepared as described in WO 94/22835) in DCM (20 ml) was treated with TFA (10 ml). After stirring at rt for 1 h, the volatiles were removed under reduced pressure. The residue was purified over silica gel (EA-Hex 1-1) to afford the title compound K2 g) as an oil. 0 MS (ESI, m/z): 294.4 ^+H+].
62. ii. rac-3-[(6-methoxy-[l,5]naphthyridin-4-ylcarbamoyl)-methoxy]-piperidi^ιe- 1-carboxylic acid benzyl ester.
Starting from intermediate 62.1 (0.598 g) and 6-methoxy-[l,5]naphthyxidin-4-ylamine (0.357 g), the title amide (0.21 g) was prepared as a gum, as described in Example 52, step 5 52.i.
MS (ESI, m/z): 451.3 [M+H+]. 62.iii. N-(6-methoxy-[l,5]naphthyridin-4-yl)-2-(piperidin-3-yloxy)-acetamide:
To a solution of intermediate 62. ii (0.21 g) in MeOH (6 ml) was added 20% palladium hydroxide on charcoal (0.1 g). The reaction mixture was stirred at rt under hydrogen atmosphere for 1 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to afford after drying a semi solid (0.145 g). MS (ESI, m/z): 317.4 ^+H+].
62.iv. rac-2- [1 -(2,3-dihydro-benzo[l ,4] dioxin-6-ylmethyl)-piperidin-3-yloxy] -N-(6-methoxy- [l,5]naphthyridin-4-yl)-acetamide:
Starting from intermediate 62.iii (0.14 g) and 2,3-dihydro-benzo[l,4-]dioxine-6-carbaldehyde (0.090 g), trie title compound (0.081 g) was prepared according to trie procedure described in Example 49, step 49. iv. MS (ESI, m/z): 465.5 [M+H+].
Example 63 : (2,3-dihydro-benzo[l,4]dioxin-6-yImethyl)-[3-(6-methoxy-quinolin- 4-yloxymetb_y l)-cy clohexy lmethyl] -amine :
63. i. 5-(ethctxycarbonyl-nitro-methyl)-cyclohex-3-enecarboxylic acid methyl ester:
To a degassed solution of tetrakis(triphenylphosphine)palladium (0.357 g) in DCM (56 ml) was added 5-methoxycarbonyloxy-cyclohex-3-enecarboxylic acid methyl ester (7.1 g) and ethyl nitroacetate (3.67 ml). The reaction was stirred at rt for 30 min. The volatiles were removed under reduced pressure and the residue was purified over silica gel (EA-Hex 1-5) to afford the title compound (7.8 g) as an equimolar mixture of diasteromers.
1H NMR (CDCl3) δ: 5.93 (m, IH); 5.53 (m, IH); 5.00 (app t, J= 8.9 Hz, IH); 4.32 (m, 2H); 3.72 (s, 1.5H); 3.71 (s, 1.5H); 3.33 (m, IH); 2.68 (m, IH); 2.38-1.90 (m, 2.5H); 1.88 (m, 0.5H); 1.66 (q, J= 12.6 Hz5 0.5H); 1.55 (q, J= 11.6 Hz, 0.5H); 1.33 (m, 3H).
63. ii. 5-nitromethyl-cyclohex-3-enecarboxylic acid methyl ester. A mixture of intermediate 63.i (7.8 g) in EtOH (17 ml) and 5Maq. NaOH (22 ml) was heated at 700C overnight. The volatiles were removed under reduced pressure and 2Maq. H2SO4 was added to reach pH 3. The mixture was extracted three times with, ether (3 x 100 ml). The combined organic layers were washed with brine, dried over Na2SO4 and evaporated under reduced pressure. The residue was further dried under HV to afford the intermediate acid (3.I g) as a pale solid. The latter was dissolved in ether (100 ml) and MeOH (15 ml). Trimethylsilyldiazomethane (2M in hexanes, 10 ml) was added. The reaction mixture was stirred for 30 min at it and AcOH (1 ml) was added. The volatiles were removed under reduced pressure. The residue was purified over silica, gel (EA-Hex 1-5) to afford the title compound as a 1.5:1 mixture of diastereomers (3.15 g).
1H NMR (CDCl3) δ: 5.89 (m, IH); 5.53 (m, IH); 4.30 (m, 2H); 3.71 (s, 3H); 3.10 (m, IH); 2.64 (m, IH); 2.38-2.15 (m, 2.6H); 2.01 (m, 0.4H); 1.85 (m, 0.4H); 1.48 (m, 0.6H). 13C NMR (CDCl3) δ: 174.75, 174.67, 128.92, 128.42, 124.91, 142.40, 79.64, 78.59, 51.56, 51.51, 38.61, 35.12, 34.74, 32.33, 28.95, 27.21, 26.84, 26.80.
63.iii. rac-3-(tert-butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid methyl ester:
To a mixture of intermediate 63. ii (3.15 g) in MeOH (73 ml) was added 10% palladium on charcoal (2.9 g). The reaction vessel was evacuated and the reaction was filled with hydrogen. The reaction mixture was stirred under hydrogen overnight. The reaction mixture was diluted with MeOH (50 ml) and \M aq. HCl (20 ml) was added. After filtration, the volatiles were removed under reduced pressure. The residue was taken up in THF (50 ml) and NaHCO3 (5 g) was added. BOC2O (4.5 g) was added and the reaction mixture was stirred at rt for 1 h. The volatiles were removed under reduced pressure and the residue was partitioned between water and EA (100 ml). The aq. layer was extracted once more and the combined extracts were washed Λvith brine and dried over Na2SO4. After filtration, the volatiles were removed under reduced pressure. The residue was purified over silica gel (EA-Hex 1-4) to afford the title compound (3.09 g) as a 1.5:1 mixture of diastereomers.
1H NMR (CDCl3) δ: 4.50 (m, IH); 3.68 (s, 1.8H); 3 .67 (s, 1.2H); 3.02 (m, 2H); 2.68 (m, 0.4H); 2.31 (m, 0.6H); 2.02-1.12 (multiple overlapped m, 7H); 1.46 (s, 9H); 1.05-0.88 (m, 2H).
63. iv. rcιc-(3-hydroxymethyl-cyclohexylmethyl)-carbarnic acid tert-butyl ester:
To an ice-chilled mixture of intermediate 63.iii (0.63 g) in ether (10 ml) was added, DIBAH (4 ml, \M in Hex). The mixture was stirred at the same temperature for 45 min. Water (0.45 ml) was added and the mixture was stirred at rt for 40 min. The solids were filtered off and the filtrate was concentrated in vacuo. The residue was purified over silica gel (EA-Hex 1-1) to afford the title compound (0.350 g) as 1.5:1 mixture of diasteromers. 1H NMR (CDCl3) δ: 4.59 (br s, IH); 3.50 (m, 2H); 3.00 (m, 2H); 1.86-1.74 (m, 3H); 1.58-1.25 (m, 5H); 1.46 (s, 9H); 0.88 (m, 1.4H); 0.64 (app q, J= 1Z.1 Hz, 0.6H).
63.v. rac-[3-(6-methoxy-quinolin-4-yloxymethyl)-cyclohexylmethyl]-carhamic acid tert-biityl ester: This compound (0.168 g) was prepared as an oil starting from intermediate 63. iv (0.35 g) and 6-methoxy-quinolin-4-ol (0.302 g) using the procedure described in Example 1, step l.i. MS (ESI, m/z): 401.3 [IVH-H+].
63.vi. rac-C-[3-(6-methoxy-quinolin-4-yloxymethyl)-cyclohexyl]-rnethylamine:
The title amine (0.115 g) was obtained as an oil, starting from intermediate 63.v (0.165 g) and using the procedure described in Example 1, step l.ii. MS (ESI, m/z): 301.4 PVB-H+].
63.vii. (2, 3-dihydro-benzo[l, 4]dioxin-6-ylmethyl)-[3-(6-methoxy-quinolin-4-yloxymethyl)- cyclohexylmethyl] -amine :
To a solution of intermediate 63.vi (0.115 g) in DCM (6 ml) and MeOH (2 ml) were added 2,3-dihydro-benzo[l,4]dioxine-6-carbaldehyde (0.070 g) and 3 A molecular sieves (2 g). The resulting mixture was stirred at rt overnight. NaBH4 (0.1 g) was added and the mixture was stirred at rt for 2 h. The reaction mixture was filtered through, a plug of Hydromatrix®, previously treated with. NaHCO3 (6 ml). The filtrate was concentrated in vacuo. The residue was chromatographed (DCM-MeOH 19-1, 1% concentrated aq. TStH4OH) to afford the title compound (0.109 g) as a thick oil. The compound was recovered as a 1:1 mixture of diastereomers. MS (ESI, m/z): 449.7 [M+H1"].
Example 64: (2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-[(li-,35)-3-(6-methoxy- quinolin-4-yloxy methy l)-cy clohexylmethyl] -amine :
64.i. (IS, 5S)-5-nitromethyl-cyclohex-3-enecarboxylic acid methyl ester:
To a solution of tris(dibenzilideneacetone) dipalladium chloroform complex (0.06 g) and (li?,2i?)-(+)-l,2-diaminocyclohexane-NJV'-bis(2'-diphenylphosphLinobenzoyl) (0.12 g) in DCM (14 ml) were added nitromethane (1.22 ml) and N,Ob>is(trimethylsilyi)-acetamide (0.77 ml). After stirring at rt for 5 min, 6-oxa-bicyclo[3.2.1]oct-3-en-7-one (0.35 g) was added and the mixture was stirred at rt for 14 h. After concentration to dryness, the residue was quickly filtered though a plug of silica gel (ether 1% AcOH) and the filtrate was concentrated to dryness. The residue was taken up in ether (45 ml) and MeOK (5 ml) and trimethylsilyldiazomethane (2M in Hex, 2.3 ml) was added. The reaction proceeded for 30 min. AcOH (0.1 ml) was added and the reaction mixture was concentrated, in vacuo. The residue was chromatographed (Hex-ether 3-1) to afford the title compound (0.35 g) as an oil. 1H NMR (CDCl3) δ: 5.89 (m, IH); 5.51 (m, IH); 4.35 (dd, J= 6.9, 12.0 Hz, IH); 4.29 (dd, J= 7.8, 12.0 Hz, IH); 3.71 (s, 3H); 3.10 (in, IH); 2.65 (m, IH); 2.36-2.17 (nx, 3H); 1.45 (td, J= ILl, 12.6 Hz, IH).
64. ii. (IR, 3S)-(3-hydroxymethyl-cyclohexyl3nethyl)-carbamic acid tert-butyl e^ter:
The title alcohol (0.148 g) was obtained as an oil starting from intermediate 64. i (0.35 g) and using the procedures described in Example 63, steps 63.iii and 63. iv. MS (ESI, mix): 244.3 [MH-H+].
64.iii. (2, 3-dihydro-benzo[l, 4]dioxin-6-ylmethyl)-[(lR, 3S)-3-(6-methoxy-quinolin-4- yloxymethyl)-cyclohexylmethyl] -amine :
The title compound (0.08 g) was obtained as a colourless oil starting from intermediate 64.ii (0.148 g) and using the procedures described in Example 63, steps 63.v, 63.vi and 63.vii. 1H NMR (CDCl3) δ: 8.60 (d, J= 5.2 Hz, IH); 7.95 (d, J= 9.2 Hz, IH); 7.47 (d, J= 2.8 Hz, IH); 7.35 (dd, J= 2.8, 9.2 Hz, IH); 6.86 (d, J= 0.9 Hz, IH); 6.82 (m, 2H); 6.70 (d, J= 5.2 Hz, IH); 4.25 (s, 4H); 4.00 (dd, J= 1, 5.9 Hz, 2H); 3.94 (s, 3H); 3.71 <s, 2H); 2.54 (d, J= 6.7 Hz, 2H); 2.02 (m, 3H); 1.92 (m, 2H); 1.68 (m, 2H); 1.42 (m, IH); 1.12 (m, IH); 0.93 (m, 2H). MS (ESI, m/z) : 449.4 [MH-H+].
Example 65: røc-3-{[(2,3-dihydro-benzo [l,4]dioxin-6-ylmethyl)-amino]-t-nethyl}- cyclohexanecarboxylic acid (2-methyl-quϊnoIin-8-yl)-amide:
65. i. rac-5~nitromethyl-cyclohex-3-enecarboxylic acid (2-methyl-quinolin-8-yl) -amide:
Starting from rαc-5-nitromethyl-cyclohex-3-enecarboxylic acid (0.377 g, prepared as described in Example 63, step 63. ii) and 2-methyl-quinolin-8-ylamine (0.322 g), the title compound (0.487 g) was obtained as a yellow oil using the procedure described in Example 52, step 52.i. MS (ESI, m/z): 326.3 [IVH-H+].
65. ii. rac-3-aminomethyl-cyclohexanecarboxylic acid (2-methyl-quinolin-S-yl)-aιnide:
To a solution of intermediate 65. i (0.48 g) in MeOH (15 ml) was added 10% palladium on charcoal (0.5 g). The reaction was stirred under hydrogen atmosphere for 4 h. The catalyst was removed by filtration. The residue was purified over silica gel (DCM-MeOH 9-1, 1% concentrated aq. NH3) to afford the title compound (0.230 g) as a yellow oil. MS (ESI, m/z): 298.4 [M+H*].
65.iii . τ-ac-3 - { [(2, 3 -dihydro-benzo [ 1 ,4]dioxin-6-ylmethyl)-amino] -methyl } - cyclohexanecarboxylic acid (2-methyl-quinolin-8-yl)-amide: This compound (0.12 g) was prepared as a yellow oil from inteπnediate 65. ii (0.115 g) and 2,3-dihydro-benzo[l,4]dioxine-6-carbaldehyde (0.069 g) using the procedure described in Example 63, step 63.vii. MS (ESI, m/z): 446.5 PvB-H+].
Example 66: rαc-3-[frα«s-(3-phenyl-aIlylamino)-methyl]-cycIohexanecarboxylic acid (2-metliyl-quinolin-8-yl)-amide:
This compound (0.102 g) was prepared as a yellow oil from intermediate 65. ii (0.115 g) and trαrø-cinnamaldehyde (0.055 g) using the procedure described in Example 63, step 63.vii. MS (ESI, m/z): 414.3 [M-HH+]
Example 67 : rac-3-{ [(2 ,3-dihydro-benzo [1,4] dioxin-6-ylmethyl)-amii3θ]-methyl}- cyclohexanecarboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide:
67. i. rcιc-3-(tert-butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid:
A solution of intermediate 63. iii (3.09 g) in dioxane (100 ml) was treated with NaOH (3M, 12 ml). The mixture was refluxed overnight. The volatiles were renxoved under reduced pressure. The residue was washed twice with ether (2 x 100 ml). The pH of the aq. layer was adjusted to 3 using 0.2M aq. HCl. The aq. layer was extracted with E-A (3 x 150 ml). The combined organic layers were washed with brine and dried over Na2SO^- After filtration, the filtrate was concentrated in vacuo to afford the title acid (2.5 g) as a colourless foam. MS (ESI, m/z): 256.2 [M-H+]. 67. ii. røc-[3-(6-methoxy-[l ,5]naphthyridin-4-ylcarbamoyl)-cyclohexylmethyl]-carbamic acid tert-butyl ester:
This compound (0.493 g) was prepared as a yellow solid from intermediate 67. i (0.78 g) and 6-methoxy-[l,5]naphthyridin-4-ylamine (0.531 g) according to the procedure described in Example 52, step 52. i.
MS (ESI, m/z): 41 5.6 [M-H+].
67.iii. røc-3-aminomethyl-cyclohexanecarboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)— amide
This compound (0.27 g) was obtained as a yellow oil starting from intermediate 67.ii (0.493 g) and using the procedure described in Example 49, step 49. ii. MS (ESI, m/z): 315.4 [M-H+].
67. iv. rac-3-{[(2, 3 -dihydro-ben∑ofl , 4]dioxin-6-ylnιethyl)-amino]-methyl}- cyclohexanecarboxylic acid (6-methoxy-[l, 5]naphthyridin-4-yl)-amide :
This compound (0.093 g) was obtained, as a pale yellow foam, from intermediate 67.Ui (0.1 g) and 2,3-dihydro-benzo[l,4]dioxine-6-carbaldehyde (0.057 g), as described in Example 63, step 63.vii). MS (ESI, m/z): 463.6 [MH+].
Example 68: rαc-3-{[(3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-6-ylmethyl)-amino]- methyl}-cy clohexanecarboxy lie acid (6-methoxy- [1 ,5] naphthy ridin-4-yl)-amide :
This compound (0.080 g) was obtained, as a pale yellow foam, from intermediate 617.iii (0.1 g) and 3-oxo-3,4-dihydro-2H-benzo[l,4]oxazine-6-carbaldehyde (0.062 g), as described in Example 63, step 63.vii. MS (ESI, m/z): 476.5 [MH+].
Example 69: cw-3-{[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-methyl}- cyclohexanecarboxylic acid (6-methoxy-[l,5]naphtIiyridin-4-yl)-amide:
69. i. cis-[(3-(6-methoxy-[l,5]naphtlτyridin-4-ylcarbarnoyl)-cyclohexylmethyl]-carbamic acid tert-butyl ester: Using cw-3-(tert-butoxycarbonylamino-methyl)-cycloliexanecarboxylic acid (0.78 g, prepared as described in J. Med. Chem. (1998), 41, 2175) and <)-methoxy-[l,5]naphthyridin-4-ylamine (0.531 g), the title compound (0.45 g) was prepared as described in Example 67, step 67. ii) MS (ESI, m/z): 415.0 [MMI+].
69. ii. cis-3-aminomethyl-cyclohexanecarboxylic acid (6-methoxy-[l, 5]naphihyridin-4-yl)- amide:
This compound (0.2I g) was prepared from intermediate 69. i (0.45 g) as described in Example 67, step 67.iii.
1H NMR (CDCl3) δ: 9.55 (s, IH); 8.70 (d, J= 5.1 Hz, IH); 8.52 (d, J= 5.1 Hz, IH); 8.22 (d, J = 9.1 Hz, IH); 7.18 (d, J= 9.0 Hz, IH); 4.13 (s, 3H); 2.69 (br d, J= 5.85 Hz, 2H); 2.-49 (tt, J = 3.2, 11.9 Hz, IH); 2.21 (m, 2H); 1.69-1.35 (m, 5H); 1.33-1.29 (m, 2H); 1.27 (q, J= 12 Hz, I H); 1.00 (qd, J= 3.7, 12.7 Hz, IH). MS (ESI, m/z): 315.3 [M-H+].
69.iii. cis- 3-{[(2, 3-dihydro-benzo[l, 4]dioxin-6-ylmethyl)-amino]-methyl}- cyclohexanecarboxylic acid (6-methoxy-[l, 5]naphthyr-idin-4-yl)-amide: The title compound (0.072 g) was prepared from intermediate 69. ii (0.1 g) following the procedure described in Example 67, step 67. iv.
1H NMR (d6-DMSO) δ: 9.75 (s, IH); 8.66 (d, J= 5.1 Hz, IH); 8.39 (d, J= 5.1 Hz3 IH);
8.26 (d, J= 9.0 Hz, IH); 7.31 (d, J= 9.0 Hz, IH); 6.81 (s,lH); 6.75 (m, 2H); 4.19 (s, 4H);
4.10 (s, 3H); 3.55 (s, 2H); 2.70 (m, IH); 2.37 (m, 2H); 2.15 (m, IH); 1.97 (m, 2H); l_80 (m 2H); 1.61 (m, IH); 1.39 (m, 2H); 1.10 (q, J= 12 Hz, IH); 0.89 (m, IH).
MS (ESI, m/z): 463.5 [M-H+]. Example 70: e/s-3-{[(3-oxo-3,4-dihydro-2H-benzo[l,4]thiazin-6-ylmetliyI)-amino]- methyl}-cycloliexanecarboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide:
The title compound (0.063 g) was prepared from intermediate 69.Ii (0.1 g) and 3-oxo- 3,4-dihydro-2i?-benzo[l,4]thiazine-6-carbaldehyde (0.074 g) following the procedure described in Example 67, step 67. iv. MS (ESI, mix): 492.4 [M+H+]
Example 71 : cis-3-{[(2,3-dihydro-[l,4]dioxino[2,3-ft]pyridin-6-ylmetliyl)-ainino]- methyl}-cycloliexanecarboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide:
This compound (0.071 g) was obtained, as a yellow gum, from intermediate 69. ii (0.100 g) and 2,3-dihydro-[l,4]dioxino[2,3-Z>]pyridine-6-carbaldehyde (0.063 g), as described in Example 19, step 19. iv. MS (ESI, m/z) : 464.6 [M+H+]
Example 72: c/5'-3-{[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-methyl}- cyclohexanecar boxy lie acid (2-cyano-quinolin-8-yl)-amide:
72.i. cis-(3-carbamoyl-cyclohexylmethyl)-carbamic acid tert-butyl ester.
This compound (2.78 g) was prepared as a white solid from cw-3-(rert-bιιtoxycarbonylamino- methyl)-cyclohexanecarboxylic acid (3.5 g) using the procedure described in Example 59, step 59.i. MS (ESI, m/z): 257.4 [M+H+].
72.ii. [3-(2-cyano-quinolin-8-ylcarbamoyl)-cyclohexylmethyl]-carbamic acid tert-butyl ester:
Starting from intermediate 72. i (1.02 g) and trifluoro-methanesulfonic acid 2-cyano-quinolin- 8-yl ester (1.2 g), the title compound (1.1 g) was obtained as a white solid using the procedure described in Example 59, step 59. ii. MS (ESI, m/z): 409.6 [M+H"1"].
72.iii. cis-3-aminomethyl-cyclohexanecarboxylic acid (2-cyano-quinolin-8-yl)-amide:
This amine (0.66 g) was obtained as a yellow foam, starting from intermediate 72.ii (1.1 g) and using the procedure described in Example 59, step 59.iii. MS (ESI, m/z) : 309.3 [MH-H+].
72. iv. cis-3-{[(2,3-dihydro-ben∑o[l , -4] ' dioxin-6-ylmethyl) -amino) '-methyl}- cyclohexanecarboxylic acid (2-cyano-quinolin-8-yl)-amide:
This compound (0.072 g) was obtained, as a yellow foam, from intermediate 72.Hi (0.11 g) and 2,3-dihydro-benzo[l,4]dioxine-6-carbaldehyde (0.065 g), as described in Example 6»7, step 67. iv. MS (ESI, m/z): 457.2 [IvB-H+] .
Example 73: cw-3-{[(3-oxo-3,4-diliydro-2H-benzo[l,4]thiazin-6-ylmethyl)-amino]- methyl}-cyclohexanecarboxylic acid (2-cyano-quinolin-8-yl)-amide:
This compound (0.054 g) was obtained, as a yellow foam, from intermediate 72.iii (0.11 g) and 3-oxo-3,4-dihydro-2H-benzo[l ,4]thiazine-6-carbaldehyde (0.075 g), as described in Example 67, step 67.iv. MS (ESI, m/z): 486.2 [TvB-H+].
Example 74: c«-3-{[(benzo[l,2,5] thiadiazol-5-ylmethyl)-amino]-methyl}- cyclohexanecarboxylic acid (2-cyano-quinolin-8-yl)-amide:
This compound (0.046 g) was obtained, as a yellow foam, from intermediate 72.iii (0.11 g) and benzo[l,2,5]thiadiazole-5-carbaldehyde (0.064 g), as described in Example 67, step 67.av. MS (ESI, m/z): 457.1 [M+H+].
Example 75: cw-3-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-6] [l,4]thiazin-6-ylmethyl)- amino] -methyl}-cyclohexanecarboxy lie acid (2-cyano-quinolin-8-yl)-amide:
This compound (0.058 g) was obtained, as a yellow foam, from intermediate 72.iii (0.11 g) and 3-oxo~3,4-dihydro-2H-pyrido[3,2-δ][l,4]thiazine-6-carbaldehyde (0.076 g), as described in Example 67, step 67. iv. MS (ESI, m/z): 487.5 [M+Η+]. Example 76: c/s-3-[(frø/ιs-3-phenyl-allylamino)-methyl]-cycIohexanecarboxylic acid (2-cyano-qui nolin-8-yl)-amide:
This compound (0.054 g) was obtained, as a yellow foam, from intermediate 72.iii (0.11 g) and trαrø-ciαnamaldehyde (0.052 g), as described in Example 67, step 67. iv. MS (ESI, m/z): 426.5 [M+H+].
Example 77: (2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-[(3i-,6S)-6-(6-methoxy- quinolin-4-yloxymethyl)-3,6-dihydro-2H-pyran-3-yl]-amine:
77. i. (3R, 6S) -(6-hydroxymethyl-3, 6-dihydro-2H-pyran-3-yl)-carbamic acid tert-butyl ester.
To a solution of [(3i?,6S)-6-(tert-butyl-dimethyl-silanyloxymeth;yl)-3,6-dihydro-2H-pyran- 3 -yl] -carbarn ic acid tert-butyl ester (obtained from 3,4,6-tri-O-acet>^l-D-glucal as described by Η. S. Overkleeft et al in Eur. J. Org. Chem. (2003), 2418-2427; 6.39 g) in TΗF (100 ml) was added TBAF (28 ml, IM solution in TΗF) at 00C. The reaction mixture was stirred at this temperature for 30 min, then at rt for 1 h. After concentration to dryness, the residue was chromatographed (EA-Ηex 1-1 to 1-0) to afford a white solid (3.52 g). 1H NMR (CDCl3) δ: 5.89 (d, J= 10.4 Hz, IH); 5.76 (td, J= 1.9, 10.4 Hz, IH); 4.57 (br. s, IH); 4.20 (rn, 2H); 4.11 (dd, J= 4.7, 11.1 Hz, IH); 3.62 (d, J= 6.1 Hz, 2H), 3.41 (m, IH), 2.00 (br. s, IH), 1.45 (s, 9H).
77. ii. [(3R,(>S)-6-(6-methoxy-quinolm-4-yloxymethyl)-3,6-dihydro-2H-pyran-3-yl]-carbamic acid tert-butyl ester: To a solution of intermediate 77.i (1 g), 6-methoxy-quinolin-4-ol (O.916 g) and PPh3 (1.715 g) in THF (32 ml) and DMF (2.2 ml) was added dropwise DIAD (1.322 g). The reaction mixture was stirred at rt for 4h and concentrated to dryness. The residue was diluted with 0.2N aq. HCl (110 ml) and the aq. layer was washed three times with ether. The pH was made basic by addition of IiV aq. NaOH (22 ml) and the aq. layer was extracted twice with EA. The combined organic layers were washed with brine and dried over Na2SO4, filtered and concentrated. The residue, was crystallized from EA, was triturated in ether to afford the title compound as a yellow solid (0.5 g). 1H NMR (d6-DMSO) δ: 8.57 (d, J=5.2 Hz, IH); 7.87 (d, J=9.8 Hz, IH); 7.38 (m, 2H); 7.03 (br. s, IH); 7.02 (d, J=5.2 Hz, IH); 5.94 (m, 2H); 4.57 (m, IH); 4.29 (m, 2H); 4.O2 (br. m, IH); 3.98 (m, IH); 3.89 (s, 3H); 3.81 (m, IH); 1.40 (s, 9H).
77.iii. (3R, 6S)-6-(6-methoxy-quinolin-4-yloxymethyl)-3, 6-dihydro-2H-pyran-3-ylamine: A solution of intermediate 77. ii (0.3 g) in TFA (3 ml) was stirred for 30 min. The reaction mixture was concentrated to dryness. The residue was basified with IN aq. NaOH and extracted six times with a mixture DCM-MeOH (9-1). The combined organic layers were dried over Na2SO4, filtered and concentrated to give a yellow gum (0.221 g). 1H NMR (CDCl3) δ: 8.61 (d, J=5.2 Hz, IH); 7.93 (d, J=9.2 Hz, IH); 7.46 (d, J=2.7 Hz, IH); 7.34 (dd, ./=2.7, 9.2 Hz, IH); 6.71 (d, J =5.2 Hz, IH); 6.02 (m, IH); 5.88 (m, IH); 4.^3 (m, IH); 4.26 (m, IH); 4.16 (m, 2H); 3.93 (s, 3EE); 3.52 (m, IH); 3.35 (m, IH), 1.54 (br. s, 2H).
77. iv. (2, 3-dϊhydro-benzo[l, 4]dioxin-6-ylmethyl)-[(3R, 6S)-6-(6-methoxy-quinolin- 4-yloxymethyl)-3,6-dihydro-2H-pyran-3-yl] -amine:
To a solution of intermediate 77.iii (0.1 g) in DCM (6 ml) and MeOH (2 ml) were added 2,3-dihydro-benzo[l,4]dioxine-6-carbaldehyde (0.064 g) and 3 A molecular sieves (2 g). The resulting mixture was stirred overnight at rt. NaBH4 (0.054 g) was added. After 2 h, the reaction mixture was filtered though Hydromatrix® (pretreated with aq. NaHCOs). After the filtrate was concentrated in vacuo, the residue was purified by column chromatography over silica gel (DCM-MeOH 19-1, 1% concentrated NH4OH) to give a yellow gum (0.040 g> 1U NMR. (CDCl3) δ: 8.60 (d, J= 5.2 Hz5 I H); 7.93 (d, J= 9.2 Hz, IH); 7.45 (d, J= 2.8 Hz, IH); 7.34 (dd, J= 2.8, 9.2 Hz, IH); 6.84 (m, 3H); 6.70 (d, J= 5.2 Hz, IH); 6.11 (rn, IH); 5.91 (m, IH); 4.65 (m, IH); 4.25 (m, 2H); 4.24 (overlapped s, 4H); 4.15 (m, IH); 3.92 (s, 3H); 3.78 (s, 2H); 3.51 (m, IH); 3.38 (m, IH), 1.66 (br. s, IH). MS (ESI, m/z): 435.6 [M+H+]
Example 78: (2,3-dihydro-benzo[l,4]dioxin-6-yImethyI)-[(3i?,65)-6-(6-methoxy- quinoliα-4-yIoxymethyl)-tetrahydro-pyran-3-yl]-amine:
78. i. (3 R, 6S)-(6-hydroxymethyl-tetrahydro-pyran-3-yl)-carbarnic acid tert-butyl ester:
To a solution of (3i?,65)-(6-hydroxymethyl-3,6-dihydro-2H-pyran-3-yl)-carbamic acid tert-butyl ester (prepared as described in Example 1, step Li, 1.3 g) in MeOH (70 ml) was added 20% palladium hydroxide on charcoal (0.16 g). The mixture was stirred under hydrogen for 3 h. The catalyst was removed by filtration and the filtrate concentrated in vacuo. The residue was purified by column chromatography (EA-Hex 4-1) to afford the title product as a white solid (0.7 g).
1H NMR (CDCl3) δ: 4.25 (br. s, IH); 4.11 (m, IH); 3.60 (dd, J= 3.4, 1 1.5 Hz, 2H); 3.53 (m, IH); 3.37 (m,l H); 3.02 (t, J= 10.7 Hz, IH); 2.10 (m,lH); 1.83 (br. s, IH); 1.62 (m, IH); 1.49 (m, IH); 1.44 (s, 9H); 1.32 <m, IH).
78. ii. [(3R, 6S)-6-(6-methoxy-quinolin-4-yloxymethyl)-tetrahydro-pyran-3-yl]-carbamic acid tert-butyl ester.
This compound (0.920 g) was prepared as a yellow solid, starting from intermediate 78. i (1 g) and 6-methoxy-quinolin-4-ol (0.907 g), according to the procedure described in Example 77, step 77. ii.
1H NMR (CDCl3) δ: 8.60 (d, J = 5.4 Hz, IH); 7.95 (d, J= 9.3 Hz, IH); 7.45 (d, J= 2.7 Hz,
IH); 7.35 (dd, J = 2.7, 9.2 Hz, IH); 6.71 (d, J= 5.4 Hz, IH), 4.26 (m, 2H); 4.15 (m, 2H);
3.94 (s, 3H); 3.81 (m, IH); 3.12 (t, J= 10.5 Hz, IH); 2.20 (m, IH); 1 .94 (m, 2H); 1.68 (m, IH); 1.45 (s, 9H).
78.iii. (3R,6S)-6-(6-methoxy-quinolin-4-yloxymethyl)-tetrahydro-pyran-3-ylamine:
A solution of intermediate 78. ii (0.9 g) in TFA (9 ml) was stirred for 30 min at rt. The reaction mixture was evaporated to dryness and the residue basified with IN aq. NaOH solution and extracted six times with a mixture DCM-MeOH 9-1. The combined organic layers were dried over Na2SO4, filtered and concentrated to give a yelloΛV gum (0.662 g).
1H NMR (CDCl3) δ: 8.60 (d, J = 5.1 Hz, IH); 7.93 (d, J= 9.0 Hz, IEC); 7.45 (d, J= 3.0 Hz, IH); 7.34 (dd, J= 3.0, 9.0 Hz, IH); 6.71 (d, J= 5.1 Hz, IH), 4.25 (dd, J= 6.0, 10.1 Hz, IH); 4.12 (dd, J= 4.5, 10.1 Hz, IH); 4.03 (m, IH); 3.94 (s, 3H); 3.81 (m, IEC); 3.13 (t, J= 10.5 Hz, IH); 2.91 (m, IH); 2.16 (m, IH); 1.91 (m, IH); 1.88 (br. s, IH); 1.63 (rn, IH); 1.38 (m, IH).
78.iv. (2, 3-dihydro-benzo[l, 4] dioxin-6-ylmethyl)-[(3R, 6S)-6-(6-methoxy-quinolin- 4-yloxymethyl)-tetrahydro-pyran-3-yl] -amine:
Starting from intermediate 78-iii (0.1 g) and 2,3-dihydro-benzo[l,4]dioxine-6-carbaldehyde (0.064 g), the title compound (0.073 g) was prepared as a yellow foam according to the procedure described in Example 77, step 77. iv. 1H NMR (CDCl3) δ: 8.60 (d, J = 5.2 Hz, IH); 7.93 (d, J= 9.2 Hz, IH); 7.46 (d, J= 2.9 Hz, IH); 7.34 (dd, J= 2.9, 9.2 Hz, IH); 6.84 (m, IH); 6.80 (m, 2H); 6.70 (d, J= 5.2 Hz, IH); 4.23 (s, 4H); 4.22 (dd, J= 5.9, 10.0 Hz, IH); 4.12 (ddd, J= 2.3, 4.3, 10.9 Hz, IH); 3.^4 (s, 3H); 3.84 (m, IH); 3.73 (d, J= 1.7 Hz, 2H); 3.20 (t, J= 10.6 Hz, IH); 2.76 (m, IH); 2.19 (m, IH); 1.55 (m, IH); 1.60 (m, 2H); 1.59 (br. s, IH); 1.43 <m, IH). MS (ESI, m/z): 437.7 [M+H+].
Example 79: (2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-yImethyl)-
[(3J?,6S)-6-(6-methoxy-quinolin-4-yloxymethyl)-tetr»hydro-pyran-3-yl]-amine:
Starting from intermediate 78.iii (0.115 g) and 2,3-dihydro-[l,4]dioxino[2,3-c]pyridine- 7-carbaldehyde (0.059 g), the title compound (0.10>9 g) was prepared as a white foam according to the procedure described in Example 77, step 77. iv. MS (ESI, m/z): 438.6 [M+H+].
Example 80: 6-{[(3R, 65)-6-(6-methoxy-quinolin-4-yloxymethyl)-tetrahydro-pyran— 3-ylamino] -methyl}-4H-benzo [ 1 ,4] oxazin-3-one :
Starting from intermediate 78.iii (0.1 g) and 3-oxo-3,4-dihydro-2H-benzo[l,4]oxazine- 6-carbaldehyde (0.069 g), the title compound (0.088 g) was prepared as a pale yellow solid according to the procedure described in Example 77, step 77. iv. MS (ESI, m/z): 450.5 [M+Η+].
Example 81 : (2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-[(3JR,6.S)-6-(6-methoxy- [ 1 ,5] naphthy ridin-4-yloxy methy l)-tetrahydro-pyran-3-yl] -amine :
81.i. [(3R, 6S)-6-(6-methoxy-[l, 5]naphthyridin-4-yloxymethyl)-tetrahydro-pyran-3-yl]- carbamic acid tert-butyl ester:
This compound (0.77 g) was obtained as a yellow solid from (3i?,6ιS)-(6-hydroxyπxethyl- tetrahydro-pyran-3-yl)-carbamic acid tert-butyl ester (1 g, prepared as described in Example 2, step 2.i), and 6-methoxy-[l,5]naphthyridin-4-ol (0.913 g), according to the procedure of Example 77, step 77. ii. MS (ESI, m/z): 390.2 [M+H+].
81. ii. (3R,6S)-6-(6-methoxy-[l,5]naphthyridin-4-yloxymethyl)-tetrahydro-pyran-3-ylair2ine\
Starting from intermediate 8 Li (0.764 g), the title compound (0.669 g) was prepared as a pale yellow oil according to the procedure described in Example 77, step 77.iii. MS (ESI, m/z): 290.4 [M+H+].
81. in. (2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-[(3R,6S)-6-(6-methoxy-[l,5]naphthyridin- 4-yloxymethyl)-tetrahydro-pyran-3-yl]-amine:
Starting from intermediate 81. ii (0.1 g) and 2,3-dihydro-benzo[l,4]dioxine-6-carbaldehyde (0.064 g), the title compound (0.056 g) was prepared as a pale yellow foam according to the procedure described in Example 77, step 77. iv.
1H NMR (CDCl3) δ: 8.60 (d, J= 5.2 Hz, IH); 8.15 (d, J= 9.1 Hz, IH); 7.L 1 (d, J= 9.1 Hz, IH); 6.92 (d, J= 5.2 Hz, IH); 6.80 (m, 3H); 4.29 (dd, J= 5.7, 10.0 Hz3 IH); 4.24 (s, 4H); 4.14 (m, IH); 4.10 (s, 3H); 3.87 (m, IH); 3.73 (d, J= 1.2 Hz, 2H); 3.20 (t, J= 10.6 Hz, IH); 2.76 (m, IH); 2.18 (m, IH); 1.90 (m, IH); 1.64 (br. s, IH); 1.63 (m, 2H); 1.42 (m, IH). MS (ESI, m/z): 438.6 [M+H+].
Example 82: 6- {[(3i?,65)-6-(6-methoxy- [1 ,5] naphthyridin-4-yloxymethy l)-tetrahydro- py ran-3-ylamin o] -methy l}-4H-benzo [1 ,4] oxazin-3-one :
Starting from intermediate 81. ii (0.1 g) and 3-oxo-3,4-dihydro-2H-benzo[l,4]oxazine- 6-carbaldehyde (0.069 g), the title compound (0.069 g) was prepared as a white solid according to the procedure described in Example 77, step 77. iv. MS (ESI, m/z): 451.5 [MfH+].
Example 83 : 6 - { [(3i?,6iS)-6-(6-methoxy-quinolin-4-yloxymethy l)-tetrahy dro-py ran- 3-ylamino]-methyl}-4JEr-benzo[l,4]thiazin-3-one:
Starting from intermediate 78.iii (0.11 g) and 3-oxo-3,4-dihydro-2H-benzo[l,4]thiazine- 6-carbaldehyde (0.081 g), the title compound (0.056 g) was prepared as a yellowish solid according to the procedure described in Example 77, step 77. iv. MS (ESI, m/z): 466.3 [M+Η+].
Example 84: 6-{[(3R,6»S)-6-(6-methoxy-[l,5]naphthyridin-4-yloxymeth;yl)-tetrahydro- pyran-3-ylamino]-methyl}-4H-benzo[l,4]thiazin-3-one:
Starting from intermediate δl.ii (0.1 g) and 3-oxo-3,4-dihydro-2H-benzo[l,4]thiazine- 6-carbaldehyde (0.074 g), the title compound (0.091 g) was prepared as a white solid according to the procedure described in Example 77, step 77, iv. MS (ESI, ΠL/Z): 467.3 [M+H+].
Example 85: 6-{[(37ϊ,6S)-6-(6-methoxy-[l,5]naphthyridiii-4-yIoxymethyl)-tetrahydro- pyran-3-ylamino]-methyl}-4H-pyrido[3,2-A][l,4]thiazin-3-one:
The title compound (0.086 g) was obtained as a white solid starting from intermediate 81.Η (0.1 g) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-έ][l,4]thiazine-6-carbaldehyde (0.073 g) using the procedure described in Example 77, step 77. iv MS (ESI, m/z): 467.3 [M+Η+].
Example 86: [(3jR,6iS)-6-(6-methoxy-[l,5]naphthyridin-4-yloxymethyl)-tetrahydro- pyran-3-yl]-(3-phenyl-allyl)-amine:
The title compound (0.064 g) was obtained as a colourless oil starting from intermediate 81.H (0.130 g) and trøπs-cinnamaldehyde (0.062 ml) using the procedure described in Example 77, step 77.iv. MS (ESI, rn/z): 406.5 [M+H+].
Example 87: benzofuran-2-ylmethyl-[(3i?,6-?)-6-(6-metli«xy-[l,5]naphthyridin- 4-yIoxymethyI)-tetrahydro-pyran-3-yl]-amine:
The title compound (0.072 g) was obtained as a colourless oil starting from intermediate 81.ii (0.130 g) and 2-benzofuran-carbaldehyde (0.06 ml) using the procedure described in Example 77, step 77. iv. MS (ESI, m/z): 420.2 [M+H+].
Example 88: (25,5U)-5-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-tetrahydro- pyran-2-carboxylic acid (2-methyI-quinolin-8-yl)-amide:
88. i . 2-me thyl-qιιinolin-8-ylamine :
To a solution of 2-methyl-8-nitroquinoline (5 g) in MeOH (200 ml) and EA (50 ml) was added 10*% palladium on charcoal (1.6 g). The reaction was stirred under hydrogen atmosphere for 4 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to afford after drying the title amine (3.94 g) as a red solid. 1H NMR (CDCl3) δ: 7.94 (d, J= 8.4 Hz, IH); 7.25 (m, 2H); 7.10 (dd, J= 1.3, 8.2 Hz, IH); 6.90 (dd, J= 1.3, 7.4 Hz, IH); 4.90 (br s, 2H); 2.71 (s, 3H). MS (ESI, m/z): 159.3 [M+H+].
88. ii. [(3JR., 6S)-6-(2-methyl-quinolin-8-ylcarbamoyl)-tetrahydro-pyran-3-yl]-carbamic acid tert-butyl ester:
To a solution of (2S',5i?)-5-tert-butoxycarbonylamino-tetrahydro-pyran~2-carboxylic acid (0.5 g, prepared as described in Eur. J. Org. Chem. (2003), 2418-24-27), DIPEA (0.338 ml) and HATU (0.776 g) in DMF (4 ml) was added 2-methyl-quinolin-8-ylamine (0.322 g). The reaction was stirred at rt for 3 d. DMF was removed under reduced pressure and the residue was partitioned between water (100 ml) and EA (100 ml). The aq. layer was extracted with EA (100 ml) and the combined extracts were washed with brine and dried over Na2SO4. After filtration and concentration to dryness, the residue was purified by chromatography (EA-Hex 1-3) to afϊbrd the title compound (0.58 g) as a yellowish solid. MS (ESI, m/z): 386.6 [M+H+].
88.iii. (2S5R)-5-amino-tetrahydro-pyran-2-carboxylic acid (2-methyl~quinolin-8-yl)-amide:
A solution of intermediate 88.ii (0.58 g) in TFA (4 ml) was stirred at rt for 20 min. The solvent was removed under reduced pressure and the residue was partitioned between IM aq.
NaOH (30 ml) and DCM-MeOH (9-1, 50 ml). The aq. layer was extracted twice more with the same solvent mixture. The extracts were washed with brine, dried over Na2SO4 and filtered. The filtrate was evaporated to dryness. The residue was triturated with heptane and the solid Λvas dried under HV to yield the title amine (0.2 g) as a yelloΛvish solid.
1H NMR (d6-DMSO) δ: 10.69 (s, IH); 8.63 (dd, J= 1.5, 8.0 Hz, I H); 8.28 (d, J= 8.4 Hz,
IH); 7.62 (dd, J= 1.5, 8.0 Hz, IH); 7.52 (d, J= 8.4 Hz, IH); 7.50 (t, J= 8.0 Hz, IH);
4.04 (ddd, J= 1.8, 4.5, 10.4 Hz, IH); 3.96 (dd, J= 2.5, 11.5 Hz, IH); 3.13 (t, J= 10.6 Hz, IH); 2.72 (overlapped m, IH); 2.71 (s, 3H); 2.13 (qd, J= 3.0, 13.1 Hz, IH); 2.0 (m, IH);
1.48 (m, IH); 1.47 (overlapped br s, 2H); 1.33 (m, IH).
MS (ESI, m/z): 286.4 [MfH+].
88.iv. (2 S, 5R)-5-[(2, 3-dihydro-benzo[l, 4]dioxin-6-ylmethyl)-aminoJ-tetrahydro-pyran~ 2-carboxylic acid (2-methyl-quinolin-8-yl)-amide\ To a solution of intermediate 88.iii (0.1 g) in 1,2-DCE (6 ml) and MeOH (2 ml) were added 2,3-dihydro-benzo[l,4]dioxine-6-carbaldehyde (0.064 g) and powdered 3 A molecular sieves (2 g). The resulting mixture was stirred at rt overnight. NaBH4 (0.1 g) was added and the mixture was stirred at rt for 1 h. The reaction mixture was filtered through a plug of Hydromatrix® (pretreated with NaHCO3). After concentration in vacuo, the residue was chromatographed (DCM-MeOH 9-1, 1% concentrated NH4OH) to afford the title compound (0.055 g) as a thick oil.
1H NMR (CDCl3) δ: 11.5 (s, IH); 8.75 (m, IH); 8.03 (d, J = 8.4 Hz, IH); 7.46 (m, 2H); 7.32 (d, J= 8.4 Hz, IH); 6.85 (m, 3H); 4.34 (ddd, J= 2.0, 4.5, 11.5 Hz, IH); 4.25 (s, 4H); 4.00 (dd, J= 2.5, 11.5 Hz, IH); 3.77 (dd, AB system, J= 13.O Hz, 2H); 3.29 (t, J= 10.5 Hz, IH); 2.84 (m, IH); 2.77 (s, 3H); 2.38 (qd, J= 2.9, 13.4 Hz, IBT); 2.22 (m, IH); 1.67 (m, IH); 1.50 (br s, IH); 1.44 (m, IH). MS (ESI, m/z): 434.5 [M+H+].
Example 89: (21Sr,5Λ)-8-{5-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-6] [l,4]thiazin- 6-yImethyl)-amino]-tetrahydro-pyran-2-ylmethoxy}-quinoline-2-carbonitrile:
Starting from 8-(5-amino-tetrahydro-pyran-2-ylmethoxy)-quiiioline-2-carbonitrile (0.076 g) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-έ][l,4]thiazine-6-carba.ldehyde (0.057 g), the title compound (0.068 g) was prepared as a beige foam according to the procedure described in
Example 88, step 88. iv.
1H NMR (CDCl3) δ: 9.27 (br.s, IH); 8.61 (br.s, IH); 8.24 (d, J= 8.4 Hz, IH); 7.75 (d,
J= 8.4 Hz, IH); 7.62 (d, J= 2.3 Hz, IH); 7.58 (dd, J= 1.1, 7.9 Hz, IH); 7.44 (d, J= 8.4 Hz, IH); 7.18 (dd, J= 1.1, 7.9 Hz, IH); 6.99 (dd, J= 3.5, 7.9 Hz, IH); 4.28 (dd, J= 6.1, 10.1 Hz,
IH); 4.18 (m, 2H); 3.89 (d, J= 3.7 Hz, 2H); 3.47 (s, 2H); 3.28 (t, J= 10.8 Hz, IH); 2.80 (m,
IH); 2.21 (m, IH); 1.98 (m, IH); 1.60 (br. m, 3H).
MS (ESI, m/z): 462.2 [M+H+].
Example 90: (25',5iϊ)-5-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-tetrahydro- pyran-2-carboxyIic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide:
90. i. (3R, 6S)-(6-carbamoyl-tetrahydro-pyran-3-yl)-carbamic acid tert-butyl ester:
To a solution of (2iS',5i?)-5-te/"t-butoxycarbonylamino-tetrahydro-pyran-2-carboxylic acid
(3 g) in EA (50 ml) was added NHS (1.5 g) and DCC (2.7 g). The reaction was stirred overnight at rt. The solids were removed by filtration. The filtrate was concentrated in vacuo and the residue was taken up in THF (180 ml). NH3 was bubbled through the solution for 10 min, and the resulting turbid mixture was stirred at it for 1 h. Silica gel (20 g) was added in the mixture, and the volatiles were removed by rotatory evaporation. The material was chromatographed over silica gel (DCM-MeOH 19-1) to afford the title compound (1.3 g) as a white solid. MS (ESI, m/z) : 245.3 [M+H+].
90. ii. [(3R,(5S)-6-(6-methoxy-[l,5]naphthyridin-4-ylcarbamoyl)-tetrahydro-pyran-3-yl]- carhamic acid tert-butyl ester:
To a mixture of intermediate 9O.i (0.8 g), cesium carbonate (1.3 g), rαc-BINAP (0.145 g) and tris(dibenzilldeneacetone) dipalladium(0)-chloroform complex (0.057 g) was added dioxane (41 ml). The mixture was sonicated 15 min and trifluoro-methanesulfonic acid 6-methoxy-
[l,5]naphthyridin-4-yl ester (1.0 g) was added. The mixture was heated at 100°C overnight.
After filtration, the filtrate was concentrated to dryness and the residue was purified over silica gel (DCM-MeOH 19-1) to afford the title amide (1.3 g) as a foam.
1H NMR (CDCl3) δ: 10.57 (s, IH); 8.70 (d, J= 5.2 Hz, IH); 8.51 (d, J= 5.2 Hz, IH); 8.22 (d, J= 9.0 Hz5 IH); 7.16 (d, J= 9.0 Hz, IH); 4.32 (m, 2H); 4.12 (s, 3H); 4.0 1 (dd, J= 2.5,
11.4 Hz, IH); 3.72 (m, IH); 3.23 (t, J= 10.6 Hz, IH); 2.39 (qd, J= 2.8, 10.2 Hz, IH);
2.22 (m. IH); 1.76 (m, IH); 1.47 (overlapped m, IH); 1.47 (s, 9H).
MS (ESI, m/z) : 403.6 [M+H"1"].
9O.iii. (2S1SR)- S-amino-tetrahydro-pyran^-carboxylic acid (6-methoxy-[l,5]naphthyridin- 4-yl)-amide:
The title amine (0.5 g) was obtained as a white solid, starting from intermediate 90. ii (1.3 g) and using the procedure described in Example 88, step 88.iii. The compound Λvas purified by chromatography (DCM-MeOH 19-1, 1% concentrated aq. NH4OH). MS (ESI, m/z): 303.2 [M+H+].
90. iv. (2S, 5 R)S- [(2, 3-dihydro-benzo[l, 4]dioxin-6-ylmethyl)-amino]-tetrahydro-pyran- 2-carboxylic acid (6-methoxy-[ 1,5] naphthyridin-4-yl) -amide:
As described in Example 88, step 88.iv, the title compound (0.024 g) was obtained as a yellow gum, starting from intermediate 9O.iii (0.1 g) and 2,3-dihydro-benzo[l,4]dioxine- 6-carbaldehyde (0.059 g). MS (ESI, m/z): 451.6 [M+H+]. Example 91 : (25",5i?)-5-[(2,3-dihydro-[l,4]dioxino[2,3-c]pyridiii-7-ylmethyl)-ainino]- tetrahydro-pyran-2-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide:
As described in Example 88, step 88. iv, the title compound (0.089 g) was obtained as a white solid, starting from intermediate 90. Hi (0.11 g) and 2,3-dihydro-[l,4]dioxino[2,3-c]pyridine-7- carbaldehyde (0.054 g).
1H NMR (d6-DMSO) δ: 10.51 (s, IH); 8.70 (d, J= 5.0 Hz, IH); 8.38 (d, J= 5.0 Hz, IH); 8.28 (d, J= 9.0 Hz, IH); 7.32 (d, J= 9.0 Hz, IH); 7.25 (d, J= 7.9 Hz, IH); 6.97 (d, J= 7.9 Hz, IH); 4.38 (m, 2H); 4.22 (m, 2H); 4.18 (partially overlapped dd, J= 3.0, 10.6 Hz, IH); 4.07 (partially overlapped m, IH); 4.06 (s, 3H); 3.67 (dd, AB system, J= 14.6 Hz, 2H); 3.25 (t, J= 10.6 Hz, IH); 2.61 (m, IH); 2.15 (m, 3H); 1.56-1.36 (m, 2H). MS (ESI, m/z): 452.5 [MH-H+].
Example 92: (2£,5i?)-5-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-Λ][l,4]*hiazin-6-ylmethyI)- amino]-tetrahydro-pyran-2-carboxyIic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide:
92. i. [(3R, 6S)-6-(6-methoxy-[l , 5]naphthyridin-4-ylcarbamoyl)-tetrahydro-pyran-3-yl]- carbamic acid tert-bietyl ester:
To a solution of C25',5i?)-5-tert-butoxycarbonylamino-tetrahydro-pyran-2-carboxylic acid (0.5 g), DIPEA (0.338 niL) and ΗATU (0.776 g) in DMF (4 ml) Λvas added 6-methoxy- [l,5]naphthyridin-4-ylamine (0.357 g) in DMF (4 ml). The reaction mixture was stirred for 24 h at rt and the solvent was evaporated under reduced pressure. The residue was partitioned between DCM and water and the phases separated. The aq. layer was extracted twice more with DCM. The combined organic layer were dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed (DCM-MeOH 19-1) to afford the title product as a yellow foam (0.614 g). MS (ESI, m/z): 403.3 [MH+].
92. ii. (2S,5R)-5-amino-tetrahydro-pyran-2-carboxylic acid (6-methoxy-[ 1,5] naphthyridin- 4-yl) -amide:
The title amine (0.360 g) was obtained as a yellow foam, starting from intermediate 92. i (0.608 g) and using the procedure described in Example 88, step 88.iiϊ. MS (ESI, m/z): 303.4 [M+H+]. 92..iii. (2S,5R)-5-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]thiazin-6-ylmethyl)-amino]- te trahydro-pyran-2-carboxylic acid (6-methoxy-[l, 5]naphthyridin-4-yl)-amide :
As described in Example 88, step 88. iv, the title compound (0.064 g) was obtained as a white solid, starting from intermediate 92.ii (0.145 g) and 3-oxo-3,4-dihydro-2H-pyrido[3,2- bj [l,4]thiazine-6-carbaldehyde (0.085 g). MS (ESI, m/z): 481.6 [M+Η+].
Example 93: (2£,5R)-5-[(2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-ylmethyI)-amino]- te trahydro-pyran-2-carboxylic acid (2-cyano-quinoIin-8-yl)-amide:
93.i. [(3R, 6S)-6-(2-methoxy-qιιinolin-8-ylcarbamoyl)-tetrahydro-pyran-3-yl]-carbamic acid te rt-butyl ester:
Tlie title amide (0.780 g) was obtained as an orange foam, starting from inteπnediate 90. i (0.489 g) and trifluoro-methanesulfonic acid 2-cyano-quinolin-8-yl ester (0.604 g) and using trie procedure described in Example 90, step 90. ii. MES (ESI, m/z): 397.2 [M+H+].
93. ii. (2S,5R)-5-amino-tetrahydro-pyran-2-c:arboxylic acid (2-cyano-quinolin-8-yl)-amide:
The title amine (0.32 g) was obtained as a colourless foam, starting from intermediate 93. i (0.780 g) and using the procedure described in Example 88, step 88.iii). The compound was purified by chromatography over silica gel (DCM-MeOH 19-1, 1% concentrated aq. NΗ40H). MS (ESI, m/z): 297.3 [M+H+].
93.iii. (2S,5R)-5-[(2,3-dihydro-[l ,4] dioxino [2,3-c]pyridin-7-ylmethyl)-amino] -tetrahydro- pyran-2-carboxylic acid (2-cyano-quinolin-8-yl)-anιide\
The title compound (0.074 g) was obtained as a yellow foam, starting from intermediate 93. ii (O.l l g) and 2,3-dihydro-[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (0.067 g) according to the procedure described in Example 88, step 88.iv. MS (ESI, m/z): 446.1 [M+H+]. Exaraple 94: (2.S',5i?)-5-[(2,3-dihydro-benzo[l,4]dioxin-6-ylinethyl)-amino]-tetralι^dro- pyran-2-carboxyIic acid (2-cyano-quioolin-8-yl)-amide:
The title compound (0.065 g) was obtained as a colourless foam, starting from intermediate 93. ii (0.11 g) and 2,3-dihydro-benzo[l,4]dioxine-6-carbaldehyde (0.064 g) according; to the procedure described in Example 88, step 88. iv. MS (ESI, m/z): 445.4 [M+H+].
Example 95: (2S,5i?)-5-[(3-oxo-3,4-dihydro-2iϊ-pyrido[3,2-ft] [l,4]thiazin-6-ylmetfayl)- amino]-tetrahydro-pyran-2-carboxylic acid (2-cyano-qιiinolin-8-yl)-amide:
The title compound (0.065 g) was obtained as a colourless foam, starting from intermediate 93. ii (0.11 g) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-έ][l,4]thia.zine-6- carbaldehyde (0.064 g) according to the procedure described in Example 88, step 88.iv_
1H NMR (CDCl3) δ: 10.52 (s, IH); 8.93 (dd, J= 1.2, 8.0 Hz, IH); 8.34 (d, J= 8.4 HCz, IH);
8.33 (br s, IH); 7.77 (d, J= 8.4 Hz, IH); 7.70 (t, J= 8.0 Hz, IH); 7.60 (m, 2H); 7.01 (d,
J= 8.0 Hz, IH); 4.42 (ddd, J= 2.0, 4.5, 11.0 Hz, IH); 4.03 (dd, J= 2.3, 11.3 Hz, IH); 3.93 (s, 2H); 3.49 (s, 2H); 3.34 (t, J= 10.6 HEz, IH); 2.86 (m, IH); 2.39 (m, IH); 2.26 (rn, IH);
1.82 Cbr,s, IH); 1.68 (m, IH); 1.54 (m, IH).
MS (ESI, m/z): 475.5[M+H+].
Example 96: (25,5i?)-5-[(3-oxo-3,4-dlihydro-2H-benzo[l,4]thiazin-6-ylmethyl)-aiiiLino]- tetraliydro-pyran-2-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide:
As described in Example 88, step 88. iv, the title compound (0.11 g) was obtained as a white foam, starting from intermediate 9O.iii (0.1 g) and 3-oxo-3,4-dihydro-2H-benzo[l,4]tfcιiazine- 6-carbaldehyde (0.07 g). MS (ESI, m/z): 480.5 [M+Η+].
Example 97: (21S',5i?)-5-[(2,3-dihydro-[l,4]dioxino[2,3-6]pyridin-6-ylmethyl)-amiMio]- tetraliydro-pyran-2-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide:
As described in Example 88, step 88.rv, the title compound (0.1 g) was obtained as a white foam, starting from intermediate 90.iii (0.1 g) and 2,3-dihydro-[l,4]dioxino[2,3-ό]p^ridine- 6-carbaldehyde (0.06 g). MS (ESI, m/z): 452.5 [MH-H+].
Example 98: 2-[(2J?,3iϊ,65)-3-[(2,3-dihydro-benz;o[l,4]dioxm-6-ylinethyl)-amino]- 6-(6-methoxy-qmiinolin-4-yloxymethyl)-tetrahydro-pyran-2-yl]-ethanol:
98.i. (2R, 3R, 6S) -[6-(tert-butyl-dimethyl-silanyloxymethyl)-2-(2-hydroxy-ethyl)-3, 6-dihydr~o- 2H-pyran-3-yl]-carbamic acid tert-butyl ester:
A mixture of 2-rnethyl-2-propanol (185 ml) and water (185 ml), containing AD mix β (50 g) was stirred at rt until two clear phases were obtained. After cooling to O0C, (2i?,3i?,65)-[2-allyl-6-(tert-butyl-dimethyl-silanyloκymethyl)-3,6-dihydro-2H-pyran-3-yl] - carbamic acid tert-butyl ester (obtained as described in Eur. J. Org. Chem. (2O03), 2418-2427, 12. S g) was added, and the reaction mixture was stirred at the same temperature for 14 h. Sodium metabisulfite (54 g) was added portion wise and the mixture was stirred 1 h. The two layers were decanted and the aq. layer was extracted with EA (3 x 150 ml). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was taken up in acetone (160 ml) and a solution of sodium periodate (10.4 g) in hot water (30 ml) was quickly added. After stirring for I h at rt, the solids were removed by filtration, and the filtrate was concentrated in vacuo. The residue was taken up in MeOH (150 ml) and NaBH4 (2 g) was added. After stirring 1 h at rt, water (100 ml) was added and the volatiles were removed by evaporation. The residue was extracted with EA (3 x 150 ml). The combined extracts were washed with brine and dried over Na^SO4, filtered and concentrated in vacuo. The residue was purified over silica gel (EA-Hex 3—1) to afford the title alcohol (4 g) as a colourless oil.
1H NMR (CDCl3) δ: 6.0 (ddd, J= 2.1, 6.0, 10.2 Hz, IH); 5.82 (dd, J= 3.0, 10.2 Hz, IH); 4.62 (m, IH); 4.23 (m, IH); 4.09 (m, IH); 3.91 (m, IH); 3.80 (m, IH), 3.62 (dd, J= 4.5, 11.1 Hz, IH); 1 .98 (broad s, 2H); 1.77 (m, 2H); 1.43 (s, 9H), 0.91 (s, 9H), 0.09 (s, 6H).
98. ii. (2R,3R, 6S)-{6-hydroxymethyl-2-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-3, 6-dihydro- 2H-pyran-3-yl}-carbamic acid tert-butyl ester:
To a solution of intermediate 98.i (4 g) in DCM (80 ml) was added PTSA (0.083 g). After stirring for 15 min, 3,4-dihydro-2H-pyran (2.3 mX) was added dropwise. The reaction was stirred at rt for 90 min. IMNaHCO3 (10 ml) was added and the two layers were sepajrated. The organic layers were collected, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was resuspended in THF (100 ml) and IMTBAF in THF (13 ml) was added. The reaction mixture was stirred for 22 ti and the volatiles were removed under reduced pressure. The residue was purified by chromatography over silica gel (EA-Hex 3-1) to afford the title alcohol (2.7 g) as an oil.
1H NMR (CDCl3) δ: 6.02 (m, IH); 5.77 (m, IH); 4.70 (m, IH); 4.59 (m, 0.5H); 4.46 (m, 0.5H); 4.26 (m, IH); 4.15 (m, IH); 3.98-3.70 (m, 4H); 3.5 S-3.70 (m, 2.5H); 2.99 (broad s, 0.5H); 1.86 (m, 4H); 1.54 (m, 4H); 1.47 (s, 9H).
98.iii. (2i?,3/?,6^)-{6-(6-methoxy-quinolin-4-yloxymethyl)-2-[2-(tetrahydro-pyran-2-yloxy)- ethyl]-3,6-dihydro-2ΛT-pyran-3-yl}-carbamic acid tert-butyl ester
To an ice-chilled solution of intermediate 98. ii (2.7 g) in THF (80 ml) were added successively 6-methoxyquinolin-4-ol (1.32 g), PPh3 (3.96 g) and DIAD (3 ml). The reaction was stirred at rt for 14 h. Silica gel (20 g) was added and the volatiles were removed under reduced pressure. This material was chromatographed over silica gel (EA-MeOH 19-1) to afford the title compound (1.6 g) as a brownish oil. MS (ESI, m/z): 516.4 [MH-H+].
98. iv. (2R, 3R, 6S)-[2-(2-hydroxy-ethyl)-6-(6-methoxy-quinoIin-4-yloxymethyl)-3, 6-dihydro- 2H-pyran-3-yl]-carbamic acid tert-butyl ester.
To a solution of intermediate 98.iii (1.6 g) in MeOH (40 ml) was added PTSA (0.8 g). The reaction mixture was refluxed for 36 h. After cooling, K2CO3 (1 g) was added and the solvent was removed in vacuo. The residue was partitioned between water (100 ml) and EA (100 ml). The aq. layer was extracted with EA (100 ml) and the combined extracts were washed with brine and dried over Na2SO4. After evaporation, the residue was chromatographed over silica gel (DCM-MeOH 19-1) to afford the title alcohol (0.7 g) as a foam.
1H NMR (CDCl3) δ : 8.61 (d, J= 5.1 Hz5 IH); 7.86 (d, J= 9.1 Hz, IH); 7.47 (d, J= 2.8 Hz,
IH); 7.37 (dd, J= 2.8, 9.1 Hz, IH); 6.71 (d, J= 5.1 Hz, IH); 6.20 (ddd, J= 2.1, 5.9, 10.3 Hz, IH); 6.00 (dd, J= 3.0, 10.3 Hz, IH); 4.80 (m, 2H); 4.38 (dd, J= 8.1, 10.4 Hz, IH); 4.22 (dd,
J= 3.8, 10.4 Hz, 2H); 4.12 (m, IH); 3.94 (s, 3H); 3.78 (m, 2H); 2.68 (br s, IH); 1.85 (m, 2H);
1.46 (s, 9H).
MS (ESI, m/z): 431.4 [M+H+]. 98.v. (2R, 3R, 6S)-[2-(2-hydτOxy-ethyl)-6-(6-methoxy-quinoTin-4-yloxyrnethyl)-tetrahydro- pyran-3-ylJ-carbamic acid tert-butyl ester:
To a solution of intermediate 98. iv (0.7 g) in EA (14 ml) was added 10% palladium on charcoal (0.5 g). The reaction was stirred for 6 h under hydrogen atmosphere and the catalyst was removed by filtration. The filtrate was concentrated in vacuo to afford the title compound (0.45 g) as a white solid. MS (ESI, m/z): 433.4 [M+HE+].
98.vi. 2-[(2R, 3R, 6S)-3-amϊno-6-(6-methoxy-quinolin-4-yloxymethyl)-tetrahydro-pyran-2-yl]- ethanol: The title amine (0.36 g) was obtained as a white solid starting from intermediate 98.v (0.45 g) and using the procedure described in Example 12, step 12.ϊii. The compound was purified by chromatography (DCM-MeOH 9-1, 1% concentrated NH4OH). MS (ESI, m/z): 333.2 [M+H+].
98.VU. 2-[(2R,3R,6S)-3-[(2,3-dihydro-benzo[l,4]dioxin-6-y>lmethyl)-amino]-6-(6-methoxy- quinolin-4-yloxymethyl)-tetτahydro-pyran-2-yl]-ethanol:
To a solution of intermediate 98.vi (0.1 g) in 1,2-DCE (6 ml) and MeOH (2 ml) were added powdered 3 A molecular sieves (2 g) and 2,3-dihydro-benzo[l,4]dioxine-6-carbaldehyde
(0.054 g). The reaction mixture was stirred at rt overnight and NaBH4 (0.1 g) was added.
After stirring for 2 h, the reaction mixture was filtered through a plug of Hydromatrix® (pretreated with NaHCOs) . After concentration in vacuo, the residue was chromatographed over silica gel (DCM-MeOH 19-1, 1% concentrated aq. NH4OH) to afford the title compound
(0.075 g) as a white foam.
1H NMR (d6-DMSO) δ: 8.55 (d, J= 5.1 Hz, IH); 7.85 (d, J= 9.1 Hz, IH); 7.44 (d,
J= 2.8 Hz, IH); 7.37 (dd, J= 2.8, 9.1 Hz, IH); 6.94 (d, J= 5.1 Hz, IH); 6.84 (s, IH); 6.78 (s, 2H); 4.43 (broad s, IH); 4.21 (s, 4H); 4.19 (partially overlapped m, IH); 4.04 (m, 3H);
3.90 (s, 3H); 3.68 (m, 2H); 3.58 (s, 2H); 2.71 (m, IH); 2.O4 (m, 2H); 1.70 (m, 3H); 1.58 (m,
IH); 1.36 (m, IH).
MS (ESI, m/z): 481.6 [M-KH+] Example 99: 6-{[(2i?,3i-,65)-2-(2-hydroxy-ethyl)-6-(6-methoxy-quinolin- 4-yloxymethyl)-tetrahydro-pyran-3-ylamino]-methyl}-4H-benzo[l,4]thiaziB-3-one:
The title compound (0.05 g) was obtained as a yellowish solid, from intermediate 98.vi (0.1 g) and 3-oxo-3,4-dihydro~2H-benzo[l,4]thiazine-6-carbaldehyde (0.064 g), using the procedure described in Example 98, step 98.vii. MS (ESI, m/z): 510.5 [M+Η+].
Example 100: 6-{[(2Λ,3Λ,61S)-2-(2-liydroxy-ethyl)-6-(6-methoxy-quinoliii- 4-yloxymethyl)-tetrahydro-pyran-3— ylamino]-methyl}-4H-pyrido[3,2-Λ][l,-4]thiazin- 3-one:
The title compound (0.10 g) was obtained as a yellowish solid, from intermediate 98.vi (0.1 g) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-ό][l,4]thiazine-6-carbaldehyde (0.064 g), using the procedure described in Example 98, step 98.vii. MS (ESI, m/z) : 511.5 [M+Η*].
Example 101: 3-oxo-3,4-dihydro-2JΪ-pyrido[3,2-6][l,4]thiazine-6-carboxylic acid {(1 α,5α,6α)-3-[(2i?)-2-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-3-aza- bicyclo [3.1.0] hex-6-yl}-amide:
To a mixture of intermediate 47.vi and 3-oxo-3,4-dihydro-2H-pyrido[3,2-&][l,4]thiazine-6- carboxylic acid (0.110 g, 0.52 mmol) in DMF (2.5 ml) and DCM (2.5 ml) were added DIPEA (0.28 ml) and ΗATU (0.225 g, 0.59 mmol). The reaction was stirred at it for 2 h. The solvents were evaporated and the crude mixture was chromatographed over silica gel (DCM-MeOH 17-3 containing 1% aq. NH4OH) affording the title amide (0.06 g, 0.12 mmol) as a beige foam. MS (ESI5 m/z): 492.3 IMfH+].
Example 102: 6-({(lα,5α,6α;-3-[(2i?)-2-hydroxy-2-(3-methoxy-quinoliii-5-yl)-ethyI]- 3-aza-bicyclo[3.1.0]hex-6-ylamino}-methyl)-4H-benzo[l,4]oxazin-3-one:
Starting from intermediate 47.vi £0.100 g) and 3-oxo-3,4-dihydro-2H-benzo[l,4]oxazine- 6-carbaldehyde (0.065 g), the title compound (0.074 g) was prepared as a white foam according to the procedure described in Example 88, step 88. iv. MS (ESI, m/z): 461.4 [M+H+].
Example 103: rac-2-{(l α,5α,6α)-3-[2-h.ydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]- 3-aza-bicy clo [3.1.0] hex-6-ylamino}-iV-tliiazol-2-y 1-acetamide :
To a solution of rαc-(lα,5α,6α)-6-amino-3-aza-bicyclo[3.1.0]hex-3-yl)-l-(6-methoxy- quinolin-4-yl)-ethanol (0.400 g) in DMF <5 ml) were added DIPEA (0.465 ml) and 2-bromo- N-thiazol-2-yl-acetamide (0.455 g). The resulting solution was heated at 80DC for 2.5 h. The reaction mixture was concentrated to dryness and purified by column chromatography over silica gel (DCM-MeOH 19-1, 1% aq. ΝH4OH) to afford the title compound as a yellow foam (0.581 g). The compound of 77% purity was contaminated with some dialkylated compound. MS (ESI, m/z): 440.5 [M+H+].
Example 104: rac-(lα,5α,6α)-2-{6-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]- S-aza-bicyclop.l.Ojhex-S-ylJ-l-P-methoxy-quinoxalin-S-yty-ethanol:
104. i. 2-cyano-N-(2-methyl-6-nitro-phenyl)-acetamide:
To a solution of 2-methyl-6-nitroaniline (25 g, 164.3 mmol) in benzene (2OO ml) were added cyanoacetic acid (14.5 g, 170.46 mmol) a.nd PCI5 (35 g, 168 mmol). The reaction mixture was heated at 6O0C for 7 h. After cooling to rt, the reaction mixture was filtered and the solid was washed with benzene and water. The solid was dried under reduced pressure to afford the title acetamide (24 g, 109 mmol) as a yellow solid.
1H NMR (d6-DMSO) δ: 10.2 (s, IH); 7.78 (d, J = 8.3 Hz, IH); 7.65 (d, J = 8.3 Hz, IH); 7.43 (t, J= 8.3 Hz, IH); 3.95 (s, 2H); 2.3O (s, 3H).
104. ii. 3-hydroxy-5-methyl-l-oxy-quinoxaline-2-carbonitrile:
To a solution mixture of intermediate 104. i (24 g, 109.5 mmol) in IM aq. NaOH (100 ml) was added pyridine (100 ml). The reaction mixture was stirred at rt for 4 h. The pH was adjusted to 6 by addition of IM aq. HCl. The solid was filtered off and washed with, water. The solid was triturated with EtOH. After drying under HV, the title nitrile (17.7 g, 87.9 mmol) was obtained as a yellow solid. MS (ESI5 m/z): 202.1 [M+H+]. 104.iii. 8-nιethyl-quinoxalin-2-ol:
To a solution of intermediate 104.U (17.7 g, 87.9 mmol) in water (300 ml) and EtOH (24 ml) was added sodium dithionite (35.4 g, 203.9 mmol). The reaction mixture was heated at 60°C for 1 h. The reaction mixture was filtered till warm, and the pH of the filtrate was adjusted to 2 by adding XM aq. HCl. The pH of the solution was subsequently made basic by adding solid NaOH (10 g). EA (150 ml) was added. The aq. layer was extracted twice more with. EA (2 x 150 ml). The combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness. The residue was dried under HV to afford the title intermediate (11.1 g, 69 rnmol) as a yellow solid. 1H NMR (d6-DMSO) δ: 11.75 (br s, IH); 8.17 (s, IH); 7.62 (d, J = 8.4 Hz, IH); 7.40 (d, J = 8.4 Hz, IH); 7.21 (t, J = 8.4 Hz, IH); 2.42 (s, 3H). MS (ESI, m/z): 161.1 [M+H+].
104.iv. 2-chloro-8-methyl-quinoxaline:
A solution of intermediate 104. iii (11.1 g, 69.5 mmol) in phosphorus oxychloride (8O ml) was heated at 1100C during 2 h. After cooling to rt, the reaction mixture was poured onto ice (200 g). The aqueous layer was extracted with EA (2 x 200 ml). The combined extracts were washed with brine (100 ml), dried over Na2SO4, filtered and concentrated to dryness. The residue was chromatographed over silica gel (Hex-EA 1-1) to afford the title intermediate (12.5 g, 69.5 mmol) as a red solid. 1U NMR (d6-DMSO) δ: 8.99 (s, IH); 7.97 (m, IH); 7.80 (m, 2H); 2.68 (s, 3H). MS (ESI, m/z): 179.2 [M+H+].
104.V. 2-methoxy-8-methyl-quinoxaline:
To a solution of intermediate 104.iv (12.5 g, 69.5 mmol) in DMF (80 ml) was added sodium methoxide (9 g, 166 mmol). The reaction mixture was heated at 45°C for 4h. After cooling to rt, the reaction mixture was partitioned between water (10 ml) and EA (200 ml). Tine organic layer was washed once with water (100 ml), dried over Na2SO4, filtered and concentrated to dryness. The residue was chromatographed over silica gel (Hex-EA 1-4) to afford the title intermediate (10.2 g, 58.55 mmol) as a yellow solid.
1H NMR (CDCl3) δ: 8.48 (s, IH); 7.88 (d, J = 7.9 Hz, IH); 7.55 (d, J = 7.9 Hz, IH); 7.47 (t, J = 7.9 Hz, IH); 4.12 (s, 3H); 2.69 (s, 3H).
MS (ESI, m/z): 175.4 [MfH+]. 104.vi. 8-dibromomethyl-2-methoxy-quinoxaline:
To a solution of intermediate 104.V (10.2 g) in CCl4 (560 ml) were added AIBN (0.96 g) and NBS (25.9 g, 145.5 mmol). The reaction mixture was heated at 8O°C for 3 h. After cooling to rt, the reaction mixture was washed with water (200 ml) and the organic layer was dried over Na2Sθ4, filtered and concentrated in vacuo. The residue was triturated with MeOH to give, after drying under HV, the title dibromide (14.4 g, 43.3 mmol) as a slightly beige solid. 1H NMR (d6-DMSO) δ: 8.69 (s, IH); 8.25 (dd, J = 1.3, 7.5 Hz, IH); 8.07 (dd, J = 1.3, 8.3 Hz, IH); 8.02 (s, IH); 7.74 (dd, J = 7.5, 8.3 Hz, IH); 4.14 (s, 3H). MS (ESI, m/z): 332.8 [M+H4"].
104.vii. 3-methoxy-quinoxaline-5-carbaldehyde:
To a solution of intermediate 104.vi (10.7 g, 32.2 mmol) in EtOH (330 ml) was added, at rt, a solution of silver nitrate (15 g) in water (70 ml). The reaction was stirred at rt for 1 h. The reaction mixture was diluted with MeCN (200 ml) and the solids were filtered off and the filtrate was concentrated in vacuo. The residue was filtered over a silica gel pad (eluent: EA) to afford the title aldehyde (6.2 g, 32.2 mmol) as a slightly yellow solid.
1H NMR (d6-DMSO) δ: 11.15 (s, IH); 8.74 (s, IH); 8.36 (dd, J = 1.3, 8.1 Hz, IH); 8.21 (dd, J = 1.3, 7.9 Hz, IH); 7.80 (dd, J = 7.9, 8.1 Hz, IH); 4.14 (s, 3H). MS (ESI, m/z): 189.2 [M+H+].
104.viii. rac-2~methoxy-8-oxiranyl-quinoxaline: To a solution of intermediate 104.vii (3 g, 15.9 mmol) in MeCN ( 120 ml) were added at 6O0C, trimethylsulfonium iodide (3.4 g, 16.6 mmol) and KOH (6.4 g). The mixture was heated at this temperature for 1 h. The reaction mixture was filtered and the filtrate was concentrated to dryness. The residue was chromatographed over silica gel (Hex-EA 2-1) to afford the title epoxide (2.9 g, 14.3 mmol) as a slightly yellow solid. 1U NMR (CDCl3) δ: 8.53 (s, IH); 7.97 (m, IH); 7.56 (m, 2H); 4.94 (dd, J = 2.6, 4.1 Hz, IH); 4.14 (s, 3H); 3.33 (dd, J= 4. 1, 5.7 Hz, IH); 2.87 (dd, J = 2.6, 5.7 Hz, IH). MS (ESI, m/z): 203.3 [MH-H+]. 104. ix. rac-(l a, 5a, 6a))-{3-[2-hydroxy-2-(3-methoxy-qumoxalin-5-yl)-ethyl]-3-czza- bicyclo[3.1.0]hex-6-yl}-carbamic acid tert-butyl ester:
To a solution of intermediate 104.viii (1 g, 4.94 mmol) and (la,5cx,6q)-(3-aza- bicyclo[3.1.0]hex-6-yl)-carbamic acid tert-butyl ester (0.98 g, 4.94 mmol) in DMF (20 ml) were added K2CO3 (0.72 g, 5.2 mmol) and lithium perchlorate (0.552 g, 5.Z mmol). The reaction mixture was heated at 80°C overnight. -After concentration to dryness, the residue was chromatographed over silica gel (DCM-MeOK 19-1) to afford the title compound (1.3 g, 3.24 mmol) as an oil. MS (ESI, m/z): 401.1 [M+H+].
104.x. rαc-(l α, 5α, 6q)-2-(6-αmino-3-αzα-bicyclo[~3.1.0]hex-3-yl)-l-(3-methoxy-quinoxαlin- 5-yl)-ethαnol:
A solution of intermediate 104.ix (1.3 g) in TRA (4 ml) was stirred at rt for 30 min. The solvent was removed under reduced pressure. The residue was basified with ITV aq. NaOH and extracted with a DCM-MeOH 9-1 mixture (5 x 20 ml). The combined organic layers were dried over MgSO4 and concentrated to dryness . The residue was purified o~ver silica gel (DCM-MeOH 9-1, 1% aq. NH4OH) to afford the title amine (0.8 g, 2.66 mmol) as a yellowish foam. MS (ESI, m/z): 301.3 [M+H+].
104.xi. rαc-(l α,5α, 6α)-2-{6-[(2, 3-dihydro-benzo/l, 4]dioxin-6-ylmethyl)-αminoJ-3-αzα- bicycloβ.1.0]hex-3-yϊ}-l-(3-methoxy-quinoxαlin-5-yl)-ethαnol:
To a solution of intermediate 104.x (0.1 g, 0.33 rnmol) in MeOH (2 ml) and 1.2-DCE (6 ml) were added 3 A molecular sieves (2 g) and 2,3-dihydro-benzo[l,4]dioxine-6-carbaldehyde (0.06 g, 0.367 mmol). The reaction was stirred at room temperature overnight. INaBH4 (0.1 g, 2.7 mmol) was added and the mixture was further stirred 1 h. The reaction, mixture was filtered through Hydromatrix® (pretreated with saturated NaHCO3). The; filtrate was concentrated to dryness and the residue was chromatographed over silica gel (DCM-MeOH 19-1 containing 1% aq. NH4OH) to afford the title compound as a white foam (0.063 g, 0.14 mmol). 1H NMR (d6-DMSO) δ: 8.60 (s, IH); 7.88 (d, J = 8.1 Hz, IH); 7.84 (d, J= 7.9 Hz, IH); 7.60 (dd, J = 7.9, 8.1 Hz, IH); 6.80-6.69 (m, 3H); 5.63 (m, IH); 5.02 (d, J= 4.4 Hz, IH); 4.21 (s, 4H); 4.04 (s, 3H); 3.51 (s, 2H); 3.06 (d, J = 8.6 Hz, IH); 2.95 (d, J = 8.6 Hz, IH); 2.56 (m, 2H); 2.45 (m, 2H); 2.16 (br s, IH); 1.26 (br s, 2H). MS (ESI, m/z): 449.5 [M+H+].
Example 105: rαc-(lα,5α,6α)-6-({3-[2-hydroxy-2-(3-methoxy-quinoxalin-5-yl)-ethyl]- 3-aza-bicy clo [3.1.0] hex-6-y lamino}-methy l)-4H-benzo [1,4] thiazin-3-o ne :
The title compound (0.055 g, 0.11 mmol) was obtained as a yellowish foam by the method of Example 35, step 35.iii, starting from 3-oxo-3,4-dihydro-2/ϊ/-benzo[l,4]thiazine- 6-carbaldehyde (0.071 g) and intermediate 104.x (0.1 g). MS (ESI, m/z): 478.5 [M+H+].
Example 106: rαc-(lα,5α,6α)-6-({3-[2-hydroxy-2-(3-methoxy-quinoxalin-5-yl)-ethyl]- 3-aza-bicyclo[3.1.0]hex-6-ylamino}-methyl)-4H-benzo[l,4]oxazin-3-»iie:
The title compound (0.059 g, 0.13 mmol) was obtained as a yellowish foam by the method of Example 35, step 35.iii, starting from 3-oxo-3,4-dihydro-2J?7-benzo[l,4]oxazine- 6-carbaldehyde (0.065 g) and intermediate 104.x (0.1 g). MS (ESI, ΠL/Z): 462.2 [M+H+].
Example 1O7: rac-(lα,5α,6α)-2-{6-[(benzo[l,2,5]thiadiazol-5-ylmetliyI)-amino]-3-aza- bicyclo[3.1-0]hex-3-yI}-l-(3-methoxy-quinoxalin-5-yl)-ethanol:
The title compound (0.035 g) was obtained as a yellowish foaim by the method of Example 35, step 35.iii starting from benzo[l,2,5]thiadiazole-5-carba.ldehyde (0.06 g) and intermediate 104.x (0.1 g).
MS (ESI, m/z): 449.5 [M+H+].
Example 108: rαc-(l α,5α,6α)-6-({3-[2-hydroxy-2-(3-methoxy-quinc»xalin-5-yl)-ethyl]- 3-aza-bicyclo[3.1.0]hex-6-ylamino}-methyl)-4H-pyrido[3,2-6][l,4]thiazin-3-one:
The title compound (0.026 g) was obtained as a yellowish foam by the method of Example 35, step 35.iii, starting from 3-oxo-3,4-dihydro-2H-pyrido[3,2-έ][l,4]thiazine- 6-carbaldehyde (0.035 g) and intermediate 104.x (0.05 g). 1H NMR (d6-DMSO) δ: 10.87 (s, IH); 8.58 (s, IH); 7.86 (d, J = 8.1 Hz, IH); 7.82 (d, J = 7.9 Hz, IH); 7.72 (d, J = 7.8 Hz, IH); 7.60 (dd, J = 7.9, 8.1 Hz, IH); 7.02 (d, J = 7.8 Hz, IH); 5.63 (m, IH); 5.02 (d, J = 4.4 Hz, IH); 4.03 (s, 3H); 3.66 (s, 2H); 3.51 (s, 2H); 3 .06 (d, J = 8.6 Hz, IH); 2.96 (d, J = 8.6 Hz, IH); 2.56 (m, 2H); 2.45 (m, 2H); 2.09 (br s, IH); 1.28 (br s, 2H).
MS (ESI, m/z): 479.5 [M+H+].
Example 109: rac-(l a,5a,6ά)-2- {6-[(benzofuran-2-yImethyI)-amino]-3-aza- bicyclo[3.1.0]hex-3-yl}-l-(3-methoxy-quinoxalin-5-yl)-ethanol:
This compound (0.024 g) was obtained as a yellowish foam by the method of Example 35, step 35.iii, using benzofuran-2-carbaldehyde (0.027 g) and intermediate 104.x (0.05 g). MS (ESI, m/z): 431.3 [M+H+].
Example 110: rac-(l α,5 a,6 a)- 1 - (3-methoxy-quinoxalin-5-yl)-2- [6-(3-phenyl- aIlylamino)-3-aza-bicyclo [3.1.0] h. ex-3-y I]-ethanol :
This compound (0.059 g) was obtained as a yellowish foam by the method of Exairxple 35, step 35,iii starting from frαrø-cinnamaldehyde (0.048 g) and intermediate 104.x (0.1 g) . MS (ESI, m/z): 417.4 [Mt-H+].
Example 111: rαc-(l a,5 α,6 α)-2- {6- [(2,2-dimethyl-chroman-7-yImethyl)-amino] -3 -aza- bicyclo[3.1.0]hex-3-yI}-l-(3-methoxy-quinoxaIin-5-yI)-ethanol:
This compound (0.068 g) was obtained as a white foam by the method of Exam_ple 35, step 35.iii, using 2,2-dimethyl-chroman-7-carbaldehyde (0.075 g) and intermediate 104.x
(0.1 g).
MS (ESI, m/z): 475.3 [MfH+].
Example 112: 6-{2-[(l α,5α,6α)-6-(6-methoxy-quinazolin-4-yloxymethyl)-3-aza- bicyclo [3.1.0] hex-3-yI]-acetyl}-4-H-benzo [1 ,4] thiazin-3-one :
This compound (0.21 g) was obtained as an orange solid by the method of Example 10, step lO.iii, using intermediate lO.ii (0.271 g, lmmol) and 6-(2-chloro— acetyl)- 4H-benzo[l,4]thiazin-3-one (0.241 g, 1 mmol). MS (ESI, m/z): 477.1 [M+ϊt].
Example 113: 6-{l-hydroxy-2-[(lα,5α,6α)-6-(6-methoxy-quinaz(>lin-4-yloxymethyI)- 3-aza-bicycIo[3.1.0] hex-3-yl]-ethyl}-4H-benzo[l ,4]thiazin-3-one :
Starting from the compound of Example 112 (0.15O g, 0.315 mmol), the title compound (0.09 g) was prepared as an orange solid using the procedure described in Example 11.
1H NMR (d6-DMSO) δ: 10.56 (s, IH); 8.66 (s, IH); 7.85 (d, J = 9.0 Hz, IH); 7.57 (dd, J = 2.8, 9.0 Hz, IH); 7.41 (d, J = 2.8 Hz, IH); 7.21 (d, J = 7.6 Hz, IH); 6.97 (s, IH); 6.90 (d, J = 7.6 Hz, IH); 5.04 (d, J = 3.5 Hz, IH); 4.51-4.34 (m, 3H); 3.93 (s, 3H); 3.42 (s, 2H); 3.05 (dd, J = 8.4, 22.4 Hz, 2H); 2.50 (overlapped m; 2H); 2.38 Cm, 2H); 1.71 (m, IH); 1.65 (br s, 2H).
MS (ESI, m/z): 479.2 [M+H+].
Example 114: 6-{[(3J?,6iS)-6-(3-methoxy-quinolin-5-yloxymethyl)-tetrahydro-pyran- 3-ylamino]-methyl}-4H-pyrido[3,2-6][l,4]thiazin-3-one:
114. i. [(3R, 6S)-6-(3-tnethoxy-quinolin-5-yloxymethyl)-tetrahydro-pyran-3-yl]-carbamic acid tert- butyl ester.
This compound (3.33 g, 8.57 mmol) was obtained as a yellowish foam from intermediate 78.i (3.47 g, 15 mmol) and 3-methoxy-quinolin-5-ol (2.62 g, 15 mrnol), according to the procedure of Example 77, step 77. ii. MS CESI, m/z): 389.0 [MfH+].
114. ii. (3R,6S)-6-(3-methoxy-quinolin-5-yloxymethyl)-tetrahydro-pyran-3-ylamine:
Starting from intermediate 114.i (3.33 g), the title compound (2.20 g, 90% yield) was prepared as a yellowish oil according to the procedure described in Example 77, step 77.iii. MS (ESI, m/z): 289.5 [M+H+].
114.iii. 6-{[(3R,6S)-6-(3-τnethoxy-quinolin-5-yloxymethyl)-tetrahydr-o-pyran-3-ylamino]- methyl}-4H-pyrido[3, 2-b][l, 4]thiazin-3-one\
The title compound (0.016 g) was obtained as a white foam by the method of Example 88, step 88.iv, using 3-oxo-3,4-dihydro-2H-pyrido[3,2-Z>][l,4]thiazine-6-carbaldehyde (0.037 g) and intermediate 114.U (0.05 g). MS (ESI, m/z): 467.5 [MfH+]
Example 115: 6-{[(3J?,65)-6-(3-methoxy-quinolin-5-yloxymethyl)-tetrahydro-pyran- 3-ylamino]-methyl}-4H-benzo[l,4]thiazin-3-one:
Starting from intermediate 114.ii (0.11 g) and 3-oxo-3,4-dihydro-2H-benzo[l,4]thiazine- 6-carbaldehyde (0.077 g), the title compound (0.03 g) was prepared as a pale yellow solid using the procedure described in Example 88, step 88. ΪΎ. MS (ESI, m/z): 466.5 [M+Η+].
Example 116: benzo[l,3]dioxol-5-ylmethyl-[(32?,6S')-6-(3-methoxy-quinoIin- 5-yloxymethyl)-tetrahydro-pyran-3-yl]-amine hydrochloride:
To a solution of intermediate 114.U (0.100 g) in MeOH (2 ml) and 1,2-DCE (5 ml) were added 3 A molecular sieves (2 g) and benzo[l,3]ciioxole-5-carbaldehyde (0.055 g). Th,e mixture was stirred at it overnight. NaBH4 (0.100 g) was added and the reaction was stirred for 2 h. The reaction mixture was filtered through Hydromatrix® (treated with saturate d NaHCO3 solution) and the filtrate was concentrated αnder reduced pressure. The residue was purified by column chromatography over silica gel (DCM-MeOH 19-1 containing 1% acq. NH4OH). The product was dissolved in ether and 2N HCl was added to form tt*e hydrochloride salt as a strong yellow solid that was collected by filtration (0.030 g). 1H MMR (d6-DMSO) δ: 8.87 (s, IH); 8.00 (s, 1O); 7.69 (d, J= 8.4 Hz, IH); 7.61 Qt, J= 7.8Hz, IH); 7.28 (d, J= 1.4 Hz, IH); 7.17 (d, J= 7.8 Hz, IH); 7.08 (dd, J= 1.4, 8.0 Hz, IH); 6.97 (d, J= 8.0 Hz, IH); 4.28 (m, IH); 4.21 (d, J= 4.7 Hz, 2H); 4.10 (m, 2H); 4.00 Cs, 3H); 3.82 (m, IH); 3.57 (t, J= 10.7 Hz, IH); 3.17 (s, 2H); 2.34 (m, IH); 1.99 (m, Iff); 1.83 (m, IH); 1.54 (m, IH), 1.21 (m, IH). MS (BSI, m/z): 423.6 [M+H+].
Example 117: (2,3-dihydro-benzo[l,4]dioxin-6-ylrnethyl)-[(3i?,6iS)-6-(3-methoxy- quinolin-5-yloxymethyl)-tetrahydro-pyran-3-yl]-arnine hydrochloride:
Starting from intermediate 114.U (0.102 g) and 2,3-dihydro-benzo[l,4]dioxine- 6-carbaldehyde (0.064 g), the title compound (0.Q61 g) was prepared as a white foaαn according to the procedure described in Example 88, step 88. iv. MS (ESI, m/z): 437.5 [MHhH+]. Example 118: 6-{[(3-R,65)-6-(3-methoxy-quinolin-5-yloxymethyl)-tetrahyrdro-pyran- 3-ylamino]-niethyI}-4./7-benzo[l,4]oxazin-3-one:
Starting from intermediate 114.ii (0.111 g) and 3-oxo-3,4-dihydro-2H-benzo[l,4]oxazine- 6-carbaldehyde (0,075 g), the title compound (0.023 g) was prepared as a yellow solid according to the procedure described in Example 88, step 88. iv. MS (ESI, m/z): 450.5 [M+H+].
Example 119: (2,3-dihydro-[l,4]dioxino[2,3-6]pyridin-6-yImethyl)- [(3J?,65)-6-(3-methoxy-quinolin-5-yIoxymethyI)-tetrahydro-pyran-3-yl]-amine:
Starting from intermediate 114.U (0.082 g) and 2,3-dihydro-[l,4]dioxino[2,3-έ]pyridine- 6-carbaldehyde (0.049 g), the title compound (0.075 g) was prepared as a white foam according to the procedure described in Example 88, step 88. iv.
1H NMR (CDCl3) δ: 8.65 (d, J= 3.0 Hz, IH); 7.80 (d, J= 3.0 Hz, IH); 7.6>4 (d, J= 8.6 Hz,
IH); 7.42 (dd, J= 7.8, 8.6 Hz, IH); 7.14 (d, J= 7.8 Hz, IH); 6.85 (m, 2H); 4.43 (m, 2H);
4.23 (m, 2H); 4.16 (m, 2H); 4.07 (dd, J= 4.3, 10.1 Hz, IH); 3.97 (s, 3H); 3.S2 (d, J= 2.4 Hz, 2H); 3.29 (t, J= 10.7 Hz, IH); 2.79 (m, IH); 2.22 (m, IH), 2.03 (m, 2EC), 1.92 (m, IH);
1.51 (m, 2H).
MS (ESI, m/z): 438.4 [M+H+].
Example 120: (2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-yImethyl)- [(3i?,65)-6-(3-methox:y-quinolin-5-yloxymethyl)-tetrahydro-pyran-3-yI]-amine:
Starting from intermediate 114.U (0.08O g) and 2,3-dhydro-[l,4]dioxiixo[2,3-c]pyridine-
7-carbaldehyde (0.048 g), the title compound (0.080 g) was prepared as a white foam according to the procedure described in Example 88, step 88.iv.
1H NMR (CDCl3) δ: 8.65 (d, J= 2.8 Hz, IH); 8.10 (s, IH); 7.80 (d, J= 2.8 Hz, IH); 7.60 (d,
J= 8.5 Hz, IH); 7.44 (dd, J= 7.8, 8.5 Hz, IH); 6.86 (d, J= 7.8 Hz, IH); 6.81 (s, IH); 4.32 (m, 2H); 4.27 (rn, 2H); 4.16 (m, 2H); 4.07 (dd, J = 4.3, 10.1 Hz, IH); 3.96 (s, 3H);
3.81 (d, J= 4.2 Hz, 2Η); 3.25 (t, J= 10.6 Hz, IH); 2.76 (m, IH); 2.20 (m. 1 H), 2.10 (m, IH),
1.90 (m, IH); 1.59 (m, IH); 1.49 (m, IH).
MS (ESI, m/z): 438.5 [M+H+]. Example 121: 7-fluoro-6-{[(3Λ,65)-6-(3-methoxy-quinolin-5-yloxymethyl)-tetrahydro- pyran-3-ylamino]-methyl}-4£af-benzo[l,4]thiazin-3-one:
Starting from intermediate 114.U (0.100 g) and 6-fluoro-3-oxo-3,4-dihydro- 2H-benzo[l,4]thiazine-7-carbaldehyde (0.081 g), the title compound (0.054 g) was prepared as a white solid according to trie procedure described in Example 88, step 88. iv. MS (ESI, m/z): 484.4 [M+Η+].
Example 122: benzofuran-2-ylmethyl-[(3i-,65)-6-(3-methoxy-quinolin-5-yloxymethyl)- tetrahydro-pyran-3-yl]-amine:
The title compound (0.028 g) Λvas obtained as a colourless oil by the method of Example 88, step 88. iv, using benzofuran-2-carbaldehyde (0.028 g) and intermediate 114. ii (0.05 g). MS (ESI, m/z): 419.4 [M+H+].
Example 123: [(3/f,6-5)-6-(3-methoxy-quinolin-5-yloxymethyl)-tetrahydro-pyran-3-yl]- (3-phenyl-allyl)-amine:
The title compound (0.061 g, 0.15 mmol) was obtained as a colourless oil by the method of Example 88, step 88. iv, using /rαws-cinnamaldehyde (0.051 g) and intermediate 114.U (0.1 g). MS (ESI, m/z): 405.6 [MfH+] .
Example 124: benzo[l,2,5]thiadiazol-5-ylmethyl-[(32?,65)-6-(3-methoxy-quinoliiι- 5-yloxymethyl)-tetrahydro-pyran-3-yl]-amine:
This compound (0.096 g) was obtained as a colourless oil by the method of Example 88, step 88.iv, using benzo[l,2,5]thiadiazole-5-carbaldehyde (0.062 g) and intermediate 114.ii
(0.1 g).
MS (ESI, m/z): 437.4 [M+H+].
Example 125: (32?,6.S)-heptyl-[6-(3-methoxy-quiiiolin-5-yloxymetIiyl)-tetrahydro- py ran-3-yl] -amine :
Starting from intermediate 114.H (0.146 g, 0.5 mmol) and «-heptaldehyde (0.O78 ml, 1.1 eq.), the title compound (0.105 g, 53% yield) was prepared as yellow oil according to the procedure described in Example 88, step 88. iv. 1H NMR (CDCl3) d: 8.66 (d, J = 3.0 Hz, IH); 7.81 (d, J = 2.9 Hz1 IH); 7.65 (d, J = 8.5 Hz, IH); 7.43 (t, J = 8.4 Hz, IH); 6.87 (d, J = 7.68 Hz, IH); 4.21 (dd overlapped, J = 6.1, 10.1 Hz, IH); 4.15 (m overlapped, 2H); 4.09 (dd, J = 4.3, 10.1 Hz, IH); 3.97 (s, 3H); 3.82 (m, IH); 3.17 (t, J = 10.5 Hz, IH); 2.68 (m, 3H); 2.17 (m, IH); 1.89 (m, IH); 1 .63 (m, IH); 1.50 (m, 2H); 1.29 (m, 9H); 0.88 (t, J = 6.9 Hz, 3H). MS (ESI, m/z): 387.4 [M+ff*"].
Example 126: 2-[(3Λ,6i_t)-6-(3-methoxy-quinolin-5-yIoxymethyl)-tetrahydro-pyran- 3-ylamino] -iV-thiazol-2-yl-acetamide :
To a solution of intermediate 114.U (0.111 g) in DMF (2.85 ml) were added DIPEA (0.150 ml) and 2-bromo-N-thiazol-2-yl-acetamide (0.13I g). The resulting solution was heated at 8O0C for 2.5 h. The reaction mixture was concentrated to dryness and purified by column chromatography over silica gel (DCM-MeOH 19-1 containing 1% aq. ΝH4OH) to afford the title compound as a yellow foam (0.059 g).
1H NMR (CDCl3) δ: 8.66 Cd, J= 3.0 Hz, IH); 7.79 (d, J= 3.0 Hz, I H); 7.66 (dd, J= 2.3, 8.5 Hz, IH); 7.46 (d, J= 3.6 Hz, IH); 7.43 (d, J= 8.5 Hz, IH); 7.00 (d, J= 3.6 Hz, IH);
6.86 (d, J= 7.1 Hz, IH); 4. 18 (m, IH); 4.12 (m, 2H); 3.97 (s, 3H); 3.83 (m, IH); 3.57 (d,
J= 5.0Hz, 2H); 3.22 (t, J= 10.6 Hz, IH); 2.75 (m, IH); 2.23 (m, IH); 1.92 (m, IH); 1.60 (m,
IH), 1.43 (m, IH).
MS (ESI, m/z): 429.2 [M+H+].
Example 127: (2,3-dihydro-benzo[l,4]dioxin-6-yImethyl)-[(3J?,6S}-6-(3-methoxy- quinoxalin-5-yloxymethyl)-tetrahydro-pyran-3-yl]-amine:
127. i. (2S, 5R)-methanesulfonic acid 5-tert-butoxycarbonylamino-tetrahydro-pyran- 2-ylmethyl ester.
To a solution of intermediate 78.i (1.9 g, 8.21 mmol) in DCM (50 ml) were added, at 0°C, TEA (2.2 ml) and MsCl Q).12 ml, 9.43 mmol). The reaction was stirred 20 min at this temperature and saturated NTaHCO3 (30 ml) was added. The two layers were separated. The organic layer was dried over Na2SO4, filtered and concentrated to dryness. The residue was chromatographed over silica gel (EA-Hex 2-1) to afford the title mesylate as a white solid (2.3 g). MS (ESI, m/z): 310.3 [M+H+] . 127. ii. [(3R,6S)-6-(3-methoxy-qιιinoxalin-5-yloxyr)tethyl)-tetrahydro-pyran-3-yl]-carbaιmic acid tert-butyl ester:
To a solution of intermediate 127.i (1.78 g, 5 .75 mmol) in MeCN (25 ml) were added successively 3-methoxy-quinoxalin-5-ol (prepared as described in WO 2004/002490, 1.12 g, 6.33 mmol), K2Cθ3 (1.39 g) and tetrabutylammonium iodide (0.2 g). The reaction mixture was refluxed for 36 h. After cooling, the reaction mixture was concentrated to dryness. The residue was partitioned between water (50 ml) and EA (100 ml). The aq. layer was extracted three times more. The combined organic layers were washed with brine, dried over NTa2SO4, filtered and concentrated to dryness. The residue was chromatographed over silica gel (Hex-EA 2-1 then 0-1) to afford the title compound (1.1 g) as a white solid.
1H NMR (CDCl3) δ: 8.49 (s, IH); 7.68 (dd, J = 1.1, 8.4 Hz, IH); 7.47 (tdd, J =7.9, 8.4 Hz, IH), 7.15 (dd, J = 1.1, 7.9 Hz, IH); 4.32 (app dd, J = 5.7, 9.9 Hz, 2H); 4.22-4.13 (overlapped m, 2H); 4.15 (s, 3H); 3.82 (m, IH); 3.70 (br s, IH); 3.14 (t, J = 10.6 Hz, IH); 2.22 (br d, J = 12.3 Hz, IH); 2.02 (qd, J = 3.5, 13.1 Hz, IH); 1.71-1.63 (m, IH); 1.47 (s, 9H), 1.40 (partially overlapped m, IH). MS (ESI, m/z): 390.4 [M+H+].
127. iii . (3R, 6S) -6- (3-methoxy-quinoxalin-5-yloxyjne thyl) -tetrahydro-pyran-3-ylamine :
The title amine (0.72 g) was prepared from intermediate 127. ii (1.1 g, 2.82 mmol) according to the procedure described in Example 77, step 77.Ui. 1H NMR (CDCl3) δ: 8.49 (s, IH); 7.68 (dd, J = 1.1, 8.4 Hz, IH); 7.47 (tdd, J =7.9, 8.4 Hz,
IH), 7.15 (dd, J = 1.1, 7.9 Hz, IH); 4.30 (dd, J = 5.7, 9.9 Hz, IH); 4.16 (partially overlapped dd, J = 4.7, 9.9 Hz, IH); 4.15 (s, 3H); 4.05 (ddd, J = 2.2, 4.5, 10.7 Hz, IH); 3.83 (πn, IH);
3.13 (t, J = 10.7 Hz, IH); 2.90 (tt, J = 4.4, 10.9 Hz, IH); 2.15 (m, IH); 2.00 (m, IH); 1 .66 (m,
IH); 1.45-1.27 (m, 3H). MS (ESI, m/z): 290.1 [M+H+].
127.iv. (2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-[(3R,6S)-6-(3-methoxy-quinoxalin- 5-yloxymethyl)-tetrahydro-pyran-3-yl] -amine:
This compound (0.085 g) was obtained as a colourless oil by the method of Exanxple 88, step 88. iv, using 2,3-dihydro-benzo[l,4]dioxine-6-carbaldehyde (0.062 g) and intermediate 127.iii (0.1 g). 1H NMR (CDCl3) δ: 8.39 (s, IH); 7.57 (dd, J = 1.1, 8.4 Mz, IH); 7.38 (dd, J = 7.9, 8.-4 Hz, IH); 7.06 (dd, J - 1.1, 7.9 Hz, IH); 6.81-6.69 (m, 3H); 4.19 (partially overlapped m, IH); 4.17 (s, 4H); 4.09 (partially overlapped m, 2H); 4.05 (s, 3H); 3.76 (m, IH); 3.65 (s, 2H); 3.12 (app t, J = 10.5 Hz, IH); 2.69 (m, IH); 2.09 (m, IH); 1.88 (m, IH); 1.57 (br s, IH); 1.55 (m, IH); 1.35 (app qd, J = 3.5, 12.3 Hz, IH). MS (ESI, m/z): 438.1 [M+H+].
Example 128 : 6- { [(3i?,6S)-6-(3-methoxy-quinoxalin-5-y loxy methyl)-tetrahydro-pyi~an- 3-ylamino]-methyl}-4H-pyrido[3,2-6][l,4]thiazin-3-oner
This compound (0.06 g) was obtained as a colourless oil by the method of Example 88, step 88.iv, using 3-oxo-3,4-dihydro-2H-pyrido[3,2-έ][l,4-]thiazine-6-carbaldehyde (0.O74 g) and intermediate 127. iii (0.1 g). MS (ESI, m/z): 468.3 [M+Η+].
Example 129: (2,3-dihydro-benzo[l,4]dioxin-6-ylmeth^l)- [(3J?,6.S)-6-(6-trifluoromethoxy-quinolin-4-yloxymethyl)-tetrahydro-pyraii-3-yl]-ain.ine:
129.i. C(3R, 6S)-6-(6-trifluoromethoxy-quinolin-4-yloxymethyl)-tetrahydro-pyran-3-yl]- carbamic acid tert-butyl ester:
This compound (2.72 g) was obtained as a yellowish foam from intermediate 78.i O-5 g, 6.48 mmol) and 6-trifluoromethoxy-quinolin-4-ol (1.56 g, 6.81 mmol), according to the procedure of Example 77, step 77. ii. MS (ESI, m/z) : 443.0 [MH-H+] .
129.U. (3R, 6S)-6-(6-trifluoromethoxy-quinolin-4-yloxymethyl)-tetrahydro-pyran-3-ylam ine:
Starting from intermediate 129. i (2.72 g), the title compound (0.571 g) was prepared as a pale yellow oil according to the procedure described in Example 77, step 77. iii. MS (ESI, m/z): 343.3 [M+H+]. 129. Hi. (2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-[(3R,6S)-6-(6-trifluoromethoxy-quinolin- 4-yloxymethyl)-tetrahydro-pyran-3-yl] -amine:
Starting from intermediate 129. ii (0.104 g) and 2,3-dihydro-benzo[l,4]dioxine- 6-carbaldehyde (0.055 g), the title compound (0.067 g) was prepared as a colourless oil according to the procedure described in Example 88, step 88. iv.
1H NMR (CDCl3) δ: 8.75 (d, J= 5.2 Hz, IH); 8.06 (d, J= 9.3 Hz, IH); 8.02 (d, J= 1.7 Hz, IH); 7.55 (m, IH); 6.84 (m, IH); 6.80 (m, IH); 6.77 (m, IH); 4.24 (s, 4H); 4.21 (m, IH); 4.12 (dd, J= 5.6, 9.3 Hz, 2H); 3.83 (m, IH); 3.74 (d, J= 1.9 Hz, 2H); 3.20 (t, J= 10.6 Hz, IH); 2.77 (m, IH); 2.19 (m, IH); 1.91 (m, IH); 1.60 (m, IH); 1.42 (m, IH). MS (ESI, m/z): 491.3 [M+H+].
Example 130: 6-{[(3i?,6-S)-6-(6-trifluoromethoxy-quinolin-4-yloxymethyl)-tetrahydro- pyran-3-ylamino]-methyI}-4H-pyrido[3,2-b][l,4]thiazin-3-one:
Starting from intermediate 129.U (0.1 g) and 3-oxo-3,4-dihydro- 2H~pyrido[3,2-ό][l,4]thiazirie-6-carbaldehyde (0.063 g), the title compound (0.065 g,) was prepared as a white solid according to the procedure described in Example 88, step 88. iv. MS (ESI, m/z): 521.4 [M+Η^].
Example 131: 8-{(25,5Λ)-5-[(3-oxo-3,4-dihydro-2H-benzo[l,4]thiazin-6-ylmethyl)- amino]-tetrahydro-pyran-2-ylmethoxy}-quinoline-2-carbonitrile:
Starting from (25',5/?)-8-(5-amino-tetrahydro-pyran-2-ylmethoxy)-quinoline-2-carbonitrile (0.036 g) and 3-oxo-3,4-dihydro-2H-benzo[l,4]thiazine-6-carbaldehyde (0.027 g), the title compound (0.015 g) was prepared as a beige foam according to the procedure described in
Example 88, step 88. iv.
1H NMR (CDCl3) δ: 8.25 <d, J= 8.4 Hz, IH); 8.16 (br. s, IH); 7.71 (d, J= 8.4 Hz, IH);
7.60 (t, J= 8.0 Hz, IH); 7.4-5 (dd, J= 1, 8.2 Hz, IH); 7.27 (m, IH); 7.18 (dd, J= 1, 7.8 Hz, IH); 6.97 (td, J= 1.6, 8.0 Hz, IH); 6.86 (dd, J= 1.2, 10.7 Hz, IH); 4.28 (dd, J= 6.1, 10.1 Hz,
IH); 4.15 (m, 2H); 3.93 (m, IH); 3.79 (dd, J= 4.3, 11.8 Hz, 2H); 3.22 (t, J= 10.8 Hz, IH);
3.04 (s, 2H); 2.79 (m, IH); 2.20 (m, IH); 1.99 (m, IH), 1.21 (m, 2H).
MS (ESI, m/z): 461.4 [M+H+]. Example 132: 6-{[(3i?,6*S)-6-(6-methoxy-quinolin-4-yloxymethyl)-tetrahydro-pyran- 3-ylamino]-methyl}-4H-pyrido[3,2-ό][l,4]thiazin-3-one:
Starting from (3i?,6<S)-6-(6-methoxy-quinolin-4-yloxymethyl)-tetrahydro-pyran-3-ylamine (0.089 g) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-ό][l,4]thiazine-6-carbaldehyde (0.060 g), the title compound (0.054 g) Λvas prepared as a beige foam according to the procedure described in Example 88, step 88. iv.
1H NMR (CDCl3) δ: 8.60 (d, J= 5.3 Hz, IH); 8.22 (br. s, IH); 7.95 (d, J= 9.2 Hz, IH); 7.58 (d, J= 7.8 Hz, IH); 7.46 (d, J= 2.8 Hz, IH); 7.35 (dd, J= 2.8, 9.2 Hz, IH); 6.97 (d, J= 7.8 Hz, IH); 6.72 (d, J= 5.3 Hz, IH); 4.25 (dd, J = 6.0, 10.2 Hz, IH); 4.16 (dd, J= 4.3, 10.2 Hz, IH); 3.94 (s, 3H); 3.88 (d, J= 2.2 Hz, 2H); 3.48 (s, 2H); 3.25 (t, J= 10.6 Hz, IH); 2.77 (m, IH); 2.22 (m, IEE); 1.94 (m, IH); 1.61 (m, IH), 1.50 (m, IH). MS (ESI, m/z): 467.5 [M-I-H+].
Example 133: 6-{[(3Λ,6_S)-6-(2-methoxy-quinolin-8-yloxymethyl)-tetrahydro-pyran- 3-ylamino]-methyl}-4H-pyrido[3,2-Z>][l,4]thiazin-3-one:
133. i. [(3R, 6S)-6-(2-metfooxy-quinolin-8-yloxymethyl)-tetrahydro-pyran-3-yl]-carbamic acid tert-hutyl ester:
This compound (0.67 g, 36% yield) was prepared as a white solid using the protocol described in Example 127, step 127. ii and starting from intermediate 127. i (1.5 g, 4.84 mmol) and 2-methoxy-quinolin-8-ol (prepared as described in WO 2004/002490, 0.934 g, 5.33 mmol).
MS (ESI, m/z): 389.5 [M-+H+].
133. ii. (3R,6S)-6-(2-methoxy-quinolin-8-yloxymethyl)-tetrahydro-pyran-3-ylamine:
This compound (0.46 g, 92% yield) was obtained as yellow gum starting from intermediate 133. i (0.67 g) and using the procedure described in Example 77, step 77.iii. MS (ESI, m/z): 289.3 [M-I-H+]. 133. iii. 6-{[(3R,6S)-6-(2-methoxy-quinolin-8-yloxymethyl)-tetrahydro-pyran-3-ylamineD]- methyl}-4H-pyrido[3, 2-b][l, 4]thiazin-3-one :
Starting from intermediate 133. ii (0.214 g) and 3-oxo-3,4-cLihydro- 2H-pyrido[3,2-Z>][l,4]thiazine-6-carbaldehyde (0.151 g), the title compound (0.175 g) was prepared as a white foam according to the procedure described in Example 88, step 88. iv. MS (ESI, m/z): 467.0 [M+Η+].
Example 134: 6-{[(32J,65)-6-(6-methoxy-quinazolin-4-yloxymethyl)-tetrahydro-p;yraii- 3-ylamino]-methyl}-4H-pyrido[3,2-Z»][l,4]thiazin-3-one:
134. i. l(3R,6S)-6-(6-methoxy-qτiinazolin-4-yloxymethyl)-tetrahydro-pyran-3-yl]-carhcιmic acid tert-hiityl ester:
This compound (1.25 g) was prepared as a white solid starting from intermediate 78.i (1.28 g, 6.6 mmol) and 4-chloro-6-methoxy-quinazoline (1.51 g, 6.54 mmol) using the procedure described in Example 10, step 1 O.i.
1H NMR (CDCl3) δ: 8.72 (s, IH); 7.93 (d, J = 9.1 Hz, IH); 7.51 (dd, J = 2.8, 9.1 Oz, IH); 7.45 (d, J = 2.8 Hz, IH); 4.66 (dd, J = 3.7, 11.6 Hz, IH); 4.59 (dd, J = 6.4, 11.6 Hz, IH); 4.30 (br s, IH); 4.16 (ddd, J = 2.1, 4.7, 10.9 Hz, IH); 3.97 (s, 3H); 3.81 (m, IH); 3.72 (m, IH); 3.10 (app t, J = 10.7 Hz, IH); 2.21 (m, IH); 1.89 (m, IH); 1.65 (qd, J = 3.4, 12.9 Hz, IH); 1.46 (s, 9H); 1.39 (partially overlapped qd, J = 3.9, 12.0 Hz, IH). MS (ESI, m/z): 390.1 [M+H*].
134. ii. (3R, 6S)-6-(6-methoxy-qwnazolin-4-yloxymethyl)-tetrahydro-pyran-3-ylamine\
This compound (0.245 g, 26% yield) was obtained as a white solid starting from intermediate 134. i (1.25 g) using the procedure described in Example 10, step lO.ii. MS (ESI, m/z): 290.3 [M+H+].
134.iii. 6-{[(3R,6S)-6-(6-methoxy-quinazolin-4-yloxymethyl)-tetrahydro-pyran-3-ylamino]- methyl}-4H-pyrido[3,2-b][l,4Jthiazin-3-one;
Starting from intermediate 134.U (0.100 g) and 3-oxo-3,4-dihydro- 2H-pyrido[3,2-Z>][l,4]thiazine-6-carbaldehyde (0.07O g), the title compound (0.O5-4 g) was prepared as a white solid according to the procedure described in Example 88, step 88. iv. 1K NMR (d6-DMSO) δ: 10.88 (s, IH); 8.67 (s, IH); 7.86 (d, J= 9.1 Hz, 1 H); 7.74 (d, J= 7.8Hz, IH); 7.60 (dd, J= 2.9, 9. 1 Hz, IH); 7.38 (d, J= 2.9 Hz, IH); 7.09 (4, J= 7.8 Hz, IH); 4.51 (d, J= 6.8 Hz, 2H); 3.98 Cm, IH); 3.92 (s, 3H); 3.77 (m, 3H); 3.53 (s, 2H); 3.02 (t, J = 10.5 Hz, IH); 2.09 (m, 2H); 1.81 (m, IH); 1.39 (m, IH); 1.28 (m, IH). MS (ESI3 m/z): 468.4 [MfH+].
Example 135: 6-{[(3/?,65)-6-(8-fluoro-6-methoxy-quinoIin-4-yloxymethyl)-tetrahydro- pyran-3-ylamino]-methyl}-4H-pyrido[3,2-6][l,4]thiazin-3-one:
135. i. (3R,6S)-6-(8-fluoro-6-methoxy-quinolin-4-yloxymethyl)-tetrahydro-pyran—3-ylamine\
To a solution of intermediate 78.i (2.38 g, 10.3 mmol) in TΗF (53 ml) at O0C: was added 8-fluoro-6-methoxy-quinolin-4-ol CPrePared as described in WO 2004/050*036; 2.09 g,
10.81 mmol), PPh3 (4.1 g, 15.44 mmol) and DIAD (2.1 ml). The reaction mixture was allowed to reach rt and further stirred overnight at rt. The reaction mixture was concentrated to dryness. The residue was dissolved in TFA (10 ml) and the reaction mixture was stirred
20 min. After evaporation to dryness, the residue was taken up in water (50 ml) and washed with DCM-MeOH 9-1 (4 x 100 ml). 8Maq. NaOH was added to the mixture until a cloud was formed (pΗ = 10 was reached). Trie aqueous layer was extracted twice with DCM-MeOH
(2 x 100 ml). The combined organic layers were washed with brine (50 mL), dried over
Na2SO4, filtered and concentrated to dryness. The residue was chromatographed over silica gel (DCM-MeOH 97-3 containing 1% aq. NH4OH to 6-1 containing 1% aq_. NH4OH) to afford the title amine (1.22 g, 3.98 mmol) as a white solid.
MS (ESI, m/z): 307.2 [MB-H+].
135.ii. 6-{[(3R, 6S)-6-(8-fluoro-6-nτethoxy-quinolin-4-yloxymethyl)-tetrahydro-pyran- 3-ylaminoJ-methyl}-4H-pyrido[3, 2-b][l, 4]thiazin-3-one :
Starting from intermediate 135. i (0.2 g, 0.65 mmol) and 3-oxo-3,4-dihydro- 2H-pyrido[3,2-Z>][l,4]thiazine-6-carbaldehyde (0.141 g, 0.729 mmol), the title compound (0.092 g) was prepared as a slightly pink foam according to the procedure described in Example 88, step 88.iv. MS (ESI, m/z): 484.9 [MH-H+]. Example 136: 6-{[(3Λ,6iS)-6-(8-fluoro-6-methoxy-quinoIin-4-yloxyinethyl)-tetrahydro- pyran-3-ylamino]-methyl}-4H-pyrido[3,2-6] [l,4]oxazin-3-one:
Starting from intermediate 135. i (0.2 g, 0.65 mmol) and 3-oxo-3,4-dihydro - 2H-pyrido[3,2-Z>][l,4]oxazine-6-carbaldehyde (0.129 g, 0.727 mmol), the title compound (0.120 g; contaminated with some starting amine (around 20%)) was prepared as a slightly pink foam according to the procedure described in Example 88, step 88. iv. MS (ESI, m/z): 469.3 [M+Η+].
Example 137: 6-{(3J?,6S)-[6-(6-methoxy-quinazolin-4-yloxymethyI)-3,6-dihydr<)- 2H-pyran-3-ylamino]-methyl}-4H-pyrido[3,2-6][l,4]thiazin-3-one:
137. i . (3i?,65)-[6-(6-methoxy-quinazolin-4-yloxymethyl)-3,6-dihydro-2H-pyran-3-yl]- carbamic acid tert-butyl ester:
This compound (1.25 g) was prepared as a white solid using the procedure described in
Example 10, step lO.i and starting from (3i?,65)-(6-hydroxymethyl-3,6-dihydro-2H-pyran-
3-yl)-carbamic acid tert-butyl ester (2.29 g, 10 mmol) and 4-chloro-6-methoxy-quinazolin.e (prepared as in WO 96/09294; 1.94 g, 10 mmol).
1H NTMR (DMSO) δ: 8.67 (s, IH); 7.86 (d, J = 9.1 Hz, IH); 7.60 (dd, J = 2.9, 9.1 Hz, IK);
7.38 (d, J = 2.9 Hz, IH); 7.02 (d, J = 8.1 Hz, IH); 5.95-5.84 (m, 2H); 4.61-4.56 (m, 3HT);
4.09 (br s, IH); 3.96 (partially overlapped m5 IH); 3.91 (s, 3H); 3.31 (dd, J = 8.5, 10.7 ILz,
IH); 1.39 (s, 9H). MS CESI, m/z): 388.1 [M+H+].
137. ii. (3/?,65)-6-(6-methoxy-quinazolin-4-yloxymethyl)-3,6-dihydro-2H-pyran-3-ylamine:
The title amine (1.32 g, 77% yield) was obtained as a yellowish oil starting from intermedia-te 137. i (2.32 g, 6 mmol) and using the procedure described in Example 77, step 77.iii. Tfcie compound was purified by chromatography (DCM-MeOH 9-1 containing 1% concentrated NH4OH).
MS CESI, m/z): 288.3 [M+H+]. 137. iii . 6- {(3R, 6S) -[6- (6-methoxy-quinazolin-4-yloxymethyl) -3, 6-dihydro-2H-pyran- 3-ylamino]-methyl}-4H-pyrido[3,2-b] [1 ,4]thiazin-3-one:
This compound (0.065 g) was prepared as a pale yellow foam according to the procedure described in Example 88, step 88. iv, starting from intermediate 137. ii (0.100 g) and 3-oxo- 3,4-dihydro-2H-pyrido[3 ,2-Z>][l,4]thiazine-6-carbaldehyde (O.071 g),
1H NMR (CDCl3) δ: 8.69 (s, IH); 8.33 (br. s, IH); 7.S5 (d, J = 9.1 Hz, IH); 7.58 (d, J= 7.8 Hz, IH); 7.47 (dd, J= 2.9, 9.1 Hz, IH); 7.41 (d, J = 2.9 Hz, IH); 7.00 (d, J = 7.8 Hz, IH); 6.12 (dd, J= 2.2, 12.7 Hz, IH); 5.94 (d, J= 10.4 Hz, IH); 4.70 (m, IH); 4.64 (m, 2H); 4.17 (dd, J = 4.6, 11.3 Hz, IH); 3.95 (s, 2H); 3.93 (s, 3H); 3.63 (dd, J = 6.6, 11.3 Hz, IH); 3.46 (s, 2H); 3.44 (m, IH).
MS (ESI, m/z): 466.3 [M+H+].
Example 138: 6-{[(3J?,65)-6-(6-difluoromethoxy-quinoliii-4-yloxymethyl)-tetrahyd[ro- pyran-3-ylamino]-raetliyl}-4H-pyrido[3,2-6][l,4]thiazin-3-one:
138.i. 6-difluoromethox.y-quinolin-4-ol: To a solution of 4-difluoromethoxy-phenylamine (5 g, 31.42 mmol) in ethanol (25 ml) were added triethyl orthoformate (5.3 ml, 31.86 mmol) and Meldrum's acid (5 g, 34.69 mmol). The reaction was refluxed for 3 h. Upon cooling, a yellowish solid formed. The solid was filtered off, washed with Hex and dried under HV. To a refluxing solution of phenyl ether (120 ml) was added portion-wise the latter solid. After heating for 2 min, the reaction mixture was cooled down to rt using an ice-water bath. The reaction mixture was diluted with ether (150 ml) and the solid was filtered off. This material was recrystallized from MeOH to afford after drying the title quinolinol as a beige solid (3.1 g)
1H NMR (d6 DMSO) δ: 11.83 (br s, IH); 7.94 (d, J= 7.4 Hz, IH); 7.78 (d, J = 2.5 Hz, IH); 7.62 (d, J = 8.9 Hz, IH); 7.49 (dd, J = 2.8, 8.9 Hz5 IH); 7.33 (t, J = 73.9 Hz, IH); 6.05 (d, J = 7.4 Hz, IH).
138. ii. (3R,6S)-[6-(6-dvfluoromethoxy-quinolin-4-yloxymethyl)-tetrahydro-pyran-3-yl]- carbamic acid tert-butyl ester.
The title compound (2.O4 g, 83% yield) was obtained as a. yellow foam using the procedure described in Example 77, step 77. ii and starting from intermediate 78. i (1.34 g, 5.8 mmol) and intermediate 138.i (1.29 g, 6.1 mmol). MS (ESI, m/z): 425.0 [M+H+].
138.iii. (3R,6S)-6-(6-diβuoromethoxy-qιιinolin-4~yloxymethyl)-tetrahydro-pyran-3-ylamine\
The title amine (0.554 g, 35% yield) was obtained as a white solid using the procedure described in Example 77, step 77.iii and starting from intermediate 138. ii (2.04 g, 4.8 mmol). The compound was purified by chromatography over silica gel (DCM-MeOH 9-1 containing 1% concentrated NH4OH). MS (ESI, m/z): 325.3 [M+H+].
138. iv. 6-{[(3R,6S)-6-(6-difluoromethoxy-quinoTin-4-yloxymethyl)-tetrahydro-pyran- 3-ylamino]-methyl}-4H-pyrido[3,2-b] [1 ,4]thiazin-3-one: Starting from intermediate 138,iii (0.100 g) and 3-oxo-3,4-dihydro- 2H-pyrido[3,2-δ][l,4]thiazine-6-carbaldehyde (O.063 g), the title compound (0.048 g) was prepared as a white foam according to the procedure described in Example 88, step 88. iv. 1H NMR (CDCl3) δ: 8.72 (d, IH); 8.35 (br. s, IH); 8.04 (d, J = 9.2 Hz, IH); 7.86 (d, J= 2.6Hz, IH); 7.59 (d, J= 7.8 Hz, IH); 7.48 (dd, J = 2.6, 9.2 Hz, IH); 6.98 (d, J= 7.8 Hz, IH); 6.75 (d, J= 5.2 Hz, IH); 6.64 (t, J= 73.7 Hz, IH); 4.18 (m, 3H); 3.90 (d, J= 2.7 Hz, 2H); 3.84 (m, IH); 3.47 (s, 2H); 3.28 (t, J = 10.6 Hz, IH); 2.79 (m, IH); 2.22 (m, IH); 1.93 (m, IH); 1.57 (m, 2H). MS (ESI, m/z): 503.5 [M+H+].
Example 139: 6-{(3J^65)-[6-(3-methoxy-quiαoxalin-5-yloxymethyl)-tetrahydro-pyran- 3-ylamino]-methyl}-4H-pyrido[3,2-6] [l,4]oxazin-3-one:
The title compound (0.038 g) was obtained as a white solid by the method of Example 88, step 88.iv, starting from 3-oxo-3,4-dihydro-2H-pyrido[3,2-έ][l,4]oxazine-6-carbaldehyde (0.068 g, 0.38 mmol) and intermediate 127.iii (0.1 g, 0.34 mmol). MS (ESI, m/z): 450.4 [M+Η+].
Example 140: 6-{(3J?,6-5)-[6-(3-methoxy-quiiioxalin-5-yloxymethyl)-tetrahydro-pyran- 3-ylamino]-methyl}-4H-benzo[l,4]oxazin-3-one:
Starting from intermediate 127.iii (0.10O g, 0.34 mmol) and 3-oxo-3,4-dihydro- 2H-benzo[l,4]oxazine-6-carbaldehyde (0.067 g, 0.38 mmol), the title compound (0.032 g) was prepared as a white solid according to the procedure described in Example 88, step 88.iv. 1HNMR (CDCl3) δ: 10.66 (s, IH); 8.59 (s, IH); 7.55 (dt, J= 1.4, 15.9 Hz, IH, overlapped); 7.54 (dd, J= 1.4, 15.9 Hz, IH, overlapped); 7.28 (dd, J = 1.4, 7.7 Hz, IH); 6.89 (d, J = 1.3 Hz, IH); 6.87 (s, 2H); 4.53 (s, 2H); 4.15 (AB, J= 5.9, 15.0, 37.0 Hz, 2H); 4.03 (s, 3H); 3.97 (ddd, J = 1.9, 4.2, 10.8 Hz, IH); 3.69 (m, 3H); 3.01 (t, J= 10.6 Hz, IH); 2.07 (m, IH); 1.88 (m, 2H); 1.49 (m, IH); 1.28 (m, IH). MS (ESI5 m/z): 451.2 [M+H+].
Example 141 : 6-{(3Λ,65)-[6-(3-methoxy-quinoxalin-5-yloxymethyl)-tetrahydro-pyran- 3-ylamino]-methyl}-4H-benzo[l,4]thiazin-3-one:
Starting from intermediate 127. iii (0.100 g, 0.34 mmol) a-nd 3-oxo-3,4-dihydro- 2H-benzo[l,4]thiazine-6-carbaldehyde (0.073 g, 0.38 mmol), the title compound (0.02O g) was prepared as a white solid according to the procedure described in Example 88, step 88. iv. MS (ESI, m/z): 467.3 [M+Η+].
Example 142: 3-oxo-3,4-dihydro-2H-pyrido[3,2-6][l,4]thiazine-6-carboxyIic acid (32f,65)-[6-(3-methoxy-quinoxaliii-5-yIoxymethyl)-tetrahydro-pyran-3-yl]-amide:
To a solution of intermediate 127. iii (0.1 g, 0.34 mmol) in DMF (S ml) were added 3-oxo- 3,4-dihydro-2H-pyrido[3,2-ό][l,4]thiazine-6-carboxylic acid C0-074 g, 0.35 mmol), ΗA.TU (0.16 g) and DIPEA (0.18 ml). The reaction mixture was stirred overnight at rt. The solvent was removed in vacuo. The residue was taken up in water a.nd the solid was filtered off. The solid was purified by chromatography (DCM-MeOH 19-1 containing 1% aq. NEL4OH) to afford the title compound (0.068 g) as a white solid. MS (ESI, m/z): 482.2 [M+H+].
Example 143: 3-oxo-3,4-dihydro-2H-pyrido[3,2-6][l,4]thiazine-6-carboxylic acid (3iC,65)-[6-(2-methoxy-quinolin-8-yloxymethyl)-tetrahydro-pyrari-3-yl]-amide:
The title compound (0.068 g, 0.14 mmol) was obtained as a λvhite solid starting from intermediate 133.ii (0.1 g, 0.34 mmol) and 3-oxo-3,4-dihydro-2H-p;yrido[3,2-Z>][l,4]thiazine- 6-carboxylic acid (0.080 g, 0.38 mmol), carrying out the procedure described in Example 142. 1H NMR (d6-DMSO) δ: 10.98 (s, IH); 8.20 (d, J = 8.9 Hz, IH); 7.97 (d, J = 7.9 Hz, IH); 7.97 (overlapped m, IH); 7.60 (d, J = 7.9 Hz, IH); 7.46 (dd, J = 1.2, 7.8 Hz, IH); 7.33 (app t, J = 7.8 Hz, IH); 7.22 (dd, J = 1,2, 7.8 Hz, IH); 7.02 (d, J = 8.9 Hz, IH); 4.25 (dd, J = 5.9, 10.7 Hz, IH); 4.16 (dd, J = 4.4, 10.7 Hz, IH); 4.01 (s, 3H); 4.00-3.86 (m, 2H); 3.80 (m, IH); 3.64 (s, 2H); 3.23 (t, J = 10.1 Hz, IH); 2.08 (m, IH); 2.01 (m, IH); 1.71-1.62 (m, 2H). MS (ESI, m/z): 481.3 [M+H+].
Example 144: 4-{(2S,5J?)-5-[(2,3-dihydro-[l,4]dioxino[2,3-φyri(lin-7-ylmethyl)- amino]-tetrahydro-pyran-2-ylm.ethoxy}-quinoline-6-carbonitrile:
144. i. 4-((2i?,5S)-5-amino-tetrahydro-pyran-2-ylmethoxy)-quinoline-6-carbonitrile:
The title amine (1.40 g) was obtained as a colourless foam starting from 4-hydroxy-quinoline- 6-carbonitrile (1.5 g, 8.8 mmol) and intermediate 78. i (2.04 g, 8.8 mmol) using the procedure described in Example 135, step 135. i. The compound was purified by chromatography (DCM-MeOH 47-3 and 1 % concentrated NH4OH).
1H NMR (d6-DMSO) δ: 8.88 (d, J = 5.3 Hz, IH); 8.62 (m, IH); 8.1 1-8.02 (m, 2H); 7.19 (d, J = 5.3 Hz, IH); 4.26 (m, 2H); 3.78 (ddd, J = 2.0, 4.4, 10.6 Hz, IH); 3.76 (m, IH); 2.97 (t, J = 10.5 Hz, IH); 2.64 (m, IH); 1.95 (m, IH); 1.85 (m, IH); 1.51 (rn, IH); 1.40 (br s , 2H); 1.27 (m, IH). MS (ESI, m/z): 284.3 [TVH-H+].
144.U. 4-{(2S, 5R)-5-[(2, 3-dihydro-[l, 4]dioxino[2, 3-c]pyridin-7-ylmethyl)-amino]- tetrahydro-pyran-2-ylmethoxy}-qwnoline-6-carbonitrile\
Starting from intermediate 144.i (0.114 g, 0.4 mmoO and 2,3-dihydro- [l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (0.066 g, 0.4 mmol), the title compound (0.103 g, 59% yield) was prepared as a white solid according to the procedure described in Example 88, step 88. iv.
1H NMR (CDCl3) δ: 8.86 (d, J = 5.3 Hz, IH); 8.64 (m, IH); 8.14 (s, IH); 8.10 (d, J = 8.7 Hz, IH); 7.84 (dd, J = 1.9, 8.7 Hz, IK), 6.89 (s, IH); 6.84 (d. J = 5.3 Hz5, IH); 4.37-4.17 (m, 7H), 3.94 (dd, AB system, J = 13.8 Hz, Δ= 0.058, 2H); 3.88 (m, IH); 3 .41 (t, J = 10.7 Hz, IH); 3.01 (br s, IH); 2.91 (m, IH); 2.32 (m, IH); 1.95 (m, IH); 1.74-1.62 Cm, 2H). MS (ESI, m/z): 433.3 [M+H+]. Example 145: 4-{(25',52?)-5-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]- tetrahydro-pyran-2-ylmethoxy}-quinoline-6-carbonitrile:
Starting from intermediate 144.i (0.1 g, 0.35 mmol) and 2,3-dihydro-benzo[l,4]dioxine- 6-carbaldehyde (0.063 g, 0.38 mmol), the title compound (0.095 g) was prepared as a white 5 foam according to the procedure described in Example 88, step 88. iv. MS (ESI, m/z): 432.4 [M+H+].
Example 146: 4-{(25',5/?)-5-[(3-oxo-3,4-dihydro-2H-benzo[l,4] thiazin-6-ylmethyl)- amino]-tetrahydro-pyran-2-ylmethoxy}-quinoline-6-carbonitrile:
Starting from intermediate 144. i (0.1 g, 0.35 mmol) (0.1 g, 0.35 mmol) and 3-oxo- I O 3,4-dihydro-2H-benzo[l,4]thiazine-6-carbaldehyde (0.075 g, 0.38 mmol), the title compound (0.035 g) was prepared as a yellowish foam according to the procedure described in Example 88, step 88.iv. MS (ESI, m/z): 461.3 [M+Η+].
Example 147: 3-oxo-3,4-dihydro-2H-pyrido[3,2-6][l,4]thiaziαe-6-carboxylic acid 15 (3jR,65)-[6-(6-cyano-quinoIin-4-yloxymethyl)-tetrahydro-pyraim-3-yl]-amide:
The title compound (0.027 g, 14% yield) was obtained as a orange solid starting from intermediate 144.i (0.114 g, 0.4 mmol) and 3-oxo-3,4-dihydro-2/^-pyrido[3,2-Z>][l,4]thiazine- 6-carboxylic acid (0.092 g, 0.44 mmol), carrying out the procedure described in Example 142. MS (ESI, m/z): 476.2 [M+H+].
0 Example 148: 3-oxo-3,4-dihydro-2H-pyrido[3,2-6][l,4]thiazine-6-carboxylic acid
(4R,7S)-[4-(6-methoxy-quinolin-4-yloxymethyl)-cw-(4J?5',5i?iS)-2,2-dimethyl-tetrahydro- [1 ,3] dioxolo [4,5-c] py ran-7-yl] -amide :
148. i. (3R, 6S)-(6-hydroxymethyl-tetrahydro-pyran-3-yl)-carbamic acid benzyl ester:
A solution of intermediate 78.i (5.45 g, 23.8 mmol) in TFA (20 ml) was stirred at rt for 30 5 min. The volatiles were removed under reduced pressure. The residue was taken up in water
(100 ml). NaHCO3 was added carefully until gas evolution ceased. Additional NaHCO3 (2 g) was added and the mixture was cooled to 0°C. Cbz-Cl (4.1 ml, 28.6 mmol) was added. The reaction proceeded for 3 h with warming to rt. The solid formed was diluted with water and filtered off. The solid was further washed with water and Hex. After drying under HV, the title compound (5.4 g, 86% yield) was obtained as a white solid. MS (ESI, m/z): 264.3 [M+H÷].
148. ii. (3 R, 6S)-[6-(6-methoxy-quinolin-4-yloxymethyl)-3, 6-dihydro-2H-pyran-3-yl]-carbamic acid benzyl ester.
This compound (1.99 g, 23%> yield) was obtained as a yellowish solid from intermediate 148. i (5.4 g, 20.5 mmol) and 6-methoxy-quinolin-4-ol (5.4 g, 30.7 mmol), according to the procedure of Example 77, step 77. ii. MS (ESI, m/z): [M+H4].
148. iii. (3S,4RS,5RS,6R)-[4, 5-dihydroxy-6-(6-methoxy-quinolin-4-yloxyrnethyl)-tetrahydro- pyran-3-yl]-carbamic acid benzyl ester:
To a solution of intermediate 148.ii (1.99 g, 4.73 mmol) in DCM (35 ml) and water (3.5 ml) were added NMO (1.89 g, 14.2 mmol) and potassium osmate dihydrate (0.086 g, 0.23 mmol) and the thick mixture was stirred overnight. The solvent was removed under reduced pressure. The residue was partitioned between water and EA, and sodium bisulfite (5 g) was added. The solids were filtered off and dried in vacuo to give the title diol (1.88 g, 87% yield). MS (ESI, m/z): 455.5 [M+H+].
148.iv. (4R, 7S)-[4-(6-methoxy-quinolin-4-yloxymethyl)-cis-(4RS,5RS)-2,2-dimethyl- tetrahydro-[l, 3]dioxolo[4, 5-cJpyran- 7-ylJ-carbamic acid benzyl ester.
To a solution of intermediate 148.iii (1.88 g, 4.14 mmol) in DMF (20 ml) was added PTSA (0.95 mg, 5 mmol) and 2,2-dimethoxypropane (3.2 ml, 26 mmol). The solution was stirred for 4 d. Water (10 ml) and solid NaHCO3 (0.42 g) were added. After evaporation to dryness, the residue was purified by column chromatography over silica gel (DCM-MeOH 97-3 then DCM-MeOH 19-1) to afford the title compound (1.97 g, 3.98 mmol) as a pale yellow oil. The compound was recovered as a 3:1 mixture of diastereomers.
1U NMR (CDCl3) δ main diastereomer: 8.57 (d, J= 3.8 Hz, IH); 7.92 (d, J= 9.2 Hz, IH); 7.45 (d, J= 2.8 Hz, IH); 7.37-7.31 (s, 5H); 7.35 (m overlapped, IH); 6.75 (d, J = 5.3 Hz, IH); 5.27 (m, IH); 5.10 (s, 2H); 4.46 (m, IH); 4.39 (dd, J= 2.6, 11.0 Hz, IH); 4.28 (m, IH); 4.10 (m, IH); 3.92 (s, 3H); 3.60 (m, IH); 3.35 (t, J= 11.1 Hz, IH); 1.52 (s, 3H); 1.36 (s, 3H). 148. v. ( 4i?,75)-4-(6-methoxy-quinolin-4-yloxymethyl)-2,2-d imethyl-tetrahydro- [l,3]dioxolo[4,5-c]pyran-7-ylamine:
To a solution of intermediate 148.iv (1.97 g, 3.98 mmol) in EA (60 ml) was added 10% palladium on charcoal (1.7 g). The reaction was stirred under hydrogen atmosphere for 5 h before being filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography over silica gel (DCM-MeOH 9-1 containing 1% concentrated NH4OH) to afford the title amine as a white foam (0.885 g, 61% yield). The compound was obtained as a 3:1 mixture of diastereomers. MS (ESI, m/z): 361.3 [M+H+].
148. vi. 3-oxo-3,4-dihydro-2H-pyrido[3,2-b] [1 ,4]thiazine-6-carboxylic acid
(4R, 7S)-[4-(6-methoxy-quinolin-4-yloxymethyl)-cis-(4RS, 5RSJ-2, 2-dimethyl-tetrahydro- [1, 3Jdioxolo[4, 5-cJpyran- 7-ylJ -amide :
To a mixture of intermediate 148.V (0.34 g) and 3-oxo-3,4-dihydro- 2H-pyrido[3,2-έ][l,4]thiazine-6-carboxylic acid (0.218 g) in DMF (9 ml) and DCM (6 ml) were added DIPEA (0.493 ml) and ΗATU (0.43O g). Trie reaction mixture was stirred overnight at rt and concentrated to dryness. The residue was purified by column chromatography over silica gel (DCM-MeOH 97-3 with 1% concentrated NH4OH then DCM- MeOH 19-1 with 1% concentrated NH4OH) to afford a yellow solid (0.206 g, 0.37 mmol). The compound was obtained as a 3:1 mixture of diastereomers. MS (ESI9 m/z): 553.4 [M+H*].
Example 149: 6-{(4J?,7S)-[4-(6-methoxy-quinolin-4-yloxymethyl)-(4S,5.S)-2,2-dimethyl- tetr-ahydro-[l,3]dioxolo[4,5-c]pyran-7-ylamino]-methyI}-4H-pyrido[3,2-6][l,4]thiazin-
3-one:
Starting from intermediate 148.V (0.539 g, 1.5 mmol) and 3-oxo-3,4-dihydro- 2H-pyrido[3,2-έ][l,4]thiazine-6-carbaldehyde (0.319 g, 1.64 mmol), the title compound (0.425 g, 52% yield) was prepared as a white solid according to the procedure described in Example 88, step 88.iv (DCM-MeOH 19-1 with 1% concentrated NH4OH being however used as chromatography eluent). MS (ESI, m/z): 539.0 [M+H+]. Example 150: 6-{(4R,7S)-([4-(6-methoxy-quinoIin-4-yloxymethyI)-
(42?,5R)-2,2-dimethyl-tetrahydro-[l,3]dioxoIo[4,5-c]pyran-7-ylamino]-methyl}-
4H-pyrido[3,2-Z>][l,4]thiazin-3-one:
Starting from intermediate 148.V (0.539 g, 1 .5 mmol) and 3-oxo-3,4-dihydro- 2H-pyrido[3,2-Z>][l,4]thiazine-6-carbaldehyde (0.319 g, 1.64 mmol), the title compound (0.105 g, 13% yield) was prepared as a brown solid according to the procedure described in Example 88, step 88.iv (DCM-MeOH 19-1 with 1% concentrated NH4OH being however used as chromatography eluent). MS (ESI, m/z): 539.3 [M+H+].
Example 151: 6-{(35r,45,55',6/?)-[4,5-dihydroxy-6-(6-methoxy-quinolin-4-yloxymethyl)- tetrahydro-pyran-3-ylamino]-methyl}-4H-pyrido[3,2-6][l,4]thiazin-3-one:
A solution of the compound of Example 149 (0.418 g, 0.77 mmol) in a TFA-water mixture (3-1, 15 ml) was stirred at rt for 1.5 h, concentrated and basifϊed with IM aq. NaOH A solid precipitated which was filtered, washed with water a.nd dried under HV to yield the title compound as a beige solid (0.337 g, 0.67 mmol). MS (ESI, m/z: 499.1 [M+H+].
Example 152: 6-{(35,4iϊ,5iϊ,6iϊ)-[4,5-dihydroxy-6-(ft-methoxy-quinolin-4-yloxymethyl)- tetrahydro-pyran-3-yIamino]-methyl}-4H-pyrido[3,Z-#][l,4]thiazin-3-one:
A solution of the compound of Example 149 (0.094 g, 0.17 mmol) in a TFA-water mixture (3-1, 3.5 ml) was stirred at rt for 1.5 h, concentrated and basifϊed with IM aq. NaOH. The mixture was concentrated to dryness and the residue purified by column chromatography (DCM-MeOH 9-1 with 1% concentrated NH4OH) to afford a beige solid (0.056 g, 0.11 mol). MS (ESI, m/z): 499.1 [MfH+].
Example 153: 8-{(2£,5R)-5-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-6][l,4]oxazin- 6-ylmethyl)-amino]-tetrahydro-pyran-2-ylmethoxy}— quinoline-2-carbonitrile:
Starting from (25',5i?)-8-(5-amino-tetrahydro-pyran-2-ylmethoxy)-quinoline-2-carbonitrile (0.179 g, 0.63 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-£][l,4]oxazine-6-carbaldehyde (0.118 g, 0.66 mmol), the title compound (0.040 g, 14% yield; purity 70%) was prepared as a yellowish foam according to the procedure described in Example 88, step 88. iv. MS (ESI, m/z): 446.0 [M-HH+].
Example 154: 6-{[(35r,6jR)-6-(6-methoxy-quinazoIin-4-yloxym ethyl)-tetrahydro-pyran- 3-ylamino]-methyl}-4H-pyrido[3,2-ft] [l,4]thiazin-3-one:
154.L (S)-(l-hydroxymethyl-pent-4-enyl)-carbamic acid tert-butyl ester.
To a suspension Of LiBH4 (1.15 g, 53 mmol) in THF (300 ml) at rt was added a solution of ($-2-ter£-butoxycarbonylaniino-hex-5-enoic acid methyl ester (12.9 g, 53 mmol, prepared according to J. Org. Chem. (1995), 60, 2210) in THF (100 ml). TThe mixture was stirred at rt for 4 h, poured into water and extracted with EA. The organic layer was washed with brine, dried over MgSO4 and concentrated to give the title alcohol (11.4 g, 99% yield) as a colourless oil.
1H NMR (CDCl3) δ: 5.75-5.65 (m, IH), 5.00-4.90 (m, 2H), 4.5 (br, IH, OH), 3.70-3.45 (m, 3H), 2.10-2.00 (m, 2H)5 1 .60-1.35 (m, 2H), 1.38 (s, 9H).
154. ii. (lS,3BS,4RS)-(l-hydroxymethyl-3-oxiranyl-propyl)-carbcemic acid tert-butyl ester.
Intermediate 154. i (11.4 g, 53 mmol) was dissolved in 1,2-DCE (300 ml) and water (250 ml) and IMphosphate buffer pH 8 (150 ml) was added. MCPBA (14.3 g, 1.1 eq, 70%) was added and the mixture vigorously stirred overnight. The two phases were separated and the aqueous phase was extracted once more with DCM. The combined organic layers were washed with a sat. NaHCO3 solution, dried over MgSO4, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel (Hex:EA 1:1 then EA) to give the title epoxide (7.74 g, 63% yield, mixture of diastereomers) as a colourless oil.
1H NMR (CDCl3) δ: 4.9O-4.85 (m, IH)3 3.75-3.50 (m, 3H), 3.0O-2.90 (m, IH), 2.80-2.51 (m, IH), 2.6 (br, IH, OH), 2.55-2.50 (m, IH), 1.80-1.40 (m, 4H), 1.42 (s, 9H).
154.iii. (3S,6R)-(6-hydrojcymethyl-tetrahydro-pyran-3-yl)-carbamic acid tert-butyl ester.
A solution of intermediate 154.ii (2.3 g, 10 mmol) in DCM (50 ml) was treated with D,Z,-10-camphor sulfonic acid (0.1 eq). The reaction was slightly exothermic. The mixture was stirred at rt for 3 h, concentrated and purified by chromatography on SiO2 (EA) to give the title tetrahydropyran (0.874 g, 37% yield) as a colourless solid. 1U NMR (CDCl3) δ: 4.28 (br, IH), 4.20-10 (m, IH), 3.70-3.30 (m, 5H), 3.04 (t, IH, J=10.6 Hz), 2.20-2.00 (m, 2H, 1.75-1.20 (m, 1 IH).
154. iv. f(3S, 6R) -6- (6-methoxy-qιιinazolin-4-yloxyme thy I) -te trahydro-pyran-3-yl]-caτbam ic acid tert-butyl ester. NaH (0.036 g, 0.82 mmol, 55% dispersion in oil) was added to a solution of 4-chloro- 8-methoxyquinazoline (0.160 g, 0.822 mmol) and intermediate 154.iii (0.190 g, 0.822 mmol) in DMF (3 ml) at rt. The mixture was stirred at rt for 2 h, then partitioned between EA and water. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (Hex:EA 1 : 1 then EA) then further purified by crystallisation from ether. The title ether (0.1 g, 3 1% yield) was obtained as a colourless solid. MS (ESI, m/z): 389.9 [M+].
154.V. (3S!6R)-6-(6-methoxy-quinazolin-4-yloxymethyl)-tetrahydro-pyran-3-ylamine:
A solution of intermediate 154.iv (0.1 g, 0.25 iramol) in DCM (10 ml) was treated "with TFA (2 ml). The mixture was stirred at rt for 3 h, concentrated in vacuo and partitioned between DCM and NH4OH. The organic layer was dried over MgSO4, filtered and concentrated to dryness to give the title amine (0.071 g, 96% yield) as a solid, which was used without further purification. MS (ESI, m/z): 290.3 [M+H+].
154.vi. 6-{[(3S, 6R)-6-(6-methoxy-quinazolin-4-yloxymethyl)-tetrahydro-pyran-3-ylcιmino]- methyl}-4H-pyrido[3, 2-b][l, 4]thiazin-3-one:
A solution of intermediate 154.V (0.072 g, 0.24 mmol) and 3-oxo-3,-4-dihydro- 2H-pyrido[3,2-Z>][l,4]thiazine-6-carbaldehyde (O.048 g) in a l,2-DCE:MeOΗ mixture (1:1, 4 ml) was stirred at rt overnight. NaBH4 (excess) was added and stirring continued for 2 h. The mixture was partitioned between DCM and concentrated NH4OH, the organic layer dried over MgSO4 and concentrated to dryness. The residue was purified by chromatography on silica gel (EA:MeOH 9:1 + 1% concentrated NH4OH) to give the title compound as a yellowish foam (0.085 g, 73% yield). 1H NMR (d6-DMSO) δ: 8.66 (s, IH), 7.78 (d, IH, J =9.1 Hz), 7.73 (d, IH5 .7=7.8 Hz)5 7.59 (dd, IH, J=9.1 Hz, J =2.9 Hz), 7.37 (d, IH, J=2.9 Hz), 7.10 (d, IH, J=7.8 Hz), 4.52 (d, IH, J =5.5 Hz), 4.05-3.90 (m, IH), 3.92 (s, 3H), 3.80-3.60 (m, 3H), 3.53 (s, 2H), 3.02 (t, IH, J=I O.4 Hz), 2.20-2.00 (m, 2H), 1.85-1.75 (m, IH), 1.60-1.20 (m, 2H). MS CESI, m/z): 468.2 [M+H+].
Example 155: (2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-[(3S',6.R)-6-(3-methoxy- quiαoIin-5-yloxymethyI)-tetrahydro-pyran-3-yl]-amine:
155.1. [(3S,6R)-6-(3-methoxy-qιιinolin-5-yloxymethyl)-tetrahydro—pyran-3-yl]-carbamic acid tert-butyl ester.
This compound (0.709 g, 50% yield) was obtained as a yellowish foam from intermediate 154.iii (0.845 g, 3.65 mmol) and 3-methoxy-quinolin-5-ol (2.62 g, 15 mmol) according to the procedure of Example 77, step 77. ii. MS (ESI, m/z): 389.0 [M+H+].
155. ii. (3S, 6R)-6-(3-methoxy-quinolin-5-yloxymethyl)-tetrahydro-pyran-3-ylamine\
Starting from intermediate 155. i (0.709 g, 1.82 mmol), the title compound (0.550 g, quant.) was prepared as a yellowish oil according to the procedure of Example 77, step 77.iii. MS (ESI, m/z): 289.2 [M+H4].
155. iii. (2, 3-dihydro-benzo[l, 4] dioxin-6-ylmethyl)-[(3S, 6R)-6-(3—methoxy-quinolin-5- yloxymethyl)-tetrahydro-pyran-3-yl] -amine:
A solution of intermediate 155. ii (0.173 g, 0.6 mmol) and 2,3-dihydro-benzo[l,4]dioxine- 6-carbaldehyde (0.0985 g, 0.6 mmol) in a DCEMeOH mixture (2:1, 6 ml) was stirred at rt overnight. NaBH4 (1 eq) was added and stirring continued for 2 h. The mixture was partitioned between DCM and concentrated NH4OH. The organic layer was dried over MgSO4 and concentrated. Chromatography over silica gel (EA-TMeOH 9:1 + 1% NH4OH) gave the title compound as a colourless oil (167 mg, 63%). MS (ESI, m/z): 437.3 [M+H+].
Example 156: 6-{[(3£,6φ-6-(3-methoxy-quinolin-5-yloxymet:hyl)-tetrahydro-pyran- 3-ylamino]-methyl}-4H-pyrido[3,2-Λ][l,4]oxazm-3-one:
A solution of intermediate 155. ii (173 mg, 0.6 mmol) and 3-oxo-3,4-dihydro- 2H-pyrido[3,2-έ][l,4]oxazine-6-carbaldehyde (107 mg, 0.6 mmol) in 1,2-DCE/MeOΗ (2:1, 6 ml) was stirred at rt overnight. NaBH4 (1 eq) was added and stirring continued for 2 Ih. The mixture was partitioned between DCM and NH4OH and the organic layer dried over MgSO4 and concentrated. Chromatography over silica gel (EA/MeOH 9:1 + 1% NH4OH) ga/ve the title compound as a colourless solid (139 mg, 51%). MS (ESI, m/z): 451.2 [M+H+].
Example 157: 6-{[(3iS',6J?)-6-(3-methoxy-quinolin-5-yloxymethyI)-tetrahydro-pyra_ii- 3-yIamino]-methyl}-4yy-pyrido[3,2-6][l,4]thiazin-3-one:
A solution of intermediate 155. ii (0.173 g, 0.6 mmol) and 3-oxo-3,4-diliydro- 2H-pyrido[3,2-Z>][l,4]thiazine-6-carbaldehyde (0.117 g, 0.6 mmol) in a 1,2-DCE: 3VIeOH mixture (2:1, 6 ml) was stirred at rt overnight. NaBH4 (1 eq) was added and stirring continued for 2 h. The mixture was partitioned between DCM and concentrated NH4OH. The organic layer was dried over MgSO4, filtered and concentrated. Chromatography over silica gel (EA:MeOH 9:1 +1% concentrated NH4OH) gave the title compound (0.146 g, 52% yield) as a colourless oil. MS (ESI, m/z): 467.1 [MfH+].
Example 158: 6-({(3i?,6iϊ)-6-[2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyI]-tetrahydro- pyran-3-ylamino}-methyl)-4//-pyrido[3,2-&][l,4]thiazin-3-one:
158. L (3R, 6S)-(6-formyl-tetrahydro-pyran-3-yl)-carbamic acid tert-butyl ester:
To a solution of oxalyl chloride (3.5 ml) in DCM (25 ml) cooled to -78°C, was added dropwise a solution of DMSO (3.5 ml) in DCM (25 ml). After 15 min stirring, a solution of
(3i?,6.S)-(6-hydroxymethyl-tetrahydro-pyran-3-yl)-carbarnic acid tert-butyl ester (prepared as described in Eur. J. Org. Chem. (2003), 2418-2427) in DCM (25 ml) was added dropwise.
The reaction was stirred 1 h and a solution of TEA (15 ml) in DCM (15 ml) was added dropwise. The reaction proceeded for 1 h, with warming to 00C. Saturated NaHCOβ (50 ml) was added. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed (Hex-EA 1-2) to afford the title aldehyde (2.5 g) as a colourless solid. 158. ii. (3R,6S)-(6-ethynyl-tetrahydro-pyran-3-yl)-carbamic acid tert-butyl ester:
To a solution of j9-toluenesulfonyl azide (3.08 g) in MeCN (20O mL) were added K2CO3 (5.38 g) and dimethyl-2-oxophosphonate (2.13 ml). The mixture was stirred 2 h at rt and a solution of intermediate 158.i (2.5 g) in MeOH (30 ml) was added. The mixture was stirred 5 overnight at rt. After concentration to dryness, the residue was partitioned between water (50 ml) and EA (100 ml). The aq. layer was extracted with EA (2 x 100 ml). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was filtered through silica gel (EA-Hex 1-3) to afford the title alkyne (1.9 g) as a white solid. O 1H NMR (CDCl3) δ: 4.78 (m, IH); 4.39 (m, IH); 4.14 (dd, J = 3.0, 11.4 Hz, IH); 3.71 (m, IH); 3.34 (m, IH); 2.50 (d, J = 2.2 Hz, IH); 2.11-1.99 (m, 2H); 1.73 (m, IH); 1.60 (m, IH); 1.46 (s, 9H). MS (ESI, m/z): 226.2 [M+H+].
158. iii. [(3R,6S)-6-(6-methoxy-[l,5]naphthyridin-4-ylethynyl)-tetrahydro-pyran-3-yl]- 5 carbaniic acid tert-butyl ester:
To a solution of intermediate 158.U (0.885 g) and trifluoromethanesulfonic acid 6-methoxy- [l,5]naphthyridin-4-yl ester (1.1 g) in DMF (5 ml) and TEA (3 ml) were added successively copper iodide (0.065 g) and bis(triphenylphosphine)palladium(II) chloride (0.125 g). The reaction mixture was stirred at rt for 90 min. The solvents were removed under reduced O pressure and the residue was partitioned between EA (1OO ml) and water (50 ml). The aq. layer was extracted twice more (2 x 100 ml). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was chromatographed over silica gel (Hex-EA 1-2) to afford the title alkyne (0.975 g) as a beige solid. 5 MS (ESI, m/z): 384.5 [NH-H+].
158, iv. {(3R, 6R)-6-[2-(6-methoxy-[l, 5]naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-3-yl}- carbamic acid tert-butyl ester:
To a solution of intermediate 158.iii (0.975 g) in MeOH (20 ml) was added 10% palladium on charcoal (0.5 g). The reaction was stirred under hydrogea for 90 min. After dilution with EA O (200 ml), the catalyst was removed by filtration and the filtrate was concentrated to dryness to afford the title compound as a beige solid (0.97 g). MS (ESI, m/z): 388.4 [M+H+].
158.v. (3R, 6R)-6-[2-(6-methoxy-[l , 5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyr(zn-3-ylamine :
The title amine (0.6 g) was obtained as a white solid starting from intermediate 158. iv (0.97 g) and using the procedure described in Example 77, step 77.iii. The compound was purified by chromatography (DCM-MeOH 9-1 containing 1% concentrated NH4OH).
1R NMR (CDCl3) δ: 8.66 (d, J = 7.5 Hz, IH); 8.20 (d, J = 9.0 Hz, IH); 7.40 Cd, J = 7.5 Hz, IH); 7.11 (d, J = 9.0 Hz, IH); 4.09 (s, 3H); 4.00 (ddd, J = 2.2, 4.4, 10.6 Hz, IH); 3.34-3.17 (m, 3H); 3.02 (t, J = 10.6 Hz, IH); 2.86 (m, IH); 2.08-1.92 (m, 3H), 1.74 (m, IH); 1.62 (br s, 2H); 1.46 (m, IH); 1.26 (m, IH). MS (ESI, m/z): 288.3 [M+H+].
158.vi. 6-({(3R,6R)-6-[2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro—pyran-3- ylamino}-methyl)-4H-pyrido[3,2-b] [1 ,4]thiazin-3-one:
To a solution of intermediate 158.V (0.1 g) in 1,2-DCE (6 ml) and MeOH (2 ml) were added poΛvdered 3 A molecular sieves (2 g) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-£>][l,4]thiazine- 6-carbaldehyde (0.074 g). The reaction mixture was stirred at 500C overnight. After cooling to rt, NaBH4 (0.1 g) was added. After 2 h, the reaction mixture was filtered through a plug of Hydromatrix® (pretreated with NaHCOs). After concentration in vacuo, th_e residue was chromatographed over silica gel (DCM-MeOH 19-1 with 1% concentrated a.q. NH4OH) to afford the title compound (0.045 g) as a white foam. 1H NMR (d6-DMSO) δ: 10.87 (s, IH); 8.66 (d, J = 4.4 Hz, IH); 8.23 (d, J = 9.O Hz, IH); 7.73 (d, J = 7.8 Hz, IH); 7.52 (d, J = 4.4 Hz, IH); 7.24 (d, J = 9.0 Hz, IH); 7.08 (d, J = 7.8 Hz, IH); 4.06 (s, 3H); 3.95 (ddd, J = 1.6, 4.4, 12.5 Hz, IH); 3.72 (br s, 2H); 3.53 (s, 2H); 3.21- 3.O9 (m, 3H); 2.93 (t, J = 10.4 Hz, IH); 2.48 (partially overlapped with DMSO, m, IH); 2.09 (br s, IH); 1.99 (m, IH); 1.84 (m, 2H); 1.73 (m, IH); 1.28-1.15 (m, 2H). MS (ESI, m/z): 466.3 [M+H+].
Example 159: 3-oxo-3,4-dihydro-2H-pyrido[3,2-£][l,4]thiazine-6-carboxy"lic acid {(3i?,6i?)-6-[2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}-amide:
To a suspension of intermediate 158.V (0.1 g, 0.348 mmol) and 3-o>co-3,4-dihydro-
2/iZ-pyrido[3,2-ό][l34]thiazine-6-carboxylic acid (0.081 g, 0.38 mmol) in DIVlF (4 ml) were added DIPEA (0.18 ml, 1.04 mmol) and ΗATU (0.15 g, 0.39 mmol). The reaction mixture was stirred at rt for 5 h and then concentrated to dryness. The residue was chromatographed (DCM-MeOH 19-1) to afford the title amide (0.081 g, 0.17 mmol) as a white solid. MS (ESI, m/z) : 480.2 [M+H+].
Example 160: 6-({(3J?,6i?)-(6-[2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro- pyran-3-ylamino}-methyl)-4H-pyrido[3,2-6] [l,4]oxazin-3-one:
This compound was prepared from intermediate 158.V (0.1 g, 0.348 mmol) and 3-oxo- 3,4-dihydro-2/ϊ-pyrido[3,2-6][l,4]oxazine-6-carbaldehyde (0.068 g, 0.38 mmol) according to the procedure of Example 88, step 88. iv. The title compound (0.O38 g, 0.084 mmol) was obtained as a foam. 1H NMR (d6-DMSO) δ: 11.17 (s, IH); 8.66 (d, J = 4.4 Hz, IH); 8.23 (d, J = 9.1 Hz, IH); 7.51 (d, J= 4.4 Hz, IH); 7.30 (d, J = 8.0 Hz, IH); 7.24 (d, J = 9.1 Hz, IH); 7.01 (d, J = 8.0 Hz, IH); 4.61 (s, 2H); 4.01 (s, 3H); 3.94 (m, IH); 3.69 (dd, AB system, J = 15.0 Hz, Δ= 0.056, 2H); 3.26-3.07 (m, 3H); 2.92 (t, J = 10.4 Hz, IH); 2.48 (partially overlapped m, IH); 1.98 (m, 2H); 1-87-1.8O (m, 2H); 1.73 (m, IH); 1.32-1.15 (m, 2H). MS (ESI, m/z) : 450.4 [M+ϊt] .
Example 161 : 6-((3i?,6Jf)-{6-[2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro- pyran-3-yIainino}-methyl)-4H-benzo[l,4]tliiazin-3-one:
Starting from, intermediate 158.v (0.100 g) and 3-oxo-3,4-dihydro-2H-benzo[l,4]thiazine- 6-carbaldehyde (0.074 g), the title compound (0.094 g) was prepared as a yellow foam according to the procedure described in Example 88, step 88. iv.
1H NMR (CDCl3) δ: 8.65 (d, J= 4.5 Hz, IH); 8.40 (br. s, IH); 8.18 (d, J= 9.0 Hz, IH); 7.37 (d, J= 4.5 Hz, IH); 7.25 (d, J= 7.9 Hz, IH); 7.10 (d, J= 9.0 Hz, IH); 6.96 (dd, J= 1.5, 7.9 Hz, IH); 6.85 (d, J= 1.5 Hz, IH); 4.10 (m, IH); 4.06 (s, 3H); 3.77 (AB, J= 3.77, 3.0, 30.1 Hz, 2H); 3.41 (s, 2H); 3.25 (m, 3H); 3.06 (t, J= 10.6 Hz, IH); 2.68 (m, IH); 2.07 (m, IH); 1.93 (m, 2H); 1.74 (m, IH); 1.39 (m, IH), 1.28 (m, IH). MS (ESI, m/z): 465.2 [M+H+]. Example 162: 6-({(3i?,6J?)-6-[2-(6-methoxy-qαiαazolin-4-yI)-ethyl]-tetrahydro-pyB-aii- 3-ylamin o} -methyl)-4/7-py rido [3 ,2-b] [1 ,4] thiazin-3-one :
162.i. [(3R, 6S)-6-(6-methoxy-quinazolin-4-ylethynyl)-tetrahydro-pyran-3-yl]-carbamic acid tert-butyl ester: Starting from 4-chloro-6-methoxy-quinazoline (0.564 g) and intermediate 158. ii (0.65 g) and using the procedure of Example 158, step 158. iii, trie title alkyne (0.49 g) was recovered as an orange solid. MS (ESI, m/z): 384.4 [M+H+].
162. ii. {(3R,6R)-6-[2-(6-methoxy-quinazolin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}-carbamic acid tert-butyl ester:
The title compound (0.39 g) was obtained as a solid starting from intermediate 162. i (0.49 g) and using the procedure described in Example 157, step 157. iv. MS (ESI, m/z): 388.4 [M+H+]
162.UL (3R,6R)-6-[2-(6-methoxy-quinazolin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamine: The title amine (0.175 g) was obtained as a white solid starting from intermediate 162.U (0.39 g) and using the procedure described in Example 77, step 77. iii. The compouuid was purified by chromatography over silica gel (DCM-MeOH 9-1 containing 1% concentrated NH4OH). MS (ESI5 m/z): 288.3 [MH-H+].
162.iv. 6-({(3R, 6R)-6-[2-(6-methoxy-quinazolin-4-yl)-ethyl]-tetrahydro-pyran-3 ylam ino}- methyl)-4H-pyrido[3, 2-b][l, 4] thiazin-3-one :
This compound was prepared from intermediate 162. iii (0.1 g) and 3-oxo-3,4-dihydro- 2H-pyrido[3,2-&][l,4]thiazine-6-carbaldehyde (0.074 g) according to the procedure described in Example 88, step 88. iv. The title compound (0.054 g) was obtained as a foam. MS (ESI, m/z): 466.5 [M+Η+]. Example 163: 6-((3Λ,6i?)-{6-[2-(6-methoxy-quinazolin-4-yl)-ethyl] -tetrahydro-pyran- 3-ylamino}-methyI)-4iϊ"-benzo[l,4]thiazin-3-one:
This was prepared from intermediate 162.iii (0.072 g) and 3-oxo-3,4-dihydro- 2H-benzo[l,4]thiazine-6-carbaldehyde (0.053 g) according to the procedure described in Example 88, step 88. iv. The title compound (0.062 g) was obtained as a foam. MS (ESI, m/z): 465.5 [M+Η+].
Example 164: 6-({(3Jf,65)-6-£-[2-(3-methoxy-quinolin-5-yl)-vinyl]-tetrahydro-pyran- 3-ylamino}-methyl)-4/Z-pyrido[3,2-6][l,4]thiazin-3-one:
164. i. (3 R, 6S)-[6-(lψhenyl-lH-tetrazol-5-ylsulfanylmethyl)-tetrahydτ~o-pyran-3-yl]-carbainic acid tert-butyl ester.
To an ice-chilled solution of intermediate 78.i (5.12 g), in THF (200 ml), were added successively dropwise PPI13 (11.40 g), phenyltetrazole thiol (5.52 g) and DIAD (6.6 ml). The resulting solution was stirred at rt overnight. The reaction mixture was concentrated to dryness and the residue was purified by column chromatography over silica gel (EA-Hex 1-9 to 1-1) to afford the title compound as a white solid (8.16 g). MS (ESI, m/z): 392.5 [M+H+].
164. ii. (3R, 6S)-[6-(l-phenyl-lH-tetrazole-5-sulfonylmethyl)-tetrahydiro-pyran-3-yl]-carbamic acid tert-butyl ester.
To a stirred solution of intermediate 164.i (8.1 g, 20.7 mmol) in EtOH (180 ml) was added at rt a solution of ammonium molybdate (3.200 g) in 30% aqueous hydrogen peroxide (27 ml) The reaction mixture was stirred at rt for 2 h. Saturated sodium thiosulfate (180 ml) was carefully added, cooling with an ice-bath. The solvent was removed under reduced pressure and the residue extracted three times with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (EA-Hex 1-2 then 1-1) to afford a white foam (439 g). MS (ESI, m/z): 424.5 [TvIHhH+]. 164.Hi. {(3R, 6S)-6-[2-(3-methoxy-qιιinGlin-5-yl)-vinyl]-tetrahydro-pyran-3-yl}-carbamic acid tert-butyl ester.
To a solution of intermediate 164.ii (4.39g, 10.3mmol) in DMF-HMPA (3-1, 60 ml) cooled to -35°C was added dropwise LiHMDS (IM in THF, 12.44 ml) and, after the addition was complete, 3 -methoxy-quinoline-5-carb aldehyde (1.9 g) in DMF-HMPA (3 -1, 120 ml). The reaction was allowed to warm slowly to rt and stirred overnight. Water and ether were added. The layers were separated and the aqueous layer was extracted three times with ether. The organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (EA-Hex 1-2 to 2-1) to afford a yellow solid (2 g) consisting of a 2:1 E:Z mixture. MS (ESI, m/z): 385.3 [M+H+]
164. iv. (3R, 6S)-6-[2-(3-methoxy-quinolin-5-yl)-vinyl]-tetrahydro-pyran-3-ylamine:
A solution of intermediate 164.iii (0.536 g) in TFA (5 ml) was stirred for 5 min. The reaction mixture was concentrated to dryness. The residue was basified with a 3MTSTaOH solution and the mixture extracted five times with DCM-MeOH 9-1. The combined organic layers were washed with brine, dried over Na2SO-*, filtered and evaporated. The residue was purified by column chromatography over silica gel (DCM-MeOH 19-1 containing 1% aq. NH4OH) to afford a yellow gum (0.187 g) consisting of a 2:1 E:Z mixture. MS (ESI, m/z): 285.3 [M+H+].
164.v. 6-({(3R, 6S)-6-E-[2-(3-methoxy-quinolin-5-yl)-vinyl]-tetrahydro-pyran-3 ylamino}- methyl)-4H-pyrido[3,2-b][l,4]thiazin-3-one:
Starting from intermediate 164.iv (0.100 g) and 3-oxo-3,4-dihydro- 2H-pyrido[3,2-δ][l,4]thiazine-6-carbaldehyde (0.072 g), the title compound (0.059 g) was obtained as a white foam according to the procedure described in Example 88, step 88. iv. The compound was obtained as an equimolar mixture of E and Z isomers. MS (ESI, m/z): 463.5 [M+Η+]. Example 165: 6-({(3J?,6if)-6-[2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro- pyran- 3-ylamino}-methyl)-4H-pyrido[3,2-6][l,4]thiazin-3-one:
165. i. /(3R, 6R)-6-[2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro-pyran-3-yl}-car'bamic acid tert-butyl ester. To a solution of intermediate 164.iii (1 g), in MIeOH (40 ml) under nitrogen was added 10% palladium on charcoal (0.5 g). The resulting mixture was stirred under hydrogen atmosphere for 1 h. The reaction mixture was diluted with EA, filtered and the filtrate concentrated under reduced pressure. The product was used in the next step without further purification. MS (ESI, m/z): 387.4 [M+Η+].
165. ii. (3 R, 6R)-6-[2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro-pyran-3-ylamirze:
A solution of crude intermediate 165. i (2.55 mmol) in TFA (5 ml) was stirred for 5 min and concentrated to dryness. The residue was basified with IMNaOH solution and extracted three times with DCM-MeOH mixture (9-1, 3 x 50 ml). The combined organic layers Λvere washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography over silica gel (DCM-MeOH 19-1 containing 1% aq Iv[H4OH then DCM-MeOH 9-1 containing 1% aq. NH4OH) to afford the title amine (0.583 gf) as a yellow oil. MS (ESI, m/z): 287.2 [MfH+].
165. iii. 6-({(3R,6R)-6-[2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro-pyran-3-y /amino}- methyZJ-4H-pyrido[3,2-b][l,4]thiazin-3-one\
Starting from intermediate 165. ii (0.100 g) and 3-oxo>-3,4-dihydro- 2H-pyrido[3,2-δ][l,4]thiazine-6-carbaldehyde (0.075 g), the title compound C0.075 g) was obtained as a foam according to the procedure described in Example 88, step 88.dv. MS (ESI, m/z): 465.4 [MfH+]. Example 166: S-oxo-S^-dihydro-lH-pyrido^^-^tl^Jthiazine-ό-carboxylic acid (3Λ,6Λ)-{6-[2-(3-methoxy-quinolin-5-yl)-ethyI]-tetrahydro-pyran-3-yl}-amide:
This compound was prepared from intermediate 165. ii (0.1 g, 0.35 mmol) and 3-oxo- 3,4-dihydro-2H-pyrido[3,2-δ][l,4]thiazine-6-carboxylic acid (0.074 g, 0.35 mmol) according to the procedure of Example 159. The title compound (0.022 g) was obtained as a white solid. MS (ESI, m/z): 479.3 [M+Η+].
Example 167: 6-{(3R,6R )-{6-[2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro-pyran- 3-ylamino}-methyl)-4H-pyrido[3,2-6][l,4]oxazin-3-one:
This compound (0.072 g) was obtained as a white foam from intermediate 165.U (O.I g, 0.35 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-δ][l,4]oxazine-6~carbaldehyde (0.0>68 g, 0.38 mmol) according to the procedure described in Example 88, step 88. iv. MS (ESI, m/z): 449.4 [M^H+].
Example 168: 6-((3J-,6Λ!)-{6-[2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyraii- 3-ylamino}-methyI)-4jH-pyrido[3,2-6][l,4]thiazin-3-one:
168. i. [(3R>6S)-6-(6-methoxy-quinolin-4-ylethynyl)-tetrahydro-pyrωτ-3-yl]-carbamic add tert-butyl ester.
This compound was prepared from intermediate 158. ii (0.942 g) and trifiuoromethanesulfonic acid 6-methoxy-quinolin-4-yl ester (1.194 g, prepared as in WO 00/40554) according to the procedure of Example 158, step 158. iii. A yellow solid (1.35 g) was obtained. MS (ESI, m/z): 383.5 [M-J-H+].
168. ii. {(3R,6R)-6-[2-(6-rnethoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}-carbamic acid tert-butyl ester:
This compound was prepared from intermediate 168.i (1.35 g) using the procedure described in Example 158, step 158. iv. The title product (1.35 g) was obtained as a white foam. MS (ESI, m/z): 387.4 [MH-H+] . 168. iii. (3R,6R) ~6-[2-(6-methoxy-quinolin-4-yl) -ethyl] -tetrahydro-pyr an— 3-ylamine:
The title amine (0.898 g) was obtained as a yellow oil starting from intermediate 168.U (1.35 g) and using the procedure described in Example 77, step 77. iii. The compound was purified by chromatography (DCM-MeOH 9-1 containing 1% concentrated NH4OH. 1U NMR (CE)Cl3) δ: 8.65 (d, J= 4.4 Hz, IH); 8.00 (d, J= 9.0 Hz, IH); 7.35 (dd, J= 2.8, 9.0 Hz, IH); 7.32 (d, J= 2.8 Hz, IH); 7.19 (d, J = 4.4 Hz, IH); 3.99 (m, IH); 3.95 (s, 3H); 3.22 (m, 2H); 3.09 (t, J = 7.8 Hz, IH); 3.0 (t, J =10.6 Hz, IH); 2. 83 (m, IH); 2.02 (m, IH); 1.88 (m, 2H); 1.64 (m, IH); 1.48 (br. s, 2H); 1.40 (m, IH); 1.23 (m, IH). MS (ESI, m/z): 287.3 [M+H+].
168.iv. 6-((3R, 6R)-{6-[2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3 ylamino}- methyl)-4H-pyrido [3, 2-b][l, 4]thiazιn-3-one :
Starting from intermediate 168. iii (0.100 g) and 3-oxo-3,4-dihydro- 2H-pyrido[3,2-ό][l,4]thiazine-6-carbaldehyde (0.066 g, 1.1 eq.), the title compound (0.062 g) was obtained as a beige foam according to the procedure described in Example 88, step 88. iv. 1R NMR (CDCl3) δ: 8.66 (d, J= 4.4 Hz, IH); 8.34 (br. s, IH); 8.01 (d, J= 9.1 Hz, IH); 7.58 (d, J= 7.8 Hz, IH); 7.36 (dd, J= 2.7, 9.1 Hz, IH); 7.31 (d, J = 2.7 Hz, IH); 7.19 (d, J = 4.4 Hz, IH); 6.96 (d, J = 7.8 Hz, IH); 4.13 (ddd, J= 2.3, 4.5, 10.9 Hz, IH); 3.94 (s, 3H); 3.87 (AB, J= 5.6, 42.8 Hz, 2H); 3.47 (s, 2H); 3.25 (m, IH); 3.13 (t, J = 10.7 Hz, IH, overlapped); 3.12 (m, 2H, overlapped); 2.71 (m, IH); 2.09 (m, IH); 1 .88 (m, 2H), 1.69 (m, IH), 1.37 (m, 2H).
MS (ESI, m/z): 465.5 [M+H÷].
Example 169 : (3Λ,6J?)-6-({6-[2-(6-methoxy-quinolin-4-yl)-ethyI]-te*rahydro-pyran- 3-yIamino}-niethyl)-4H-benzo[l,4]thiazin-3-one:
Starting from, intermediate 168.iii (0.100 g) and 3-oxo-3,4-dihydro-2H-benzo[l,4]thiazine- 6-carbaldehyde (0.074 g), the title compound (0.085 g) was obtained as a yellow foam according to the procedure described in Example 88, step 88. iv.
1H NMR (CDCl3) δ: 8.67 (d, J= 4.4 Hz, IH); 8.44 (br. s, IH); 8.01 (d, J = 9.1 Hz, IH);
7.36 (dd, J= 2.7, 9.1 Hz, IH); 7.31 (d, J= 2.7 Hz, IH); 7.26 (d, J= 7.9 Hz, IH); 7.19 (d,
J= 4.4Hz, IH); 6.97 (dd, J= 1.5, 7.9 Hz, IH); 6.86 (d, J= 1.5 Hz, IH); 4.10 (ddd, J = 2.0, 4.2, 10.9 Hz, IH); 3.94 (s, 3H); 3.78 (AB, J= 4.6, 31.6 HEz, 2H); 3.41 (s, 2H); 3.22 (m, 2H); 3.10 (t, J= 10.3 Hz, IH, overlapped); 3.06 (m, IH, overlapped); 2.70 (m, IH); 2.07 (m, IH); 1.86 (m, 2H), 1.66 (m, IH), 1.39 (m, IH), 1.25 (m, IH). MS (ESI, m/z): 464.4 [M+H+].
Example 170: 6-((3ϋ,6if)-{6-[2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran- 3-ylamino}-methyl)-4H-benzo[l,4]oxazin-3-one:
This compound (0.034 g) was obtained as a white solid from intermediate 168. iii (0.100 g, 0.345 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-6][l,4]oxazine-6-carbaldetιyde (0.068 g, 0.38 mmol) according to the procedure described in Example 88, step 88. iv. MS (ESI, m/z): 449.6 [M-KH+].
Example 171: 6-({3/-,6S')-6-[(lJ?,2i?)-l,2-dihydroxy-2-(3-methoxy-quinoliα-5-yl)-ethyI]- tetrahydro-pyran-3-yIainino}-methyl)-4H-pyrido[3,2-6][l,4]thiazin-3-one:
171.i. (2R, 5S)-toluene-4-sulfonic acid 5-tert-butoxycarbonylamino-tetrάhydro-pyran- 2-ylmethyl ester.
To an ice-chilled solution of intermediate 78. i (10.3 g, 44.53 mmol) in DCM (250 ml) were added TEA (12.4 ml, S 9 mmol), DMAP (0.5 g) and j?-toluenesulfonyl chloride (9.4 g,
49 mmol). The reaction was stirred at rt for 4 h. Saturated NaHCO3 (100 ml) xvas added. The volatiles were removed under reduced pressure and the residue was taken up In EA (400 ml).
The organic layer was washed with saturated copper sulfate (2 x 150 ml), water (3 x 150 ml) and brine (100 ml). The organic layer was dried over Na2SO4, filtered and concentrated to dryness to afford after drying the title tosylate (17.1 g, 100%) as a white solid.
171. ii. (3R,6S)-(6-iodomethyl-tetrahydro-pyran-3-yl)-carbamic acid tert-butyZ ester.
To a solution of intermediate 171. i (17.1 g, 44.5 mmol) in acetone (150 ml) was added NaI (20 g, 133.8 mmol). The mixture was heated at 650C for 20 h. After cooling, water (200 ml) was added and the volatiles were removed under reduced pressure. The residue was filtered and the solid was thoroughly washed with water, Hex and water. The solid v^as collected and dried in vacuo to afford the title iodide (13.72 g, 90.1% yield) as a beige solid - MS (ESI3 m/z): 342.2 [M+H+]. 005/010154
- 181 -
171.iii. (3R.,6S)-[6-(l-phenyl-lH-tetrazol-5-ylsulfanylmethyl)-tetrahydro-pyran-3-yl]- carbamic acid tert-butyl ester.
To a solution of l-phenyl-lH-tetrazole-5-thiol (7.9 g) in EtOH (90 ml) was added KOBE (2.8 g, 49.9 mmol). The reaction mixture was refluxed for 1 h and intermediate 171. ii (13.7 gς, 40.2 mmol) was added. The mixture was refluxed overnight. Water (150 ml) was added and the volatiles were removed under reduced pressure. The solid was filtered off and thoroughly washed with water. After drying, the title sulphide (15.6 g, 39.8 mmol) was obtained as a white solid. MS (ESI, rn/z): 342.2 [M+Η+].
171.iv. (3JR.,6S)-[6-(l-phenyl-lH-tetrazole-5-sulfonylmethyl)-tetrahydro-pyran-3-yl]~ carbamic acid tert-butyl ester:
To a solution of intermediate 171. Hi (15.6 g, 39.8 mmol) in EtOH (300 ml) were addend ammonium molybdate (11 g, 8.8 mmol) and then 30% aq. hydrogen peroxide (50 ml). Trie mixture was heated at 650C for 4 h. The reaction mixture was diluted with water (1 1) and EtOH was removed under reduced pressure. The aqueous layer was extracted twice with E^A (2 x500 ml). The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The title compound was crystallized from EA (50 ml) and Hex (1 1). The solid was then further washed with water and Hex and dried in vacuo to yield the title sulfone (15.2 g, 35.89 mmol) as a beige solid. MS (ESI, m/z): 424.4 [MH-H+].
171.v. {(3R, 6S)-trans-6-[2-(3-methoxy-quinolin-5-yl)-vinyl]-tetrahydro-pyran-3-yl}- carbamic acid tert-butyl ester:
To a solution of 3-methoxy-quinoline-5-carbaldehyde (0.64 g, 3.41 mmol) aaid intermediate 171. iv (1.9 g, 4.48 mmol) in 1,2-DME (20 ml,), cooled to -600C, was add.ed dropwise over 15 min, potassium bis(trimethylsilyl) amide (0.5M in toluene, 14 ml). The mixture was warmed gradually to rt over 2 h and water (20 rnl) and EA (100 ml) were added.
The two layers were decanted and the aq. layer was extracted once more with EA (100 ml).
The combined organic layers were dried over Na2SO^ filtered and concentrated to dryn&ss.
The residue was chromatographed over silica gel (EA) to afford the title that was furttier triturated in Hex to afford the title alkene (0.55 g, 1.43 mmol) as an off-white solid. 1H NMR (d6-DMSO) δ: 8.64 (d, J = 2.8 Hz, IH); 7.87 (d, J = 8.1 Hz, IH); 7.81 (d, J = 2.8 Hz, IH); 7.72 (d, J = 6.6 Hz, IH); 7.53 (dd, J = 6.6, 8.1 Hz, IH); 7.36 (d, J = 15.7 Hz, IH); 6.82 (d, J = 8.1 Hz, IH); 6.32 (dd, J = 6.2, 15.7 Hz, IH) ; 4.00 (m, IH); 3.97 (s, 3H); 3.88 (m, IH); 3.38 (br s, IH); 3.08 (t, J = 10.7 Hz, IH); 1.88 (m, 2H); 1.51 (m, 2H); 1.38 (s, 9H). MS (ESI, m/z): 385.0 [M+H+].
171.vi. {(3R, 6S)-6-[(lR,2R)-l,2-dihydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro- pyran-3-yl}-carbamic acid tert-butyl ester:
To a mixture of intermediate 171.V (0.55 g, 1.43 mmol) in 2-methyl-2-propanol (7 mL), EA (2 mL) and water (8 mL) were added AD mix β® (2.5 g) and methanesulfonamide (0.163 g, 1.71 mmol). The reaction mixture was stirred vigorously over 3 d. Sodium bisulfite (2.7 g) was added carefully and the mixture was stirred 30 min. EA (50 ml) was added and the two layers were decanted. The aq. layer was extracted with EA twice more. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was chromatographed (DCM-MeOH 19-1) to afford the title diol (0.52 g, 86% yield) as a white foam.
1H NMR (CDCl3) δ: 8.69 (d, J = 2.4 Hz, IH); 8.04 (d, J = 8.4 Hz, IH); 7.82 (d, J = 2.4 Hz, IH); 7.72 (d, J = 6.3 Hz, IH); 7.58 (dd, J = 6.3, 8.1 Hz, 1O); 5.44 (d, J = 6.9 Hz, IH); 4.82 (br s, 2H); 4.13 (m, 2H); 3.96 (s, 3H); 3.67 (d, J = 6 Hz, IH); 3.59 (br s, IH); 2.94 (m, IH); 2.79 (t, J = 10.8 Hz, IH); 2.02 (m, IH); 1.88 (qd, J = 4.2, 11.7 Hz, IH); 1.50 (partially overlapped m, IH); 1.43 (s, 9H); 1.15 (qd, J = 5.1, 12.6 Hz, IH). MS (ESI, m/z): 419.2 [M+H+].
171. vii. (lR,2R)-l-((2S,5R)-5-amino-tetrahydro-pyran-2-yl)-2-(3-methoxy-quinolin-5-yl)- ethane-l,2-diol:
A solution of intermediate 171.vi (0.52 g, 1.24 mmol) in TFA (5 ml) was stirred at rt for 15 min. After evaporation to dryness the residue was partitioned between IN aq. NaOH (20 ml) and DCM-MeOH (9-1, 60 ml). The aq. layer was extracted three times with the same mixture. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was chromatographed over silica gel (DCM-MeOH 6-1 with 1% aq. NH4OH) to afford the title amine (0.250 g, 0.78 mmol) as a white foam. MS (ESI, m/z): 319.2 [M+H+]. 171.viii. 6-({3R, 6S)-6-f(lR, 2R)- 1, 2-dihydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]- tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-b][l,4]thiazin-3-one:
To a solution of intermediate 171.vii (0.1 g) in MeOH (1.5 ml) and DCE (5 ml) -were added 3 A molecular sieves (2 g) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-έ][l ,4]thiazine- 6-carbaldehyde (0.067 g). The reaction mixture was heated at 500C overnight. NaIBH4 (0.1 g) was added and the reaction proceeded for 2 h. The reaction mixture was then filtered through Hydromatrix® and the filtrate was concentrated to dryness. The residue was chromatographed over silica gel (DCM-MeOH 9-1 containing 1% aq. NH4OH) to afford the title compound (0.015 g) as a beige foam. MS (ESI, m/z): 497.2 [M+H+].
Example 172: 3-oxo-3,4-dihydro-2f/-pyrido[3,2-6][l,4]thiazine-6-carboxylic acid
{(3i?,65)-6-[(li?,2i-)-l,2-dihydroxy-2-(3-methoxy-quinolin-5-yI)-ethyl]-tetrahydro-pyran-
3-yl}-amide:
To a solution of intermediate 171.vii (0.052 g) in DMF (3 ml) were added 3-oxo-3,4-dihydro- 2H-pyrido[3,2-έ][l,4]thiazine-6-carboxylic acid (0.04 g), ΗATU (0.08I g) and DIPEA
(0.09 ml). The reaction mixture was stirred overnight at rt. The solvent was removed in vacuo.
The residue was taken up in water and the solid was filtered off. The solid was purified by chromatography over silica gel (DCM-MeOH 19-1 with 1% aq. NH4OH) to afford the title compound (0.010 g, 12%) as a beige solid. MS (ESI, m/z): 511.0 [M+H+] .
Example 173: 6-({(3i?,61S)-6-[(lJR,2i?)-l,2-dihydroxy-2-(6-methoxy-[l,5]naphthyridin- 4-yI)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-6][l,4]thiazϊn-3-one:
173. i. cis,trans-[(3R,6S)-6-(2-tributylstannanyl-vinyl)-tetrahydro-pyran-3-yl]-carmbamic acid tert-butyl ester. To a solution of intermediate 158.Η (1.95 g, 8.65 mmol) in THF (26 ml) was added bis(triphenylphosphine) palladium dichloride (0.12 g, 0.17 mmol) and then tributyltin hydride (2.75 ml, 10.38 mmol). The mixture was stirred at rt for 20 min. The reaction mixture was concentrated to dryness and the residue was chromatographed (Hex then Hex-EA 9-1) to afford the title stannane (3.4 g) as an equimolar mixture of cis and trans isomers. 173.ii. trans-{(3R, 6S)-6-[2-(<5-methoxy-[l, 5]naphthyridin-4-yl)-vinyl]-tetrahydro-pyran- 3-yl}-carbamic acid tert-butyl ester:
To a solution of intermediate 173. i (3.4 g, 6.58 mmol) and trifluoromethanesulfonic acid 6-methoxy-[l,5]naphthyridiri-4-yl ester (1.91 g, 6.2 mmol) in 1,4-dioxane (30 ml) were added successively LiCl (0.78 g, 18.6 mmol), 2,6-di-fert-butyl-4-methylphenol (few seeds) and tetrakis(triphenylphosphine) palladium (0.14 g, 0.12 mmol). The reaction mixture was heated at 1000C overnight. After cooling, the solids were filtered off and the filtrate was concentrated to dryness. The residue was chromatographed (Hex-EA 1-1) to afford a white solid that was triturated in Hex to yield the title (is)-alkene (1.1 g,) as a white solid. 1H NMR (d6-DMSO) δ: 8.72 (d, J = 4.7 Hz, IH); 8.25 (d, J = 9.0 Hz, IH); 7.84 (d, J = 4.7 Hz, IH); 7.55 (d, J = 16.5 Hz, I H); 7.28 (d, J = 9.0 Hz, IH); 6.93 (dd, J = 5.3 Hz, 16.5 Hz, IH); 6.85 (d, J = 7.7 Hz, IH); 4.04 (s, 3H); 4.01 (partially overlapped m, IH); 3.90 (m, IH); 3.39 (br s, IH); 3.10 (t, J = 10.6 Hz, IH); 1.89 (m, 2H); 1.50 (m, 2H); 1.39 (s, 9H). MS (ESI, m/z): 386.1 [M+H+].
173.iii. (3R, 6S)-{6-[(lR, 2R) -1, 2-dihydroxy-2-(6-methoxy-[l, 5]naphthyridin-4-yl)-ethyl]- tetrahydro-pyran-3-yl}-carbamic acid tert-butyl ester:
This compound was obtained as a white foam (1.1 g, 92%) from intermediate 173.H (1.1 g, 2.85 mmol) according to the procedure of Example 171, step 171.vi.
1R NMR (d6-DMSO) δ: 8.76 (d, J= 4.5Hz, IH); 8.25 (d, J= 9.0Hz, IH); 7.74 (d, J= 4.5Hz, IH); 7.25 (d, J= 9.0Hz, IH); 6.81 (br s, IH); 6.75 (d, J= 7.8Hz, IH); 5.65 (br d, J= 6.6Hz, IH); 5.28 (d, J= 6.8Hz, IH); 4.41 (d, J= 6.4Hz, IH); 4.00 (s, 3H); 3.79 (m, 2H); 3.3 3 (m, IH); 2.92 (t, J= 10.7Hz, IH); 1.96 (m, 2H); 1.47 (m, 2H); 1.38 (s, 9H). MS (ESI, m/z): 420.2 [M+H+].
173.iv. (lR,2R)-l-[(2S,5R)-(5-amino-tetrahydro-pyran-2-yl)-2-(6-methoxy- [I15] naphthyridin-4-yl) -ethane- 1, 2-dioh
This compound was obtained as a yellowish foam (0.53 g, 80% yield) from intermediate 173. iii (0.872 g, 2.08 mmol) according to the procedure of Example 171, step 171.vii. 1H NMR (CDCl3) δ: 8.78 (d, J = 4.5 Hz, IH); 8.25 (d, J = 9.3 Hz, IH); 7.56 (d, J = 4.5 Hz, IH); 7.14 (d, J = 9.0 Hz, IH); 5.59 (d, J = 3.3 Hz, IH); 4.04 (s, 3H); 3.98 (partially overlapped m, 2H); 3.38 (br d, J = 11.4 Hz, IH); 3.01 (t, J = 10.8 Hz, IH); 2.S6 (m, IH); 2.08 (m, IH); 1.85 (m, IH); 1.63 (m, IH); 1.28 (br s, 4H); 1.26 (overlapped m, IH). MS (ESI, m/z): 320.2 [IVH-H+].
173.v. 6-({(3R, 6S)-6-[(l Ji, 2R)-1, 2-dihydroxy-2-(6-methoxy-[l, 5]naphthyridin-4 yl)-ethyl]- tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-b][l,4]thiazin-3-orie:
To a solution of intermediate 173.iv (0.1 g, 0.31 mmol) in MeOH (1.5 ml) and 1,2-DCE (5 ml) were added 3 A molecular sieves (2 g) and. 3-oxo-3,4-dihydro- 2H-pyrido[3,2-&][l,4]thiazine-6-carbaldehyde (0.067 g, 0.35 mmol). The mixture was heated at 500C overnight. After cooling, NaBH4 (0.1 g) was added and the reaction proceeded for 2 h. The reaction mixture was filtered through Hydromatrix® (treated with saturated aq. NaHCOs). The filtrate was concentrated to dryness and the residue chromatographed (DCM-MeOH 9-1 with 1% aq. NH4OH) to afford the title compound (0.043 g, 27% yield) as a white solid. MS (ESI, m/z): 498.2 [M+H+].
Example 174: 3-oxo-3,4-dihydro-2H-pyrido[3,2-#][l,4]thiazine— 6-carboxyIic acid
{(3Λ,65)-6-[(lJ.,2J?)-l,2-dihydroxy-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]- tetrahydro-pyran-3-yl}-amide:
The title compound (0.04 g, 25%) was produced as a white solid from intermediate 173.iv (0.1 g, 0.314 mmol) using the procedure of Example 172.
1H NMR (d6-DMSO) δ: 10.95 (s, IH); 8.77 (d, J = 4.5 Hz, IK); 8.27 (d, J = 9.1 Hz, IH); 7.97 (d, J = 7.9 Hz, IH); 7.97 (overlapped br s, IH); 7.76 (d, J = 4.5 Hz, IH); 7.60 (d, J = 7.9 Hz, IH); 7.26 (d, J = 9.1 Hz, IH); 5.70 (dd, J = 1.6, 6.7 Hz, IH); 5.32 (d, J = 6.7 Hz, IH); 4.48 (d, J = 6.3 Hz, IH); 4.02 (s, 3H); 3.93 (m, 2H); 3.82 (td, J = 2, 7.0 Hz, IH); 3.64 (s, 2H); 3.46 (m, IH); 3.11 (t, J = 10.4 Hz, IH); 2.09 (m, 2H); 1.62 <m, 2H). MS (ESI5 m/z): 512.2 [M+H+].
Example 175: (3jR,6iS)-6-({6-[(li?,22?)-l,2-dihydroxy-2-(2-ni.ethoxy-quinoIin-8-yI)-ethyπ- tetrahydro-pyran-3-ylamino}-methyI)-4H-pyrido[3,2-6][l,43thiazin-3-one:
175. i. trans-{(3Ro6S)-6-[2-(2-methoxy-quinolin-8-yl)-vinyl]-tetrahydro-pyran-3-yl}-carbafrtic acid tert-butyl ester:
This compound (0.23 g, 11% yield) was prepared as a white solid, starting from intermediate 173.i (3.0 g, 5.8 mmol) and trifluoromethanesulfonic acid 2-methoxy-quinolfcn-8- yl ester (1.69 g, 5.5 mmol; prepared as in WO 2004/002490) and using the procedure of Example 173, step 173. ii.
1H NMR (d6-DMSO) δ: 8.23 (d, J = 8.9 Hz, IH); 7.90 (d, J = 6.5 Hz, IH); 7.79 (d, J = 8.0 Hz5 IH); 7.61 (d, J = 16.0 Hz, IH); 7.40 (dd, J = 6.5, 8.0 Hz, IH); 7.03 (d, J = 8.9 Hz, IH); 6.83 (d, J = 7.8 Hz, IH); 6.58 (dd, J = 5.9, 16.0 Hz, IH); 4.02 (s, 3H); 3.99 (m, IH); 3.88 (dd, J = 3.4, 10.7 Hz, IH); 3.40 (br s, IH); 3.09 (t, J = 10.5 Hz, IH); 1.88 (m, 2H); 1.51 (m, 2H). MS (ESI, m/z): 385.3 [M+H+].
175.U. {6-[(lR,2R)-l,2-dihydroxy-2-(2-methoxy-quinolin-8-yl)-ethyl]-tetrahydro-pyran-3-yl}- carbamic acid tert-butyl ester: This compound (0.23 g, 92% yield) was prepared as a white solid, starting from inteπnediate 175. i (0.23 g, 0.6 mmol) and using the procedure of Example 173, step 173. iii. MS (ESI, m/z): 419.2 [M+H+].
175.iii. (IR, 2R)-I -[(2S, 5R)-amino-tetrahydro-pyran-2-yl)-2-(2-nιethoxy-quinolin-8-yl)- ethane-l,2-diol: This compound (0.15 g, 85% yield) was obtained as a colourless solid starting from intermediate 175. ii (0.23 g, 0.55 mmol) and using the procedure of Example 173, step 173. iv. MS (ESI, m/z): 319.2 [M+H+].
175.iv. (3R,6S)-6-({6-[(lR,2R)-l,2-dihydroxy-2-(2-methoxy-quinolin-8-yl)-ethyl]-tetrahydro- pyran-3-ylamino}-methyl)-4H-pyrido[3,2-b][l,4]thiazin-3-one: This compound (0.055 g, 35% yield) was prepared as a beige solid, starting from intermediate 175. iii (O.l g, 0.315 mmol) and 3-oxo-3,4-dihydro-
2H-pyrido[3,2-Z?][l,4]thiazine-6-carbaldehyde (0.067 g, 0.35 mmol) and using the procedure of Example 173, step 173.V.
1H NMR (d6-DMSO) δ: 10.87 (s, IH); 8.21 (d, J = 9.0 Hz, IH); 7-79-7.72 (m, 3H); 7.41 (app t, J = 7.6 Hz3 IH); 7.09 (d, J = 7.6 Hz, IH); 7.00 (d, J = 8.8 Hz, IH); 5.68 (dd, J = 2.6, 6.6 Hz,
IH); 5.02 (d, J = 6.6 Hz, IH); 4.19 (d, J = 6.2 Hz, IH); 3.96 (s, 3H); 3.95 (overlapped m, IH);
3.74 (dd, AB system, J = 2.7, 15.0 Hz, 2H); 3.67 (td, J = 2.7, 6.4 Hz, IH); 3.53 (s, 2H);
3.28 (m, IH); 2.87 (t, J = 10.5 Hz, IH); 2.07 (m, 2H); 1.89 (br d, J = 12.2 Hz, IH); 1.49 (m,
IH); 1.30-1.11 (m, 3H). MS (ESI, m/z): 497.1 [M+H+]. Example 176: 3-oxo-3,4-dihydro-2/7-pyrid» [3,2-6] [l,4]thiazine-6-carboxyIic acid
{(3Λ,65)-6-[(lΛ,2i?)-l,2-dihydroxy-2-(2-metlioxy-quinolin-8-yl)-ethyI]-tetrahydro-iϊyran-
3-yl}-araide:
The title compound (0.045g, 54% yield) was obtained as a white solid starting from intermediate 175. iii (0.052 g, 0.164 mmol) and using the procedure of Example 172.
1H NMR (d6-DMSO) δ: 10.93 (s, IH); 8.23 (d, J = 9.0 Hz, IH); 7.96 (two overlapped d, J = 7.9Hz and J = 8.2 Hz, 2 x IH); 7.81-7.74 (m, 2H); 7.59 (d, J = 7.9 Hz, IH); 7.43 (t, J = 7.5 Hz, IH); 7.02 (d, J = 8.8 Hz, IH); 5.72 (dd, J = 2.5, 6.6 Hz, IH); 5.08 (d, J = 6.6 Hz, IH); 4.31 (d, J = 6.4 Hz, IH); 4.00 (s, 3H); 3.9» 8-3.86 (m, 2H); 3.75 (td, J = 2.6, 6.5 Hz, IH); 3.64 (s, 2H); 3.78 (m, IH); 3.10 (t, J = 10.2 Hz, IH); 2.04 (m, 2H); 1.70-1.54 (m, 2H). MS (ESI, m/z): 511.2 [M+H+].
Example 177: (3Λ,6ιSr)-6-({6-[(li?,2i?)-l,2-dihydroxy-2-(3-methoxy-quinoxaIin-5-yI)- ethyl]-tetrahydro-pyran-3-ylamino}-methyl)— 4H-pyrido[3,2-6][l,4]thiazin-3-one:
177. i. trans-{(3R, 6S)-{6-[2-(3-methoxy-quinoxcιlin-5-yl)-vinyl]-tetrahydro-pyran-3-yl}— carhamic acid tert-butyl ester:
The title (ϋ)-alkene (2.01 g, 57% yield) was prepared as a beige solid, starting from intermediate 104.vii (1.5 g, 7.97 mmol) and intermediate 164.M (3.81 g, 9 mmol) and using the procedure of Example 171, step 17 Lv.
1H NMR (d6-DMSO) δ: 8.62 (s, IH); 7.99 (d, J = 7.4 Hz, IH); 7.91 (dd, J = 1.2, 8.2 Hz, IH); 7.60 (dd, J = 7.4, 8.2 Hz, IH); 7.53 (d, J = 15.8 Hz, IH); 6.84 (d, J = 8.0 Hz, IH); 6.63 (dd, J = 5.7, 15.8 Hz, IH); 4.08 (s, 3H); 3.99 (m, IH); 3.89 (br dd, J = 3.0, 10.2 Hz, IH); 3.38 (br s, IH); 3.09 (t, J = 10.5 Hz, IH); 1.91-1.86 (m, 2H); 1.53-1.45 (m, 2H); 1.39 (s, 9H). MS (ESI, m/z): 386.2 [M+H+].
177.U. (3R,6S)-{6-[(lR,2R)-l,2-dihydroxy-2-(3-methoxy-quinoxalin-5-yl)-ethyl]-tetrahy>dro- pyran-3-yl}-carbamic acid tert-butyl ester.
The title diol (1.89 g, 86%) was prepared as a white foam starting from intermediate 177.i (2.01 g, 5.2 mmol) and using the procedure of Example 171, step 171. vi. MS (ESI, m/z): 419.2 [M+H+]. 177.iii. (lR,2R)-l-[(2S,5R)-(5-amino-tetrahydro-pyran-2-yl)-2-(3-methoxy-quinoxalin-5-yl)- ethane- 112-diol:
This compound (0.252 g) was prepared as a yellowish foam, starting from intermediate 177.ii (0.315 g, 0.79 mmol) and using the procedure of Example 173, step 173. iv. 1H NMR (d6-DMSO) δ: 8.60 (s, IH); 7.90-7.85 (m, 2H); 7.62 (dd, J = 7.7, 7.8 Hz, IH); 5.68 (br s, IH); 5.11 (br d, J= 4.3 Hz, IH); 4.27 (br s, IH); 4.03 (s, 3H); 3.77 (ddd, J = 1.7, 4.3, 10.4 Hz, IH); 3.62 (dd, J = 2.3, 6.1 Hz, IH); 3.23 (ddd, J = 1.7, 6.4, 11.0 Hz, IH); 2.75 (t, J = 10.4 Hz, IH); 2.56 (m, IH); 1.95-1.84 (m, 2H); 1.52 (m, IH); 1.45 (br s, 2H); 1.13 (m, IH). MS (ESI, m/z): 320.2 [M+H+].
177. iv. (3R,6S)-6-({6-[(lR,2R)-l,2-dihydroxy-2-(3-methoxy-qιιinoxalin-5-yl)-ethyl]- tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3, 2-b][l, 4Jthiazin-3-one :
Starting from intermediate 177. iii (0.100 g) and 3-oxo-3,4-dihydro- 2H-pyrido[3,2-έ][l,4]thiazine-6-carbaldehyde (0.067 g), the title compound (0.087 g) was prepared as a yellow foam according to the procedure of Example 88, step 88. iv. MS (ESI, m/z): 498.2 [M+Η+].
Example 178: 6-({(3Λ,65)-6-[(l1S',25)-l,2-dihydroxy-2-(6-methoxy-[l,5]naphthyridin- 4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-6][l,4]thiazin-3-one:
178. i. 2-methoxy-8-styryl-[l,5]naphthyridine: Trifluoromethanesulfonic acid 6-methoxy-[l,5]naphthyridin-4-yl ester (1.5 g, 4.86 mmol), trøm-phenylvinyl boronic acid (0.8 g, 5.35 mmol) and K2CO3 (0.9 g, 6.32 mmol) were introduced in a two-neck flask. The atmosphere was flushed with nitrogen. Dioxane (20 ml) and water (5 ml) were added. The mixture was stirred at rt for 5 min and tetrakis(triphenylphosphine) palladium (0.28 g, 0.24 mmol) was added. The mixture was heated at reflux for 5 h. After cooling, the reaction mixture Λ?vas diluted with EA (10 ml) and water (50 ml). The aqueous layer was extracted with EA (2 κ 100 ml). The combined extracts were concentrated to dryness. The residue was chromatographed (Ηex-EA 1-1) to afford the title alkene (1.26 g, 4.8 mmol) as an oil that crystallized on standing. 1H NMR (d6-DMSO) δ: 8.77 (d, J = 4.7 Hz, IH); 8.28 (d, J = 9.0 Hz, IH); 8.19 (d, J = 16.7 Hz, IH); 8.01 (d, J = 4.7 Hz, IH); 7.91 (d, J = 16.7 Hz, IH); 7.74 (m, 2H); 7.40-7.34 (m, 3H); 7.30 (d, J = 9.0 Hz, IH); 4.12 (s, 3H).
178. ii. l-(6-methoxy-[l, 5]naphthyridin-4-yl)-2-phenyl-ethane-l, 2-diol: To a mixture of intermediate 178. i (1.26 g, 4.8 mmol) in 2-methyl-2-propanol (24 ml) and water (24 ml) were added methanesulfonamide (0.52 g) arid AD mix β® (7 g). The mixture was stirred at rt for 12 h. Sodium bisulfite (7.5 g) was added carefully and stirring was continued 20 min. The two layers were decanted and the aqueous layer was extracted with EA (2 x 100 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness. The residue was triturated in Hex-EA (1-3, 3 O mI) and the resulting solid was filtered off and dried in vacuo to afford the title diol (1.3 g) as a white solid. MS (ESI, m/z): 297.1 [M+H+].
178.iii. 6-methoxy-fl, 5]naphthyridine-4-carbaldehyde:
To a solution of intermediate 178. ii (1.3 g, 4.4 mmol) in acetone (15 ml) was added a solution of sodium periodate (2.35 g, 10.96 mmol) in water (5 ml). The reaction mixture was stirred at rt for 30 min. The reaction mixture was diluted with THF (1 OO ml) and the solids were filtered off. The filtrate was concentrated to dryness and the residue was resuspended in water
(100 ml), ether (10 ml) and Hex (100 ml). The slurry was stirred at rt for 15 min and filtered.
The solids were washed with water and Hex. After drying, the title aldehyde (0.42 g) was recovered as a white solid.
1H NMR (d6-DMSO) δ: 11.25 (s, IH); 9.02 (d, J = 4.4 Hz, IH); 8.42 (d, J = 9.1 Hz, IH);
7.92 (d, J = 4.4 Hz, IH); 7.40 (d, J = 9.1 Hz, IH); 4.11 (s, 3H).
178. iv. ((5R16S)-6-[2-(6-methoxy-[l, 5]naphthyridin-4-yl)-vinyl]-tetrahydro-pyran-3-yl}- carbamic acid tert-butyl ester. Starting from intermediate 178. iii (0.4 g, 2.12 mmol) and intermediate 164.ii (0.9 g, 2.2 mmol), the title alkene (0.44 g, 51% yield) was obtained as a white solid using the protocol of Example 171, step 171.V. MS (ESI, m/z): 386.0 [M+jf]. 178.V. (S^ό^-lό-tCl^l^-l^-dihydroxy-S-Cό-methoxy-tl^Jnaphthyridin^-yO-ethyl]- tetrahydro-pyran-3-yl}-carbamic acid ter/-butyl ester:
The title diol (0.47 g, 98%) was obtained as a white foam starting from intermediate 178. iv (0.44 g, 1.14 mmol) and using the protocol of Example 171, step 171.vi, except that AD mix α® was used instead of AD mix β®.
1H NMR (d6-DMSO) δ: 8.75 (d, J = 4.5 Hz, IH); 8.24 (d, J = 9.0 Hz, IH); 7.74 (d, J = 4.5 Hz, IH); 7.23 (d, J = 9.0 Hz, IH); 6.81 (br s, IH); 6.75 (br d, J = 8.3 Hz, IH); 5.83 (d, J = 6.1 Hz, IH); 5.25 (d, J = 6.6 Hz, IH); 4.49 (d, J = 8.1 Hz, IH); 4.00 (s, 3H); 3.76 (m, IH); 3.67 (app t, J = 6.6 Hz, IH); 3.36 (m, IH); 2.99 (t, J = 10.9 Hz, IH); 1.99-1.86 (m, 2H); 1.38 (s, 9H); 1.35-1.13 (m, 2H).
MS (ESI, m/z): 420.2 [M+H+].
178.vi. (IS, 2S)-I -[(2S, 5R)-(5-amino-tetrahydro-pyran-2-yl)-2-(6-methoxy-[l, 5]naphthyridin- 4-yl) -ethane- 1 ,2-diol:
This was obtained as a yellowish foam (0. 17 g, 47% yield) from intermediate 178.V (0.47 g, 2.08 mmol) according to the procedure of Example 77, step 77.iii.
1H NMR (d6-DMSO) δ: 8.75 (d, J = 4.5 Hz, IH); 8.24 (d, J = 9.0 Hz, IH); 7.74 (d, J = 4.5 Hz, IH); 7.23 (d, J = 9.0 Hz, IH); 5.84 (d, J = 5.3 Hz, IH); 5.21 (d, J = 6.5 Hz, IH); 4.46 (d, J = 8.3 Hz, IH); 3.99 (s, 3H); 3.76 (ddd, J = 2.5, 4.6, 8.8 Hz, IH); 3.65 (td, J = 1.5, 8.0 Hz, IH); 3.32 (m, IH); 2.86 (t, J = 10.4 Hz, IH); 2.54 (partially overlapped m, IH); 1.93 (m, 2H); 1.55, br s, 2H); 1.2-1.09 (m, 2H). MS (ESI, m/z): 320.2 [MHhH+].
178.vii. 6-({(3R,6S)-6-[(lS,2S)-l,2-dϊhydraxy-2-(6-methoxy-[l,5]naphthyridin-4yl)-ethyl]- tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-b][l,4]thiazin-3-one\
This compound (0.06 g, 22% yield) was obtained as a white solid from intermediate 178.vi (0.17 g, 0.53 mmol) and 3-oxo-3,4-dih.ydro-2H-pyrido[3,2-έ][l,4]thiazine-6-carbaldehyde (0.113 g, 0.58 mmol), using the procedure of Example 173, step 173.V. MS (ESI, m/z): 498.2 [M+Η+]. Example 179: 3-oxo-3,4-dihydro-2H-pyrido[3,2-6][l,4]thiazine-6-carboxyIic acid (3i?,6ΛS)-{6-[(li?,2J?)-l,2-dihydroxy-2-(3-methoxy-quinoxaliii-5-yl)-ethyl] tetrahydro- pyran-3-yl}-ainide:
The title compound (0.051 g) was obtained as a yellowish solid, starting from intermediate 177.iii (0.100 g) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-έ][l,4]thiazine- 6-carboxylic acid (0.072 g) and using the procedure of Example 172. MS (ESI, m/z): 512.2 [M+Η+].
Example 180: 6-({(3jR,65)-6-[(li?,2i?)-l,2-dihydroxy-2-(3-inethoxy-quiiioxaIiii- 5-yl) ethyl]-tetrahy dro-pyran-3-ylamino}-methyl)-4H-pyrido [3,2-6] [1 ,4] oxazin-3-one:
Starting from intermediate 177.iii (0.096 g) and 3-oxo-3,4-dihydro- 2H-pyrido[3,2-ό][l,4]oxazine-6-carbaldehyde (0.059 g), the title compound (0.038 g) was obtained as a yellow solid according to the procedure of Example 88, step 88. iv. MS CESI, m/z): 482.2 [M+Η+].
Example 181 : 8-((lJ?,2i?)-l,2-dihydroxy-2-{(2)S,5i?)-[(3-oxo-3,4-dihydro- 2H-pyrido[3,2-6] [l,4]thiazin-6-yImethyI)-amino]-tetrahydr o-pyran-2-yl}-ethyl)- quinoline-2-carbonitrile :
181. i. trans-(3R, 6S)-{6-[2-(2-cyano-quinolin-8-yl)-vinyl]-tetrcιhydro-pyran-3-yl}-carbamic acid tert-butyl ester:
The title (£)-alkene (1.8O g, 71%) was obtained as a white solid, starting from intermediate 173.i (5.0 g, 9.7 mmol) and trifluoromethanesulfbnic acid 2-cyano-quinolin-8-yl ester (2.0 g, 6.6 mmol) and using the procedure of Example 173, step 173. ii.
1H NMR (d6-DMSO) δ: 8.89 (d, J = 8.5 Hz, IH); 8.16 (d, J = 63 Hz, IH); 8.06 (d, J = 8.5 Hz,
IH); 8.03 (dd, J = 1.2, 7.1 Hz, IH); 7.78 (dd, J = 6.3, 7.1 Hz, IH); 7.67 (d, J = 16.3 Hz, IH);
6.85 (d, J = 7.7 Hz, IH); 6.61 (dd, J = 5.3, 16.3 Hz, IH); 4-.03 (m, IH); 3.93 (dd, J = 2.7, 10.7 Hz, IH); 3.41 (br s, IH); 3.12 (t, J = 10.5 Hz, IH); 1.92-1.87 (m, 2H);
1.54-1.46 (partially overlapped m, 2H); 1.40 (s, 9H).
MS (ESI, m/z): 380.3 [M+H+]. 181.il. C-3R, 6S)-{6-[(lR,2R)-2-(cyano-quinolin-8-yl)-l,2-dihydroxy-ethyl]-tetrahydro-pyran- 3-ylj-carbamic acid tert-butyl ester:
The title diol (1.60 g, 81%) was obtained as a white solid starting from intermediate 181.i (1.80 g, 4.74 mmol) and using the procedure of Example 173, step 173. iii. MS (ESI, m/z): 419.2 [M+H+J.
181.iii. 8-[(1R, 2R)-2-((2S, 5R)-5-amino-tetrahydro-pyran-2-yl)-l, 2-dihydroxy-ethyl]- quinoline-2-carbonitrile :
The title amine (0.62 g, 74% yield) was obtained as a colourless solid starting from intermediate 181. ii (1.1 g, 2.61 mmol) and using the procedure of Example 173, step 173. iv. MS (ESI, m/z): 314.2 [M+H"1"].
181 ,iv. 8-((1R, 2R)-1, 2-dihydroxy-2-{(2S, 5R)-[(3-oxo-3, 4-dihydro-
2H-pyrido[3,2-bJ[l,4Jthiazin-6-ylmethyl)-amino]-tetrahydro-pyran-2-yl}-ethyl)-quinoline- 2-car bo nitrite:
The title compound (0.142 g, 28%) was obtained as white flakes, starting from intermediate 181.iii (0.314 g, 1 mmol) and 3-oxo-3 ,4-dihydro-2H-pyrido[3,2-b][l,4]thiazine-
6-carbaldehyde (0.214 g, 1.1 mmol) and using the procedure of Example 173, step 173.V.
1H NMR (d6-DMSO) δ: 10.87 (s, IH); 8.65 (d, J = 8.5 Hz, IH); 8.04-7.99 (m, 3H); 7.81 (dd,
J = 7.0, 8.3 Hz, IH); 7.73 (d, J= 7.8 Hz, IH); 7.O9 (d, J = 7.9 Hz, IH); 5.77 (dd, J= 2.6,
6.8 Hz, IH); 5.19 (d, J = 6.3 Hz, IH); 4.35 (d, J = 6.3 Hz, IH); 3.92 (dd, J = 2.4, 10.8 Hz, IH); 3.77 (br s, 2H); 3.60 (td, J = 2.9, 6.3 Hz, IH); 3.53 (s, 2H); 3.24 (dd, J = 6.3, 9.6 Hz,
IH); 2.81 (t, J = 10.5 Hz, IH); 2.50 (overlapped m, IH); 2.08 (m, 2H); 1.89 (br d, J = 13.9 Hz,
IH); 1.50 (m, IH); 1.19 (m, IH).
MS (ESI, m/z): 492.1 [M+H1"].
Example 182: 3-oxo-3,4-dihydro-2H-pyrido[3,2-Λ][l,4]thiazine-6-carboxylic acid {(35,6S^)-6-[(li?,2i?)-2-(2-cyano-quinolin-8-yl)-l,2-dihydroxy-ethyl]-tetrahydro-pyran- 3-yl}-arnide:
This compound (0.045 g) was obtained as a yellowish solid, starting from intermediate 181. iii (0.092 g, 0.29 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]thiazine-6-carboxylic acid (0.068 g, 0.32 mmol) and using the procedure of Example 172. MS (ESI, m/z): 506.2 [M+Η+]. Example 183: 8-((liϊ,2i?)-l,2-dihydroxy-2-{(25,5i?)-5-[(3-oxo-3,4-ciihydro- 2H-pyrido[3,2-6][l,4]oxazin-6-ylmethyl)-amino]-tetrahydro-pyran-2-yl}-ethyl)- quinoline-2-carbonitrile :
This compound (0.064 g, 21%> yield) was obtained as a white solid, starting from intermediate 181. iii (0.2 g, 0.64 rnmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-έ][l,4]oxazine- 6-carbaldehyde (0.12 g, 0.67 mmol) and using the procedure of Example 88, step 88. iv. MS (ESI, m/z): 476.2 [M+Η+].
Example 184: 6-((3JR,65r)-{6-[^αn5-(liϊ5',2i?ιS)-l,2-dihydroxy-2-(3-inethoxy-quinolin- 5-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-&][l,4]thiazin-3-one:
184.i. (3R,6S)-{6-[((2S,3R)-3-(3-methoxy-quinolin-5-yl)-oxiranyl]-tetr-ahydro-pyran-3-yl}- carbamic acid tert-butyl ester:
To a solution of intermediate 171.vi (0.504 g, 1.21 mmol) and triethyl orthoacetate (0.264 ml, 1.45 mmol) in DCM (3.6 ml), cooled to 00C, was added trimethylsilyl chloride (0.185 ml, 1.45 mmol). The solution was stirred for 1 h and the reaction mixture concentrated to dryness. The residue was dissolved in MeOH (2.4 ml). K2CO3 (0.416 g, 3.01 irimol) was added and the suspension was vigorously stirred for 3 h. The suspension was concentrated to dryness and the residue was partioned between in EA and water. The phases were separated and the aq. layer extracted once with EA. The combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica gel (DCM-MeOH 19-1) to afford the title epoxide (0.254 g, 52% yield) as a white foam.
1H NMR (CDCl3) δ: 8.63 (d, J = 2.8 Hz, IH); 7.94 (dd, J = 1.7, 7.9 Hz, IH); 7.61 (d, J = 2.5 Hz, IH); 7.47-7.39 (m, 2H); 4.28 (br d, J = 1.3 Hz3 IH); 4.23 (br s, IH); 4.12 (ddd, J = 2.1, 5.0, 10.8 Hz, IH); 3.90 (s, 3H); 3.63 (br s, IH); 4.89 (ddd, J = 2.3, 5.0, 11.2 Hz, IH); 3.11 (dd, J = 2.3, 5.0 Hz, IH); 3 .05 (t, J = 10.6 Hz, IH); 2.15 (m, IH); 1.83 (m, IH); 1.67 (m, IH); 1.38 (s, 9H); 1.35 (overlapped m, IH). MS (ESI, m/z): 401.0 [M+H+]. 184.ii. trans-(lRS,2RS)-l-((2S,5R)-5-amino-tetrahydro-pyrart-2-yl)-2-(3-methoxy-quinolin- 5-yl)-ethane-l, 2-diol:
A solution of intermediate 184.i (0.253 g, 0.63 mmol) in TTA (5 ml) was stirred at rt for 5 min. The volatiles were removed in vacuo and IM aq, NaOH was added until pH 9 was reached. The mixture was extracted eight times with a DCM-MeOH (9-1) mixture. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (DCM-MeOH 9-1 containing 1% concentrated NH4OH to DCM-MeOH 4-1 containing 1% NH4OH) to afford the title diol (0.136 g, 67% yield, 1.5:1 mixture of diastereomers) as a white foam. MS (ESI, m/z): 319.2 [M+H+].
184.iii. 6-((3R, 6S)-{6-[trans-(lRS,2RS)-l,2-dihydroxy-2-(3-methoxy-quinolin-5 yl)-ethyl]- tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3, 2-b][l, 4]thiazin-3-one :
Starting from intermediate 184.ii (0.136 g, 0.43 mmol) and 3-oxo-3,4-dihydro- 2H-pyrido[3,2-Z>][l,4]thiazine-6-carbaldehyde (0.092 g, 1.1 eq.), the title compound (0.113 g, 57% yield, 1.5:1 mixture of diastereomers) was obtained as a yellowish foam. MS (ESI, m/z): 497.2 [M+Η+].
Example 185: 6-((3Λ,65f)-{6-[(liϊ,2i?)-l,2-dihydroxy-2-(6-methoxy-quinoIin-4-yl)-ethyl]- tetrahydro-pyran-3-ylamino}-methyI)-4H-pyrido[3,2-A][l,4]thiazin-3-one:
185.i. trans-(3R, 6S)-{6-[2-(6-methoxy-quinolin-4-yl)-vinyl]-tetrahydro-pyran-3-yl}-carbamic acid tert-butyl ester:
The title (E)-alkene (3.16 g, 41%) was obtained as a yellowish solid, starting from intermediate 164.U (8.47 g, 20 mmol) and 6-methoxy-quinoline-4-carbaldehyde (5.5 g, 22 mmol) and using the procedure of Example 164, step 164. iii. MS (ESI, m/z): 385.3 [M+H+].
185.U. (3R,6S)-{6-[(lR,2R)-l!2-dihydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro- pyran-3-yl}-carbamic acid tert-butyl ester.
The title diol (0.814 g, 38%) was obtained as a white foam, starting from intermediate 185. i (1.96 g, 5.1 mmol) and using the procedure of Example 173, step 173. iii. 1H NMR (CDCl3) δ: 8.72 (d, J = 4.5 Hz, IH); 8.03 (d, J = 9.2 Hz, IH); 7.57 (d, J = 4.5 Hz, IH); 7.38 (dd, J = 2.7, 9.2 Hz, IH); 7.32 (d, J = 2.7 Hz, IH); 5.51 (d, J = 5.3 Hz, IH); 4.21 (br d, partially overlapped, J = 6.2 Hz, IH); 4.18 (ddd, J = 1.8, 4.6, 10.5 Hz., IH); 3.94 (s, 3H); 3.69 (dd, J = 2.6, 5.2 Hz, IH); 3.63 (br s, IH); 3.15 (td, J = 2.2, 11.4 Hz, IH); 2.91 (t, J = 10.6 Hz, IH); 2.07 (m, IH); 1.91 (qd, J = 4.0, 13.4 Hz, IH); 1.90 (br s, 2H); 1.62 (m, IH); 1.45 (s, 9H); 1.19 (qd, J = 4.2, 12.5 Hz, IH). MS (ESI, m/z): 419.4 [M+H+].
185.iii. (lR,2R)-l-((2S,5R)-5-amino-tetrahydro-pyran-2-yl)-2-(6-methoxy-quinolin-4-yl)- ethane- 1,2-diol: The title amine (0.605 g) was obtained as a white foam, starting from intermediate 185.U (0.810 g, 1.94 mrnol) and using the procedure of Example 173, step 173. iv. MS (ESI, m/z): 3 19.1 [M+H+].
185.iv. 6-((3R,6S)-{6-[(lR,2R)-l,2-dihydroxy-2-(6-methoxy-quinolin-4-yl)-ethyZJ-tetrahydro- pyran-3-ylaminoJ-methyl)-4H-pyrido[3,2-b][l,4]thiazin-3-one: This compound (0.064 g, 21%) was prepared as a white solid, starting from intermediate 185.Hi (0.105 g, 0.33 mmol) and 3-oxo-3,4-dihydro-2.i7-pyrido[3,2- έ][l,4]thiazine-6-carbaldehyde (0.07 g, 0.36 mmol) and using the procedure described in Example 88, step 88. iv. 1H NMR (DMSO) δ: 10.87 (s, IH); 8.71 (d, J= 4.5 Hz, IH); 7.93 (d, J= 9.1 Hz, IH); 7.73 (d, J= 7.9 Hz, IH); 7.54 (d, J= 4.5 Hz, IH); 7.44 (d, J= 2.6 Hz, I H); 7.40 (dd, J= 2.6, 9.1 Hz, IH); 7.07 (d, J= 7.9 Hz, IH); 5.41 (d, J = 5.2 Hz, IH); 5.35 <t, J = 5.2 Hz, IH); 4.79 (d, J = 6.4 Hz, IH); 3.94 (m, IH); 3.88 (s, 3H); 3.72 (br. d, J = 4.0 Hz, IH); 3.53 (s, 2H); 2.92 (m, IH); 2.71 (t, J= 10.8 Hz, IH); 2.01 (m, IH); 1.63 (m, 2H); 1.23 (m, IH); 1.06 (m, IH). MS (ESI, m/z): 497.2[M+^].
Example l86: 6-((3Λ,65)-{6-[(lS,2J?)-l,2-dihydroxy-2-(6-methoxy-quiαolin-4-yl)-ethyI]- tetrahydro-pyran-3-yIamino}-metliyI)-4H-pyrido[3,2-6][l,4]thiazin-3-one:
186.L (3R, 6S)-{6-[(lS, 2S)-1, 2-dihydroxy-2-(6-methoxy-quinolm-4-yl)-ethyTJ-tetrahydro- pyran-3-yl}-carbamic acid tert-butyl ester: To a solution of intermediate 185.i (1-04 g, 2.71 mmol) in DCM (20 ml) and water (2 ml) was added NMO (1.08 g, 8.13 mmol) and potassium osmate (0.05 g, 0.14 mmol, 5 mol%). The reaction was stirred for 3.5 h atrt. Water (30 ml) and sodium bisulfite (1.5 g) were added. The mixture was stirred at rt for 15 min and the phases separated. The aq. layer xvas extracted once more with EA. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (DCM-MeOH 19-1 then 9-1) to afford the title compound as a white solid (0.850 g, 75% yield). MS (ESI, m/z): 419.3 [M+H+].
186. ii. {lS,2S)-l-((2S,5R)-5-ωnino-tetrahydro-pyran-2-yl)-2-(6-methoxy-g[uinolin-4-yl)- ethane-l,2-diol: This compound (0.537 g, 83% yield) was obtained as a white foam, starting from intermediate 186. ii (0.810 g, 1.94 mmol) and using the procedure of Example 173, step 173.iv.
186.iii. 6-((3R, 6S)-{6-[(lS, 2R)-1, 2-dihydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro- pyran-3-ylamino}-methyl)-4H-pyrido[3,2-b][l,4]thiazin-3-one\ The title compound (0.047 g, 15%> yield) was obtained as a yellowish solid, starting from intermediate 186.U (0.20 g, 0.63 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-Z>][l,4]thiazine- 6-carbaldehyde (0.134 g, 0.69 mmol), using the procedure of Example 88, step 88. iv. The title compound was the major isomer in a 1.5 to 1 mixture with the compound of Example 185. MS (ESI, m/z): 497.2 [M+Η+]. Example 187: (ϋ?1S)-l-{(2,S',5i?)-5-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-aiiiino]- tetrahydro-pyran-2-yI}-2-(6-methoxy-quinoIin-4-yI)-ethanol:
187. i. (3R, 6S)-6-[(lRS)-l-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran- 3-yl}-carbamic acid tert-butyl ester: To a solution of N,N-diisopropylamine (2 ml) in THF (9.25 ml), cooled to -78°C, was added rø-BuLi (1.6 M in Hex, 8.75 ml). The mixture was stirred 10 min at this temperature, then 15 min at 0°C. To a solution of 6-methoxy-4-methyl-quinoline (2.23 g) in THF (24 ml), cooled to -78°C, was added LDA (20 ml). The mixture was stirred 15 rnin at -780C and 15 min at 00C. After cooling to -78°C, a solution of intermediate 158.i (1 g) in THF (5 ml + 3 ml rinse) was added. The mixture was then stirred 10 min at -78°C and 3O min at O0C. Water (20 ml) and EA (50 ml) were added, the two layers were decanted and the aq. layer was extracted with EA (2 x 50 ml). The combined organic extracts were washed with brine, dried over Νa2SO4, filtered and concentrated to dryness. The residue was criromatographed over silica gel (EA) to afford the title alcohol (0.78 g, 1.93 mmol) as a white foam. The compound was obtained as 1.2:1 mixture of diastereomers. MS (ESI, m/z): 403.1 [M+H+]
187.U. (litS)-l-((25',5i?y)-5-amino-tetrahydro-pyran-2-yl)-2-(6-methoxy-quinolin-4-yl)- ethanol:
This compound (0.49 g) was obtained as a white solid, starting from intermediate 187.i (0.78 g, 1.93 mmol) and using the procedure of Example 173, step 173. iv. MS (ESI, m/z): 303.2 [M+H+].
187.iii. (1 RS)-I -{(2S,5R)-5-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-cιmino]-tetrahydro- pyran-2-yl}-2-(6-methoxy-quinolin-4-yl)-ethanol:
This compound (0.085 g) was obtained as a white foam, starting from intermediate 187.U (0.1 g, 0.33 mmol) and 2,3-dihydro-benzo[l,4]dioxine-6-carbaldehyde (0.06 g, 0.36 mmol), and using the procedure of Example 88, step 88.iv. MS (ESI, m/z): 451.2 [M+H+]. Example 188: 6-({(3Λ,6.S)-6-[(li?S)-l-hydroxy-2-(6-inethoxy-quinolin-4-yl)-ethyI]- tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[l,4]thiazin-3-one:
This compound (0.087g, 57% yield) was obtained as a white foam, starting from intermediate 187.U (0.1 g, 0.33 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-Z>][l,4]thiazine- 6-carbaldehyde (0.070 g, 0.36 mmol) and using the procedure of Example 88, step 88. iv. MS (ESI, m/z): 481.5 [M+Η+].
Example 189: 3-oxo-3,4-dihydro-2H-pyrido[3,2-6][l,4]thiazine-6-carboxylic acid
{(3JR,6S)-6-[(li?S)-l-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}- amide:
The title compound (0.030 g) was obtained as a white solid, starting from intermediate 187.ii (0.115 g, 0.38 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-6][l,4]thiazine-6-carboxylic acid (0.095 g, 0.45 mmol) and using the procedure of Example 172. The compound was obtained with a purity of 85% (as judged by 1H NMR). MS (ESI, m/z): 493.2 [M-H+].
Example 190: 6-({(3ii,6S)-6-[(15r)-l-hydroxy-2-(6-methoxy-quinolin-4-yI)-ethyl]- tetrahyc3ro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-6][l,4]thiazin-3-one:
19O.i. (3R, 6S)-{6-[(4R, 5R)-5-(6-methoxy-quinolin-4-yl)-2-oxo-[l, 3]dioxolan-4-yl]- tetrahydro-pyran-3-yl}-carbamic acid tert-butyl ester:
To a solution of intermediate 185.ii (3.06 g) in DCM (40 ml) was added TEA (2.04 ml). The solution was cooled to 00C and triphosgene (2.17 g) was added in one portion. The reaction mixture was stirred at this temperature for 30 min then concentrated to dryness. The residue was purified by column chromatography over silica gel (DCM-MeOH 19-1 containing 1%
NH4OEQ to afford the title product as a pale yellow foam (2.75 g).
1H NMR (CDCl3) δ: 8.82 (d, J= 4.5 Hz, IH); 8.10 (d, J= 9.3 Hz, IH); 7.49-7.43(m, 2H); 7.21 (br. s, IH); 6.27 (d, J= 4.2 Hz, IH); 4.61 (m, IH); 4.28 (ddd, J= 2.0, 4.7, 10.6 Hz, 2H);
3.95 (s, 3H); 3.70 (m, 2H); 3.18 (t, J= 10.7Hz, IH); 2.27 (m, IH); 1.84 (m, 2H); 1.46 (s, 9H);
1.45 (m overlapped, IH).
MS (ESI, m/z): 445.0 [M+H+]. 190. ii. (3 R, 6S)-{6-[(lS)-l-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyIJ-tetrahydro-pyran- 3-ylj-carbamic acid tert-butyl ester:
To a solution of intermediate 19O.i (2.75 g) in EA (250 ml) under argon was added Pd/C (1.32 g). The resulting suspension was stirred under hydrogen atmosphere. After 2.5 h, more Pd/C (0.66 g) was added and the reaction was stirred overnight under hydrogen atmosphere. The catalyst was filtered off and the filtrate concentrated in vacuo. The residue was purified by column chromatography over silica gel (DCM-MeOH 19-1 containing 1% concentrated NH4OH) to afford the title compound as a white foam (1.23 g). 1H NMR (DMSO) δ: 8.62 (d, J= 4.4 Hz, IH); 7.92 (d, J= 9.0 Hz, IH); 7.42 (d, J= 2.5 Hz, IH); 7.40 (dd, J= 2.7, 9.0 Hz, IH); 7.33 (d, J= 4.4 Hz, IH); 6.76 (br. d, J= 8.0 Hz, IH); 4.83 (d, J= 6.4 Hz, IH); 3.91 (s, 3H); 3.90 (overlapped m, IH); 3.74 (m, IH); 3.38 (br. s, IH); 3.29 (overlapped dd, visible J= 3.8 Hz, IH); 3.12 (d, J = 10.4 Hz, IH); 2.98 (t, J = 10.3 Hz, IH); 2.97 (m overlapped, IH); 1.90 (d, J= 9.2 Hz, IH); 1.60 (m, 2H); 1.39 (s, 9H); 1.38 (m overlapped, IH). MS (ESI, m/z): 403.O [M+H+].
190. iii. (IS)-I -((2S, 5 R)-(5-amino-tetrahydro-pyran-2-yl)-2-(6-metho?cy-quinolin-4-yl)- ethanoh
A solution of intermediate 19O.ii (1.23 g) in TFA (15 ml) was stirred for 10 min. The solution was concentrated to dryness, basified with a 2M NaOH solution, diluted with DCM-MeOH 9-1 and the phases separated. The aqueous layer was extracted 6 time s with DCM-MeOH 9-1. The combined organic layers were dried over Na2SO^ filtered and concentrated to dryness to afford a white solid (0.768 g).
1H NMR (DMSO) δ: 8.62 (d, J= 4.4 Hz, IH); 7.92 (d, J= 9.1 Hz, IH); 7.44 (d, J= 2.7 Hz, IH); 7.39 (dd, J= 2.8, 9.1 Hz, IH); 7.32 (d, J= 4.4 Hz, IH); 4.79 (d, J = 6.3 Hz, IH); 3.91 (s, 3H); 3.88 (ddd, J= 1.8, 4.4, 10.5 Hz, IH); 3.73 (m, IH); 3.31 (dd, J= 4.0, 13.6 Hz, IH); 3.10 (dt, J = 3.4, 10.4 Hz, IH); 2.93 (m overlapped, IH); 2.87 (t overlapped, J= 10.5 Hz, IH); 2.61 (m, IH); 1.92 (m, IH); 1.56 (m, 2H); 1.39 (br s, 2H)1.13 (m, IH). MS (ESI, m/z): 303.2 [M+H+]. 190. iv. 6-({(3R,6S)-6-[(lS)-l-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran- 3-ylam ino}-methyl)-4H-pyrido[3, 2-h][l, 4]thiazin-3-one :
Starting from intermediate 19O.iii (0.1 g, 0.33 mmol) and 3-oxo-3,4-dϊhydro- 2#-pyrido[3,2-έ][l,4]thiazine-6-carbaldehyde (O.071 g, 0.36 mmol), the title compound (0.095 g, 60% yield) was obtained as a foam using the procedure of Example 88, step & 8.iv. MS (ESI, m/z): 481.0 [M+H+].
Example 191: 6-((32f, 65)-{6-[l-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-tetraliydro- pyraα-3-yIamino}-methyl)-4H-pyrido[3,2-ό] [1 ,4]oxazin-3-one:
Starting from intermediate 19O.iii (0.102 g) and 3-oxo-3,4-dihydro- 2H-pyrido[3,2-Z>][l,4]oxazine-6-carbaldehyde (0.066 g), the title compound (0.034 g) was obtained as a white foam using the procedure of Example 88, step 88. iv.
1H NMR (DMSO) O: 11.19 (s, IH); 8.62 (d, J= 4.4 Hz, IH); 7.92 (d, J= 9.0 Hz, IH); 7.42 (d overlapped, J= 2.4 Hz, IH); 7.39 (dd overlapped, J = 2.7, 8.9 Hz, IH); 7.32 (m, 2H); 7.03 (d,
J= 8. 1 Hz, IH); 4.78 (d, J= 6.3 Hz, IH); 4.62 (s, 2H); 4.05 (m, IH); 3.90 (s, 3H); 3.71 (m, 3H); 3.32 (dd, J= 9.7, 13.6 Hz, IH); 3.14 (m, IH); 2.97 (t overlapped, J= 10.4 Hz, IH);
2.93 (m overlapped, IH); 2.51 (overlapped m, IH); 2.07 (m, IH); 1.65 (m, IH); 1.50 (xn, IH);
1.24 (br s, IH); 1.22 (m, IH).
MS (BSI, m/z): 465.4 [M+H+].
Example 192: 7-((3i?,6S)-{6-[(llS)-l-hydroxy-2-(6-methoxy-quinoliii-4-yl)-ethyl]- tetrahydro-pyran-3-ylamino}-methyl)-lH-pyrido[3,4-6][l,4]oxazin-2-one:
This compound (0.005 g, 4% yield) was obtained as a white solid, starting from intermediate 19O.iii (0.07 g, 0.23 mmol) and 2-oxo-2,3-dihydro- lH-pyrido[3,4-έ][l,4]oxazine-7-carbaldehyde (0.037 g, 0.21 mmol; prepared as described in WO 03/087098) and using the procedure of Exajmple 88, step 88.iv. MS (ESI, m/z): 465.1 [M+Η+]. Example 193: 3-oxo-3,4-dihydro-2H-pyrido[3,2-έ][l,4]thiazine-6-carboxylic acid
(3J?,65)-{6-[(15)-l-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyI]-tetrahydro-pyran-3-yI}- amide:
This compound (0.060 g, 36% yield) was obtained as a. white solid, starting from intermediate 19O.iii (0.1 g, 0.33 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-Z>][l,4]thiazine- 6-carboxylic acid (0.076 g, 0.36 mmol) and using the procedure of Example 172. MS (ESI, m/z): 495.0 [M+Η+].
Example 194: 6<{(3R,6S)-6-[(lΛ)-l-hydroxy-2-(6-methoxy-quinolin-4-yI)-ethyl]- tetrahydro-pyran-3-yIamino}-methyl)-4H-pyrido[l,4]thiazin-3-one:
Starting from intermediate 190. iii (0.1 g, 0.33 mmol) and 3-oxo-3,4-dihydro- 2H-pyrido[3,2-Z>][l ,4]oxazine-6-carbaldehyde (0.070 g, 0.36 mmol), and using the procedure described in Example 88, step 88. iv, a mixture of compounds was obtained. The two diastereomers were separated by chromatography over silica gel (DCM-MeOH 9-1 1% aq. NΗ4OΗ). The first eluting diastereomer (0.017g, 11% yield) was obtained as a yellowish foam. The second eluting diastereomer (0.007g, 4% yield) was prepared as a yellowish foam.
First diastereomer i
Analytical data (1H-NMR, MS) are identical to the ones recorded for the compound of
Example 191.
Second diastereomer. 1H NMR (DMSO) δ: 11.19 (s, IH); 8.62 (d, J= 4.4 Hz, IH); 7.92 (d, J= 9.0 Hz, IH); 7.42-7.35 (m, 2H); 7.32 (m, 2H); 7.03 (d, J = 8.1 Hz, IH); 4.88 (d, J= 6.3 Hz, IH); 4.62 (s, 2H); 4.03 (m, IH); 3.91 (s, 3H); 3.72 (dd, AB system, J= 14.8 Hz, Δ = 0.057, 2H); 3.59 (m, IH); 3.51 (dd, J= 1.8, 12.0 Hz, IH); 3.14 (m, IH); 2.97 (t, J = 10.5 Hz3 IH); 2.84 (m, IH); 2.51 (overlapped rn, IH); 1.95 (m, 2H); 1.69 (m, IH); 1.08-0.9T (m, 2H). MS (ESI, m/z): 465.5 [M+H+] . Example 195: 6-({(3R,6S)-6-[(lRS)~ l-hydroxy-2-(6-methoxy-[l,5]naplithyridin-4-yl)- ethyI]-tetrahydro-pyran-3-yIamino}-methyl)-4H-pyrido[3,2-έ][l,4]thiazin-3-one:
195. i. (3R,6S)-[6-(6-methoxy-[l,5]nap>hthyridin-4-ylethynyl)-tetranydro-pyran-3-yl]- carbamic acid benzyl ester: A solution of intermediate 158. iii (0.307 g, 0.8 mmol) in TFA (5 ml) was stirred at rt for 10 min. After evaporation to dryness, the residue was partitioned between aq. NaOH (20 ml) and a DCM-MeOH mixture (9-1, 50 rnl). The aq. layer was extracted with the same mixture (2 x 50 ml). The combined extracts were washed with brine, dried over NTa2SO4, filtered and concentrated to dryness. The residue (0.24 g) was taken up in EA (4 ml) and water (4 ml). NaHCO3 (0.2 g) and ben2yl chloroformate (0.14 ml, 0.9 mmol) were added. The reaction proceeded for 30 min. The two layers Λvere decanted and the aq. layer was extracted once with EA. The combined organic layers were concentrated to dryness and the residue was chromatographed over silica gel (Hex-EA 1-2) to afford the title alkyne as a white solid (0.24 g). 1H NMR (CDCl3) δ: 8.73 (d, J = 4.6 Hz, IH); 8.23 (d, J = 9.0 Hz, IH); 7.64 (d, J = 4.6 Hz, IH); 7.42-7.31 (m, 5H); 7.18 (d, J = 9.0 Hz, IH); 5.22 (d, J = 8.2 Hz, IH); 5.13 (s, 2H); 4.86 (t, J = 4.1 Hz, IH); 4.43 (dd, J = 2.5, 11.7 Hz, IH); 4.13 (s, 3H); 3.83 (m, IH); 3.55 (dd, J = 4.5, 12.1 Hz, IH); 2.35-2.16 (m, 2H); 1.94-1.78 (m, 2H).
195. ii. (3R,6S)-{6-[2-(6-methoxy-[l,5]naphthyndin-4-yl)-acetyl]-tetrahyciro-pyran-3-yl}- carbamic acid benzyl ester:
To a solution of intermediate 195.i (0.24 g, 0.57 mmol) in MeOH (2 ml) and THF (2 ml) was added a solution of mercury oxide, (5.1 ml, prepared from 0.075 g of mercury oxide in 12 ml of a 4% wt-wt H2SO4 solution in water). The reaction mixture was heated at 55°C for 4 h, then cooled to rt. NaHCO3 was added until pH 8 was reached. The aq. layer was extracted with EA (2 x 100 ml). The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed over silica gel (DCM- MeOH 19-1) to afford the title ketone (0.17 g, 67% yield) as a semi-solid. MS (ESI, m/z): 436.4 [M+H1"]. 195.iii. (3R, 6S)-{6-[(l RS)-I -hydroxy-2-(6-methoxy-[l, 5]naphthyridin-4-yl)-ethyl]- tetrahydro-pyran-3-yl}-carbamic acid benzyl ester.
To a solution of intermediate 195. ii (0.17 g, 0.39 mmol) in THF (2 ml) and MeOH (2 ml) was added, at rt, NaBH4 (0.077 g). The reaction was stirred 30 min a,nd water (5 ml) was added. The volatiles were removed under reduced pressure and the residxie was extracted twice with EA (2 x 25 ml). The combined extracts were concentrated to dryness and the residue was chromatographed over silica gel (DCM-MeOH 19-1) to afford the title alcohol (0.045 g, 27% yield) as a pale yellow solid. MS (ESI5 m/z): 438.4 [M+H+].
195.iv. (lRS)-l-((2S,5R)-5-amino-tetrahydro-pyran-2-yl)-2-(6-methoxy[l,5]naphthyridin- 4-yl)-ethanol:
A solution of intermediate 195. iii (0.045 g, 0.10 mmol) in TFA (3 ml) was let at rt for 3 days. The volatiles were removed under reduced pressure and the residue was taken up in THF (2 ml) and 2M NaOH (2 ml). The mixture was stirred at rt 30 min and the volatiles were removed under reduced pressure. The residue was chromatographed over silica gel (DCM-MeOH 6-1 with 1% aq. NH4OH) to afford the title amine (0.029 g, 92% yield) as a colourless oil. MS (ESI3 m/z): 304.4 [M+H+].
195.V. 6-({(3R,6S)-6-[(lRS)-l-hydroxy-2-(6-methoxy-[l,5]napht?ιyridin-4-yl)-ethyl]- tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-b][l,4]thiazin-3-one:
Starting from intermediate 195.iv (0.029 g, 0.096 minol) and 3-oxo-3,4-dihydro- 2H-pyrido[3,2-ό][l,4]thiazine-6-carbaldehyde (0.02O g5 0.106 rnmol), the title compound (0.030 g, 59% yield) was obtained as a off-white solid according "to the procedure described in Example 88, step 88. iv. The compound was obtained as an equim-olar mixture of epimers. 1B. NMR (DMSO) δ: 10.87 (s, 1Η); 8.66 (d5 J = 4.5 Hz, IH); 8.24 (d, J = 9.0 Hz, IH); 7.73 (d5 J = 7.4 Hz, IH); 7.53 (two overlapped d, J = 4.5 Hz5 2 x 0.5H); 7.23 (d5 J = 9.0 Hz, IH); 7.09 (d, J = 7.4 Hz5 IH); 4.70 (d, J = 6.4 Hz, 0.5H); 4.57 (d, J = 6.4 Hz, 0.5H), 4.00 (s, 3H); 3.99 (overlapped m, IH); 3.88 (m, IH); 3.74 (br s, 2H); 3.59 <dd, J= 3.1, 13.2 Hz, 0.5H); 3.53 (s, 2H); 3.44 (dd, J = 3.5, 10.8 Hz, 0.5H); 3.13 (m, IH); 3.02-2.83 (m, 2H); 2.50 (overlapped m, IH); 2.14-2.02 (m, 2H); 1.86 (m, 0.5H); 1.65 (m5 0.5H); 1.57-1.13 (m, 3H). MS (ESI, m/z): 482.4 [M+H+].
Example 196: 3-oxo-3,4-dihydro-2H-pyrido[3,2-A][l,4]thiazine-6-carboxylic acid (3Λ,65)-{6-[(-?5)-l-hydroxy-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydr-o- pyran-3-yl}-amide :
196.i. {(3R, 6S)-6-[(4R, 5R)-5-(6-methoxy-[l, 5]naphthyridin-4-yl)-2-oxo-[l, 3]dioxolan-4-yl]- tetrahydro-pyran-3-yl}-carbamic acid tert-butyl ester:
The title cyclic carbonate (0.75 g, 64%) was obtained as a foam, starting from intermediate 173. iii (1.1 g, 2.62 mmol) and using the procedure of Example 191, step 191. i. 1H NMR (CDCl3) δ: 8.84 (d, J = 4.5 Hz, IH); 8.39 (d, J = 9.1 Hz, IH); 7.60 (d, J = 4.5 Hz, IH); 7.21 (d, J = 9.0 Hz, IH); 6.22 (br d, J = 4.1 Hz, IH); 4.70 (dd, J = 1.8, 4.2Hz, IH); 4.30 (ddd, J = 2.0, 4.6, 10.5 Hz, IH); 4.30 (overlapped br s, IH); 4.08 (s, 3H); 3.80 (td, J = 2.4, 11.5 Hz, IH); 3.69 (br s, IH); 3.13 (q, J = 8.2, 10.4 Hz, IH); 2.22 (m, IH); L .89 (qd, J = 3.8, 12.9 Hz, IH); 1.71 (m, IH); 1.47 (s, 9H); 1.32 (partially overlapped m, IH). MS (ESI, m/z): 445.7 [M+H+].
196.ii. (3R,6S)-{6-[(lS)-l-hydroxy-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetraΑydro- pyran-3-yl}-carbamic acid tert-butyl ester:
The title alcohol (0.22 g, 32%) was obtained as a white solid starting from intermediate 196.i
(0.75 g, 1.68 mmol) and using the procedure of Example 191, step 191. ii.
1H NMR (CDCl3) δ: 8.70 (d, J= 4.5Hz, IH); 8.25 (d, J = 9.1 Hz, IH); 7.49 (d, J= 4.5 Hz, IH); 7.14 (d, J = 9.0 Hz, IH); 4.26 (br s, IH); 4.18 (ddd, J = 2.0, 4.7, 10.5 Hz, IH)- 4.08 (s,
3H); 4.02 (m, IH); 3.73 (br s, IH); 3.68 (overlapped br s, IH); 3.41 (dd, J = 3.5, 13.2 Ηz, IH);
IH); 3.31 (dd, J = 8.5, 13.2 Hz, IH); 3.24 (ddd, J = 2.3, 5.0, 11.2 Hz, IH); 3.03 (t,
J = 10.6 Hz, IH); 2.17 (m, IH); 1.86 (m, IH); 1.77-1.63 (m, IH); 1.46 (s, 9H); 1.31 (qd,
J = 4.3, 12.4 Hz, IH). MS (ESI, m/z): 4-03.9 [M+].
196. iii. (1S)-1-((2S, 5R)-5-amino-tetrahydro-pyran-2-yl)-2-(6-methoxy-[l, 5]naphthyridin- 4-yl)-ethanol:
The title amine (0.158 g, 95%) was obtained as a colourless foam, startixig from intermediate 196. ii (0.22 g, 0.55 mmol) and using the procedure of Example 173, step 173. iv. MS (ESI, m/z): 304.1 [M+H*]. 196. iv. 3-oxo-3,4-dihydro-2H-pyrido[3,2-bJfl,4]thiazine-6-carboxylic acid (3R,6S)-{6-[(lS)-l-hydroxy-2-(6-methoxy-[l ,5]naphthyridin-4-yl)-ethyl]-tetrahydr4D-pyran- 3-ylJ-amide:
This compound (0.016 g, 24%) was obtained as a white solid, starting from intermediate 196. iii (0.04 g, 0.13 mmol) and 3-oxo-3 ,4-dihydro-
2H-pyrido[3,2-Z>][l,4]thiazine-6-carboxylic acid (0.033 g, 0.16 mmol) and using the procedure of Example 172. MS (ESI, m/z): 496.2 [M+Η+].
Example 197: (3Λ,65)-6-({6-[(l-S)-l-hydroxy-2-(6-methoxy-[l,5]naphthyridiα-4-yI)- ethyl]-tetrahydro-pyran-3-ylamino}-metliyl)-4H-pyrido[3,2-6][l,4]thiazin-3-0Bie:
Starting from intermediate 196.iii (0.O55 g, 0.182 mmol) and 3-oxo-3,4-dihydro- 2H-pyrido[3,2-6][l,4]thiazine-6-carbaldehyde (0.039 g, 0.2 mmol), the title compound (0.033 g, 37%) was obtained as an off-white solid using the procedure of Example 88, step 88. iv. 1H NMR (DMSO) δ: 10.93 (s, 1Η); 8.67 (d, J = 4.4 Hz, IH); 8.25 (d, J = 9.0 Hz, 1 H); 7.97 (d, J = 7.8 Hz, IH); 7.93 (d, J = 8.5 Hz, IH); 7.60 (d, J = 7.8 Hz, IH); 7.55 (d, J = 4.4 Hz, IH); 7.25 (d, J = 9.0 Hz, IH); 4.69 (d, J= 6.4 Hz, IH); 4.10 (s, 3H); 4-10-3.S4 (partially overlapped m, 3H); 3.64 (s, 2H); 3.50 (dd, J = 3.7, 12.6 Hz, IH); 3.21 (m, IDH); 3.13 (t, J = 10.4 Hz, IH); 3.03 (dd, J = 8.9, 12.8 Hz, IH); 2.03 (m, IH); 1.79-1.50 (m, 3H) _ MS (ESI, m/z): 482.2 [M+H+].
Example 198: 6-((3R, 65)-{6-[(l1S)-l-hydroxy-2-(6-methoxy-[l,5]naphthyridiM-4-yl)- ethyl]-tetrahydro-pyran-3-ylamino}-methLyl)-4H-pyrido[3,2-6][l,4]oxazin-3-omie:
Starting from intermediate 196.iii (0.055 g, 0.18 mmol) and 3-oxo-3,4-dihydro- 2H-pyrido[3,2-έ][l,4]oxazine-6-carbaldehyde (0.036 g, 1.1 eq), the title compouxid (0.017 g, 20% yield) was prepared as pale yellow solid according to the procedure of Example 88, step 88.iv. MS (ESI, m/z): 466.3 [M+Η+]. Example 199: (3»S',6i?)-(6-({6-[(15r,2lS)-l,2-dihydroxy-2-(6-inethoxy- [l,5]naphthyridin- 4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-b] [l,4]thiazin-3-one:
199. i. (3S,6R)-[6-(l-phenyl-lH-tetrazole-5-sulfonylmethyl)-tetrahydro-pyran-3-yl]-carbamic acid tert-butyl ester: This compound (5.9 g) was obtained as a colourless solid, starting from intermediate 154.iii (8.2 g, 35.5 mmol) and using the procedure of Example 171, steps 171.i to 171.iv. MS (ESI, rn/z): 424.4 [M+Η+].
199. ii. ( 3S, 6R)-{6-[2-(6-methoxy-[l, 5]naphthyridin-4-yl)-vinyl]-tetrafoydro-pyran-3-yl}- carbamic acid tert-butyl ester: Julia coupling was carried out as described for Example 171, step 171.V, starting from intermediate 199. i (4.95 g, 11.7 mmol) and 6-methoxy-[l,5]naphtrryridine-4-carbaldehyde (1.9 g, 10.9 mmol) to give 3.4 g (75.4%) of product as a colourless solid. 1H NMR (d6-DMSO) δ: 8.70 (d, IH, J=4.65 Hz), 8.23 (d, IH, J=9.06 Hz), 7.82 (d, IH, J= 4.65 Hz), 7.54 (d, IH, J= 16.3 Hz), 7.26 (d, IH, J= 9.06 Hz), 6.91 (dd, IH, J= 16.3, 5.34 Hz), 6.88 (br, IH, NH), 4.03 (s, 3H), 4.05-3.95 (m, IH), 3.90-3.80 (m, IH), 3.45-3.35 (in, IH), 3.08 (t, IH, J=10.6 Hz), 2.00-1.80 (m, 2H), 1.60-1.40 (m, 2H), 1.36 (s, 9H).
199.iii. (3S,6R)-{6-[(lS,2S)-l,2-dihydroxy-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]- tetrahydro-pyran-3-yl}-carbamic acid tert-butyl ester: Intermediate 199.U (1.6 g, 4.15 mmol) was treated with AD mix α according to the procedure of Example 171, step 171.vi to give 1.53 g (88%) of title diol as a coloxirless solid. MS (ESI, rn/z): 464.1 [MH-H+].
199. iv. (lS,2S)-l-((2R,5S)-5-amino-tetrahydro-pyran-2~yl)-2-(6-methoxy-[l,5]naphthyridin- 4-yl)-ethane-l, 2-diol: A solution of intermediate 199.iii (500 mg, 1.2 mmol) in DCM (10 ml) was treated with TFA (4 ml). The mixture was stirred at rt for 3 h, concentrated in vacuo, partitioned between DCM and NH4OH. The organic layer was dried over MgSCU and concentrated to give the title amine (243 mg, 64%) as a colourless foam. MS (ESI, m/z): 320.2 [M+H+]. 199.V. (3S,6R)-(6-({6-[(lS,2S)-l,2-dihydroxy-2-(6-methoxy-[l,5]naphthyridin-4yl)-ethyl]- tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-h][l,4]thiazin-3-one\
A mixture of intermediate 199.iv (120 mg, 0.37 mmol) and 3-oxo-3,4-dihydro- 2H-pyrido[3,2-£][l,4]thiazine-6-carbaldehyde (73 mg, 1 eq) in 1,2-DCE/MeOΗ 1:1 (5 ml) was stirred at rt overnight. NaBH4 (excess) was added and stirring was continued for 1 h. The mixture was partitioned between DCM and NH4OH and the organic layer was dried over MgSO4 and concentrated in vacuo. The product was isolated in 32% yield (60 mg) as a beige foam. MS (ESI, m/z): 498.1 [M+H+].
Example 200: 6-((3/?,65)-{6-[(l.S)-l-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]- tetrahydro-pyran-3-yIamino}-methyl)-4H-pyrido[3,2-6][l,4]oxazin-3-one:
200. i. (3R,6S)-{(4R,5R)-6-[5-(3-methoxy-quinolin-5-yl)-2-oxo-[l,3]dioxolan-4-yl]- tetrahydro-pyran-3-yl}-carbamic acid tert-butyl ester:
The title carbonate (0.96 g, 30%) was prepared from intermediate 171.vi (3.0 g, 7.16 mmol) according to the procedure of Example 191, step 191.i. MS (ESI, m/z): 445.0 [M+Η+].
200. ii. (3R,6SJ-{6-[(lS)-l-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro-pyran- 3-yl}-carbamic acid tert-butyl ester:
The title alcohol (0.52 g, 60% yield) was prepared from intermediate 200. i (0.96 g, 2.16 mmol) ac cording to the procedure of Example 191, step 191. ii . MS (ESI, m/z): 403.1 [M+H+].
200. Hi. ( IS)-J -((2S, 5R)-5-amino-tetrahydro-pyran-2-yl)-2-(3-methoxy-quinolin-5-yl)- ethanol:
The title amine (0.39 g, 99% yield) was obtained from intermediate 200.ii (0.52 g, 1.29 mmol) according to the procedure of Example 173, step 173.iv.
1H NMR (DMSO) δ: 8.64 (d, J = 2.8 Hz, IH); 7.83-7.79 (in., 2H); 7.49 (dd, J = 7.0, 8.1 Hz, IH); 7.42 (dd, J = 1.3, 7.0 Hz, IH); 4.70 (d, J = 6.2 Hz, IH); 3.94 (s, 3H); 3.88 (ddd, J = 2.0, 4.5, 10.5 Hz, IH); 3.64 (m, IH); 3.31 (overlapped m, IH); 3.03 (m, IH); 2.95 (dd, J = 8.0, 13.8 Hz, IH); 2.84 (t, J = 10.4 Hz, IH); 2.60 (m, IH); 1.90 (m, IH); 1.60-1.46 (m, 2H); 1.42 (br s, 2H); 1.1 1 (m, IH). MS (ESI, m/z): 303.1 [M+H+].
200. iv. 6-((3R,6S)-{6-[(lS)-l-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro-pyrmι- 3-ylamino}-methyl) -4H-pyrido[3, 2-b][l, 4]oxazin-3-one :
Starting from intermediate 200. iii (0.042 g, 0.14 mmol) and 3-oxo-3,4-dihydro- 2H-pyrido[3,2-i][l ,4]oxazine-6-carbaldehyde (0.027 g, 1.1 eq), the title compound (0.015 g, 23% yield) was obtained as pale yellow solid using the procedure of Example 88, step 88. iv. MS (ESI, m/z): 465.1 [M+Η+].
Example 201: 6-ζ(3R, 65)-{6-[(l1S)-l-hydroxy-2-(3-methoxy-quimolin-5-yl)-ethyl]- tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-ό][l,4]thiazin-3-one:
Starting from intermediate 200. iii (0.100 g, 0.33 mmol) and 3-oxo-3,4-dihydro- 2H-pyrido[3,2-δ][l,4]oxazine-6-carbaldehyde (0.07O g, 1.1 eq), the title compound (0.081 g, 50% yield) was obtained as a pale yellow solid using the procedure of Example 88, step 88. iv. The purity of the compound was 90%.
1H NMR (DMSO) δ: 10.87 (s, 1Η); 8.64 (d, J = 2.8 Hz, IH); 7.83-7.75 (m, 2H); 7.74 (d, J = 7.8Hz, IH); 7.49 (dd, J = 7.0, 8.2 Hz, IH); 7.41 (dd, J = 1 .3, 7.0 Hz, IH); 7.09 (d, J = 7.9 Hz, IH); 4.70 (d, J = 6.3 Hz5 IH); 4.04 (m, IH); 3.93 (s, 3H); 3.75 (d, AB system, J = 14.9 Hz, Δ= 0.058, 2H); 3.65 (m, IH); 3.53 (s, 2H); 3.30 (overlapped m, IH); 3.09 (m, IH); 2.99-2.90 (m, 2H); 2.13 (br s, IH); 2.04 (m, IH); 1.63-1.47 (m, 2H); 1.23 (br s, IH); 1.19 (m, IH). MS (ESI, m/z) : 481.0 [M+H"1"].
Example 202: (ZiS)-l-((2.S',5iϊ)-5-heptylamino-tetrahydro-pyraα-2-yl)-2-(6-methoxy- quinolin-4-yl)-etl»anol:
Starting from intermediate 19O.iii (0.113 g, 0.375 mmol) and 7?-heptaldehyde (0.057 ml, 0.412 mmol), the title compound (0.065 g, 43% yield) was obtained as a yellow gum using the procedure of Example 88, step 88. iv.
1H NMR (CDCl3) δ: 8.66 (d, J = 4.4 Hz, IH); 8.00 (d, J = 9.1 Hz, IH); 7.36 (dd, J = 2.7, 9.1 Hz, IH); 7.28 (m, 2H); 4.15 (ddd, J = 2.2, 4.7, 11.0 Hz, IH); 3.94 (s, 3H); 3.88 (m, IH); 3.31 (dd, J = 5.6, 13.9 Hz, IH); 3.17 (m, 2H); 3.06 (t, J = 10.6 Hz, IH); 2.64 (m, 3H); 2.09 (m, IH); 1 .66 (m, 2H); 1.45 (m, 2H); 1.23 (m, 10H); 0.88 (t9 J = 6.9 Hz, 3H). MS (ESI, mix): 401.2 [M+H+].
Example 203: 6-((3i?,65)-{6-[(2/?)-2-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]- tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-6][l,4]tliiazin-3-oιie and
6-((3i?,61S}-{6-[(21S)-2-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro-pyran- 3-ylamino}-methyl)-4iϊ-pyrido[3,2-£][l,4]thiazin-3-one:
203.i. (3R, 6S)—(6-vinyl-tetrahydro-pyran-3-yl)-carbatnic acid tert-butyl ester:
To a mixture of methyltriphenylphosphonium bromide (11 .65 g, 32.71 mmol) in TΗF (100 ml) cooled to -78°C, was added M-BuLi (2.35Nin Hex, 13.6 ml). The mixture was stirred
15 min at this temperature and then 45 min at 00C. After cooling to -78°C, a solution of intermediate 1 58.i (3 g, 13.08 mmol) in THF-HMPA (2-1, 30 ml) was added. The mixture was stirred 30 min at this temperature and allowed to warm up to rt over 30 min. The mixture was quenched by adding water (50 ml) and ether (100 ml). The two layers were decanted and the aq. layer was extracted twice with ether (2 x 150 ml). The combined organic layers were washed with brine and concentrated to dryness. The residue wa.s chromatographed over silica gel (Hex-EA 4-1) to afford the title alkene (1.47 g) as a white solid.
1H ΝMR (CDCl3) δ: 5.86 (dddd, J = 5.5, 10.7, 17.3 Hz, IH); 5.26 (td, J = 1.5, 17.3 Hz, IH);
513 (td, J= 1.5, 10.7 Hz, IH); 4.32 (br s, IH); 4.13 (ddd, J = 2.1, 4.6, 10.7 Hz, IH), 3.76 (m, IH); 3.63 (br s, IH); 3.08 (t, J= 10.5 Hz, IH); 2.12 (m, IH); 1.80 (qd, J = 3.8, 13.6 Hz, IH);
1.55 (partially overlapped m, IH); 1.46 (s, 9H); 1.33 (m, IH).
203.ii. (3 R, 6S)-[6-(2-hydroxy-ethyl)-tetrahydro-pyran-3-yl]-caτ-bamic acid tert-butyl ester:
To an ice-chilled solution of intermediate 2O3.i (1.47 g, 6.46 mmol) in THF (30 ml) was added 9-borabicyclononane (2.37 g, 19.4 mmol). The mixture was then let overnight at rt. After cooling to 00C, 3N aq. NaOH (25 ml) and 50% aq. hydrogen peroxide (12 ml) were cautiously added. The resulting mixture was stirred at rt for 2 h. The two layers were decanted and the aq. layer was extracted with EA (2 x 200 ml). The combined organic layers were washed with 10% aq. sodium bisulfite (100 ml), water (50 ml) and dried over Na2SO4. After filtration and concentration to dryness, the residue was chromatographed over silica gel (Hex-EA 1 - 1 then 1 -3) to afford the title alcohol (1.15 g, 4.68 mmol) as a white solid. 1H NMR (CDCl3) δ: 4.16 (br s, IH); 4.01 (ddd, J = 2.2, 4.7, 10.7 Hz, IHQ; 3.69 (t, J = 5.2 Hz, 2H); 3.52 (br s, IH); 3.39 (m, IH); 2.93 (t, J = 10.7 Hz, IH); 2.02 (br s, IH); 2.00 (m, IH); 1.72-1.58 (m, 3H); 1.45 (m, IH); 1.37 (s, 9H); 1.24 (qd, J = 4.1, 12.2 Hz, IH). MS (ESI, m/z): 246.4 [M+H+].
203.iii. (3R, 6S)-[6-(2-oxo-ethyl)-tetrahydro-pyran-3-yl]-carbamic acid tert-butyl ester:
To a ice-chilled solution of intermediate 203. ii (1.15 g, 4.68 mmol) in DCM (20 ml) was added a solution of Dess-Martin periodinane (15wt% in DCM, 18 ml). The mixture was stirred at O0C for 15 min before warming to rt. The reaction proceeded for 2 h. The reaction mixture was concentrated to dryness and the residue chromatographed (Hex-EA 1-1) to afford the title aldehyde (1.06 g, 4.35 mmol) as a white solid.
1HNMR (CDCl3) δ: 9.79 (t, J = 2.3 Hz, IH); 4.29 (br s, IH); 4.07 (ddd, J = 2.1, 4.7, 10.7 Hz, IH); 3.77 (m., IH); 3.61 (br s, IH); 3.04 (t, J = 10.7 Hz, IH); 2.65 (ddd, J = 2.3, 7.6, 16.5 Hz, IH); 2.49 (ddd, J = 2.3, 4.8, 16.5 Hz, IH); 2.12 (m, IH); 1.79 (m, IH); 1.50 (overlapped m, IH); 1.49 (s, 9H); 1.33 (qd, J = 4.1, 12.2 Hz, IH).
203.iv. {(3R, 6S)-6-[(2RS)-2-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl/-tetrahydro-pyran- 3-ylj-carbamic acid tert-butyl ester:
To a solution of 5-bromo-3-methoxy-quinoline (3.08 g, 12.94 mmol; prepared as in DE 10316081) in THF (75 ml), cooled to -78°C, was added quickly rc-BuLi (2.35N in Hex, 5.4 ml). The mixture was stirred at the same temperature for 15 minutes and a solution of (3J?,6iS)-[6-(2-oxo-ethyl)-tetrariydro-pyran-3-yl]-carbamic acid tert-butyl ester (1.05 g, 4.35 mmol) in THF (10 ml) was added. The mixture was stirred at the same temperature for 5 min. 10% aq. NaHSO4 (20 ml) and EA (10 ml) were added. The two layers were decanted and the aq. layer was extracted with EA (2 x 100 ml). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was chromatographed over silica gel (Hex-EA 2-1 then 1-1 then 1-4) to yield the title compound (0.45 g, 1.11 mmol) as a yellowish foam. The compound was obtained as a 3.5:1 mixture of epimers. MS (ESI, m/z): 403.2 [M+H+] . 203.v. (2RS)-I -((2S, 5R)-5-amino-tetrahydro-pyran-2-yl)-2-(3-methoxy-quinolin-5-yZ)- ethanol:
This compound was prepared starting from intermediate 203. iv (0.45 g, 1.11 mmol) and using the procedure of Example 171, step 171.vii. A 3.5:1 mixture of epimers was obtained as a white foam (0.204 g, 0.67 mmol).
1H NMR (CDCl3) δ: 8.70 (app d, J = 2.8 Hz, IH); 7.99 (app d, J = 8.3 Hz, IH) ; 7.82 (d, J = 2.8 Hz, 0.77H); 7.74-7.67 (m, 1.23H); 7.60-7.53 (2 overlapped dd, J = 7.5, 8.0 YJz, 0.23H, J = 7.3, 8.3 Hz, 0.77 H); 5.69 (m, 0.23H); 5.57 (dd, J = 3.3, 9.2 Hz, 0.77H); 4.0S-4.02 (m, IH); 3.99 (s, 2.31H); 3.97 (s, 0.69H); 3.57 (m, IH); 3.09 (app t, J = 10.5 Hz, IH); 2.87 (m, IH); 2.19-1.99 (m, 2.77H), 1.95 (t, J = 3.0 Hz, 0.23H); 1.75-1.38 (m, 5H); 1.25 (app qd, J = 4.0, 12.8 Hz, IH). MS (ESI, m/z): 303.0 [M+H+]
203.vi. 6-((3R, 6S)-{6-[(2R)-2-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydr-o-pyran- 3-ylamino}-methyl)-4H-pyrido[3,2-b][l,4]thiazin-3-one and 6 ((3R,6S)-{6-[(2S)-2-hydroxy- 2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro-pyr-an-3 ylaminoj -methyl) - 4H-pyrido[3, 2-b][l, 4]thiazin-3-one :
To a solution of intermediate 203.V (0.1 g, 0.33 rnmol) in 1,2-DCE (6 ml) and MeOH (2 ml) were added 3 A molecular sieves (2 g) and 3~oxo-3,4-dihydro-2H-pyrido[3,2-δ][l,<4]thiazine- 6-carbaldehyde (0.07 g, 0.364 mmol). The mixture was heated at 500C overnight. After cooling to rt, NaBlfy (0.1 g) was added and the reaction proceeded 2 h. The reaction mixture was filtered through a plug of Ηydromatrix® ζpretreated with NaHCO3). The filtrate was concentrated to dryness and the residue was chromatographed over silica gel (DCM-MeOH 93-7 with 0.5% aq. NH4OH) to afford a first diastereomer (0.062 g, 0.13 mmol) as a yellowish foam. The second eluting diastereomer (0.020 g, 0.041 mmol) was then obtained as a yellowish foam.
First diastereomer:
1H NMR (d6-DMSO) δ: 10.85 (s, IH); 8.65 Cd5 J = 2.8 Hz, IH); 7.86 (m, 2HT); 7.72 (d, J = 7.9Hz, IH); 7.65 (d, J = 7.3 Hz, IH); 7.56 (dd, J = 7.3, 8.2 Hz, IH); 7.07 (d, J = 7.9 Hz, IH); 5.38 (m, 2H); 3.93 (s, 3H); 3.92 (overlapped m, IH); 3.71 (dd, AB system, J = 15.0 Hz, Δ= 0.061, 2H); 3.52 (s, 2H); 3.01 (m, IH); 2.77 Qt, J = 10.5 Hz, IH); 2.50 (overlapped m, IH); 2.09-1.68 (m, 2H); 1.81-1.69 (m, 2H); 1.36-1.22 (m, 2H); 1.17-1.01 (m, IH). MS (ESI, m/z): 481.2 [M+H+].
Second diastereomer:
1H NMR (d6-DMSO) δ: 10.86 (s, IH); 8.65 (d, J = 2.7 Hz, IH); 7.86 (d, J = 2.7 Hz, IH); 7.82 (d, J = 7.9 Hz, IH); 7.74 (d, J = 7.7 Hz, IH); 7.65 (d, J = 7.2 Hz, IH); 7.54 (dd, J = 7.2, 7.7 Hz, IH); 7.09 (d, J = 7.9 Hz, IH); 5.46-5.38 (m, 2H); 4.02 Cm, IH); 3.90 (s, 3H); 3.75 (dd, AB system, J = 14.9 Hz, Δ = 0.062, 2H); 3.58 (m, IH); 3 .53 (s, 2H); 3.07 (t, J = 10.7 Hz, IH); 2.29 (br s, IH); 1.98 (m, IH); 1.78-1.47 (m, 3H); 1.40- 1.09 (m, 3H). MS (ESI, m/z): 481.4 [M+H+].
Example 204 : 3-oxo-3,4-dihydro-2H-pyrido[3,2-ό] [l,4]thiazine-6-carboxylic acid (3i?,6-5)-{6-[(2R,S)-2-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro-pyran-3-yl}- amide:
This compound was prepared from intermediate 203.V (0.1 g) and 3-oxo-3,4-dihydro- 2H-pyrido[3,2-b][l,4]thiazine-6-carboxylic acid (0.083 g), using the procedure of Example 159. The title compound (0.08 g, 49% yield) was obtained as a white solid in a 3.5:1 mixture of di astereomers .
MS (ESI, m/z): 493.2 [M+Η+].
Example 205: rαc-frøns-(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)- [6-(6-methoxy- quinolin-4-yloxymethyl)-piperidin-3-yI]-amine:
205. i. rac-trans-piperidine-l,2,5-tricarboxylic acid 1-bemyl ester 5-methyl ester: Cbz-Cl (3.75 g, 22 mmol) was added dropwise to a vigorously stirred mixture of rac-trαrø-piperidine-2,5-dicarboxylic acid 5-methyl ester (3.74 g, 20 mmol, prepared according to J. Heterocycl. Chem. (1995), 32, 857), NaHCO3 (6.7 g>, acetone (80 ml) and water (80 ml). The mixture was stirred until gas evolvement stopped. The mixture was acidified with IN aq. HCl (160 ml) and extracted with EA (2 x 250 ml). The combined organic layers were washed with brine, dried over MgSCU, filtered and concentrated in vacuo to give the Cbz-protected compound (602 g, 96% yield) as a colourless oil, which was used in the next step without purification. MS (ESI, m/z): 322.3 [M+H+]. 205. ii. rac-trans-o-hydroxymethyl-piperidine-l^-dicarboxylic acid 1-benzyl ester 3-methyl ester.
A solution of borane in THF (IM, 60 ml, 3 eq) was added dropwise to a solution of intermediate 205. i (6.4 g, 20 mmol) in THF at O0C. The mixture was stirred at O0C for 1 h and at rt for 3 h. Excess of reagent was destroyed by careful addition of MeOH and the volatiles were removed under reduced pressure. MeOH was added and again removed under reduced pressure. The residue was purified by chromatography on silica gel (EA) to give the desired alcohol as a colourless oil (3.16 g, 51% yield).
1H NMR (CDCl3) δ: 7.40-7.20 (m, 5H), 5.20 (d, IH, J =12 A Hz), 5.10 (d, IH, J=12.4 Hz), 4.40-4.10 (m, 2H), 3.85-3.60 (m, 2H), 3.62 (s, 3H), 3.40-3.25 (m, IH), 2.65-2.55 (m, IH), 2.46 (br, IH), 2.05-1.50 (m, 4H).
205. iii. rαc-trαns-6-(6-methoxy-quinolin-4-yloxyrnethyl)-piperidine-l,3-dicαrboxylic acid I -benzyl ester 3-methyl ester:
To a suspension of 6-methoxy-quinolin-4-ol (1.75 g, 10 mmol) and intermediate 205.U (3-07 gs io mmol) in THF (50 ml) at 00C was added triphenylphosphine (3.15 g, 12 mmol), and dropwise DIAD (2.43 g, 12 mmol). The mixture was gradually warmed to rt and stirred at this temperature for 2 d. Volatiles were removed under reduced pressure and the residue was chromatographed on silica gel (Hex:EA 2:1) to give 1.26 g (27% yield) of product, which was still contaminated with some triphenylphosphine but used as such in the next step.
205.iv. rac-trans-6-(6-methoxy-quinoHn-4-yloxyjjιethyl)-piperidine-l, 3-dicarboxylic acid J -benzyl ester.
Intermediate 2O5.iii (1.26 g, 2.72 mmol) was dissolved in THF-water-MeOH 3:1:1 (100 ml> and LiOH hydrate (0.23 g, 2 eq) was added. The mixture was stirred at rt overnight and at 500C for 2 h. The mixture was concentrated in vacuo, neutralised with IN aq. HCl and extracted with EA. The organic extracts were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with ether and filterecl to give the desired acid (0.736 g, 60% yield) as a. colourless solid. MS (ESI, m/z): 451.3 [M-H+]. 205.V. rac-trans-5-amino-2-(6-methoxy-quinolin-4-yloxymethyl)-piperidine-l-carboxylic acid benzyl ester.
A solution of intermediate 205. iv (0.736 g, 1.63 mmol) in ter/-butanol (10 ml) was treated with TEA (0.5Ol ml, 2.2 eq) and DPPA (0.494 g, 1.1 eq). The mixture was heated at reflux for 4 h, concentrated and filtered over silica gel (EA then EA/MeOH 9:1 as eluent). The filtrate was concentrated in vacuo, taken up in DCM (10 ml) and treated with TFA (2 ml). After 2 h, the volatiles were removed under reduced pressure. The residue was dissolved in DCM, washed xvith NH4OH and water. After drying over MgSO4, filtration and concentration in vacuo, the residue was purified by chromatography over silica gel (EA:MeOH 9:1 + 1% concentrated NH4OH then MeOH) to give the title amine (0.410 g, 60 % yield) as an oil. MS (ESI, m/z): 422.5 [M+H+].
205.vi. rac-trans-5-[(2, 3-dihydro-benzo[l, 4]dioxin-6-ylmethyl)-amino]-2-(6-methoxy- quinolin-4-yloxymethyl)-piperidine-l-carboxylic acid benzyl ester:
A mixture of intermediate 205.V (0.210 g, 0.5 mmol) and 2,3-dihydro-benzo[l,4]dioxine- 6-carbaldehyde (0.082 g, 0.5 mmol) in a 1,2-DCE-MeOH mixture (1:1, 4 ml) was stirred at rt overnight. NaBH4 (excess) was added and stirring was continued for 1 h. The mixture was partitioned between DCM and concentrated NH4OH. The organic layer was dried over
MgSO4, filtered and concentrated to dryness. The residue was purified by chromatography over silica gel (EA:MeOH 9:1 + 1% NH4OH) to give the product (0.125 g, 43% yield) as a colourless foam.
MS (ESI, m/z): 570.6 [M+H+].
205.vii. rac-trans-(2, 3-dihydro-benzo[l, 4]dioxin-6-ylmethyl)-[6-(6-methoxy-quinolin- 4-yloxymethyl) -piperidin-3-yl] -amine :
Intermediate 2O5.vi (0.121 g, 0.21 mmol) was dissolved in EtOH (5 ml). 10% palladium on charcoal (0.064 g) and cyclohexene (2 ml) were added and the mixture stirred at rt for 5 h.
The catalyst was filtered off and the filtrate concentrated. The residue was purified by chromatography on silica gel (EA:MeOH 9:1 +1% NH4OH) to give the title compound
(0.077 g, 83% yield) as a colourless foam.
1H NMR (d6-DMSO) δ: 8.55 (d, IH, J =5.1 Hz), 7.86 (d, IH, J =9.2 Hz), 7.45 (d, IH, J=2.8 Hz), 7.38 (dd, IH, J=9.2 Hz, J=2.8 Hz), 6.98 (d, IH, ./=5.1 Hz), 6.83 (s, IH), 6.76 (s, 2H), 4.24 (s, 4H), 4.20-4.0O (m, 3H), 3.90 (s, 3H), 3.20-3.05 (m, 3H), 3.00-2.90 (m, IH), 2.45-2.15 (m, 3H), 2.00-1.9O (m, IH), 1.90-1.80 (m, IH) MS (ESI, m/z): 436.2 [M+H+].
Example 206: røc-*rø«s-6-{[6-(6-methoxy-quinazolin-4-yloxymethyl)-piperidiii- 3-ylamino]-methyI}-4H-py rido[3,2-6] [l,4]thiazin-3-one:
206. i. rac-trans-piperidine- 1 ,2, 5 -tricarboxylic acid 1-tert-butyl ester 5-methyl ester:
A suspension of rαc-#"α?«-piperidine-2,5-dicarboxylic acid 5-methyl ester (9.36 g, 50 mmol, prepared according to J. Heterocycl. Chem. (1995), 32, 857) in TΗF (100 ml) Λvas treated with BOC2O (16.3 g, 1.5 eq) and IM aq. NaOH (50 ml). The mixture was stirred at rt overnight, acidified with lΛ/ aq. HCl and extracted with EA. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (Ηex/EA 1:1) to give 7.8 g (54% yield) of title compound as a colourless oil. MS (ESI, m/z): 286.4 [M-HTI .
206. ii. rac-trans-6-hydroxymethyl-piperidine-l, 3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester.
Intermediate 2O6.i (7.8 g, 27 mmol) was reduced with borane (IM in TΗF, 82 ml) using the procedure of Exemple 205, step 205. ii. After chromatography on SiO2 (Ηex/EA 1 :1), the title alcohol (5.4 g, 73 % yield) Λvas obtained as a colourless oil. 1H NMR (d6-DMSO) δ: 4.69 (t, 1Η, J=5.5 Hz), 4.25-4.15 (m, IH), 4.05-3.90 (m, IH), 3.60 (s, 3H), 3.55-3.35 (rn, 2H), 3.05-2.95 (m, IH), 2.65 (br, IH), 1.90-1.50 (m, 4H), 1.38 (s, 9H).
206. iii. rac-trans-6-(tert-bzιtyl-dimethyl-silanyloxymethyl)-piperidine-l, 3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester: TBDMSCl (3.3 g, 22 mmol) was added to a solution of intermediate 2O6.ii (5.4 g, 20 mmol) and imidazole (1.63 g, 24 mmol) in THF (50 ml). The mixture was stirred at rt overnight, poured into a NH4CI solution and extracted with ether. The combined organic extracts were washed with water and brine, dried over MgSO4 and concentrated to give 8.38 g of a colourless oil which was used without further purification. 1H NMR (d6-DMSO) δ: 4.25-4.15 (m, IH), 4.05-3.90 (m, IH), 3.50 (s, 3H), 3.55-3.35 (m, 2H), 3.05-2.95 (m, IH), 2.65 (br, IH), 1.90-1.50 (m, 4H), 1.38 (s, 9H), 1.80 (s, 9H), 0.50 (s, 6H).
206. iv. rac-trans-6-(tert-butyl-dirnethyl-$ilanyloxymethyl)-piperidine-l,3-dicarboxylic acid 1-tert-butyl ester.
A solution of intermediate 2O6.iii (7.7 g, 19.9 mmol) in MeOHTH2O 3:1 (150 ml) and THF (10 ml) was treated with LiOH1H2O (1.7 g, 2 eq). The mixture was stirred at rt for 4 h and then concentrated in vacuo. Ether and XM HCl (35 ml) were added and the two phases separated. The aqueous layer was extracted once more with ether and trie combined organic extracts were washed with brine, dried over MgSO4 and concentrated. Trie acid (5.47 g, 73 % yield) was isolated after chromatography over silica gel (Hex/EA 4:1, 2:1) as a colourless solid.
1H NMR (d6-DMSO) δ: 12.20 (br, 1OH), 4.25-4.15 (m, IH), 4.05-3.90 (m, IH), 3.70-3.45 Cm, 2H), 3.05-2.95 (m, IH), 2.65 (br, IH), 1.90-1.50 (m, 4H), 1.38 (s, 9H), 1.80 (s, 9H), 0.50 (s, 6H).
206.V. rac-trans-5-amino-2-(tert-butyl-dimethyl-silanyIoxymethyl)-pipericIine-l-carboxylic acid tert-bτityl ester:
A suspension of intermediate 2O6.iv (5.46 g, 14.6 mmol) in benzene ClOO mI) was treated with TEA (1.62 g, 1.1 eq) and DPPA (4.4 g, 1.1 eq). The resulting solution was heated at reflux for 60 min, benzyl alcohol (4.5 ml, 3 eq) was added and heating continued overnight. The mixture was cooled to rt, diluted with 100 ml of EA and washed with NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo. Chromatography over silica gel (Hex/EA 9:1, 4:1) separated the undesired isocyanate (700 mg) and the Cbz-protected derivative (3.65 g, 52% yield). The isocyanate was dissolved in THF (20 ml) and treated with NaOH (IM, 6 ml). The mixture was vigorously stirred at rt for 1 h. The organic layer was separated and the aq. layer was once more extracted with EA. The combined organic phases were washed with NaHCO3, dried over MgSO4 and concentrated to give 270 mg of the title amine as a colourless solid. MS (ESI, m/z): 345.4 [M+K1"]. 2O6.vi. rac-trans-2-(tert-butyl-dimethyl-silanyloxymethyl)-5-[(3-oxo-3,4-dihydro- 2H-pyrido[3,2-b][l,4]thiazin-6-ylmethyl)-amino]-piperidine-l-carboxylic acid tert-bvetyl ester:
A mixture of intermediate 206.V (270 mg, 0.78 mmol) and 3-oxo-3,4-dihydro- 2H-pyrido[3,2-Z>][l,4]thiazine-6-carbaldehyde (152 mg, 078 mmol) in 1,2-DCE/MeOΗ 1:1 (10 ml) was stirred at rt overnight. NaBH4 (excess) was added and stirring was continued for 1 h. The mixture was partitioned between DCM and NH4OH and the organic layer v^as dried over MgSO4 and concentrated in vacuo. 400 mg (97% yield) of product were obtained, which were used without purification in the next step. MS (ESI, m/z): 524.2 [M+H4"] .
2O6.vii. rac-trans-5-[tert-bιιtoxycarbonyl-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]thiazin- 6-ylmethyl)-amino]-2-hydroxymethyl-piperidine-l-carboxylic acid tert-butyl ester.
A solution of intermediate 206.vi (400 mg, 0.76 mmol) in THF (10 ml) was treεtted with BOC2O (2 eq) and stirred at rt overnight. The mixture was concentrated in vacuo and purified by chromatography over silica gel (Hex /EA 4:1, 2:1, 1:1). This intermediate (440 mg) was dissolved in THF and treated with IM TBAF solution (0.8 ml) and reaction was allowed to proceed for 4 h. The mixture was concentrated in vacuo and purified by chromatogra-phy over silica gel (Hex/EA 2:1, 1:1, EA) to give 290 mg of title alcohol (74%) as a colourless foam. MS (ESI, m/z): 623.2 [M+H"1"].
2O6.viii. rac-trans-5-[tert-bzitoxycarbonyl-(3-oxo-3, 4-dihydro-2H-pyrido[3,2-b] [1 , 4Jthiazin- 6-ylmethyl)-amino]-2-(6-methoxy-quinazolin-4-yloxymethyl)-piperidine-l-carboxylic acid tert-butyl ester:
This compound was prepared from 4-chloro-8-methoxyquinazoline (50 mg, 0.25 irumol) and intermediate 2O6.vii (130 mg, 0.25 mmol), using the procedure of Example 154, step 154.iv. After chromatography over silica gel (Hex/EA 1:1, EA ), the title compound (90 xng, 53% yield) was obtained as a yellowish foam. MS (ESI, m/z): 667.1 [M+H+]. 206. ix. rac-trans-<5-{[6-(6-methoxy-quinazoHn-4-yloxymethyl)-piperidin-3-ylamino]-methyl}- 4H-pyrido[3, 2-bJfJ, 4]thiazin-3-one :
A solution of intermediate 2O6.viii (90 mg, 0.135 mmol) in DCM (5 ml) was treated with TFA (1 ml). The mixture was stirred at rt for 2 h, concentrated in vacuo and partitioned between DCM and NH4OH. The organic layer was dried o^ver MgSO4 and the residue purified by chromatography over silica gel (EA/MeOH 9:1 + YVa NH4OH) to give 30 mg of title compound as a colourless foam. MS (ESI, m/z): 467.2 [M+H+].
Example 207: røc-*rø«s-(2β-dihydro-benzo[l,4]dioxin-6-ylmethyI)-[6-(6-methoxy- qumazolin-4-yloxymethyl)-piperidin-3-yl]-amine:
207. i. rac-trans-6-(6-methoxy-quinazolin-4-yloxymethyl)-piperidine-l,3-dicarboxylic acid 1-tert-butyl ester 3 -methyl ester:
This compound was prepared from 4-chloro-8-methoxyc[uinazoline (390 mg, 2 mmol) and intermediate 2O6.ii (547 mg, 2 mmol), using the procedure of Example 206, step 2O6.viii. After chromatography over silica gel (Hex/EA 1:1, EA), the title compound (610 mg, 71% yield) was obtained as a colourless foam. MS (ESI, m/z): 432.5 [M+H+].
207. ii. rac-trans-<5-(6-methoxy-quinazolin-4-yloxymethyl) -piper idine-1, 3-dicarboxylic acid 1-tert-butyl ester: Intermediate 207. i (600 mg, 1.4 mmol) was hydrolysed using the procedure of Example 206, step 2O6.iv. The title acid (180 mg, 31% yield) was obtained after crystallisation from ether. MS (ESI, m/z): 41 8.1 [M+H+].
207. iii. rac~trans-5-amino-2-(6-methoxy-quinazolin-4-ylσjcymethyl)-piperidine-l-carboxylic acid tert-butyl ester: To a suspension of intermediate 207.U (170 mg, 0.4 mmol) in benzene (10 ml) was added TEA (1.2 eq) and DPPA (1.1 eq). The mixture was heated to reflux for 2 h. The mixture was cooled to rt and partitioned between EA and water. The organic phase was dried over MgSO4 and concentrated. The residue was dissolved in THF (6 ml) and treated with NaOH IM (2 ml) and the mixture vigorously stirred for 1 h at rt and 1 h at 500C. The mixture was diluted with water and extracted with EA. The combined organic phases were dried over MgSO4 and concentrated to give 100 mg (63% yield) of title amine as a colourless oil. MS (ESI, m/z): 389.1 [M+H+].
207. iv. rac-trans-5-[(2, 3-dihydro-benzo[l, 4]dioxin-6-ylmethyl)-amino]-2-(6-methoxy- quinazolin-4-yloxymethyl)-piperidine-l -carboxylic acid tert-butyl ester:
A mixture of intermediate 207. iii (1OO mg, 0.26 mmol) and 2,3-dihydro-benzo[l,4]dioxine- 6-carbaldehyde (42 mg, 0.26 mmol) in DCE:MeOH 1 : 1 (3 ml) was stirred at rt overnight. NaBKU (excess) was added and stirring was continued for 1 h. The mixture was partitioned between DCM and NH4OH. The orgajnic layer was dried over MgSO4 and concentrated in vacuo. Purification by chromatography over silica gel (EA/MeOH 9:1 + 1% NTH4OH) gave 80 mg (58% yield) of product as a colourless oil. MS (ESI, m/z): 537.3 [M+H+].
207.v. rac-trans-(2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-[6-(6-methoxy-quincxzolin- 4-yloxymethyl)-piperidin-3-yl] -amine: A solution of intermediate 2O7.iv (80 xng, 0.15 mmol) in DCM (4 ml) was treated with TFA (1 ml). The mixture was stirred at rt for 2 h, concentrated in vacuo and partitioned between DCM and NH4OH. The organic layer was dried over MgSO4, concentrated in vacuo and the residue was purified by chromatography over silica gel (EA/MeOH 9:1 + 1% NH4OH) to give 60 mg of title compound as a colourless oil. MS (ESI, m/z): 437.4 [M+H+].
Example 208: /<αc-frα«5-{2-(6-methoxy-quinazolin-4-yloxymethyI)-5-[(3-oxo- S^-dihydro-ZH-pyridotSjl-ftltl^lthiazin-β-ylmethyO-aminoJ-piperidin-l-yl^-acetic acid tert-butyl ester:
208. i. rac-trans-5-benzyloxycarbonylezmino-2-hydroxymethyl-piperidine-l-carb<)xylic acid tert-butyl ester:
5-benzyloxycarbonylamino-2-(tert-butyl-dimethyl-silanyloxymethyl)-piperidine:-l-carboxylic acid tert-butyl ester (3.65 g, 7.625 mmol; obtained as secondary product at Example 206, step 2O6.v) was dissolved in TΗF (50 ml) and TBAF (IM in TΗF, 1.1 eq) was added. The mixture was stirred at rt for 1 h, concentrated in vacuo, partitioned between EA and water. The organic extracts were washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography over silica gel (Hex/EA 2:1, 1:1 then EA) to afford the title alcohol (2.37 g, 85%) as a colourless oil. MS (BSI, m/z): 365.2 [M+H+].
208.il. 5-benzyloxycarbonylamino-2-(6-methoxy-quinazolin-4-yloxymethyl)-piperidine- 1-carboxylic acid tert-butyl ester:
To a solution of 4-chloro-8-methoxyquinazoline (290 mg, 1.49 irimol) and intermediate 208. i (544 mg, 1 eq) in DMF (5 ml) at 00C was added NaH (60% dispersion in oil, 143 mg, 2 eq). The mixture was stirred at 00C for 3 h, quenched with water and extracted with ether. Organic extracts were washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography over silica gel (Hex/EA 1:1, EA) to give 422 mg (54%> yield) of coupling product as a colourless oil. MS CESI, m/z): 523.2 [M+H+].
208. iii. rac-trans-[6-(6-methoxy-quinazolin-4-yloxymethyϊ)-pip&r'idin-S-yl]-carbamic acid benzyl ester: To a solution of intermediate 208.H (422 mg, 0.808 mmol) in DCM (5 ml) was added TFA (2 ml). The mixture was stirred at it for 2 h, concentrated in vacuo and partitioned between DCM and NH4OH. The organic extracts were dried over MgSO4 and concentrated to give the title piperidine (340 mg, 99% yield), which was used without further purification. MS (ESI, m/z): 423.5 [M+H+].
208. iv. rac-trans-[5-benzyloxycarbonylamino-2-(6-methoxy-qwrjazolin-4-yloxymethyl)- piperidm-1-yl] -acetic acid tert-butyl ester:
To a solution of intermediate 2O8.iii (340 mg, 0.8 mmol) in THCF (5 ml) were added DIPEA (0.16 ml, 1.2 eq) and tert-butyl bromoacetate (0.141 ml, 1.2 eq) the mixture was stirred at rt for 2 d. The resulting suspension was poured into a sat. NH4Cl solution and extracted with EA. The organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography over silica gel (Hex/EA 1:1, EA) to give 260 mg (60% yield) of desired compound as a colourless oil. MS (ESI, m/z): 537.2 [MH-H+]. 208.V. rac-trans-[5-amino-2-(6-methoxy-quinazolin-4-yloxymethyl)-piperidin-l-yl]-acetic acid tert-butyl ester:
Intermediate 208. iv (260 rng, 0.48 mmol) was dissolved in EA (50 ml), degassed several times and treated with 1 0% Pd/C (170 mg). The reaction was stirred under hcydrogen atmosphere (1 bar) for 5 hi, filtered over Celite and concentrated in vacuo to give 170 mg (87% yield) of a colourless oil. MS (ESI, m/z): 403.2 [M+H+].
2O8.vi. rac-tι-ans-{2-(6-methoxy-quinazolin-4-yloxymethyl)-5-[(3-oxo-3,4 dihydro- 2H-pyrido[3, 2-b][l, 4]thia∑in-6-ylmethyl)-amino]-piperidin-l-yl}-acetic acid tert-butyl ester: Reductive amination was carried out as described in Example 206, step 206. vi, starting from intermediate 208.V (170 mg, 0.4 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-Z>][l,4]-thiazine- 6-carbaldehyde (82 mg, 1 eq). The product (146 mg, 59% yield) was isolated as a beige foam. MS (ESI, m/z): 581.2 [M4-Η+].
Example 209: rac-trans- {2-(6-methoxy-quinazolin-4-yloxyinethyl)-5-[(3-oxo- 3,4-dihydro-2H-pyrido[3 ,2-b] [l,4]thiazin-6-yImethyl)-amino]-piperidin-l-yl}-ac& tic acid:
A solution of the compound of Example 208 (100 mg, 0.17 mmol) in TFA (2 ml) was stirred at rt for 3 h. The mixture was concentrated in vacuo and crystallised from ether to give the title compound (130 mg) as its trifluoroacetate salt. MS (ESI, m/z): 525.2 [M-HH+].
Example 210: rac-trans— 6-({6-[2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-piperidin- 3-yIamino}-methyl)-4H-pyrido[3,2-Λ][l,4]thiazin-3-one:
210. i. rac-trans-ό-formyl-piperidine-l^-dicarboxylic acid 1-tert-butyl ester 3-methyl ester:
A solution of oxalyl chloride (4.5 ml, 52.9 mmol) in DCM (33 ml) was cooled to -78°C. A solution of DMSO (4.7 ml, 64.85 mmol) in DCM (33 ml) was added dropwise and the solution was stirred at -780C for 15 min. A solution of intermediate 2O6.ii (4.66 g, Y7.1 mmol) dissolved in DCM (33 ml) was added dropwise. The solution was stirred at -78°<3 for 1 h before dropwise addition, of TEA (33 ml in 20 ml of DCM). The solution was allowed to warm to rt and was stirred for 3 h. Saturated aq. NaHCO3 (75 ml) was added. The two phases were separated and the aq. phase was extracted once more with DCM. Combined organic phases were washed with brine, dried over MIgSO4 and concentrated in vacuo. Chromatography over silica gel (Hex/EA 2:1) afforded the title aldehyde (1.14 g, 25 % yield) as a yellowish oil in a 3: 1 mixture of cis/trans isomers. MS (ESI, m/z): 272.3 [MH-H+].
210.iL rac-trans-ό-ethynyl-piperidine-l^-dicarboxylic acid 1-tert-butyl ester 3-methyI ester:
To a solution of /?-toluenesulfonyl azide (1.8 g, 9.08 mmol) in MeCN (115 ml) was added K2CO3 (3.1 g, 22.1 mmol) and dimethyl acetylmethylphosphonate (1.2 ml, 8.87 mmol). The mixture was stirred at rt for 2 h and a solution of intermediate 210. i (1.14 g, 4.2 mmol) in MeOH (17 ml) was added. The mixture was stirred at rt overnight. The volatiles were removed under reduced pressure and the residue dissolved in water (50 ml) and EA (100 ml). The aqueous layer was extracted with EA (2 x 100 ml). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was filtered through SiO2 (Hex/EA 4:1) to afford the title alkyne (mixture of cis and trans, 450 mg, 40%) as a yellowish oil. MS (ESI, m/z): 268.5 [MH-H+].
210. iii. rac-trans-6-(6-methoxy-[l,5]naphthyridin-4-ylethynyl)-piperidine-l,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester:
To a solution of intermediate 210. ii (450mg, 1.68mmol) and trifluoromethanesulfonic acid 6-methoxy-[l,5]naphthyridin-4-yl ester (517 mg, 1 eq) in DMF (5 ml) and TEA (1.4 ml) were added successively copper iodide (35 mg) and bis(triphenylphosphine)palladium(II) chloride (59 mg). The reaction mixture was stirred at rt for 3 h. The mixture was poured on water and extracted with EA. The aq. layer was extracted twice more (2 x 100 ml). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was chromatographed over silica gel (Hex/EA 1:2) to afford the title alkyne (300 mg, 42 % yield) as a beige solid. MS (ESI, m/z): 426.1 [MH-H+]. 210.iv. rac-frans-6-[2-(6-methoxy-[l , 5]naphthyridin-4-yl)-ethyl]-piperidine -1, 3-dicarboxylic acid 1-tert-hutyl ester 3-methyl ester.
Intermediate 21O.iii (300 mg, 0.706 mmol) was hydrogenated over PtO2 OO mg) in EtOH (20 ml) for 5 h (1 bar of H2). The mixture was filtered through Celite and concentrated to give 225 mg (74% yield) of a colourless oil. MS (ESI, m/z): 430.3 [M+H+]
210.v. rac-trans-6-[2-(6-methoxy-[l, 5]naphthyridin-4-yl)-ethyl]-piperidine- 1, 3-dicarboxylic acid 1-tert-hutyl ester:
This compound (216 mg; 99% yield) was obtained as a colourless solid from intermediate 210. iv (225 mg, 0.52 mmol), using the procedure of Example 206, step 206. ii. MS (ESI, m/z): 416.3 [M+H+].
21O.vi. rac-trans-5-amino-2-[2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-p>iperidine- 1-carboxylic add tert-butyl ester:
Starting from intermediate 21O.v (216 mg, 0.52 mmol), Curtius degradation was carried out as described in Example 207, step 2O7.iii, affording the target amine (137 mg, 68% yield) as a colourless solid. MS (ESI, m/z): 387.2 [M+H+].
210.vii. rac-trans- 2-[2-(6-methoxy-[l , 5]naphthyridin-4-yl)-ethyl]-5-[(3-oχ:o-3, 4-dihydro- 2H-pyrido[3,2-b] [1,4] thiazin-6-ylmethyl) -amino] -piperidine-1 -carboxylic cecid tert-butyl ester:
Starting from intermediate 21O.vii (135 mg, 0.35 mmol) and 3-oxo-3,4-dihydro- 2H-pyrido[3,2-δ][l,4]thiazine-6-carbaldehyde (68 mg, 1 eq), reductive amixiation was carried out as described in Example 206, step 2O6.vi. The product (133 mg, 67% ^yield) was isolated as a yellowish, foam. MS (ESI, m/z): 565.3 [M+Η1"]. 21O.viii. rac-trans-6-({6-[2-(6-methoxy-[l,5]ncephthyridin-4-yl)-ethyl]-piperidin-3ylamino}- methyl)-4H-pyrido[3,2-b][l,4]thiazin-3-one:
Deprotection was carried out as described in Example 206, step 206. ix, starting from intermediate 21O.vii (113 mg, 0.23 mmol) to give the title compound (100 mg, 91 % yield) as an off-white foam.
MS (ESI, m/z): 465.4 [M+H+].
Example 211: rαc-frø»s-5-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-6][l,4]thiazin- 6-ylmethyl)-amino]-piperidine-2-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yI)- amide:
21 l.i. rac-trans-6-carbamoyl-piperidine-l,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester:
Intermediate 206. i (1.7 g, 5.9 mmol) and NHS (715 mg, 1.05 eq) were added to a solution of DCC (1.28 g, 1.05 eq) in EA (25 ml). A precipitate formed and the mixture was stirred at rt overnight. The precipitate was filtered off and the filtrate concentrated in vacuo. The residue was dissolved in THF (100 ml) and NH3 (gas) was bubbled through for 15 min. A white precipitate formed which was filtered off. The filtrate was concentrated in vacuo and the title amide (800 mg, 47% yield; colourless solid) was obtained after chromatography (SiO2 / EA), 1HE NMR (d6-DMSO) δ: 7.31 (br, IH), 7.04 O", IH), 4.4-4.30 (m, IH), 4.20-4.10 (m, IH), 3.61 (s, 3H), 3.40-3.20 (m, IH), 2.70 (br, IH), 2.00-1.40 (m, 4H), 1.37 (s, 9H).
21 l.ii. rac-trans-6-(6-methoxy-[l,5]naphth,yritdin-4-ylcarbamoyl)-piperidine- 1, 3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester:
This compound (880 mg, 70% yield) was obtained as a colourless solid, starting from intermediate 21 Li (800 mg, 2.8 mmol) and trifluoromethanesulfonic acid 6-methoxy- [1 ,5]naphthyridin-4-yl ester (861 mg, 1 eq) and using the procedure of Example 28, step 28.U. MS (ESI, m/z): 444.8 [M+H+].
211.in. rac-trans-6-(6-methoxy-[l, 5]naphthyridin-4-ylcarbamoyl)-piperidine- 1, 3-dicarboxylic acid 1-tert-butyl ester:
This compound (650 mg; 98% yield) was obtained as a colourless solid from intermediate 21 l.ii (680 mg, 1.53 mmol), using the procedure of Example 206, step 206.H. MS (ESI, m/z): 432,0 [M+H+].
211.iv. rac-trans-5-amino-2-(6-methoxy-[l,5]naphthyridin-4-ylcarbamoyl) -piperidine- 1-carboxylic acid tert-butyl ester:
Starting from intermediate 21 l.iiϊ (178 mg, 0.41 mmol), Curtius degradation was carried out as described in Example 207, step 207. iii, affording the target amine (136 rog, 82% yield) as a colourless solid. MS (ESI, m/z): 402.1 [M+H+].
211.v. rac-trans-2-(6-rnethoxy-[l , 5]naphthyridin-4-ylcarbamoyl)-5-[(3-oxo-3, 4-dihydro- 2H-pyrido[3, 2-b][l, 4]thiazin-6-ylmethyl)-amino]-piperidine-l-carboxylic acid tert-butyl ester.
Starting from intermediate 21 l.iv (136 mg, 0.34 mmol) and 3-oxo-3,4-dihydro- 2H-pyrido[3,2-δ][l,4]thiazine-6-carbaldehyde (66 mg, 1 eq), reductive amination was carried out as described in Example 206, step 2O6.vi. The product (110 mg, 56% yield) was isolated as a yellowish foam. MS (ESI, m/z): 580.2 [M+Η+].
211.vi. rac-trans-5-[(3-oxo-3, 4-dihydro-2H-pyrido[3, 2-b][l, 4]thiazin-6 y Imethyl) -amino] - piperidine-2-carboxylic acid (6-methoxy-fl, 5]naphthyridin-4-yl)-amide:
Deprotection was carried out as described in Example 206, step 206.ix, starting from intermediate 211.v (l lO mg, 0.19 mmol), to give after crystallisation from ether/MeOH the title compound (52 mg, 57 % yield) as an off-white solid.
1H NMR (d6-DMSO) δ: 8.70 (d, IH, J=5.04 Hz), 8.43 (d, IH, J=5.04 Hz), 8.27 (d, IH, J=9.03 Hz), 7.70 (d, IH, J =7.89 Hz), 7.32 (d, IH, J=9.03 Hz), 7.07 (d, IH, J=7.89 Hz), 4.04 (s, 3H), 3.70 (s, 2H), 3.65-3.60 (m, IH), 3.51 (s, 2H), 3.25-3.10 (m, IH), 3.05-2.95 (m, IH), 2.60-2.40 (m, 2H), 2.30-2.05 (m, 2H), 1.90-1.80 (m, IH), 1.70-1.50 (m, IH), 1.30-1.10 (m, IH). Example 212: rαc-*ra»s-5-[(3-oxo-3,4-dihydro-2H-benzo[l,4]thiazin-6-ylmethyl)- amino]-piperidine-2-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yI)-amide:
212.i. rac-trans-2-(6-methoxy-[l,5]naphthyridin-4-ylcarbamoyl)-5-[(3-oxo-3,4-dihydro- 2H-benzo[l, 4]thiazin-6-ylmethyl)-amino]-piperidine-l-carboxylic acid tert-hutyl ester: Starting from intermediate 211.iv (110 mg, 0.27 mmol) and 3-oxo-3,4-dihyrdro- 2H-benzo[l,4]thiazine-6-carbaldehyde (55 mg, 1 eq), reductive amination was carried out as described in Example 206, step 206. "vi. The product (90 mg, 57% yield) was isolated as a yellowish foam. MS (ESI, m/z): 579.2 [M+Η+].
212. ii. rac-trans-5-[(3-oxo-3, 4-dihydro-2H-benzo[l , 4]thiazin-6-ylmethyl)-amino]- piperidine-2-carboxylic acid (6-methoxy-[l, 5]naphthyridin-4-yl)-amide\
Deprotection was carried out as described in Example 206, step 206. ix, starting from intermediate 212.i (90 mg, 0.19 mmol), to give after chromatography (EA/MeOH 9:1 + 1% NH4OH) the title compound (42 mg, 56 % yield) as an off-white solid. 1H NMR (d6-DMSO) δ: 8.70 (d, IH, J=5.04 Hz), 8.43 (d, IH, J=5.04 Hz), 8.27 (d, IH, J=9.03 Hz), 7.34 (d, IH, J =9.03 Hz), 7.20 (d, IH, J=7.89 Hz), 7.00-6.85 (m, 2H), 4.O4 (s, 3H), 3.65-3.50 (m, 3H), 3.41 (s, 2H), 3.25-3.10 (m, IH), 3.05-2.95 (m, IH), 2.60-2.4O (m, 2H), 2.30-2.05 (m, 2H), 1.90-1.80 (m, IH), 1.70-1.50 (m, IH), 1.30-1.10 (m, IH). MS (ESI, m/z): 479.3 [M+H+].
Example 213: /-ac-rra/is-5-[(2,3-diliydro-benzo[l,4]dioxin-6-ylmethyl)-ainino]- piperidine-2-carboxyIic acid (6-met hoxy- [1,5] naphthy ridin-4-yl)-amide :
213.i. rac-trans-5-[(2, 3-dihydro-ben∑o[l, 4]dioxin-6-ylmethyl)-amino]-2-(6-methoxy- [1, ojnaphthyridin^-ylcarhamoyty-piperidine-l-carboxylic acid tert-butyl ester.
Starting from intermediate 211.iv (1 10 mg, 0.27 mmol) and 2,3-dihydro-benzo[l,4]dioxine- 6-carbaldehyde (45 mg, 1 eq), reductive amination was carried out as described in Example 206, step 2O6.vi. The product (100 mg, 66% yield) was isolated as a coloxirless foam. MS (ESI, m/z): 550.3 [MfH+]. 213. ii. rac-trans-5~[(2,3-dihydro-benzo[l ,4] ' dioxin-6-ylmethyl) -amino] '-piper idine- 2-carboxylic acid (6-methoxy-[l, 5]naphthyridin-4-yl)-amide:
Deprotection was carried out as described in Example 206, step 206. ix, starting from intermediate 213.i (100 mg, 0.18 mmol), to give after chromatography (EA/lMeOH 9:1 + 1% NH4OH) the title compound (40 mg, 49 % yield) as an off-white solid.
1H NMR (d6-DMSO) δ: 8.70 <d, IH, J=5.04 Hz), 8.43 (d, IH, J=5.04 Hz), 8.27 (d, IH, J =9.03 Hz), 7.34 (d, IH, J=9.O3 Hz), 6.80 (s, IH), 6.74 (s, 2H), 4.18 (s, 4H), 4.04 (s, 3H), 3.65-3.50 (m, 3H), 3.41 (s, 2H), 3.25-3.10 (m, IH), 3.05-2.95 (m, IH), 2.60-2.40 (m, 2H), 2.30-2.05 (m, 2H), 1.90-1.80 (m, IH)3 1.70-1.50 (m, IH), 1.30-1.10 (m, IH). MS (ESI, m/z): 450.2 [M+H+].
Example 214: c/s-3-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-6] [l,4]thiazin-6-ylmethyl)- amino]-methyl}-cyclohexanecarboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide:
214. i. cis- [(3-(6-methoxy-[l,5Jnaphthyridin-4-ylcarbamoyl)-cyclohexylmethyl]-carbamic acid tert-butyl ester: This compound (1.08 g, 60% yield) was obtained as a white solid, starting from intermediate 72. i (1.1 g, 4.3 mmol) and trifluoro-methanesulfonic a.cid 6-methoxy- [l,5]naphthyridin-4-yl ester ( 1.32 g, 4.3 mmol), using the procedure of Example 59, step 59. ii. After recrystallization in an EA-Hex mixture, the compound wa.s obtained as the unique eώ-isomer. MS (ESI, m/z): 415.5 [M+H+].
214. ii. cis-3-aminomethyl-cyclohexanecarboxylic acid (6-methoxy-[l ,5]naphthyridin-4-yl)- amide:
This compound (0.8 g, 97% yield) was prepared from intermediate 214.i (1.08 g, 2.6 mmol) as described in Example 67, step 67. Ui. The title amine was obtained as a colourless oil. MS (ESI, m/z): 315.3 [M+H+].
214.iii. cis-3-{[(3-oxo-3, 4-dihydro-2H-pyrido[3, 2-b][l, 4]thiazin-6-ylmethyZ)-amino]- methylj-cyclohexanecarboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-am ide:
This compound (0.055 g, 3O% yield) was obtained as a white solid, starting from intermediate 214.ii (0.1 g, 0.32 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[332-έ][l,4]thiazine- 6-carbaldehyde (0.072 g, 0.37 rnmol) and using the procedure of Example 63, step 63.vii. MS (ESI, m/z): 493.2 [Mt-H+].
Example 215: 3-{[(3-oxo-3,4-dihydro-2H-py rido[3,2-ό] [l,4]oxazin-6-yImethyl)-amino]- methyl}-cyclohexanecarboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide:
The title compound (0.059 g, 39% yield) was prepared as a white solid, starting from intermediate 69.H (0.100 g, 0.32 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-έ][l ,4]oxazine- 6-carbaldehyde (0.062 g, 0.35 mmol) and using the procedure of Example 63, step 63.vii. MS (ESI, m/z): 477.4 [M+Η4].
Example 216: 6-((3R,6S)- {6-trans- [2-(3-fluo r o-6-methoxy- [1 ,5] naphthy ridin-4-y I)- vinyl]-tetrahydro-pyran-3-ylamino}-methyl)— 4H-pyrido[3,2-6][l,4]thiazin-3-one:
216. i. trans-7-fluoro-2-methoxy-8-styryl-[l,5]naphthyridine:
This compound (2.5 g, 89% yield) was obtained as a yellowish solid from 8-bromo— 7-fluoro- 2-methoxy-[l,5]naphthyridine (2.57 g, 10 mmol; prepared as in WO 2004/058 144) and trø«s-phenylvinyl boronic acid (1.62 g, ll rramol), using the procedure of Example 178, step 178.i. MS (ESI, m/z): 281.0 [M+Η÷] .
216. ii. l-(3-fluoro-6-methoxy-[l,5]naphthyridin-4-yl)-2-phenyl-ethane-l,2-diok
The title diol (2.3 g, 81% yield) was obtained as a white foam, starting from intermediate 216. i (2.5 g, 8.9 mmol) and using the procedure of Example 178, step 1 78. ii. 1H NMR (CDCl3) δ: 8.42 (d, J = 0.7 Hz, IH); 8.28 (d, J = 9.1 Hz, IH); 7.24-7.15 (m, 4H); 7.08 (m, 2H); 6.70 (br s, IH); 5.28 (br s, IH); 5.10 (d, J = 7.9 Hz, IH); 4.11 (s, 3H); 3.85 (br s, IH).
216. iii. 3-fluoro-6-nιethoxy-[l,5]naphthyridine-4-carbaldehyde\
This compound (1.34 g, 89% yield) was obtained as a white solid, starting from intermediate 216. ii (2.3 g, 7.25 mmol) and using the procedure of Example 178, step 178. iii. 1H NMR (d6-DMSO) δ: 11.08 (s, IH); 9.01 (d, J = 1.3 Hz, IH); 8.41 (d, J = 9.1 Hz, IH); 7.37 (d, J 9.1 Hz, IH); 4.09 (s, 3H). MS (ESI, m/z): 206.9 [MfH+]. 216. iv. (3 R, 6S) - {6-trans-[2- (3-fluoro-6-methoxy-[l, 5]naphthyridin-4-yl) -vinyl] -te trahydro- pyran-3-ylj-carbamic acid tert-butyl ester:
This compound (1.5 g, 59% yield) was obtained as a yellowish, solid, starting from intermediate 164.ii (2.66 g, 6.3 mmol) and intermediate 216. iii (1.3 g, 6.3 mmol) and using the protocol of Example 171, step 171.V. MS (ESI, m/z): 404.0 [M+H+].
216.V. (3R,6S)-6-trans-[2-(3-fluoro-6-methoxy-[l,5]naphthyridin-4-yl) -vinyl] -tetrahydro- pyran-3-ylamine :
This compound (0.090 g) was obtained as a yellowish foam, starting from intermediate 216.iv (0.2 g) and using the procedure of Example 164, step 164.iv. MS (ESI, m/z): 304.1 [M+H+].
216.vi. 6-((3R,6S)-{6-trans-[2-(3-fluoro-6-methoxy-[l,5]naphthyridin — t-yl)-vinyl]- tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3, 2-b][l, 4]thiazin-3-one :
This compound was obtained as a white solid (0.045 g, 31% yield) from intermediate 216.V (0.09 g, 0.3 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-ό][l,4]tliiazine-6-carbaldehyde
(0.063 g, 1.1 eq), using the procedure of Example 88, step 88. iv.
1H NMR (d6-DMSO) δ: 10.83 (s, IH); 8.85 (s, IH); 8.31 (d, J = 9.0 Hz, IH); 7.70 (d,
J = 7.8Hz, IH); 7.26 (d, J = 9.0 Hz, IH); 7.05 (d, J = 7.8 Hz, IH); 6.72 (d, J = 11.9 Hz, IH),
6.04 (dd, J = 8.1, 11.9 Hz, IH); 4.01 (s, 3H); 3.84-3.75 (m, 2H); 3.68 Cbr s, 2H); 3.42 (s, 2H); 2.83 (t, J = 10.8 Hz, IH); 2.50 (overlapped m, IH); 2.03-1.94 (m, 2H); 1.58 (m, IH); 1.38 (m,
IH); 1.12 (m, IH).
MS (ESI, m/z): 482.2 [M+H+]
Example 217: 6-(3R,61S)-{6-[(li-,2ϋ!)-2-(3-fluoro-6-methoxy-[l,5]iιaphthyridin-4-yl)- l,2-dihydroxy-ethyl]-tetrahydro-pyran-3-ylamino}-methyI)- 4H-pyrido[3,2-6] [l,4]thiazin-3-one:
217.L (3R,6S)-{6-[(lR,2R)-2-(3-fluoro-6-methoxy-[l,5]naphthyridin-4-yl)-l,2-dihydroxy- ethyl]-tetrahydro-pyran-3-yl}-carbamic acid tert-butyl ester.
This compound (0.525 g, 42% yield) was obtained as a brown oil, starting from ntermediate 216.iv (1.13 g, 2.8 mmol) and applying the protocol of Example 171, step 171.vi. The diol was obtained as a 6:1 mixture of diastereomers. MS (ESI, m/z): 437.9 [M+H*].
217.il. (lR,2R)-l-((2S,5R)-5-amino-tetrahydro-pyran-2-yl)-2-(3-fluoro-6-methoxy- [1, 5]naphthyridin-4-yl)-ethane-l, 2-diol:
This compound (0.4 g, 98% yield) was obtained as a yellowish foam, starting from intermediate 217. i (0.525 g, 1.2 mmol) and applying the protocol of Example IVl _, step 171. vii. It was obtained as a 6:1 mixture of diastereomers. MS (ESI, m/z): 338.2 [M+H+].
217.iii. 6-(3R, 6S)-{6-[(lR, 2R)-2- (3-fluoro-6-methoxy-[l, 5]naphthyridin-4-yl)-l, 2 dihydroxy- ethyl] -tetrahydro-pyran-3-ylamino}-methyl)-4H pyrido[3, 2 b][l, 4]thiazin-3-one : This compound (0.098 g, 32°/ό yield) was obtained as a white solid, starting from intermediate 217. ii (0.2 g, 0.59 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-έ][l,4]thiazine-
6-carbaldehyde (0.126 g, 1.1 eq) and applying the protocol of Example 171, step 171.viii.
1H NMR (d6-DMSO) δ: 10,83 Cs, 1Η); 8.75 (d, J = 1.5 Hz, IH); 8.29 (d, J = 9.1 Hz, 1H>;
7.68 (d, J = 7.8 Hz, IH); 7.22 (d, J = 9.1 Hz, IH); 7.02 (d, J = 7.8 Hz, IH); 5.70 (br t, J = 7.1Hz, IH); 5.45 (d, J = 7.1 Hz, IH); 4.83 (d, J = 6 Hz, IH); 4.00 (s, 3H); 3.88 (m, 1H>;
3.73 (m, IH); 3.65 (br s, 2H); 3.53 (s, 2H); 2.90 (m, IH); 2.58 (overlapped m, IH); 2.32 (trm,
IH); 2.09-1.90 (m, 2H); 1.67-1.53 (m, 2H); 1.09 (m, IH).
MS (ESI, m/z): 516.1 [MH-H+].
Example 218: 6-({6-[2-(8-fluoro-6-methoxy-quinolin-4-yl)-vinyl]-tetrahydro-pyran- 3-ylamino}-methyl)-4H-pyrido [3,2-b] [l,4]thiazin-3-one:
218. i. 4-bromo-8-fluoro-6-methoxy-qιιinoline:
To a solution of 8-fluoro-6-methoxy-quinolin-4-ol (13.2 g, 68.3 mmol; prepared as Ln WO 2004/041210) in DMF (70 ml), heated to 40°C in a water-bath, was added PBr3 (7 mJ, 75 mmol). The mixture was stirred at this temperature for 1 h. The reaction mixture was diluted with water (0.5 1) and saturated NaHCO3 was added until pH 8 was reached. Thie solids were filtered off, taken up in EA and evaporated with silica gel (40 g). The material was eluted (Hex-EA 3-1) to afford the title bromide (7.0 g, 40% yield) as a yellow solid. 1H NMR (d6-DMSO) δ: 8.60 (d, J = 4.6 Hz, IH); 8.00 (d, J = 4.6 Hz, IH); 7.48 (del, J = 2.6, 11.9 Hz, IH); 7.24 (dd, J = Ll, 2.6 Hz, IH); 3.96 (s, 3H). 218.ii. trans-8-fluoro-6-methoxy-4-styryl-quinoline:
This compound (5.4 g, 99% yield) was obtained as a yellowish solid from intermediate 218. i (5 g, 19.52 mmol) and frvms-phenylvinyl boronic acid (3.17 g, 1.1 eq), using the procedure of Example 1 78, step 178.i. MS (ESI, rn/z): 279.9 [M+H+].
218. hi. 1- (8-fluoro-6-methoxy-quinolin-4-yl)-2-phenyl-ethane-l,2-diol:
This compound (5.4 g, 89% yield) was obtained as a beige solid, starting from intermediate 218. ii (5.4 g, 19.4 mmol) and using the procedure of Example 178, step 178. ii. 1H NMR (CDCl3) δ: 8.67 (d, J = 4.5 Hz, IH); 7.56 (d, J = 4.5 Hz, IH); 7.23-7.14 (m, 5H); 6.96 (d, J = 2.5, 11.5 Hz, IH); 6.68 (d, J = 2.5 Hz, IH); 5.34 (d, J = 6.3 Hz, IH); 4.97 (d, J = 6.3 Hz, IH); 4.83 (br s, IH); 3.78 (s, 3H); 3.51 (br s, IH).
218.iv. 8-β.uoro-6-methoxy-qu\noline-4-carbaldehyde\
This compound (2.67 g, 76% yield) was obtained as a white solid, starting from intermediate 218. iii (5.3 g, 17 mmol) and using the procedure of Example 178, step 178. iii. 1H NMR (d6-DMSO) δ: 10.51 (s, IH); 9.09 (d, J = 4.2 Hz, IH) ; 8.21 (dd, J = 1.1, 2.6 Hz, IH); 8.10 (d, J = 4.2 Hz, IH); 7.47 (dd, J = 2.6, 12.0 Hz, IH); 3.96 (s, 3H).
218.V. {(3i?,65)-trα«^-6-[2-(8-fluoro-6-methoxy-quinolin-4-yl)-vinyl]-tetrahydro-pyran- 3-yl}-carbamic acid tert-butyl ester:
This compound (4.08 g, 74% yield) was obtained as a yellowish solid, starting from intermediate 164.U (5.82 g, 13.7 mmol) and intermediate 218.rv (2.67 g, 13.5 mmol) and using the protocol of Example 171, step 17 Lv. MS (ESI5 m/z): 403.0 [M+H+].
218.vi. (3R, 6S)-trans-6-[2-(8-fluoro-6-methoxy-quinolin-4-yl)-vinyl]-tetrahydro-pyran- 3-ylamine: This compound (0.220 g, 69% yield) was obtained as a yellowish foam, starting from intermediate 218.V (0.425 g, 1.05 mmol) and using the protocol of Example 164, step 164.iv. MS (ESI, m/z): 303.0 [M+H+]. 218.vii. 6-({6-[2-(8-fluoro-6-rnethoxy-quinolin-4-yl)-vinyl]-tetrahydro-pyran-3 ylam ino}- methyl)-4H-pyrido[3, 2-b][l, 4]thiazin-3-one :
This compound (0.178 g) was obtained as a white solid, starting from intermediate 218. vi (0.220 g) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-έ][l,4]thiazine-6-carbaldehyde (0.155 g) and using the procedure of Example 88, step 88. iv.
1H NMR (CDCl3) δ: 10.88 (s, 1Η); 8.70 (d, J= 4.5 Hz, IH); 7.75 (d, J= 7.8 Hz, IH); 7.67 (d, J= 4.5 Hz, IH); 7.36 (overlapped m, 2H); 7.31 (overlapped m, IH); 7.12 (d, J= 7.9» Hz, IH); 6.59 (dd, J = 5.6, 15.8 Hz5 I H); 4.08 (m, 2H); 3.95 (s, 3H); 3.77 (s, 2H); 3.54 (s, 2HC); 3.11 (t, J= 10.6 Hz, IH); 2.56 (overlapped m, IH); 2.18 (br. s, IH); 2.09 (m, IH); 1.90 (m, IH); 1.40 (m, 2H).
MS (ESI, m/z): 481.3 [M+H+].
Example 219: 6-((3Λ, 65)-{6-[2-(8-fluoro-6-methoxy-quinolin-4-yl)-ethyl]-tetraliydro- pyran-3-ylamino}-methyl)-4H-pyrido[3,2-6][l,4]thiazin-3-one:
219.i. (3R, 6S)-{6-[2-(8-fluoro-6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3-y>l}- carbamic acid tert-butyl ester:
To a solution of intermediate 218. v (0.899 g, 2.23 mmol) in EA (35 ml) under nitrogen was added 10% palladium on charcoal (0.54 g). The resulting mixture was stirred under hydrogen for 90 min.The catalyst was removed by filtration and the filtrate concentrated to dryness. The residue was purified by column chromatography over silica gel (EA-Ηex 1-1) to afford the title product (0.553 g, 61% yield) as a white solid. MS (ESI, m/z): 404.9 [M+].
219. ii. 6-[2-(8-fluoro-6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamine:
This amine (0.374 g, 910So yield) was obtained as a pale yellow solid, starting from intermediate 219.i (0.545 g, 1.35 mmol) and using the procedure of Example 164, step 164.iv. MS (ESI, m/z): 305.0 [M+Η^]. 219. iii. 6-((3R, 6S)-{6-[2- (8-fluoro-6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran- 3-ylamino}-methyl)-4H-pyrido[3,2-b][l,4]thiazm-3-one:
This compound (0.143 g) was obtained as a white foam, starting from intermediate 219.ii (0.150 g) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-δ][l,4]thiazine-6-carba.ldehyde (0.105 g) and using the procedure of Example 88, step 88. iv.
1H NMR (CDCl3) δ: 10.85 (s, 1Η); 8.66 (d, J= 4.4 Hz, IH); 7.73 (d, J= 7.8 Hz, IH); 7.40 (d, J= 4.4 Hz, IH); 7.32 (dd, J= 2.6, 12.1 Hz, IH); 7.23 (d, J= 2.0 Hz, IH); 7.09 (d, J= 7.9 Hz, IH); 3.98 (m, IH); 3.93 (s, 3H); 3.73 (d, J = 2.1 Hz, 2H); 3.53 (s, 2H); 3.23 (m, IH); 3.10 (m, 2H); 2.96 (t, J= 10.5 Hz, IH); 2.51 (overlapped m, IH); 2.09 (br. s, IH); 1.99 (m, IH); 1.76 (m, 2H); 1.69 (m, IH); 1.22 (m, 2H). MS (ESI, m/z): 483.2 [M-I-H+].
Example 220: 6-((3i?,6Sr)-{6-[(lR,2J?)-2-(8-fluoro-6-methoxy-quinolin-4-yl)- l,2-dihydroxy-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-
4H-pyrido[3,2-ό][l,4]thiazin-3-one:
22O.i. {(3R, 6S)-6-[(lR,2R). -2-(8-fluoro-6-methoxy-quinolin-4-yl)-l,2-dihydroxy-ethyl]- tetrahydro-pyran-3-yl}-carbamic acid tert-butyl ester.
This diol (2.35 g, 79% yield) was obtained as a brown oil, starting from intermediate 218.V (2.73 g, 6.8 mmol) and applying the protocol of Example 171, step 171 .vi. MS (ESI, m/z): 437.3 [M-+H+].
220.U. (lR,2R)-l-((2S,5R)-(5-amino-tetrahydro-pyran-2-yl)-2-(8-fluor4J-6-methoxy-quinolin- 4-yl) -ethane- 1, 2-diol:
This amine (0.241 g, 72% yield) was obtained as a pale yellow solid, starting from intermediate 220. i (0.432 g, 1 mmol) and using the protocol of Example 164, step 164.iv. MS (ESI, m/z): 337.2 [M-H-H+].
22O.iii. 6-((3R, 6S)-{6-[(2 R,2R)-2-(8-fluoro-6-methoxy-quinolin-4-yl)-Z ,2 dihydroxy-ethyl]- tetrahydro-pyran-3-ylamino}-methyl)-4H pyrido[3,2 b] [l,4]thiazin-3-one\
This compound (0.063 g) was obtained as a pale yellow solid, starting from intermediate 220.U (0.105 g) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-έ][l,4]thiazine- 6-carbaldehyde (0.067 g) and using the procedure of Example 88, step 88. iv. 1B. NMR (CDCl3) δ: 10.85 (s, IH); 8.76 (d, J= 4.4 Hz5 IH); 7.73 (d, J= 7.8 Hz, 1H>; 7.64 (d, J= 4.5 Hz, IH); 7.32 (dd, J = 2.4, 11.9 Hz, IH); 7.28 (d, J= 2.6 Hz, IH); 7.07 (d, J = 7.9 Hz, IH); 5.46 (d, J = 5.5 Hz, IH); 5.33 (t, J = 4.9 Hz, IH); 5.17 (d, J = 5.8 Hz, IH); 3.92 (overlapped m, IH); 3.89 (s, 3H); 3.72 (d, J = 3.9 Hz, 2H); 3.53 (overlapped m, IH); 3.52 (s, 2H); 2.96 (m, IH); 2.74 (t, J = 10.4 Hz, IH); 2.52 (overlapped m, 2H); 2.03 (m, IH); 1.59 (m, 2H); 1.05 (m, IH). MS (ESI, m/z): 515.0 [MH-H+].
Example 221: 6-((3i?,65)-{6-[(li?,2Λ)-2-(8-fluoro-6-methoxy-quinolin-4-yl)- l,2-dihydroxy-ethyI]-tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-6][l,4]oxazin- 3-one:
This compound (0.025 g) was obtained as a pale yellow solid, starting from intermediate 220.H (0.119 g) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-6][l,4]oxazine- 6-carbaldehyde (0.069 g) and using the procedure of Example 88, step 88. iv. 1B. NMR (CDCl3) δ: 11.16 (s, 1Η); 8.76 (d, J= 4.4 Hz, IH); 7.63 (d, J= 4,4- Hz, IH); 7.32 (dd, J= 2.4, 9.4 Hz, IH); 7.29 (m, 2H); 7.00 (d, J= 8.1 Hz, IH); 5.46 (d, T = 5.5 Hz, IH); 5.33 (t, J = 4.8 Hz, IH); 4.80 (d, J= 6.4 Hz, IH); 4.62 (s, 2H); 3.92 (overlapped m, IH); 3.89 (s, 3H); 3.69 (d, J= 4.2 Hz, 2H); 3.54 (m, IH); 2.96 (m, IH); 2.73 (t, J= 10.5 Hz, IH); 2.51 (overlapped m, 2H); 2.00 (m, IH); 1.64 (m, 2H); 1.17 (m, IH). MS (ESI, m/z): 499.2 [M+H^].
Example 222: 6-(3R,6S)-{6-[(lJR,2i?)-2-(3-fluoro-6-methoxy-[l,5]naphthyridin-4-yl)- l,2-dihydroxy-ethyl]-tetraliydro-pyraii-3-ylamino}-methyl)-4H-pyrido[3,2-6][l ,4]oxazin- 3-one:
This compound (0.07 g, 22% yield) was obtained as a white solid, starting from intermediate 217.Η (0.21 g, O.62 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-δ][l,4]oxazine- 6-carbaldehyde (0.123 g, 1.1 eq) and applying the protocol of Example 171, step 17 l.viii.
1H NMR (d6-DMSO) δ: 11.14 (s, 1Η); 8.75 (d, J = 1.5 Hz, IH); 8.29 (d, J = 9. 1 Hz, IH); 7.27 (d, J = 8.1 Hz, IH); 7.23 (d, J = 9.1 Hz, IH); 6.96 (d, J = 8.1 Hz, IH); 5.64 (br t, J = 6.3Hz, IH); 5.45 (d, J = 7.1 Hz5 IH); 4.83 (d, J = 6 Hz, IH); 4.61 (s, 2H); 4.00 (s, 3H); 3.88 (m, IH); 3.73 (m, IH); 3.65 (br S5 2H); 2.95 (m, IH); 2.58 (overlapped m, IHC); 2.32 (m5 IH); 2.04-1.88 (m, 2H); 1.58-1.50 (m, 2H); 1.09 (m, IH). MS (ESI, m/z): 500.1 [M+H+].
Example 223: (35,6R)-6-({6-[(lS,25)-l,2-dihydroxy-2-(6-methoxy-[l,5]naphthyridltM- 4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-A][l,4]oxazin-3-one:
This compound (38 mg, 21% yield) was obtained as a beige foam, starting from intermediate 199.iv (120 mg, 0.37 mmol) and 3-oxo-3,4-dihydro-
2#-pyrido[3,2-Z>][l,4]oxazine-6-carbalderiyde (67 mg, 1 eq) and using the procedure of Example 206, step 2O6.vi. MS (ESI, m/z): 482.2 [M+H+].
Example 224: (3S,6Λ)-(6-({6-[(li?,2Jf)-l,2-dihydroxy-2-(6-methoxy-[l,5]naplithyridin- 4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyI)-4.H-pyrido[3,2-Z>] [l,4]thiazin-3-oα «:
224.L (3S,6R)-{6-[(lR,2R)-l,2-dihydroxy-2-(6-jnethoxy-[l,5]naphthyridin-4-yl)-ethyl]- tetrahydro-pyran-3-yl}-carbamic acid tert -butyl ester:
Intermediate 199.ii (1.6 g, 4.15 mmol) was treated with AD mix β®, as described for Example 171, step 171.vi, to give 943 mg (54% yield) of the title diol as a colourless solid. MS (ESI, m/z): 464.1 [M+H+].
224. ii. (lR,2R)-l-((2R,5S)-5-amino-tetrahydro-pyran-2-yl)-2-(6-methoxy-[l,5]naphthyrϊdin- 4-yl) -e thane- 1, 2 -diol:
A solution of intermediate 224.i (283 mg, 0.675 mmol) in DCM (5 ml) was treated with TFA (2 ml). The mixture was stirred at rt for 3 h, concentrated in vacuo, partitioned between E)CM and NTH4OH. The organic layer was dried over MgSO4 and concentrated to give the title amine (200 mg, 92% yield) as a colourless foam. MS (ESI, m/z): 320.2 [M+H+].
224.iii. (3SM)-(6-({6-[(lR,2R)-lJ-dihydroxy-2-(6-methoxy-fl,5Jnaphthyridin-4yl)-ethrylJ- tetrahydro-pyran-3-ylamino}-methyl)-4H-pyndo[3, 2-bJfl, 4]thiazin-3-one : This compound (93 mg, 60% yield) was obtained as a beige foam, starting from intermediate 224. ii (100 mg, 0.31 mmol) and 3-oxo-3,4-dihrydro-
2#-pyτido[3,2-£][l,4]thiazine-6-carbaldehyde (61 mg, 1 eq) and using the procedure of Example 206, step 2O6.vi. MS (ESI, m/z): 498.1 [M+H+].
Example 225: (S^ό^-δ-Clδ-Klit^^-l^-dihydroxy^Kό-methoxy-tljSlnaphth^ridin- 4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-6][l,4]oxazin-3-one:
This compound (67 mg, 44% yield) was obtained as a beige foam, starting from intermediate 224. ii (100 mg, 0.31 mmol) and S-oxo-S^-dihydro-
2H-pyrido[3,2-έ][l,4]oxazine-6-carbaldehyde (56 mg, 1 eq) and using the procedure of Example 206, step 2O6.vi. MS (ESI, m/z): 482.2 [M+Η+],
Example 226: (35',6-R)-6-({(6-[(l^ϊ)-l-hydroxy-2-(6-methoxy-[l,5]naphthyridiα-4-yl)- ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-fe][l,4]thiazin-3-on«:
226.i. {(3S,6R)-6-[(4S,5S)-5-(6-methoxy-[l,5]naphthyridin-4-yl)-2-oxo-[l,3]dioxoran-4-yl]- tetrahydro-pyran-3-yl}-carbamic acid tert-butyl ester.
This compound (970 mg, 91% yield) was obtained as an orange foam, starting from intermediate 199. iii (1 g, 2.38 mmol) and using the procedure of Example 191, step 191. i. MS (ESI, m/z): 446.3 [M)-H+].
226.U. (3S, 6R)-{6-[(lR)-l-hydroxy-2-(6-methoxy-[l, 5]naphthyridin-4-yl)-ethyl]-te trahydro- pyran-3-yl}-carbamic acid tert-butyl ester:
This compound (400 mg, 45% yield) was obtained as a yellowish foam, starting from intermediate 226. i (970 mg, 2.18 mmol) and using the procedure of Example 191, step 191. ii. MS (ESI, m/z): 403.9 [M+H+].
226.iii. (li?)-l-((2i?,55)-5-amino-tetrahydro-pyran-2-yl)-2-(6-methoxy-[l,5]naphttiyridin- 4-yl)-ethanol:
A solution of intermediate 226.ii C400 mg, 0.992 mmol) in DCM (6 ml) was treated with TFA (2 ml). The mixture was stirred at rt for 3 h, concentrated in vacuo, partitioned betrween DCM and NH4OH. The organic layer Λvas dried over MgSO4 and concentrated to gWe the title amine (270 mg, 90%) as a colourless foam. MS (ESI, m/z): 403.4 [M+H+] 226.iv. (3S, 6R)-6-({(6-[(lR)-l-hydroxy-2-(6-methoxy-[l, 5]naphthyridin-4-yl)-ethyl]- tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-b][l,4]thiazin-3-one:
A mixture of intermediate 226.iii (145 mg, 0.48 mmol) and 3-oxo-3,4-dihydro- 2H-pyrido[3,2-έ][l,4]thiazine-6-carbaldehyde (93 mg, 1 eq) in DCE/MeOΗ 1:1 (4 ml) was stirred overnight at it. An excess of NaCNBH3 was added and stirring continued for 3 h_ The mixture was diluted with DCM and washed with aq. ammonia. The organic phases Λvere combined, dried over MgSO4 and concentrated. The residue was purified by chromatography over silica gel (EA/MeOH 9:1, 4:1 +1% NH4OH) and crystallised from ether to give 82 mg (36% yield) of title compound as a colourless solid. 1H NMR (d6-DMSO) δ: 8.66 (d, IH, J=4.44 Hz), 8.23 (d, IH, J =9.03 Hz), 7.73 (d., IH, J=7.83 Hz), 7.53 (d, IH, J= 4.44 Hz), 7.24 (d, IH, J=9.03 Hz), 7.09 (d, IH, J=7.83 Hz), 4.55 (d, IH, J=6.39 Hz), 4.00 (s, 3H), 4.05-3.95 (in, IH), 3.90-3.80 (m, IH), 3.73 (br, 2H), 3.53 (s, 2H), 3.50-3.35 (m, IH), 3.15-2.90 (m, 3H), 2.10-1.80 (m, 2H), 1.80-1.40 (m, 2H), 1.30-1.10 (m, 3H). MS (ESI, m/z): 482.1 [M+H+].
Example 227: (3.S',6i?)-6-({6-[(li-)-l-hydroxy-2-(S-methoxy-[l,5]naphthyridm-4-yl)- ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4H/-pyrido[3,2-Λ][l,4]oxazin-3-one:
This compound (78 mg, 35% yield) was obtained as a colourless solid, starting from intermediate 226. iii (145 mg, 0.48 rnmol) and 3-oxo-3,4-dilrydro- 2H-pyrido[3,2-ό][l,4]oxazine-6-carbaldehyde (85 rng, 1 eq) and using the procedure of Example 226, step 226.iv. MS (ESI, m/z): 466.2 [M+Η+].
Example 228: (35,6i?)-6-({(6-[(15)-l-hydroxy-2-C6-metlioxy-[l,5]naphtliyridiii-4-yl>- ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4£-r-pyrido[3,2-6][l,4]thiazin-3-one:
228.L {(3S, 6R)-6-[(4R, 5R)-5-(6-methoxy-[l, 5]naphthyridin-4-yl)-2-oxo-[l, 3]dioxolan-4'-yl]- tetrahydro-pyran-3-yl}-carbamic acid tert-butyl este r:
This compound (540 mg, 771% yield) was obtained as an orange oil, starting from intermediate 224.i (1 g, 2.38 mmol) and using the procedure of Example 191, step 191. i. MS (ESI, m/z): 446.3 [M+H+]. 228.ii. (3S, 6Jl)-{6-[(lS)-l-hydroxy-2-(6-methoxy-[l, 5]naphthyridin-4-yl)-ethyl]-tetrahydro- pyran-3-yl}-carbamic acid tert-hutyl ester.
This compound (190 mg, 39% yield) was obtained as a yellowish foam, starting: from intermediate 228. i (540 mg, 1.21 mmol) and using the procedure of Example 191, step 191. ii. MS (ESI, m/z): 403.9 [M+H+].
228. Hi. (lS)-l-((2R,5S)-5-amino-tetrahydro-pyran-2-yl)-2-(6-methoxy-[l,5]naphthyridzn- 4-yl)-ethanol:
A solution of intermediate 228.ii (190 mg, 0.47 mmol) ia DCM (6 ml) was treated witli TFA (2 ml). The mixture was stirred at rt for 3 h, concentrated in vacuo, partitioned between DCM and NH4OH. The organic layer was dried over MgSO4. and concentrated to give trie title amine (130 mg, 90%) as a colourless foam. MS (ESI, m/z): 403.4 [M+H+].
228.iv. (3S,6R)-6-({(6-[(lS)-l-hydroxy-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]- tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-b][l \,4]thiazin-3-one: A mixture of intermediate 228. iii (120 mg, 0.-4 mmol) and 3-oxo-3,4-diliydro- 2H-pyrido[3,2-δ][l,4]thiazine-6-carbaldehyde (77 mg, 1 eq) in DCE/MeOΗ 1:1 (4 ml) was stirred overnight at rt. An excess Of NaCNBH3 was added and stirring continued for 3 h. The mixture was diluted with DCM and washed with aq. ammonia. The organic phases were combined, dried over MgSO4 and concentrated. The residue was purified by chromatography over silica gel (EA/MeOH 9:1, 4:1 + 1% NH4OH) and cxystallised from ether to give 30 mg (16% yield) of title compound as a yellowish solid. MS (ESI, m/z): 482.1 [M+H+].
Example 229: 6-({(3R,6,S)-6-[(15',21S)-l,2-dihydroxy-2-(3-methoxy-qumoxalin-5-yl>- ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-6][l,4]thiazin-3-one:
229.L (3R,6S)-{6-[(lS,2S)-l,2-dihydroxy-2-(3-methoxy-qztinoxalin-5-yl)-ethyl]-temhy<dro- pyran-3-yl}-carbamic acid tert-butyl ester.
This compound (0.304g, 69%) was obtained as a colourless foam starting from intermediate 177. i (0.401 g, 1.04 mmol) and using the protocol of Example 171, step 171. vi, except that AD mix α® Λvas employed as reagent. MS (ESI, m/z): 420.2 [M+Η+]. 229. ii. (lS,2S)-l-[(2S,5R)-(5-amino-tetrahydro-pyran-2-yl)-2-(3-methoxy-quinoxalin-5-yl)- ethane- 1,2-dioh
This compound was obtained as a colourless solid (0.171 g, 75% yield) from intermediate 229. i (0.3 g, 0.71 mmol), using the protocol of Example 77, step 77.iii. 1U NMR (d6-DMSO) δ: 8.59 (s, IH); 7.87 (app d, J = 7.8 Hz, 2H); 7.62 (t, J = 7.8 Hz, IH) ; 5.80 (br s, IH); 5.09 (br d, J = 5.5 Hz, IH); 4.42 (br d, J = 7.5 Hz, IH); 4.03 (s, 3H> ; 3.74 (ddd, J = 2.8, 4.5, 8.9 Hz, IH); 3.54 (m, IH); 3.24 (m, IH); 2.81 (t, J = 10.4 Hz, 1H> ; 2.53 (overlapped m, IH); 1.92 (m, 2H); 1.43 (br s, 2H); 1.26 (m, IH); 1.07 (m, IH). MS (ESI, m/z): 320.0 [M+H+].
229.iii. 6-({(3R, 6S)-6-[(lS, 2S)-1, 2-dihydroxy-2-(3-methoxy-quinoxalin-5-yl)-ethyl]- tetrahydro-pyran-3-ylamino} -methyl)-4H-pyrido[3, 2-b][l, 4]thiazin-3-one :
This compound was prepared from intermediate 229. ii (0.167 g, 0.52 mmol) and 3-oxo>- 3,4-dihydro-2H-pyrido[3,2-&][l,4]thiazine-6-carbaldehyde (0.111 g, 0.57 mmol), using th_e procedure described in Example 171, step 171.V. The title compound (0.178 g, 68% yield) was obtained as a beige foam .
1U NMR (d6-DMSO) δ: 10.86 (s, 1Η); 8.59 (s, 1Η); 7.87 (app d, J = 7.8 Hz, 2H); 7.73 (<d, J = 7.8 Hz, IH); 7.62 (t, J = 7.8 Hz, IH); 7.08 (d, J = 7.8 Hz, IH); 5.79 (dd, J = 2.7, 6.3 Hz, IH); 5.10 (d, J = 6.3 Hz, IH); 4.43 (d, J = 7.8 Hz, IH); 4.04 (s, 3H); 3.89 (dd, J = 2.2, 10.4 Hz, IH); 3.75 (dd, AB system, J = 11.9 Hz, Δ= 0.055, 2H); 3.54 (overlapped m, IHT); 3.53 (s, 2H); 3.28 (m, IH); 2.90 (t, J = 10.5 Hz, IH); 2.46 (m, IH); 2.05-1.91 (m, 3K); 1.31-1.11 (m, 2H). MS (ESI, m/z): 498.2 [M+H+]
Example 230: 6-({(35r,6i?)-6-[(liϊ,2J?)-l,2-dihydroxy-2-(3-methoxy-quinoxalin-5-yI)- ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-6][l,4]thiazin-3-one:
230. i. trans-{(3S, 6R)-{6-[2- (3-methoxy-quinoxalin-5-yl)-vinylJ-tetrahydro-pyran-3-yl}- carbamic acid tert-butyl ester:
The title (£)-alkene (1.90 g, 99% yield) was obtained as a white solid, starting fro>m 3-methoxy-quinoxaline-5-carbaldehyde (0.92 g, 4.88 mmol) and intermediate 171. iv (2.27 g, 3.4 mmol) and using the procedure described in Example 171, step 171.V. The purity of title compound was around 80%. MS (ESI, m/z): 498.2 [M+H+].
230. ii. (3S,6R)-{6-[(lR, 2R)-l,2-dihydroxy-2-(3-methoxy-quinoxalin-5-yl)-ethyl]-tetrahydro- pyran-3-yl}-carbamic acid tert-biityl ester:
The title diol (0.29 g, 17% yield) was obtained as a colourless solid, starting from intermediate 230. i (1.5 g, 3.89 mmol) and using the protocol described in Example 171, step 171.vi.
1H NMR (CDCl3) δ: 8.52 (s, IH); 7.99 (dd, J = 1.3, 8.2 Hz, IH); 7.85 (d, J = 7.1 Hz, IH); 7.62 (dd, J = 7.1, 8.2 Hz, IH); 5.84 (br s, IH); 4.75 (br s, IH); 4.28 (m, IH); 4.20-4.07 (m, IH); 4.07 (s, 3H); 3.93 (br s, IH); 3.65 (br s, IH); 3.43-3.34 (m, 2H); 3.00 (t, J = 10.6 Hz, IH); 2.16 (m, IH); 1.96 (m, IH); 1.75 (m, IH); 1.46 (s, 9H); 1.28 (rn, IH). MS (ESI, m/z): 420.1 [M+H+].
230. iii. (IR, 2R)-1-[(2R, 5S)-(5-amino-tetrahydro-pyran-2-yl)-2-(3-methoxy-quinoxalin-5-yl)- ethane- 1,2-dioh
This compound was obtained as a colourless solid (0.14 g, 75% yield) from intermediate 230. ii (0.29 g, 0.68 mmol), using the protocol of Example 77, step 77. iii. MS (ESI, m/z): 320.1 [M+H+].
23O.iv. 6-({(3S,6R)-6-f(lR,2R)-l,2-dihydroxy-2-(3-methoxy-quinox:alin-5-yl)-ethylJ- tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-b][l,4]thiazin-3-one\
This compound (0.62 g, 28% yield) was obtained as a beige foam from intermediate 23O.iii (0.14O g, 0.44 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-έ][l ,4]thiazine-6-carbaldehyde (0.093 g, 0.48 mmol), using the procedure of Example 173, step 173.V. MS (ESI, m/z): 498.2 [M+Η+].
Example 231 : 6-({(3JR,65)-6-[(15)-2-(8-fluoro-6-methoxy-quinolin-4-yl)-l-hydroxy- ethyI]-tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-6][-l,4]thiazin-3-one:
231.i. {(3R, 6S)-6-[(4R, 5R)-5-(8-fluoro-6-methoxy-quinolin-4-yl)-2-oxo-[l, 3]dioxolan-4-yl]- tetrahydro-pyran-3-yl} -carbamic acid tert-butyl ester:
This compound (0.762 g, 37% yield) was obtained as a colourless foam, starting from intermediate 220.i (1.92 g, 4.41 mmol) and using the procedure described in Example 190, step 190.L 1E NMR (d6-DMSO) δ: 8.84 (d, J = 4.5 Hz, IH); 7.64 (d, J = 4.5 Hz, IH); 7.44 C<id, J = 2.4, 12.0 Hz, IH); 7.13 (d, J= 1.5 Hz, IH); 6.82 (br d, J = 8.1 Hz, IH); 6.57 (d, J = 4.8 Hz, IH); 4.86 (dd, J = 2.5, 4.8 Hz, IH); 3.97 (overlapped m, IH); 3.96 (s, 3H); 3.67 (d, J = 11.2 Hz, IH); 3.57 (br s, IH); 3.19 (t, J = 10.7 Hz, IH); 1.92 (m, IH); 1.69 (m, IH); 1.57 (m, IH); 1.40 (overlapped m, IH); 1.38 (s, 9H). MS (ESI, m/z): 463.3 [M+H"1"].
231.ii. {(3R, 6S)-6-[(lS)-2-(8-fluoro-6-methoxy-quinolin-4-yl)-l-hydroxy-ethyl]-tetrahydro- pyran-3-yl}-carbamic acid tert-butyl ester:
This compound (0.347 g, 50% yield) was obtained as a colourless foam, starting from inteπnediate 231. i (0.751 g, 1.62 mmol) and using the procedure of Example 190, step 190.U. MS (ESI, m/z): 421.2 [M+H+].
231.iii. (IS)-I -((2S, 5R)-5-ctmino-tetrahydro-pyran-2-yl)-2-(8-fluoro-6-methoxy-q τiinolin- 4-yl)-ethanol:
This compound (0.21 g, 95% yield) was obtained as a colorless solid, starting from intermediate 23 l.ii (0.344 g, 0.819 mmol) and using the procedure of Example 173, step 173.iv. MS (ESI, m/z): 321.2 [M+H+].
231.iv. 6-({(3R, 6S)-6-[(lS)-2-(8-fluoro-6-methoxy-quinolin-4-yl)-l-hydroxy-ethyTJ- tetrahydro-pyran-3-ylamino}-methyl)-4H-pyndo[3,2-b][l,4]thiazin-3-one: This compound (0.109 g, 64 % yield) was obtained as a colourless foam, starting from intermediate 231. iii (0.109 g, 0.34 mmol) and 3-oxo-3,4-dihydro-
2H-pyrido[3,2-δ][l,4]thiazme-6-carboxylic acid (0.072 g, 0.37 mmol) and using the procedure of Example 172. MS (ESI, m/z): 496.2 [M+Η+].
Example 232: 6-{[6-(6-fluoro-quinolin-4-yloxymethyl)-tetrahydro-pyran-3-yrlamino]- methyl}-4H-pyrido[3,2-6][l,4]thiazin-3-one:
232.L 6-fluoro-quinoHn-4-oh
This compound (1.9O g, 83% yield) was obtained as a yellow solid, starting from 4-fluoroaniline (1.55 g, 14 mmol) and using the procedure of Example 138, step 138. i. MS (ESI, m/z): 164.1 [M+H+]
232. ii. (3R,6S)-6-(6-fluoro-quinolin-4-yloxymethyl)-tetrahydro-pyran-3-ylamine:
This compound (1.08 g, 3.9 mmol) was obtained as a colourless solid, starting from intermediate 78. i (2.55 g, 11 mmol) and intermediate 232.i (1.89 g, 11.6 mmol) and using the procedure described in Example 135, stepl35.i. MS (ESI, m/z): 277.1 [M+H+].
232. iii. 6-{[6-(6-fluoro-quinolin-4-yloxymethyl)-tetrahydro-pyran-3-ylamino]-methyl}-4H- pyrido[3, 2-b][l, 4]thiazin-3-one :
Starting from intermediate 232.H. (0.135 g, 0.49 mmol) and 3-oxo-3,4-dihydro- 2H-pyrido[3,2-δ][l,4]thiazine-6-carbaldehyde (0.105 g, 1.1 eq.), the title compound (0.133 g,
59% yield) was obtained as a pale yellow foam using the procedure of Example 88, step 88. iv.
1H NMR (CDCl3) δ: 10.87 (s, IH); 8.71 (d, J= 5.2 Hz, IH); 8.03 (dd, J= 5.4, 9.3 Hz, IH);
7.75 (m, 2H); 7.66 (m. IH); 7.09 (m, 2H); 4.22 (d, J= 4.9 Hz, 2H); 4.02 (m, IH);
3.76 (overlapped d, J = 2.4 Hz, 2H); 3.74 (overlapped m, IH); 3 .53 (s, 2H); 3.07 (t, J = 10.5 Hz, IH); 2.56 (overlapped m, IH); 2.12 (m, 2H); 1.84 (m, IH); 1.48 (m, IH);
1.32 (m, IH).
MS (ESI, m/z) : 455.5 [M+H+].
Example 233: 6-{[(3J?,<ι5)-6-(6,8-difluoro-quinolin-4-yloxymethyl)-tetrahydro-pyran- 3-ylamino]-methyl}-4H-pyrido[3,2-6][l,4]thiazin-3-one:
233. i. 6,8-difluoro-quinolin-4-ol:
This compound (4.2 g, 29% yield) was prepared as a tan solid, starting from 2,4-difluoroaniline (10 g, 14 mmol) and using the procedure of Example 138, step 138. i. 1H NMR (d6-DMSO) δ: 7.87 (d, J = 7.4 Hz, IH); 7.74 (ddd, J = 2.8, 8.6, 11.3 Hz, IH); 7.58 (ddd, J = 1.5, 2.8, 9. 1 Hz, IH); 6.19 (d, J = 7.4 Hz, IH). MS (ESI, m/z): 164.1 [MH-H+].
233. ii. (3R,6S)-6-(6,8-diJluoro-quinolin-4-yloxymethyl)-tetrahydro-pyran-3-ylamine\
This compound (1.8 g, 61% yield) was prepared as a colourless foam, starting from intermediate 78. i (2.31 g, 10 mmol) and intermediate 233. i (1.90 g, 10.5 mmol) and using the procedure of Example 135, step 135. i. The purity of the product was 70-80%. MS (ESI, m/z): 295.3 [M+H+].
233. Hi. 6-{[(3R, 6S)-6-(6, 8-difluoro-quinolin-4-yloxymethyl)-tetrahydro-pyran-3 yl amino] - methyl}-4H-pyrido[3, 2-b][l, 4]thiazin-3-one :
Starting from intermediate 233. ii. (0.3 g, 1.02 mmol) and 3-oxo-3 .,4-dihydro- 2H-pyrido[3,2-£][l,4]thiazine-6-carbaldehyde (0.188 g, 0.97 mmol), the title compound (0.230 g, 47% yield) was obtained as a colourless solid using the procedure of Example 88, step 88. iv. MS (ESI, m/z): 473.3 [M+Η+].
Example 234: 3-oxo-3,4-dihyclro-2//-pyrido[3,2-6][l,4]oxaziiie-6-carboxyIic a.cid (3J?,65)-{6-[(lS)-l-hydroxy-2<3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro-pyran-3-yl}- amide:
Starting from intermediate 203. iii. (0.155 g, 0.51 mmol) and 3-oxo-3 ,4-dihydro- 2H-pyrido[3,2-£][l,4]oxazine-6-carboxylic acid (0.118 g, 1.1 eq), the title compound (0.070 g, 27% yield) was obtained as a colorless solid using the procedure of Example 172. Purification on silica gel was carried out using a DCM-MeOH 9-1 mixture containing 1% aq. NH4OH. MS (ESI, m/z): 495.2 [M+H+].
Example 235: (15)-l-{(25',5Λ)-5-ϊrαn5-[3-(2,5-difluoro-phenyl)-allylamino]-te^:rahydro- pyran-2-yI}-2-(6-methoxy-quinolin-4-yl)-ethanol:
235. i. trans-3-(2,5-difluoro-phenyl)-acrylic acid ethyl ester.
To an iced chilled suspension of NaH (1.13 g, 60% oil dispersion, 28.2 mmol) in XHF (32 ml) was added triethylphosphonoacetate (5.6 ml, 28.2 mmol). The reaction mixture was stirred at rt for 20 min. 2,5-difluoro-benzaldehyde (3.34 g, 23.5 mmol) was added dropwise. After 30 min, 10% aq. NaHSO4 (100 ml) was added and the mixture was diluted with EA (150 ml). The two phases were separated and the aq layer was extracted twice (2 x 100 inl) with EA. The combined organic layers were washed with brine (100 ml), dried over Na2SO4, filtered and concentrated to dryness. The residue was chromatographed over silica gel (Hex-EA 19-1) to afford the title unsaturated ester (5.0 g, 100%) as a colourless oil. 1H NMR (CDCl3): 7.76 (dd, J = 1, 16.1 Hz, IH); 7.26-7.21 (m, IH); 7.13-7.03 (m, 2H); 6.52 (d, J = 16.1 Hz, IH); 4.29 (q, J = 7.1 Hz, 2H); 1.36 (t, J = 7.1 Hz, 3H).
235. ii. trans- 3-(2, 5-difluoro-phenyl)-prop-2~en- 1 -oh
To a solution of intermediate 235. i (5.0 g, 23.5 mmol) in ether (100 ml), cooled to 00C, was added a DIBAH (IM in hexanes, 60 ml, 60 mmol). The mixture was stirred at the saoie temperature for 40 min. Water (6 ml) was added and the mixture was stirred 30 min. The so lid was filtered off and thoroughly washed with etlxer. The filtrate was concentrated to dryness to afford the title alcohol (4.0 g, 98% yield) as a colourless oil.
1H NMR (CDCl3): 7.15 (ddd, J = 3.1, 5.9, 9.0 Hz, IH); 7.00 (td, J = 4.6, 9.0 Hz, IEi); 6.95-6.87 (m, IH); 6.75 (dd, J = 1.3, 16.1 Hz, I H); 6.45 (td, J = 5.3, 16.1 Hz, IH); 4.38 (br d, J = 5.3 Hz, 2H); 1.63 (s, IH).
235.iii. trans -3-(2, 5-difluoro-phenyl)-propenah
To a solution of intermediate 235. ii (1.70 g, 1 O mmol) in DCM (20 ml) was added, at rfc, a solution of E>ess-Martin periodinane (15 wt% in DCM, 20 ml). The mixture was stirred art rt for 3 h. After concentration to dryness, the residue was chromatographed over silica gel (Hex-EA 9-1 ) to afford the title aldehyde (1.06 g, 63% yield) as a white solid. 1H NMR (d6-DMSO): 9.74 (d, J = 7.6 Hz, IH); 7.88-7.81 (m, IH); 7.79 (overlapped dd, J = 1.4, 16.0 Hz, IH); 7.46-7.37 (m, 2H); 6.67 Cdd, J = 7.6, 16.0 Hz, IH).
235. iv. (lS)-l-{(2S,5R)-5-trans-[3-(2,5-difluoro-phenyl)-allylamino]-tetrahydro-pyran-2-yl}- 2-(6-methoxy-quinolin-4-yl)-ethanol:
Starting from intermediate 190. iii (0.105 g, 0.34 mmol) and intermediate 235. iii (0.064 g,
1.1 eq.), the title compound (0.126 g, 80% yield) was obtained as a colourless foam according to the procedure described in Example 88, step 88. iv.
1H NMR (d6-DMS0): 8.62 (d, J = 4.4 Hz, IH); 7.92 (d, J = 9.1 Hz, IH); 7.48 (ddd, J = 3.2, 6.1, 9.5 Hz, IH); 7.43 (m, IH); 7.39 (dd, J = 2.8, 9.1 Hz, IH); 7.32 (d, J = 4.4 Hz, L H);
7.27 (m, IH); 7.11 (m, IH); 6.62 (d, J = 16.2 Hz, IH); 6.49 (td, J = 5.3, 16.2 Hz, IH); 4.75 (d,
J = 6.3 Hz, IH); 4.08 (m, IH); 3.90 (s, 3H); 3.74 (m, IH); 3.40 (m, 2H); 3.30 (m, LH);
3.15 (m, IH); 2.94 (m, 2H); 2.57 (m, IH); 2.07 (m, IH); 1.84 (br s, IH); 1.58 (m, 2H);
1.18 (m, IH). MS (ESI, m/z): 455.5 [M+H+]. Example 236: 6-({(3i?,65)-6-[(2ΛiS)-2-hydroxy-2-(6-methoxy-[l,5]naphthyridin-4-yl)- ethyl]-tetrahydro-pyran-3-ylamiαo}-methyl)-4H-pyrido[3,2-A][l,4]thiazin-3-one:
236. i. {(3R,6S)-6-[(2RS)-2-hydroxy-2-(6-methoxy-[l,5]naphthyridm-4-yl)-ethyl]-tetrcihydro- pyran-3-ylj-carbamic acid tert-butyl ester: Starting from 8-bromo-2-methoxy-[l,5]naphthyridine (5.88 g, 24.6 mmol) and intermediate 203. iii (2.O g, 8.22 mrnol), the title benzylic alcohol (1.6 g, 3.96 mrnol) was obtained as a yellowish foam using the procedure described in Example 203, step 203. iv. The compound was recovered as a 1:1 mixture of epimers with a purity of 90%. MS (ESI, m/z): 404.1 [M+H+].
236.U. (2RS)-2-((2S,5R)-5-amino-tetrahydro-pyran-2-yl)-l-(6-methoxy-[l,5]naphthyridin- 4-yl)-ethanol:
This amine (0.45 g, 74% yield) was prepared from intermediate 236. i (1.6 g, 3.96 mmol), using the procedure described in Example 171, step 171.vii. A 1:1 mixture of epirners was obtained as a colourless foam. MS (ESI, m/z): 304.2 [M+H+] .
236.iii. 6-({(3R,6S)-6-[(2RS)-2-hydroxy-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethylJ- tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-b][l,4]thiazin-3-one:
Starting from intermediate 236. ii (0.11 g, 0.36 mmol) and 3-oxo-3,4-dihydro- 2H-pyrido[3,2-Z>][l,4]thiazine-6-carbaldehyde (0.077g, 1.1 eq), the title compound (0.125 g, 71% yield) was obtained as a yellowish foam using the procedure of Example 88, step 88. iv. 1H NMR (d6-DMSO) mixture of epimers : 10.86 (s, IH); 8.77 (d, J = 4.6 Hz, 0.5H); 8.75 (d, J = 4.6 Hz, 0.5H); 8.25 (d, J = 9.1 Hz, 0.5H); 8.24 (d, J = 9.1 Hz, 0.5H); 7.75-7.71 (m, 2H); 7.25 (d, J = 9.1 Hz, 0.5H); 7.23 (d5 J = 9.1 Hz, 0.5H); 7.08 (d, J = 7.8 Hz, 0.5H); 7.06 (d, J = 7.8 Hz, 0.5H); 5.74 (m, 0.5H); 5.63 (m, 0.5H); 5.39 (d, J = 4.9 Hz, 0.5H); 5.35 (d, J = 5.2 Hz, 0.5H); 4.01 (s, 1.5H), 4.00 (s, 1.5H); 4.00-3.79 (m, IH); 3.71 (br S5 2H); 3.52 (s, 2H), 3.52 (overlapped m, 0.5H); 3.43 (m, 0.5H); 2.96 (t, J = 10.3 Hz, 0.5H); 2.90 (t, J = 10.5 Hz, 0.5H); 2.46 (m, IH); 2.08-1.74 (m, 4H); 1.64-1.55 (m, IH); 1.31-1.14 (tn, 2H). MS (ESI, m/z): 482.1 [M+H+]. 5 010154
- 246 -
Example 237: 3-oxo-3,4-dihydro-2H-pyrido[3,2-6][l,4]thiazine-6-carboxylic acid {(3Λ,65)-6-[(2Λ5)-2-hydroxy-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-fcetrahydro- pyran-3-yl} -amide:
Starting from intermediate 236. ii (0.45 g, 1.48 mmol) and 3-ox.o-3,4-dihydro- 2H-pyrido[3,2-b][l,4]oxazine-6-carboxylic acid (0.343 g, 1.1 eq), the title compound (0.4 g, 54% yield) was obtained as a colourless solid according to the procedure described in Example 172. Purification on silica gel was carried out using a DCM-MeOK 93-7 mixture containing 1 % aq. NH4OH. MS (ESI, m/z): 496.0 [M+H+].
Example 238: 2-{(2^,5i?)-5-[frα«5-3-(2,5-difluoro-phenyI)-allylamino]-tetM-ahydro- pyran-2-yl}-l-(6-methoxy-[l,5]naphthyridin-4-yl)-ethanol:
Starting from intermediate 236.U (0.15 g, 0.49 mmol) and intermediate 235. iii (0.091 g, 1.1 eq), the title compound (0.160 g, 71% yield) was obtained as a colourless semi-solid using the procedure of Example 88, step 88. iv. Purification was carried out by chromatography over silica gel (DCM-MeOH 19-1 containing 0.5% NH4OH). The compound was obtained as a 1:1 mixture of epimers. MS (ESI, m/z): 456.2 [M+H+].
Example 239: rrαns-3-(2,5-difluoro-phenyl)-iV-{(3JR,6S)-6-[(2JR-y)-2-hydroxy- 2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}-aciylamide:
Starting from intermediate 236.ii (0.1 g, 0.33 mmol) and frα«s-3-(2,5-difiuoro-phenyi)-acrylic acid (0.067 g, 1.1 eq), the title compound (0.116 g, 75% yield) was obtained as a beige solid using the procedure of Example 172. Purification was carried out by chromatography over silica gel (DCM-MeOH 19-1 containing 1% aq. NH4OH). The compound was obtained as a 1:1 mixture of epimers. 1H NMR (d6-DMSO) mixture of epimers : 8.78 (d, J = 4.7 Hz, 0.5H); 8.76 (d, J = 4.7 Hz, 0.5H); 8.26 (d, J = 9.1 Hz, 0.5H); 8.25 (d, J = 9.1 Hz, 0.5H); 8.14-8.10 (m, IK); 7.77-7.75 (m, IH); 7.53-7.23 (m, 5H); 6.73 (d, J = 16.0 Hz, 0.5H); 6.72 (d, J = 16.0 Hz5. 0.5H); 5.78 (m, 0.5H); 5.66 (m, 0.5H); 5.43 (d, J = 5.0 Hz, 0.5H); 5.40 (d, J = 5.2 Hz, 0.5HI); 4.02 (s, 1.5H); 4.01 (s, 1.5H); 3.91-3.76 (m, 2H); 3.61 (m, 0.5H); 3.48 (m, 0.5H); 3.06 (t, J = 10.5 Hz, 0.5H); 2.98 (t, J = IO Hz, 0.5H); 2.06-1.35 (m, 6H). MS (ESI, m/z): 470.1 [M+H+].
Example 240: *røws-3-(2,5-difluoro-phenyl)-I^(31^6S)-6-[(l»SH-hydroxy- 2-(6-methoxy-quinoIin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}-acrylamide:
Starting from intermediate 19O.iii (0.055 g, 0. 182 mmol) and tr<ms-3-(2,5-difluoro-phenyl)- acrylic acid (0,064 g, 1.1 eq.), the title compound (0.070 g, 82% yield) was obtained as a colourless solid according to the procedure described in Example 172. 1H NMR (d6-DMSO) mixture of epimers : 8.63 (d, J = 4.4 Hz, IH); 6.16 (d, J = 7.8 Hz, IH); 7.92 (d, J = 9.1 Hz, IH); 7.54-7.26 (m, 7H); 6.72 (d, J = 16.0 Hz, IH); 4.86 (d, J = 6.4 Hz, IH); 4.00 (m, IH); 3.91 (s, 3H); 3.90-3,75 (m, 2H); 3.33 (m, IH); 3.20 (m, IH); 3.05 (t, J = 10.5 Hz, IH); 2.97 (dd, J = 5.1, 13.7 Hz, IH); 2.00 (m IH); 1.72-1.62 (m, 2H); 1.44 (m, IH). MS (ESI, m/z): 469.3 [M+H+].
Example 241 : (lR,2S)A-{(2S,5R)-5-[trans-3-(2,5-dinuoro-phenyl)-allyl&mino]- tetrahydro-pyran-2-yl}-2-(6-methoxy-[l,5]n»phthyridin-4-yl)-ethane-l,2-diol:
Starting from intermediate 173.iv (0.054 g, O.17 mmol) and intermediate 235. iii (0.031 g, 1.1 eq), the title compound (0.044 g, 56% yield) was obtained as a colorless foam using the procedure of Example 88, step 88. iv. Purification was carried out by chromatography over silica gel (DCM-MeOH 19-1 containing 1% aq_. NH4OH). Rf (TLC over SiO2): 0.18 (DCM-MeOH 19-1 containing 1% aq. NH4OH). MS (ESI, m/z): 472.2 [M+H+].
Example 242: 3-oxo-3,4-dihydro-2H-pyrido[3,2-6][l,4]thiazine-6-carboxylic acid
{(3R,65)-6-[(lS,2iϊ)-2-(3-fluoro-6-methoxy-[X,5]naphthyridin-4-yl)-l,2-dihydroxy-ethyl]- tetrahydro-pyran-3-yl}-amide:
Starting from intermediate 217.H (0.3 g, 0.89 mmol) and 3-oxo-3,4-dihydro- 2H-pyrido[3,2-έ][l,4]oxazine-6-carboxylic acid (0.205 g, 1.1 eq), the title compound (0.3 g, 63% yield) was prepared as a light beige solid according to the procedure described in Example 172. Purification was carried out by trituration of the crude material in ether. MS (ESI, m/z): 530.3 [M+Η+]. Example 243: S-oxo-S^-dihydro^H-pyridoP^-δπi^oxazine-ό-carboxylic acid
{(Si-jδSO-δ-ICl^lΛ^-CS-fluoro-β-methoxy-IljSlnaphth-yridin-^-yO-ljl-dihydroxy- ethyl]-tetrahydro-pyran-3-yl}amide:
243.i. S-oxo-S^-dihydro^H-pyridoβ^-Z^tl^oxazine-ό-carboxylic acid: To a mixture of 3-oxo-3,4-dihydro-2H-pyrido[3,2-Z>][l,4]oxazine-6-carbaldehyde (1 g, 5.61 mrnol) in acetone (30 ml) and water (5 ml) was added potassium permanganate (1.77 g, 2 eq.). The reaction proceeded 1 h at rt and TΗF (50 ml) and water (50 ml) were added. The reaction mixture was filtered and the filtrate concentrated in vacuo. The pΗ of the aq. residue was brought to 1 adding IN HCl. The solid that formed was filtered off, washed with water and dried in vacuo. The title acid (0.560 g, 52% yield) was obtained as a orange solid. MS (ESI, m/z): 195.1 [M+Η+].
243. ii. 3-oxo-3,4-dihydro-2H-pyrido[3,2-b] [1 ,4]oxazine-6-carboxylic acid {(3R,6S)-6-[(lS,2R)-2-(3-fluoro-6-methoxy-[l,5]naphth-yridin-4-yl)-l,2-dihydroxy-ethyl]- tetrahydro-pyran-3-yl} amide : Starting from intermediate 217.ii (0.32 g, 0.89 mmol) and intermediate 243.i (0.202 g, 1.1 eq), the title compound (0.007 g, 1.4% yield) was obtained as a colourless solid according to the procedure described in Example 172. Purification over silica gel was carried out using DCM-MeOH 9-1 1% aq. NH4OH. MS (ESI, m/z): 514.1 [M+H+].
Example 244: (3,4-dichloro-benzyl)-{6-[2-(8-fluoro-6-methoxy-quinoIin-4-yl)-ethyl]- tetrahydro-pyran-3-yl}-amine:
Starting from intermediate 219.ii (0.106 g, 0.34 mmol) and 3,4-dichlorobenzaldehyde (0.067 g, 1.1 eq.), the title compound (0.100 g, 62% yield) was obtained as a colourless solid according to the procedure described in Example 88, step 88. iv. The product was purified by chromatography over silica gel (DCM-MeOH 93-7 1% aq. NH4OH).
1H NMR (d6-DMSO): 8.65 (d, J = 4.4 Hz, IH); 7.60 (d, J = 1.9 Ηz, IH); 7.56 (d, J = 8.2 Hz5 IH); 7.39 (d, J = 4.4 Hz, IH); 7.34-7.23 (m, 3H); 3.97 (m, IH); 3.92 (s, 3H); 3.73 (d, J = 4.1 Hz, 2H); 3.21 (m, IH); 3.08 (m, 2H); 2.94 (t, J = 10.6 Hz, IH); 2.44 (m, IH); 2.23 (br. s, IH); 1.97 (m IH); 1.77 (m, 2H); 1.68 (m, IH); 1.31-1.16 (m, 2H). MS (ESI, m/z): 463.0 [M+H*]. Exaniple 245: 3-oxo-3,4-dihydro-2H-pyrido[3,2-6][l,4]thiazine-6-carboxylic acid
[(2J?,3Λ,61S)-6-[(l1S,2JR)-l,2-dihydroxy-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyI]-
2-(2-hydroxy-ethyl)-tetrahydro-pyran-3-yl]-amide:
245.i. (2R, 3R, 6S)~(2-allyl-6-hydroxymethyl- 3, 6-dihydro-2H-pyran-3-yl)-carbamic acid tert-butyl ester:
A solution of (2i?,3i?,65)-[2-allyl-6-(tert-butyl-dimethyl-silanyloxymethyl)-3,6-dihydro- 2H-pyran-3-yl]-carbamic acid tert-butyl ester (obtained as described in Eur. J. Org. Chem. (2003), 2418-2427; 26 g, 67.7 mmol) in AcOH (180 ml), water (60 ml) and TΗF (60 ml) was heated at 700C for 7 h. The volatiles were removed in vacuo and the residue was partitioned between saturated NaΗCU3 (200 ml) and EA (500 ml). The org. layer was washed with saturated NaHCO3 (2 x 100 ml), brine (100 ml), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified over silica gel (Hex-EA 1-3) to afford the title alcohol (13.6 g, 74% yield) as a colourless oil. 1HNMR (CDCl3): 6.07-5.76 (m, 3H); 5.22-5.12 (m, 2H); 4.72 (br d, J = 10 Hz, IH); 4.28 (qd, J = 2.7, 6.6 Hz, IH); 4.04 (m, IH); 3.84 (rn, IH); 3.73 (dd, J = 9.6, 11.7 Hz, IH); 3.49 (m, IH); 2.34 (m, 2H); 2.07 (br s, IH); 1.47 (s, 9H).
245.ii. (2R, 3R, 6S)-[2-((2RS)-2, 3-dihydroxy-propyl)-6-hydroxymethyl-3, 6-dihydro-2H-pyran- 3-yl]-carbamic acid tert-butyl ester:
Intermediate 245. i (13.6 g, 50 mmol) was converted to the title triol (13.8 g, 90% yield, colorless oil) using the protocol described in Example 171, step 171.vi. MS (ESI, m/z): 304.5 [M+H÷].
245.iii. (2R,3R,6S)-[2-((4RS)-2,2-dimethyl-[l,3]dioxolan-4-ylmethyl)-6-hydroxymethyl- 3, 6-dihydro-2H-pyran-3-yl]-carbamic acid tert-butyl ester:
Intermediate 245. ii (13.8 g, 45.4 mmol) was converted into the title acetonide (13.2 g, 38.4 mmol, colourless oil) using the protocol described in Example 148, step 148.iv. Purification over silica gel was carried out using Hex-EA 1-2 mixture as an eluent. MS (ESI, m/z): [M+H+]. 245.iv. (2R,3R,6S)- [2-((4RS)-2,2-dimethyl-[l,3]dioxolan-4-ylmethyl)-6-hydroxymethyl- tetrahydro-pyran-3-yl] -carbamic acid tert-butyl ester:
To a solution of intermediate 245. iii (13.2 g, 38 mmol) in EA (190 ml) Λvas added platinum oxide (1.5 g). The reaction was stirred under hydrogen atmosphere for two hours, filtered and the filtrate was concentrated to dryness to afford the title pyran derivative (12.57 g, 94% yield) as a colourless foam. MS (ESI, m/z): [M+H+].
245.V. (2R,3R,6S)-[2-((4RS)-2,2-dimethyl-[l,3]dioxolan-4-ylmethyl)-6-(l-phenyl- lH-tetrazole-5-sulfonylmethyl)-tetrahydro-pyran-3-yl] -carbamic acid ter-t-butyl ester. Intermediate 245. iv (12.57 g, 36.2 mmol) was converted into the title sulfone (4.07 g, 7.57 mmol, colourless foam) using the protocols of Example 164, steps 164.L and 164. ii. MS (ESI, m/z): 538.1 [M+H+].
245.vi. (2R, 3R, 6S)-{2-(2,2-dimethyl-[l, 3]dioxolan-4-ylmethyl)-6-trans-£2-(6-methoxy- [l,5]naphthyridin-4-yl)-vinyl]-tetrahydro-pyran-3-yl}-carbamic acid Urt-butyl ester: Starting from intermediate 245. v (4.O g, 7.45 mmol) and 6-methoxy-[l,5]naphthyridine- 4-carbaldehyde (1.7 g, 9 mmol), the title alkene (2.8 g, 62% yield) was obtained as a colourless foam. MS (ESI, m/z): 500.4 [M+H+].
245.VU. (2R,3R,6S)-{2-(2-hydroxy-ethyl)-6-lrans-[2-(6-methoxy-[l,5]naphthyridin-4-yl)- vinyl]-tetrahydro-pyran-3-yl}-carbamic acid tert-butyl ester and (2R.3JR., 6R)-{2-(2-hydroxy- ethyl)-6-[2-(6-rnethoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyraτι-3-yl}-carbamic acid tert-butyl ester:
A solution of intermediate 245.vi (2.8 g) in a THF-AcOH-water mixture (1-3-1, 50 ml) was heated at 600C for 6 h. The reaction mixture was concentrated to dryness and the residue partitioned between EA and saturated NaHCO3. If necessary, the pH was adjusted to 7 by adding solid ISTaHCO3. The aq. layer was extracted once with EA and the combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was taken up in acetone (100 ml) and a warm solution of sodium periodate (3 g) in water (10 ml) was added. The mixture was stirred for Ih. The reaction mixture was filtered through a pad of celite and the solvent removed in vacuo. The residue was extracted twice with EA. The combined org. layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was taken up in MeOH (30 ml) and NaBH4 (0.7 g) was added. The reaction proceeded 15 min. 10% aq. NaHSO4 (100 ml) was added. The volatiles were removed in vacuo and the aq. residue was extracted three times with EA (3 x 100 ml). The combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was chromatographed (DCM-MeOH 19-1) to afford a colourless foam (1.76 g), characterized as an unseparable mixture of alkane and alkene derivatives. The mixture was carried on without further purification. MS (EI): 430.1 [M+H+] (alkene).
245.viii. (2R,3R,6S)-[6-[(lR,2R)-l,2-dihydroxy-2-(6-methoxy-fl,5Jnaphthyridin-4-yl)-ethylJ- 2-(2-hydroxy-ethyl)-tetrahydro-pyran-3-yl]-carbamic acid tert-hutyl ester:
To a solution of intermediate 245.vii (1 .76 g, mixture of compounds), was added potassium ferricyanide (4.04 g), K2CO3 (1.7 g), methanesulfonamide (0.47 g), (DHQD)2PHAL (0.035 g) and potassium osmate dihydrate (0.005 g). The mixture was stirred 40 h at rt. Sodium bisulfite (6 g) was added. The two layers were decanted and the aq. layer was extracted twice with EA
(2 x 150 ml). The combined org. layers were washed with brine, dried over Na2SO4, filtered. and concentrated to dryness. The residue was chromatographed over silica gel (DCM-MeOK
19-1) to afford first the unreacted alkane (2i?,3i?,6i?)-{2-(2-hydroxy-ethyl)-6-[2-(6-methoxy-
[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}-carbamic acid fert-butyl ester (1.34 g, 3.10 mmol) as a colourless foam.
MS (EI): 432.0 [M+H+]
Elution was continued with DCM-MeOH 6-1 to give the desired triol (0.4 g, 0.86 mmol) as a, colourless foam.
1U NMR (CDCl3): 8.80 (d, J = 4.5 Hz, IH); 8.26 (d, J = 9.1 Hz, IH); 7.64 (d, J = 4.5 Hz, IH)- 7.16 (d, J = 9.1 Hz, IH); 5.60 (br s, IH); 4.96 (br d, J = 8.9 Hz, IH); 4.46 (br s, IH); 4.23 (m,
IH); 4.03 (s, 3H); 4.06-4.03 (m, 2H); ;3.88-3.75 (m, 4H);2.06-1.83 (m, 4H); 1.68-1.62 (m,
3H), 1.47 (s, 9H).
MS (EI): 464.3 [M+H*].
245.ix. (IR, 2R)-I -[(2R, 5R)-5-amino-6- (2-hydroxy-ethyl)-tetrahydro-pyran-2-yl]- 2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethane-l,2-dioh
Intermediate 245.viii (0.4 g, 0.86 mmol) was converted to the title amine (0.13 g, 41% yield, colourless foam) according to the procedure of Example 171, step 171.vii. MS (EI): 364.2 [M+H+].
245.x. 3-oxo-3, 4-dihydro-2H-pyrido[3, 2-b][l, 4]thiazine-6-carboxylic acid
[(2R, 3R, 6S)-6-[(lS, 2R)-1, 2-dihydroxy-2-(6-methoxy-[l, 5]naphthyridin-4-yl)-ethyl]-
2- (2-hydroxy-ethyl) -tetrahydro-pyran-3-yl]-am ide : Starting from intermediate 245. ix (0.13 g, 0.35 mmol) and 3-oxo-3,4-dihydro- 2H-pyrido[3,2-ό][l,4]thiazine-6-carboxylic acid (0.082 g, 1.1 eq), the title compound (0.090 g, 45% yield) was obtained as a light beige solid according to the procedure of Example 172. Purification over silica gel was carried out using DCM-MeOH 9-1 containing 1% aq. NΗ4OΗ as an eluent. 1H NMR (d6-DMSO) : 11.24 (s, IH); 8.78 (d, J = 4.5 Hz, IH); 8.28 d, J = 9.1 Hz, IH); 8.27 (d, J = 8.8 Hz, IH); 7.97 (d, J = 7.9 Hz, IH); 7.79 (d, J = 4.5 Hz, IH); 7.62 (d, J = 7.8 Hz, IH); 7.27 (d, J = 9.0 Hz, IH); 5.67 (d, J = 6.9 Hz, IH); 5.40 (d, J = 6.9 Hz, IH); 4.41 (t, J = 5.2 Hz, IH); 4.32 (d, J = 5.8 Hz, IH); 4.05-3.95 (m, 4H); 3.99 (s, 3H); 3.65 (d, AB system, J = 15.0 Hz, Δ = 0.0577, 2H); 3.48 (m, 2H); 2.10-1.99 (m, 2H); 1.83-1.66 (m, 3H); 1.47 (m, IH).
MS (ESI, m/z): 556.1 [M+H+].
Example 246: 3-oxo-3,4-dihydro-2H-pyrido[3,2-6][l,4]thiazine-6-carboxylic acid
(2i?,3i?,6JR)-{2-(2-hydroxy-ethyl)-6-[2-(6-methoxy-[l,5]naphthyridin-4-yI)-ethyI]- tetrahydro-pyran-3-yI}-amide:
246.L 2-{(2R, 3R, 6R)-3-amino-6-[2-(6-methoxy~[l, 5]naphthyridin-4-yl)-ethyl]-tetrahydro- pyran-2-yl}-ethanol:
(2i?,3JR,6i?)-{2-(2-hydroxy-ethyl)-6-[2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro- pyran-3-yl}-carbamic acid terf-butyl ester ester (collected from step 245.viii; 1.34 g, 3.1 mmol) was converted to the title amine (0.65 g, 63*% yield, colourless foam) according to the procedure of Example 171, step 171. vii. MS (EI): 332.3 [M+Η+]. 246. ii. 3-0X0-3, 4-dihydro-2H-pyrido[3,2-b] [1 ,4]thiazine-6-carboxylic acid
(2R, 3R, 6R)-{2-(2-hydroxy-ethyl)-6-[2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-te trahydro- pyran-3-ylj-amide :
Starting from intermediate 246.i (0.2 g, 0.6 mmol) and 3-oxo-3-,4-dihydro- 2H-pyrido[3,2-b][l,4]thiazϊne-6-carboxylic acid (0.082 g, 1.1 eq), the title compound (0.115 g, 36% yield) was obtained as a light beige solid using the procedure of Example 172. Purification over silica gel was carried out using DCM-MeOH 9-1 containing 1% aq. NH4OH as an eluent.
1H NMR (d6-DMSO) : 1 1.23 (s, IH); 8.69 (d, J = 4.5 Hz, IH); 8.26 (d, J = 9.0 Hz, 2H); 7.97 (d, J = 7.9 Hz, IH); 7.61 (d, J = 7.9 Hz, IH); 7.58 (d, J = 4.5 Hz, IH); 7.26 (d, J = 9.0 Hz, IH); 4.44 (t, J = 5.1 Hz, IH); 4.05 (s, 3H); 4.06-3.99 (m, 2H); 3.8^ (m, IH); 3.65 (d, AB system, J = 15.0 Hz, Δ = 0.059, 2H); 3.49 (m, 2H); 3.24 (m, IH); 3.O9 (m, IH); 2.27 (m, IH); 1.99-1.83 (m. 3H); 1.73-1.66 (m, 2H); 1.52-1.43 (m, 2H). MS (ESI, m/z): 524.2 [M+H+].
Example 247: 6-((2Λ,3if,6R)-{2-(2-hydroxy-ethyl)-6-[2-(6-methoxy-[l,5]naphthyridin- 4-yl)-ethyl]-tetrahydro-pyran-3-yIamino}-methyl)-4H-pyrido[3,2-6][l,4]thiaziri-3-one:
Starting from intermediate 246. i (0.15 g, 0.45 mmol) and 3-oxo-3 ,4-dihydro- 2H-pyrido[3,2-έ][l,4]thiazine-6-carbaldehyde (0.097 g, 1.1 eq), the title compound (0.08 g, 34% yield) was obtained as a colourless solid using the procedure of Example 88., step 88.iv. The product was purified by chromatography over silica gel (DCM-MeOH !?-l 1% aq. NH4OH). MS (ESI, m/z): 510.2 [M+H+].
Example 248: trans-3-(2 ,5-difluoro-phenyl)-N-{(2/?,3tf,6i?)-2-(2-hydroxy-ethy I)- 6- [2-(6-methoxy- [1 ,5] nap hthy ridin-4-yI)-ethyl] -tetrahydro-pyran-3-yl}-acrylarnide :
Starting from intermediate 246.i (0.180 g, 0.54 mmol) and trαrø-3-(2,5-difluo>ro-phenyl)- acrylic acid (0.110 g, 1.1 eq.), the title compound (0.09 g, 33% yield) was obtained as a colourless solid using the procedure of Example 172. The product was purified by chromatography over silica gel (DCM-MeOH 9-1 1% aq. NH4OH). MS (ESI, m/z): 498.1 [M-HH+]. Example 249: ?ra«s-3-(2,5-difluoro-phenyl)-N-{(2i?,3i?,6if)-6-[2-(6-methoxy-quinolin- 4-yI)-ethyl]-tetrahydro-pyran-3-yl}-acrylamide:
Starting from intermediate 168.iii (0.098 g, 0.34 mmol) and fr*<ms-3-(2,5-difiuoro-phenyl)- acrylic acid (0.071 g, 1.1 eq.), the title compound (0.02 g, 12% yield) was obtained as a colourless solid using the procedure of Example 172. The product was purified by chromatography over silica gel (DCM-MeOH 19-1 1% aq. NH4OH). MS (ESI, m/z): 453.3 [M+H^].
Example 250: 6-({(3J?,65)-6-[(2R)-2-(3-fluoro-6-methoxy-quinoIin-4-yl)-2-hydroxy- ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-A][l,4]thiazin-3-one and 6-({(3i?,6.y)-6-[(25r)-2-(3-fluoro-6-methoxy-quinolin-4-yl)-2-hydroxy-ethyl]-tetrahydro- pyran-3-ylamino}-methyl)-4i7-pyrido[3,2-6][l,4]thiazin-3-one:
25O.i. {(3R,6S)-6-[(2RS)-2-(3φιoro-6-methoxy-quinolin-4-yl)-2-hydroxy-ethyl]-tetrahydro- pyran-3-yl}-carbamic acid tert-butyl ester.
To a solution of diisopropylamine (0.492 ml, 3.5 mmol) in TΗF (20 ml) cooled to -78°C, was added M-BuLi (1.4 ml, 2.5N in hexanes, 1 eq.). After stirring 20 min at this temperature, a solution of 3-fluoro-6-methoxy-quinoline (prepared as described in WO 2005/049575,
0.626 g, 3.55 mmol), in TΗF (6 ml) was added. The reaction mixture was kept 4 h at the same temperature and a solution of intermediate 203. iii (0.43 g, 1.76 mmol) in TΗF (3 ml) was added. The reaction mixture was stirred 15 min at low temperature and allowed to reach rt over Ih. Water (15 ml) was added. The two layers were decanted. The aq. layer was extracted twice with EA (2 x 50 ml). The combined organic layers were washed with brine, dried over
Na2SO4, filtered and concentrated to dryness. The residue was purified by chromatography over silica gel (EA-Ηex 3-1 then 1-0) to afford the title benzylic alcohol (0.103 g, 13% yield) as a yellowish foam. The compound was obtained as a equimolar mixture of epimers. MS (ESI, m/z): 421.0 [M+Η^].
250. ii. (2RS)-2-((2S,5R)-5-amino-tetrahydro-pyran-2-yl)-l-(3-fluoro-6-methoxy-quinolin- 4-yl)~ethanol:
This amine (0.078 g, 100% yield) was prepared from intermediate 25O.i (0.103 g, 0.25 mmol) using the procedure of Example 171, step 171.vii. A 1:1 mixture of epimers was obtained as a colourless foam. MS (ESI, m/z): 321.O [M+lf].
25O.iii. 6-({(3R,6S)-6-[(2R)-2-(3-fluoro-6-methoxy-quinolin-4-yl)-2-hydroxy-ethyl]- tetraJrydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-b][l,4]thiazin-3-one and 6-({(3R,6S)-6-[(2S)-2-(3-fluoro-6-methoxy-quinolin-4-yl)-2-hydroxy-ethyl]-tetrcehydro-pyran- 3-ylamino}-methyl)-4H-pyrido[3, 2-b][l, 4]thiazin-3-one :
Starting from intermediate 25O.ii (0.078 g, 0.25 mmol) and 3-oxo-3,4-dihydro- 2H-pyrido[3,2~έ][l,4]thiazine-6-carbaldehyde (0.050 g, 1.1 eq), the two title compoundswere obtained using the procedure of Example 88, step 88. iv. Purification on silica gel using DCM-MeOH 9-1 containing 1% aq. NH4OH led to the separation of the two epixners. First eluting epimer:
This epimer was obtained as a colourless foam (0.035 g, 30% yield). Rf (TLC over SiO2): 0.47 (DCM-MeOH 9-1 containing 1% aq. NH4OH). MS (ESI, m/z): 499.O [M+H+].
Second eluting epimer: This epimer was obtained as a light orange foam (0.047 g, 39% yield). Rf (TLC over SiO2): 0.43 (DCM-MeOH 9-1 containing 1% aq. NH4OH) MS (ESI, m/z): 499.1 [M+H+].
Example 251 : N-(2,5-difluoro-phenyl)-2-{(3i?,6i?)-6-[2-(6-methoxy-quinoliHi-4-yI)- ethyl]-tetrahydro-pyran-3-ylamino}-acetamide:
251.i. 2-bromo-N-(2,5-diflιιoro-phenyl)-acetamide:
To a mixture of 2.5-difluoroaniline (2.01 g, 15.6 mmol) and TEA (1.56 ml, 15.6 mmol) in DCM (50 ml) cooled to 100C, was added dropwise a mixture of bromo acetylbromide (3.13 g, 15.6 mmol) in DCM (30 ml), After stirring two hours at rt, water (100 ml) w^as added. The organic layer was washed with saturated NaHCO3 (100 ml) and water (100 ml). The org. layer was washed over Na2SO4, filtered and concentrated to dryness to afford the title bromide (2.74 g, 70% yield) as a reddish solid.
1HNMR (CDCl3): 8.41 (br s, IH); 8.12 (ddd, J = 3.1, 6.2, 9.3 Hz, IH); 7.08 (m9 IH); 6.80 (m, IH); 4.04 (s, 2H). 251.ii. N-(2, 5-dtfluoro-phenyl)-2-{(3R, 6R)-6-[2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydr(r- pyran-3-ylamino}-acetamide:
This compound (0.12 g, 13% yield) was obtained as a yellowish solid, starting from intermediate 25 Li (0.49 g, 1.96 mmol) and intermediate 168.iii (0.48 g, 1.67 mmol) and using the procedure of Example 103. MS (ESI, m/z): 456.3 [M+H+].
Biological assays
In vitro assay
Experimental method:
These assays have been performed following the description given in "Methods for dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, 4th ed.; Approved standard: NCCLS Document M7-A4; National Committee for Clinical Laboratory Standards: Villanova, PA, USA, 1997". Minimal inhibitory concentrations (MICs; mg/1) we Te determined in cation-adjusted Mueller-Hinton Broth (BBL) by a microdilution method following NCCLS guidelines (National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility). The pH of the test medium was 7.2-7.3 .
All Examples were tested against several Gram positive and Gram negative bacteria.
Typical antibacterial test results are given in the table hereafter (MIC in mg/1).
Figure imgf000257_0001
Figure imgf000258_0001

Claims

1. A compound selected selected from the group consisting of a compound of the formula I
Figure imgf000259_0001
wherein R1 represents alkyl, alkoxy, haloalkoxy, halogen or cyano; one or two of U, V, W and X represent(s) N, the remaining represent CH, or, in case of U, V and/or W, may also represent CRa and, in the case of IX, may also represent CRb; Ra represents halogen; Rb represents halogen or alkoxy; D represents alkyl, aryl or heteroaryl; M is selected from the group consisting of M1, M2, MI3 and M4:
Figure imgf000259_0002
wherein
A1 represents NHCO, OCH2, CH2CH2, CH=CH or CO(OH)CH2;
A2 represents NHCH2, NHCO, NHCH2CONH, NHCH2CH=CH, CH2CH2, CH2CO, COCH2, CH2CH(OH) or CH2CH(OCONH2); B1 and B2 each represent independently from each other N or CH; when A1 represents OCH2, B1 represents CH; n is 1; or n is also O when B1 is CH; and p is 1; or p is also O when B2 is CH;
Figure imgf000260_0001
wherein
A3 represents NHCO, CH2CH2, CH=CH, COCH2, CH(OH)CH2, CH2CH<OH), CH(OH)CH(OH) or OCH2;
A4 represents CH2, CO, CH2CH=CH, COCH=CH or CH2CONH; R2 represents hydrogen, alkyl, hydroxyalkyl, alkylcarbonyloxyalkyl, carbamoyloxyalkyl, carboxyalkyl or carbamoylalkyl;
R3 and R4 each independently represent hydrogen, hydroxy or alkylcarbonyloxy; or R3 a-nd R4 together represent a bridged dimethylmethylenedioxy chain attached to the carbons bearing R3 and R4; R5 represents hydrogen, alkyl or hydroxyalkyl; and the dotted line represents a single bond or, when R3 and R4 represent hydrogen, also a double bond;
Figure imgf000260_0002
wherein
A5 represents CH2CH2, CH=CH, COCH2, CH(OH)CH2, NHCO(CH2)m, NHCOCH2O, NHCOOCH2 or O(CH2)q; m is O, 1 or 2; q is 1, 2 or 3 and
B6 represents N and A6 represents CH2, CH2CH2, CH2CH=CH or CH2CH2S; or B6 represents CH and A6 represents CH2NHCH2, CH2NHCH2CONH or CH2NHCH2CH=CH.
Figure imgf000260_0003
wherein
A7 represents NHCO, CH2CH2 or OCH2;
A8 represents CH2; and
R6 represents hydrogen or alkyl; and a prodrug, a tautomer, an optically pure enantiomer, a mixtures of enantiomers, a racemate, an optically pure diastereoisomer, a mixtures of diastereoisomer, a diastereoisomeric racemate, mixtures of diastereoisomeric racemates, a meso-form, a morphological form, a salt or a solvent complex of such a compound.
2. A compound according to claim 1, wherein D is a heteroaryl of the formula
Figure imgf000261_0001
wherein P is a ring selected from
Figure imgf000261_0002
Q is O or S;
K, Y and Z are each independently N or CR3; and
R3 is hydrogen or halogen.
3. A compound according to claim 1, wherein R1 is alkyl, alkoxy, haloalkoxy or cyano.
4. A compound according to claim 1, wherein M is M1.
5. A compound according to claim 1, wherein M1 is selected from the groups M111, M112 and
M 113.
Figure imgf000262_0001
wherein
A11 represents NHCO, OCH2, CH(OH)CH2 or CH2CH2; and A21 represents CH2, CO, CH(OH) or CH(OCONH2).
6. A compound according to claim 4, which is selected from "the group consisting of:
• (2,3-dihydro-[l,4]dioxino[2,3-&]pyridin-6-ylmethyl)-[(lcκ,5cc,6α)-6-(6-methoxy- [l,5]naphthyridin-4-yloxymethyl)-bicyclo[3.1.0]hex-3-yl]-amine;
• (2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-[(lα,5α,6α;)-6-(6-methoxy-[l,5]naphthyridin- 4-yloxymethyl)-bicyclo[3.1.0]hex-3-yl]-amine;
• 7-fluoro-6-{(lo;,5α;,6«)-[6-(6-methoxy-[l,5]naphthyridia-4-yloxymethyl)- bicyclo[3.1.0]hex-3-ylamino]-methyl}-4H-benzo[l,4]thiazin-3-one;
• 6-{[(la,5a,6 α)-6-(6-methoxy-[ 1 , 5]naphthyridin-4-yloxyrnethyl)-bicyclo [3.1.0]hex- 3-ylamino]-methyl}-4H-benzo[l,4]oxazin-3-one; • 6-{[(l«,5α,6α)-6-(6-methoxy-[l,5]naphthyridin-4-yloxyrnethyl)-bicyclo[3.1.0]hex- 3-ylamino]-methyl}-4H-benzo[l,4]thiazin-3-one;
• (lα,3/?,5«,6α)-{3-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]- bicyclo[3.1.0]hexane-6-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide; • (1 a,3β, 5α,6α)-3-[(3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-6-ylmethyl)-aniino]- bicyclo [3.1.0]hexane-6-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide;
• (1 a,3β, 5α,6αO-3-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-έ][l,4]thiazin-6-ylmethyl)-amino]- bicyclo [3.1.0]hexane-6-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide; • (lα,3y?,5α,6α)-3-[(7-fluoro-3-oxo-3,4-dihydro-2H-benzo[l,4]thiazin-6-ylnietbiyl)-aniino]- bicyclo [3.1.0]hexane-6-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-arnide;
• l-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-2-[(l o;,5o:,6a)-6-(6-methoxy-quinazoliii- 4-yloxymethyl)-3-aza-bicyclo[3.1.0]hex-3-yl]-ethanone;
• 7"flc-l-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-2-[(lcc,5ci;,6α)-6-(6-methoxy-quina.zolin- 4-yloxymethyl)-3-aza-bicyclo[3.1.0]hex-3-yl]-ethanol;
• røc-carbamic acid l-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-2-[(lα,5o;,6α>6-(6-rnethoxy- quinazolin-4-yloxymethyl)-3-aza-bicyclo[3.1.0]hex-3-yl]-ethyl ester;
• 4-{(lor,5α,6α)-3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-3-aza-bicyclot3.1.0]hex- 6-ylmethoxy}-6-methoxy-quinoline; • 4-{(l«r,5α,6α)-3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-3-aza-bicycloπ3.1.0]hex- 6-ylmethoxy}-6-methoxy-quinazoline;
• 8-{(l ^S^όc^-S-p^^-dihydro-benzotl^ldioxin-ό-yO-ethylJ-S-aza-bicyclofS.1.0]hex- 6-ylmethoxy}-2-methoxy-[l,5]naphthyridine;
• l-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-2-[(la,5Q;,6a)-6-(6-niethoxy-[lJ5]napb.thyridin- 4-yloxymethyl)-3-aza-bicyclo[3.1.0]hex-3-yl]-ethanone;
• rac-l-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-2-[(lo;,5«,6Q;)-6-(6-methoxy- [l,5]naphthyridin-4-yloxymethyl)-3-aza-bicyclo[3.1.0]hex-3-yl]-ethanol;
• røc-carbamic acid l-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-2-[(lo;,5a,6o;)-6-(6-methoxy- [l,5]naphthyridin-4-yloxymethyl)-3-aza bicyclo[3.1.0]hex-3-yl]-ethyl ester; • røc-(l cκ,5α,6Q;)-4-{3-[2-(2,3-dihydro-benzo[l,4]dioxm-6-yl)-ethyl]-3-aza- bicyclofS.l.OJhex-δ-ylmethoxyJ-quinoline-ό-carbonitrile;
• 3-chloro-4-{(lα,5α,6o;)-3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-3-aza- bicyclo [3.1.0]hex-6-y lmethoxy } -6-methoxy-quinoline;
• roc-4-{(l α;,5α,6α)-3-[2-hydroxy-2-(3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-6-yl)-ethyl]- 3-aza-bicyclo[3.1.0]hex-6-ylmethoxy}-quinoline-6-carbonitrile;
• rac-2-[(l α,5α,6α)-6-(3-chloro-6-methoxy-quinolin-4-yloxymethyl)-3-aza- bicyclo[3.1.0]hex-3-yl]-l-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethanol; • rαc-carbamic acid 2-[( 1 <2,5α,6α)-6-(3-chloro-6-methoxy-quinolin-4-yloxymethyl)-3-aza- bicyclo[3.1.0]hex-3-yl]-l-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl ester;
• 6- {2-[( 1 a,5 a,6ά)-6-(3 -chloro-6-methoxy-quinolin-4-yloxymethyl)-3-aza- bicyclo[3.1.0]hex-3-yl]-l-hydroxy-ethyl}-4H-benzo[l,4]oxazin-3-one; • 5-{(lQ;,5α,6α)-3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-3-aza-bicyclo[3.1.0]he2c- 6-ylmethoxy}-3-methoxy-quinoline;
• 6- {( 1 a,5 a,6ά)-2-[6-(3 -methoxy-quinolin-5-yloxymethyl)-3 -aza-bicyclo [3.1.0]hex-3 -yL] - acetyl} -4H-benzo[l ,4] oxazin-3-one;
• 6-{l-hydroxy-2-[(la,5 o;,6Q;)-6-(3-methoxy-quinolin-5-yloxymethyl)-3-aza- bicyclo[3.1.0]hex-3-yl]-ethyl}-4H-benzo[l,4]oxazin-3-one;
• (lcc,5α;,6α)-3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-3-aza-bicyclo[3.1.0]hexaixe- 6-carboxylic acid (2-cyano-quinolin-8-yl)-amide;
• (l«,5α,6α)-3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-3-aza-bicyclo[3.1.0]hexanLe- 6-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide; • (lα,5α,6α)-3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-3-aza-bicyclo[3.1.0]hexar.Le- 6-carboxylic acid (3-chloro-6-methoxy-quinolin-4-yl)-amide;
• (l«,5cc,6α)-3-[2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-3-aza-bicyclo[3.1.0]hexaixe- 6-carboxylic acid (3-methoxy-quinoxalin-5-yl)-amide;
• 3-[(lα,5o;,6α)-2-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-2-oxo-ethyl]-3-aza- bicyclo[3.1.0]hexane-6-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide;
• rαc-S-^lαjSαjόoiJ^-CS^-dihydro-benzofl^Jdioxin-ό-y^^-hydroxy-ethylj-S-aza- bicyclo[3.1.0]hexane-6-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide;
• rac-4-{(la,5a,6a)-3-[2-hydroxy-2-(3-oxo-3,4-dihydro-2H-benzo[l,4]thiazin-6-yl)-eth.yl]- 3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-ami<le; • mc-(l«,5α,6o;)-6-({3-[2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-3-aza- bicyclo[3.1.0]hex-6-ylamino}-methyl)-4H-pyrido[3,2-έ][l,4]thiazin-3-one;
• rαc-(lα,5α,6ci!:)-6-({3-[2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-3-aza- bicyclo[3.1.0]hex-6-ylamino}-methyl)-4H-benzo[l,4]oxazin-3-one;
• mc-(la,5o;,6a)-2-{6-n(2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-3-a-za- bicyclo[3.1.0]hex-3-yl}-l-(6-methoxy-quinolin-4-yl)-ethanol;
• rαc-2-{(lα,5α,6ct;)-6-C(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-3-aza- bicyclo [3.1.0]hex-3 -y 1 } - 1 -(6-methoxy-quinolin-4-yl)-ethanol; • rac-2-{(lα,5α,6α)-6-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-3-aza- bicyclo[3.1.0]hex-3-yl}-l -(6-methoxy-[l,5]naphthyridin-4-yl)-ethanol;
• rac-6-( { ( 1 a, 5 a,6 α)-3-[2-hydroxy-2-(6-methoxy-[ 1 ,5]naphthyridin-4-y l)-ethyl] -3 -aza- bicyclo[3.1.0]hex-6-ylamino}-methyl)-4H-benzo[l,4]thiazin-3-one; • rac-2-{{\ α,5o;,6Q:)-6-[(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-6-ylnietliyl)-amino]-3-aza- bicyclo[3.1.0]hex-3-yl}-l-(6-methoxy-[l,5]naphthyridin-4-yl)-ethanol;
• rac-6-( { ( 1 a, 5 a, 6 ά)~3 -[2-hy droxy-2-(3 -methoxy-quinolin-5 -y l)-ethyl] -3 -aza- bicyclo [3.1.0]hex-6-ylam ϊno } -methyl)-4H-benzo [1,4] oxazin-3 -one;
• rαc-2-{(lα,5α,6o;)-6-[(2,3-dihydro-[l,4]dioxino[2,3-δ]pyridin-6-ylmetliyl)-aniino]-3-aza- bicyclo [3.1.0]hex-3 -yl} - 1 -(3 -methoxy-quinolin-5 -yl)-ethanol;
• rac-6-{ { ( 1 a, 5 a,6 ά)-3 - [2-hy droxy-2-(3 -methoxy-quinolin-5 -y l)-ethyl] -3 -aza- bicyclo[3.1.0]hex-6-ylamino}-methyl)-4H-pyrido[3,2-έ][l,4]thiazin-3-oiie;
• rac-6-({(la,5 α,6α)-3-[2-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-3 -aza- bicyclo [3.1.0]hex-6-y lam ϊno } -methyl)-4H-benzo [ 1 ,4]thiazin-3 -one; • mc-2-{(lα,5α,6ct;)-6-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-3-aza- bicyclo[3.1.0]hex-3-yl}-l -(3-methoxy-quinolin-5-yl)-ethanol;
• 6-({(l α,5 α,6o;)-3-[(2i?)-2-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-3-aza- bicyclo [3.1.0]hex-6-ylam ino } -methyl)-4H-benzo [ 1 ,4] thiazin-3 -one;
• (2i?)-2-{(lα,5«,6α)-6-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-3-aza- bicyclo[3.1.0]hex-3-yl}-l -(3-methoxy-quinolin-5-yl)-ethanol;
• 3-oxo-3,4-dihydro-2H-pyrido[3,2-ό][l,4]thiazine-6-carboxylic acid
{ ( 1 a, 5 a, 6 ά)~3 - [(2i?)-2-hy droxy-2-(3 -methoxy-quinolin-5 -yl)-ethy 1] -3 -a.za- bicyclo[3.1.0]hex-6-yl}-amide;
• 6-({(lα,5α,6α;-3-[(2i?)-2-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-3-aza- bicyclo [3.1.0]hex-6-ylamino } -methyl)-4Η-benzo [1,4] oxazin-3 -one;
• rac-2-{(l a,5 «,6α)-3-[2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-3-aza- bicyclo[3.1.0]hex-6-ylamino} -N-thiazol-2-yl-acetamide;
• ?'αc-(lα,5α,6α)-2-{6-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-3-aza- bicyclo[3.1.0]hex-3-yl}-l-(3-methoxy-quinoxalin-5-yl)-ethanol; • rac-(\ α,5α,6o;)-6-({3-[2-hydroxy-2-(3-methoxy-quinoxalin-5-yl)-ethyl]-3-aza- bicyclo[3.1.0]hex-6-ylamino}-methyl)-4H-benzo[l,4]thiazin-3-one; • rαc-(lα,5o;,6(2)-6-({3-[2-hydroxy-2-(3-methoxy-quinoxalin-5-yl)-ethyl]-3-aza- bicyclo[3.1.0]hex-6-ylamino} -methyl)-4H-benzo[ 1 ,4]oxazin-3-one;
• rac-(lα,5α,6α)-2-{6-[(benzo[l,2,5]thiadiazol-5-ylmethyl)-amino]-3-aza- bicyclo[3.1.0]hex-3-yl}-l-(3-methoxy-quinoxalin-5-yl)-ethanol; • rac-{\ «,5Q;,6α)-6-({3-[2-hydroxy-2-(3-methoxy-quinoxalin-5-yl)-ethyl]-3-aza- bicyclo[3.1.0]hex-6-ylamino}-methyl)-4H-pyrido[3,2-ό][l,4]thiazin-3-one;
• rac-(lα,5α,6α)-2-{6-[(benzofuran-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex:-3-yl}-l- (3-methoxy-quinoxalin-5-yl)-ethanol;
• rαc-(lα,5α,6Q;)-l-(3-methoxy-quinoxalin-5-yl)-2-[6-(3-phenyl-allylamino)-3-aza- bicyclo[3.1.0]hex-3-yl]-etlianol;
• rac-(la,5a:,6Q;)-2-{6-[(2,2-dimethyl-chronian-7-ylmethyl)-amino]-3-aza- bicyclo[3.1.0]hex-3-yl}-l-C3-methoxy-quinoxalin-5-yl)-ethanol;
• 6-{2-[(l«,5«,6α)-6-(6-methoxy-quinazolin-4-yloxymethyl)-3-aza-bicyclo[3.1.0]hex- 3 -y 1] -acetyl } -4H-benzo [ 1 ,4] thiazin-3 -one; • 6-{l-hydroxy-2-[(l α,5α,6αr)-6-(6-methoxy-quinazolin-4-yloxymethyl)-3-aza- bicyclo [3.1.0]hex-3 -y 1] -ethyl } -4H-benzo [ 1 ,4]thiazin-3 -one. and the salts of these compounds.
7. A compound according to claim 1, wherein M is M2.
8. A compound according to claim 7, wherein the stereochemistry of M2 is the folio Λving:
_ 2.
Figure imgf000266_0001
9. A compound according to claim 7, wherein M is selected from the following groups:
Figure imgf000267_0001
Figure imgf000268_0001
10. A compound according to claim 7, which is selected from the group consisting of:
• (2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-[(3i?,5/S)-6-(6-methoxy-quinolin- 4-yloxymethyl)-3 , 6-dihydro-2H-pyran-3 -y 1] -am iae;
• (2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-[(3i?,5<S)-6-(6-methoxy-quinolin- 4-y loxymethy l)-tetrahydro-pyran-3 -yl] -amine;
• (2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-ylmeth3^1)-[(3i?,65)-6-(6-methoxy-quinolin- 4-yloxymethyl)-tetrahydro-pyran-3-yl]-amine;
• 6-{[(3i?,65)-6-(6-methoxy-quinolin-4-yloxymethyl)-tetrahydro-pyran-3-ylamino]- methyl}-4H-benzo[l,4]oxazin-3-one; • (2,3-dihydro-benzo[ 1 ,4]dioxin-6-ylmethyl)-[(3i?,56)-6-(6-methoxy-[ 1 ,5]naphthyridin- 4-yloxymethyl)-tetrahydro-pyran-3-yl]-amine;
• 6-{[(3i?,65)-6-(6-methoxy-[l,5]naphthyridin-4-yloxymethyl)-tetrahydro-pyran- 3-ylamino]-methyl} -4H-benzo [ 1 ,4]oxazin-3 -one;
• 6-{[(3i?,65)-6-(6-methoxy-quinolin-4-yloxymethyl)-tetrahydro-pyran-3-ylamino]- methyl}-4H-benzo[l,4]thiazin-3-one;
• 6- { [(3R, 65)-6-(6-methoxy- [ 1 , 5]naphthyridin-4-y loxymethy l)-tetrahydro-pyran- 3 -ylamino] -methyl } -4H-benzo [ 1 ,4]thiazin-3 -one;
• 6-{[(3i?,65)-6-(6-methoxy-[l,5]naphthyridin-4-yloxymethyl)-tetrahydro-pyran- 3 -ylamino] -methyl } -4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one ; • [(3i?,65)-6-(6-methoxy-[l,5]naphthyridin-4-yloxymethyl)-tetrahydro-pyran-3-yl]- (3-phenyl-allyl)-amine;
• benzofuran-2-ylmethyl-[(3i?,6.S)-6-(6-methoxy- [ 1 ,, 5]naphthyridin-4-yloxymethyl)- tetrahydro-pyran-3-yl]-amine;
• (2,S',5i?)-5-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmet;hyl)-amino]-tetrahydro-pyran- 2-carboxylic acid (2-methyl-quinolin-8-yl)-amide-
• 8- { 5-[(3 -oxo-3,4-dihydro-2H-pyrido[3 ,2-b] [ 1 ,4]thLiazin-6-ylmethyl)-amino]-tetrahydτo- pyran-2-ylmethoxy}-quinoline-2-carbonitrile;
• (2»S,5i?)-5-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-tetrahydro-pyran- 2-carboxylic acid (6-methoxy-[l,5]naphthyridin-4— yl)-amide; • (2>S',5jR)-5-[(2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-tetrahydro-pyran- 2-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide;
• (2,Sr,5i?)5-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-ό][l,4]thiazin-6-ylmethyl)-amino]- tetrahydro-pyran-2-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide; • (25r,5/?)-5-[(2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-tetrahydro-pyran- 2-carboxylic acid (2-cyano-quinolin-8-yl)-amide;
• (2S,5/Q-5-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-tetrahydro-pyran- 2-carboxylic acid (2-cyano-quinolin-8-yl)-amide;
• (25',5i?)-5-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-έ][l,4]thiazin-6-ylmethyl)-amino]- tetrahydro-pyran-2-carboxylic acid (2-cyano-quinolin-8-yl)-amide;
• (2S,5R)-5 - [(3 -oxo-3 ,4-dihydro-2H-benzo [ 1 ,4]thiazin-6-ylmethyl)-amino]-tetrahydro- pyran-2-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide;
• (25',5i?)-5-[(2,3-dihydro-[l,4]dioxino[2,3-έ]pyridin-6-ylmethyl)-amino]-tetrahydro-pyran- 2-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide; • 2-[(2i?,3i?,6JS)-3-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-6-(6-methoxy- quinolin-4-yloxymethyl)-tetrahydro-pyran-2-yl]-ethanol;
• 6-{[(2/?,3i!?,6lS)-2-(2-hydroxy-ethyl)-6-(6-methoxy-quinolin-4-yloxymethyl)-tetrahydro- pyran-3-ylamino]-methyl}-4H-benzo[l,4]thiazin-3-one;
• 6- { [(2i?,3i?,6»S)-2-(2-hydroxy-ethyl)-6-(6-methoxy-quinolin-4-yloxymethyl)-tetrahy dro- pyran-3 -y lamino] -methyl} -4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one;
• 6-{[(3i?,6iS)-6-(3-methoxy-quinolin-5-yloxymethyl)-tetrahydro-pyran-3-ylammo]- methylJ^iy-pyridop^-^tl^lthiazin-S-one;
• 6-{[(3i?,6jS)-6-(3-methoxy-quinolin-5-yloxymethyl)-tetrahydro-pyran-3-ylamino]- methyl} -Φ^H-benzof 1 ,4]thiazin-3-one; • benzo[l,3]dioxol-5-ylmethyl-[(3i?,6iS)-6-(3-methoxy-quinolin-5-yloxymethyl)-tetraliydro- pyran-3 -y 1] -amine;
• (2,3 -dihydro-benzo [ 1 ,4]dioxin-6-ylmethyl)-[(3i?,65)-6-(3 -methoxy-quinolin- 5-yloxymethyl)-tetrahydro-pyran-3-yl]-amine;
• 6-{[(3i?,6<S)-6-(3-methoxy-quinolin-5-yloxymethyl)-tetrahydro-pyran-3-ylamino]- methyl} -4_H-benzo [1,4] oxazin-3 -one;
• (2,3-dihydro-[l,4]dioxino[2,3-ό]pyridin-6-ylmethyl)-[(3i?,65)-6-(3-methoxy-quinolin- 5-yloxymethyl)-tetrahydro-pyran-3-yl]-amine; • (2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)-[(3i?,65)-6-(3-methoxy-quinolin- 5 -y loxymethy l)-tetrahydro -pyran-3 -y 1] -amine;
• 7-fluoro-6-{[(3i?,65)-6-(3-methoxy-quinolin-5-yloxymethyl)-tetrahydro-pyran- 3 -y lamino] -methyl } -4H-benzo [ 1 ,4]thiazin-3 -one ; • benzofuran-2-ylmethyl-[(3i?,65)-6-(3-methoxy-quinolin-5-yloxymethyl)-tetrahydro- pyran-3-yl]-amine;
• [(3R,6S)-6-(3 -methoxy-quinolin-5 -y loxymethy l)-tetrahydro-pyran-3 -y 1] -(3 -pheny 1-allyl)- amine;
• benzo[l,2,5]thiadiazol-5-ylmethyl-[(3i?,65)-6-(3-methoxy-quinolin-5-yloxymethyl)- tetrahydro-pyran-3 -yl] -am. ine ;
• (3i?,65)-heptyl-[6-(3-meth.oxy-quinolin-5-yloxymethyl)-tetrahydro-pyran-3-yl]-amine;
• 2-[(3i?,65)-6-(3-methoxy-quinolin-5-yloxymethyl)-tetrahydro-pyran-3-ylamino]- N-thiazol-2-yl-acetamide;
• (2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-[(3i?,6S)-6-(3-methoxy-quinoxalin- 5-yloxymethyl)-tetrahydro-pyran-3-yl]-amine;
• 6- { [(3i?,65)-6-(3-methoxy-quinoxalin-5-yloxymethyl)-tetrahydro-pyran-3-ylamino]- methyl}-4H-pyrido[3,2-Z>] [l,4]thiazin-3-one;
• (2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-[(3i?,6iS)-6-(6-trifluoromethoxy-quinolin- 4-yloxymethyl)-tetrahydro-pyran-3-yl]-amine; • 6-{[(3i?,65)-6-(6-trifluoromethoxy-quinolin-4-yloxymethyl)-tetrahydro-pyran-3-ylamino] methyl}-4H-pyrido[3,2-b] [l,4]thiazin-3-one;
• 8-{(25",5i?)-5-[(3-oxo-3,4-dihydro-2H-benzo[l,4]thiazin-6-ylmethyl)-amino]-tetrahydro- pyran-2-ylmethoxy}-quinoline-2-carbonitrile;
• 6-{[(3i?,6iS)-6-(6-methoxy-quinolin-4-yloxymethyl)-tetrahydro-pyran-3-ylamino]- methyl} -4H-pyrido[3,2-Z>] [l,4]thiazin-3-one;
• 6-{[(3i?,6>S)-6-(2-methoxy-quinolin-8-yloxymethyl)-tetrahydro-pyran-3-ylamino]- methyl}-4H-pyrido[3,2-&][l,4]thiazin-3-one;
• 6-{[(3i?,65)-6-(6-methoxy-quinazolin-4-yloxymethyl)-tetrahydro-pyran-3-ylamino]- methyl}-4H-pyrido[3,2-&][l54]thiazin-3-one; • 6-{[(3i?,6iS)-6-(8-fluoro-6-methoxy-quinolin-4-yloxymethyl)-tetrahydro-pyran- 3-ylamino]-methyl}-4H-pyrido[3,2-Z>][l,4]thiazin-3-one;
• 6-{[(3i-,6>S)-6-(8-fluoro-6-methoxy-quinolin-4-yloxymethyl)-tetrahydro-pyran- 3-ylamino]-methyl}-4H-pyrido[3,2-Z>][l,4]oxazin-3-one; • 6-{(3i?,6iS)-[6-(6-methoxy-quinazolin-4-yloxymethyl)-3,6-dihydro-2H-pyran-3-ylamino]- methyl}-4H-pyrido[3,2-ό][l,4]thiazin-3-one;
• 6-{[(3i?,6>S)-6-(6-difluoromethoxy-quinolin-4-yloxymethyl)-tetrahydro-pyran-3-ylamino]- methyl } -4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one; • 6-{(37?,65)-[6-(3-methoxy-quinoxalin-5-yloxymethyl)-tetrahydro-pyran-3-ylamino]- methyl}-4H-pyrido[3,2-Z>][l,4]oxazin-3-one;
• 6- { (3R, 6S)- [6-(3 -methoxy-quinoxalin-5 -y loxymethyl)-tetrahydro-pyran-3 -y lamino] - methyl} -4H-benzo [1,4] oxazin-3 -one ;
• 6-{(3i?,65)-[6-(3-methoxy-quinoxalin-5-yloxymethyl)-tetrahydro-pyran-3-ylamino]- methyl}-4H-benzo[l,4]thiazin-3-one;
• 3-oxo-3,4-dihydro-2H-pyrido[3,2-έ][l,4]thiazine-6-carboxylic acid (3i?,6S)-[6-(3-methoxy-quinoxalin-5-yloxymethyl)-tetrahydro-pyran-3-yl]-amide,
• 3-oxo-3,4-dihydro-2H-pyrido[3,2-έ][l,4]thiazine-6-carboxylic acid (3i?,65)-[6-(2-methoxy-quinolin-8-yloxymethyl)-tetrahydro-pyran-3-yl]-amide; • 4-{(25,5i?)-5-[(2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-tetrahydro- pyran-2-ylmethoxy}-quinoline-6-carbonitrile;
• 4-{(25',5/?)-5-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-tetrahydro-pyran- 2-ylmethoxy}-quinoline-6-carbonitrile;
• 4-{(2,S',5i?)-5-[(3-oxo-3,4-dihydro-2H-benzo[l,4]thiazin-6-ylmetliyl)-amino]-tetrahydro- pyran-2-ylmethoxy } -quinoline-6-carbonitrile;
• 3-oxo-3,4-dihydro-2H-pyrido[3,2-ό][l,4]thiazine-6-carboxylic acid (3i?,65)-[6-(6-cyano- quinolin-4-yloxymethyl)-tetrahydro-pyran-3-yl]-amide;
• 3-oxo-3,4-dihydro-2H-pyrido[3,2-ό][l,4]thiazine-6-carboxylic acid (4i?,7lS)-[4-(6-methoxy-quinolin-4-yloxymethyl)-cώ-(4ΛS',5ΛS)-2,2-dimethyl-tetrahydro- [l,3]dioxolo[4,5-c]pyran-7-yl]-amide;
• 6- { (4i?,75)-[4-(6-methoxy-quinolin-4-yloxymethyl)-(45',55)-2,2-dimethyl-tetrahydro- [l,3]dioxolo[4,5-c]pyran-7-ylamino]-methyl}-4H-pyrido[3,2-έ][l,4]thiazin-3-one;
• 6-{(4i?,75)-([4-(6-methoxy-quinolin-4-yloxymethyl)-(4i?,5i?)-232-dimethyl-tetrahydro- [l,3]dioxolo[4,5-c]pyran-7-ylamino]-methyl}-4H-pyrido[3,2-Z7][l,4]thiazin-3-one; • 6-{(3,S',45',55',6i?)-[4,5-dihydroxy-6-(6-methoxy-quinolin-4-yloxyinethyl)-tetrahydro- pyran-3-ylamino]-methyl}-4H-pyrido[3,2-Z)][l,4]thiazin-3-one;
• 6-{(3<S',4i?35i?,6i?)-[4,5-dihydroxy-6-(6-methoxy-quinolin-4-yloxymethyl)-tetrahydro- pyran-3-ylamino]-methyl}-4H-pyrido[3,2-ό][l,4]thiazin-3-one; • 8-{(2ιS',5i?)-5-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-Z>][l,4]oxazin-6-ylmethyl)-amino]- tetrahydro-pyran-2-ylmethoxy}-quinoline-2-carbonitrile;
• 6-{[(3S,6R)-6-(6-m. ethoxy-qumazolin-4-yloxymethyl)-tetrahydro-pyran-3-ylamino]- methyl}-4H-pyrido[3,2-δ][l,4]thiazin-3-one; • (2,3-dihydro-benzo [l,4]dioxin-6-ylmethyl)-[(3<S',6i?)-6-(3-methoxy-quinolin- 5 -y loxymethyl)-tetrahydro-pyran-3 -yl] -amine;
• 6-{[(31S',6i?)-6-(3-nαethoxy-quinolin-5-yloxymethyl)-tetrahydro-pyran-3-ylainino]- methyl} -4H-pyrido [3 ,2-b] [ 1 ,4]oxazin-3 -one;
• 6- {[(3 S, 6R)-6-(3 -nnethoxy-quinolin-5 -yloxymethy l)-tetrahydro-pyran-3 -y larnino] - methyl} -4H-pyrido [3,2-b] [ l,4]thiazin-3-one;
• 6-({(3i?,6i?)-6-[2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyra.ii- 3-ylamino } -methyl)-4H-pyrido [3,2-έ] [ 1 ,4]thiazin-3-one;
• 3-oxo-3,4-dihydro-2H-pyrido[3,2-ό][l,4]thiazine-6-carboxylic acid {(3i?,6i?)-6-[2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}-amide; • 6-({(3i?,6i?)-(6-[2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran- 3 -y lamino } -methy l)-4H-pyrido [3 ,2~b] [ 1 ,4] oxazin-3 -one;
• 6-((3/?,6i?)-{6-[2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyra.n- 3 -y lamino } -methy l)-4H-benzo [ 1 ,4]thiazin-3 -one ;
• 6-({(3Λ,67?)-6-[2-(6-methoxy-quinazolin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}- methyl)-4H-pyrido[3,2-Z>][l,4]thiazin-3-one;
• 6-((3R, 6R)- { 6-[2-( 6-methoxy-quinazolin-4-y l)-ethy 1] -tetrahydro-pyran-3 -y lamino } - methyl)-4H-benzo[l,4]thiazin-3-one;
• 6-({(3i?,6.S)-6-£-[2-(3-methoxy-quinolin-5-yl)-vinyl]-tetrahydro-pyran-3-ylaniino}- methyl)-4H-pyrido [3,2-b] [1 ,4]thiazin-3-one; • 6-({(3i?,6i?)-6-[2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro-pyran-3-ylairxino} -methyl)- 4H-pyrido[3,2-δ][ 1 ,4]thiazin-3-one;
• 3 -oxo-3 ,4-dihydro -2H-pyrido [3 ,2-Z)] [ 1 ,4]thiazine-6-carboxylic acid (3i?,6i?)-{6-[2-(3-rnethoxy-quinolin-5-yl)-ethyl]-tetrahydro-pyran-3-yl}-amide;
• 6-((3R,6R)- { 6-[2-(3 -methoxy-quinolin-5 -yl)-ethy 1] -tetrahydro-pyran-3 -ylaioino } -methy I)- 4H-pyrido[3,2-6] [ 1 ,4] oxazin-3 -one;
• 6-((3i?,6i?)-{6-[2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3-ylanαino}-methyl)- 4H-pyrido[3,2-&][l,4]thiazin-3-one; • (37?,6i?)-6-({6-[2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-metliyl)- 4£*r-benzo [ 1 ,4]thiazin-3-one;
• 6-((3i?,6i?)-{6-[2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3-ylamino}-met]iyl)- 4/^-benzo [ 1 ,4]oxazin-3 -one; • ό-dSΛjβ^-ό-fCliϊ^^-l^-dihydroxy^-CS-methoxy-quinolin-S-yO-ethyη-tetrahydro- pyran-3 -y lamino } -methyl)-4H-pyrido [3 ,2-6] [ 1 ,4]thiazin-3 -one;
• 3-oxo-3 ,4-dihydro-2H-pyrido[3 ,2-b] [ 1 ,4]thiazine-6-carboxylic acid {(3JR,65)-6-[(li?,2i?)-l,2-dihydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro-pyran- 3-yl} -amide; • 6-({(3i?,65)-6-[(li?,2i?)-l,2-dihydroxy-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]- tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-έ][l,4]thiazin-3-one;
• 3-oxo-3,4-dihydro-2H-pyrido[3,2-&][l,4]thiazine-6-carboxylic acid {(3-R,65)^-[(l/^2J?)-l,2^ihydroxy-2<6-me1hoxy-[l,5]iiaphthyridin-^yl)-ethyl]- tetrahydro-pyran-3 -y 1 } -amide ; • (3^,65)-6-({6-[(li?,2JR)-l,2-dihydroxy-2-(2-methoxy-quinolin-8-yl)-ethyl]-tetrahydro- pyran-3-ylamino}-methyl)-4H-pyrido[3,2-έ][l,4]thiazin-3-one;
• 3-oxo-3,4-dihydro-2H-pyrido[3,2-&][l,4]thiazine-6-carboxylic acid {(3i?,65)-6-[(li?,2i?)-l,2-dihydroxy-2-(2-methoxy-quinolin-8-yl)-ethyl]-tetrahydro-p3'ran- 3-yl} -amide; • (3i?,65)-6-({6-[(li?,2i?)-l,2-dihydroxy-2-(3-methoxy-quinoxalin-5-yl)-ethyl]-tetrahydro- py ran-3 -y lamino } -methyl)-4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one;
• 6-({(3i?,65)-6-[(l.S,25)-l,2-diliydroxy-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]- te trahy dro-pyran-3 -y lamino } -methyl)-4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one;
• 3-oxo-3,4-dihydro-2H-pyrido[3,2-έ][l,4]thiazine-6-carboxylic acid (S^β^-lβ-tCliϊ^^-l^-dihydroxy^-CS-methoxy-quinoxalin-S-yO-ethyll tetrahydro- pyran-3-yl}-amide;
• 6-({(3i?,65)-6-[(li?,2i?)-l,2-dihydroxy-2-(3-methoxy-quinoxalin-5-yl)ethyl]-tetrahydLro- pyran-3-ylamino}-methyl)-4H-pyrido[3,2-ό][l,4]oxazin-3-one; t 8-((li?32Λ)-l,2-dihydroxy-2-{(2,S;5i?)-[(3-oxo-3,4-dihydro-2H-pyπdo[3,2-ό][l,4]thiazin- 6-ylmethyl)-amino]-tetrahydro-pyran-2-yl}-ethyl)-quinoline-2-carbonitrile;
• S-oxo-S^-dihydro^H-pyrido^^-δJfl^^hiazine-ό-carboxylic acid {C3i?,65)-6-[(li?,2i?)-2-(2-cyano-quinolin-8-yl)-l,2-dihydroxy-ethyl]-tetrahydro-pyran- 3-yl}-amide; • 8-((li?,2i?)-l,2-dihydroxy-2-{(2S,5i?)-5-[(3-oxo-3,4-dihydro- 2H-pyrido[3,2-Z>][l,4]oxazin-6-ylmemyl)-amino]-tetrahydro-pyran-2-yl}-ethyl)- quinoline-2-carbonitrile;
• 6-((3R,6S)-{6-ltrans-(lI^,2RS)A,2-dihydroxy-2-(3-methoxy-qumo\m-5-yiyethy\y tetrahydro-pyra.n-3 -ylamino } -methy l)-4H-pyrido [3 ,2-b] [ 1 ,4]thiazin.-3 -one;
• 6-((3i?,65)-{6-[(li?,2i?)-l,2-dihydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro- pyran-3-ylamino}-methyl)-4H-pyrido[3,2-Z>][l,4]thiazin-3-one;
• β-CCS^ό^-lβ-πCli'^^-l^-dihydroxy^-Cβ-methoxy-quinolin^-y^-ethyll-tetrahydro- pyran-3 -ylamino } -methy l)-4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one; • (li?5)-l-{(25,5i?)-5-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-tetrahydro-pyran- 2-yl}-2-(6-methoxy-quinolin-4-yl)-ethanol;
• 6-({(3i?,65)-6-[(li?5)-l-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran- 3-ylamino}-methyl)-4H-pyrido[l,4]thiazin-3-one;
• 3-0X0-3 ,4-dihy dro-2H-pyrido [3 ,2-b] [ 1 ,4]thiazine-6-carboxylic acid {(3/?,6.S)-6-[(lJ?5)-l-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}- amide;
• 6-({(3R,6S)-6- [(1,S)-I -hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl] -tetrahydro-pyran- 3-ylamino} -methy l)-4H-pyrido[3,2-Z>] [ 1 ,4]thiazin-3 -one;
• 6-((3R, 6S)- { 6 - [ 1 -hydroxy-2-(6-methoxy-quinolin-4-y l)-ethy 1] -tetrahydro-pyran- 3 -ylamino } -methy l)-4H-pyrido [3 ,2-b] [ 1 ,4]oxazin-3 -one;
• 7-((3i?,65)-{6-[(l>S)-l-hydroxy-2-(6-methoxy-qumolin-4-yl)-ethyl]-tetrahydro-pyran- 3 -ylamino } -methy I)- 1 H-pyrido [3,4-ό][l,4] oxazin-2-one;
• 3-oxo-3,4-dihydro-2H-pyrido[3,2-Z>][l,4]thiazine-6-carboxylic acid
(3R, 6S)-{6-[(lS)-l -hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl] -tetrahydro-pyran-3 -yl } - amide;
• 6-({(3i?,6S)-6- [(li?)-l -hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl] -tetrahydro-pyran- 3 -ylamino } -methy l)-4H-pyrido [ 1 ,4]thiazin-3 -one;
• 6-({(3i?,65)-6-[(li?1S)-l-hydroxy-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro- pyran-3 -ylamino } -methy l)-4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one; • 3-oxo-3,4-dihydro-2H-pyrido[3,2-Z>][l,4]thiazine-6-carboxylic acid (3i?,65)-
{6-[(i,S)-l-hydroxy-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}- amide; • (3i?,6δ)-6-({6-[(l»S)-l-hydroxy-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro- pyran-3 -y lamino } -methy l)-4H-pyrido [3 , 2-b] [ 1 ,4]thiazin-3 -one;
• 6-((3i?, ό^-lό-tCl^-l-hydroxy^-Cό-methoxy-tl^lnaphthyridin^-y^-ethyπ-tetrahydro- pyran-3 -y lamino } -methyl) -4H-pyrido [3 ,2-b] [ 1 ,4]oxazin-3 -one; • (S^ό^-Cβ-dό-tCl^^^-l^-dihydroxy^-Cό-methoxy-tUSlnaphthyridin^-y^-ethyl]- tetrahydro-pyran-3 -y lamino } -methy l)-4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one;
• 6-((3i?,65)-{6-[(15)-l-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro— pyran- 3 -y lamino } -methy l)-4H-py rido [3,2-6] [1,4] oxazin-3 -one;
• 6-((3R, 65)-{6-[(15)-l-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro-pyran-3- ylamino}-methyl)-4H-pyrido[3,2-έ][l,4]thiazin-3-one;
• (IS)- 1 -((2S, 5i?)-5-heptylamino-tetrahydro-pyran-2-yl)-2-(6-methoxy-quinolin-4-yl)- ethanol;
• 6-((3i?,6,S)-{6-[(2i?)-2-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydrc>-pyran-3- ylamino}-methyl)-4H-pyrido[3,2-έ][l,4]thiazin-3-one; • 6-((3i?,65)-{6-[(2,S)-2-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydrc> -pyran- 3 -y lamino } -methy l)-4H-py rido [3 ,2-b] [ 1 ,4]thiazin-3 -one;
• 3-oxo-3,4-dihydro-2H-pyrido[3,2-Z>][l,4]thiazine-6-carboxylic acid (3i?,65)-{^-[(2i?5)-2- hydroxy-2-(3-methoxy-quϊnolin-5-yl)-ethyl]-tetrahydro-pyran-3-yl} -amide;
• 6-((3R,6S)-{ 6-trans-[2-(3 -fluoro-6-methoxy- [ 1 , 5]naphthyridin-4-yl)-viny 1] -tetrahydro- pyran-3 -ylamino} -methyl) -4H-pyrido [3 ,2-b] [ 154]thiazin-3 -one;
• 6-(3i?,65)-{6-[(li?,2i?)-2-(3-fluoro-6-methoxy-[l,5]naphthyridin-4-yl)-l,2-dihiydroxy- ethy 1] -tetrahydro-pyran-3 -ylamino } -methy l)-4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one ;
• 6-({6-[2-(8-fluoro-6-methoxy-quinolin-4-yl)-vinyl]-tetrahydro-pyran-3-ylarniτιo}- methyl)-4H-pyrido[3,2-έ][l,4]thiazin-3-one; • 6-((3R, 6-S)-{6-[2-(8-fluoro-6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro-pyrarι- 3 -ylamino } -methy l)-4H-py rido [3 ,2-b] [ 1 ,4]thiazin-3 -one;
• 6-((3i?,65)-{6-[(li?,2i?)-2-(8-fluoro-6-methoxy-quinolin-4-yl)-l,2-dihydroxy-ethyl]- tetrahydro-pyran-3 -ylamino } -methy l)-4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one;
• 6-((3i?,65)-{6-[(li?,2i?)-2-(8-fluoro-6-methoxy-quinolin-4-yl)-l,2-dihydroxy-ethyl]- tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-έ][l,4]oxazin-3-one;
• 6-(3i?,61S)-{6-[(li?,2i?)-2-C3-fluoro-6-methoxy-[l,5]naphthyridin-4-yl)-l,2-dihydroxy- ethyl]-tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-δ][l,4]oxazin-3-one; • (3S,6i?)-6-({6-[(l S,2S)-l ,2-dihydroxy-2-(6-methoxy-[l ,5]naphthyridin-4-yl)-ethyl]- tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-Z>][l,4]oxazin-3-one;
• (35,6Λ)-(6-({6-[C 1R,2R)- 1 ,2-dihydroxy-2-(6-methoxy-[ 1 , 5]naphthyridin-4-yl)-ethyl]- tetrahydro-pyran-3-ylamino}-methyl)-4H-pyrido[3,2-έ][l,4]thiazin-3-one; • (3S,6R)-6-({6-[( 1 R,2R> 1 ,2-dihydroxy-2-(6-methoxy-[l ,5 ]naphthyridin-4-yl)-ethyl]- tetrahydro-pyran-3 -ylamino } -methy l)-4H-pyrido [3 ,2-έ] [ 1 ,4] oxazin-3 -one ;
• (3,S,6i?)-6-({(6-[Cli?)-l-hydroxy-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro- pyran-3 -ylamino } -methy l)-4H-pyrido [3,2-b] [ 1 ,4]thiazin-3 -one;
• (3S,6R)-6-({6-[( IR)-I -hydroxy-2-(6-methoxy-[ 1 , 5]naphthyridin-4-yl)-ethyl]-tetrahydro- pyran-3 -ylamino }-methyl)-4H-pyrido[3,2-δ][l,4]oxazin-3-one;
• (3,S',6i?)-6-({(6-[C15)-l-hydroxy-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro- pyran-3-ylamino }-methyl)-4H-pyrido[3,2-ό][l,4]thiazin-3-one;
• 6-({(3i?,65)-6-[(15',2)S)-l,2-dihydroxy-2-(3-methoxy-quiπLθxalin-5-yl)-ethyl]-tetrahydro- pyran-3 -ylamino } -methy l)-4H-pyrido [3 ,2-b] [ 1 ,4]thiazin- 3 -one; • 6-({(35r,6i?)-6-[(li?52i?)-l,2-dihydroxy-2-(3-methoxy-quinoxalin-5-yl)-ethyl]-tetrahydro- pyran-3 -ylamino } -methy l)-4H-pyrido [3 ,2-b] [ 1 ,4]thiazin- 3 -one;
• 6-({(3i?,6iS)-6-[(l<S)-2-(8-fluoro-6-methoxy-quinolin-4-yl)-l-hydroxy-ethyl]-tetrahydro- pyran-3 -ylamino } -methy l)-4H-pyrido [3 ,2-b] [ 1 ,4]thiazin- 3 -one;
• 6- { [6-(6-fluoro-quinolin-4-y loxymethyl)-tetrahy dro-pyra.n-3 -ylamino] -methyl } - 4H-pyrido[3,2-&][l,4]thiazin-3-one;
• 6-{[(3i?,6iS)-6-(6:>8-difluoro-quinolin-4-yloxymethyl)-tetrahydro-pyran-3-ylamino]- methyl} -4H-pyrϊdo [3,2-b] [ 1 ,4]thiazin-3-one;
• 3-oxo-3,4-dihydro-2H-pyrido[3,2-Z>][l,4]oxazine-6-carboxylic acid (3^,65)-{6-[(15>-l-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-tetrahydro-pyran-3-yl}- amide;
• (15)-l-{(25,5i?)-5-trα«5-[3-(2,5-difluoro-phenyl)-allylarrxino]-tetrahydro-pyran-2-yl}- 2-(6-methoxy-quinolin-4-yl)-ethanol;
• 6-({(3i?,65)-6-[(2i?5)-2-hydroxy-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro- pyran-3-ylamino}-methyl)-4H-pyrido[3,2-έ][l,4]thiazin-3-one; • 3-oxo-3,4-dihydro-2H-pyrido[3,2-έ][l,4]thiazine-6-carboxylic acid
{(3i?,65)-6-[(2^S)-2-hydroxy-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro- pyran-3 -yl } -amide; • 2-{(25r,5Λ)-5-[ft"αm-3-(2,5-difluoro-phenyl)-allylamino]-tetralnydro-pyran-2-yl}- l-(6-methoxy-[l,5]naphttiyridin-4-yl)-ethanol;
• /rαw-3-(2,5-difluoro-phenyl)-iV-{(3Λ,65)-6-[(2ΛS)-2-hydroxy-2-(6-methoxy- [l,5]naphthyridin-4-yl)-etliyl]-tetrahydro-pyran-3-yl}-acrylannide; • trαw-3-(2,5-difluoro-phenyl)-N-{(3i?,65)-6-[(15)-l-hydroxy-2-(6-methoxy-quinolin- 4-y l)-ethyl] -tetrahydro-pyran-3 -yl} -acrylamide ;
• (lJR,25)-l-{(25',5i?)-5-[tra«5-3-(2,5-difluoro-phenyl)-allylamino]-tetrahydro-pyran-2-yl}- 2-(6-methoxy-[l,5]naphtrryridin-4-yl)-ethane-l,2-diol;
• 3-oxo-3,4-dihydro-2H-pyrido[3,2-έ][l,4]thiazine-6-carboxylic acid {(3i?,65)-6-[(lδ',2JR)-2-(3-fluoro-6-methoxy-[l,5]naphthyridin-4-yl)-l,2-dihydroxy-ethyl]- tetrahydro-pyran-3-yl}-amide;
• 3-oxo-3,4-dihydro-2H-pyrido[3,2-Z>][l,4]oxazine-6-carboxylic acid {(3#,6S)-6-[(lS;2;?)-2-(3-fluoro-6-inethoxy-[ 1 ,5]naphth-yridin-4-yl)- 1 ,2-dihydroxy- ethyl]-tetrahydro-pyran-3 -yl} amide; • (3,4-dichloro-benzyl)-{6- [2-(8-fluoro-6-memoxy-quinolin-4-3d)-ethyl]-tetrahydro-pyran- 3 -yl} -amine;
• 3-oxo-3,4-dihydro-2H-pyrido[3,2-&][l,4]thiazine-6-carboxylic acid [(2i?,3i?,6JS)-6-[(l.S,2i?)-U2-dihydroxy-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]- 2-(2-hydroxy-ethyl)-tetraliydro-pyran-3-yl]-amide; • 3-oxo-3,4-dihydro-2H-pyrido[3,2-έ][l,4]thiazine-6-carboxylic acid
(2i?,3i?,6R)-{2-(2-hydroxy-ethyl)-6-[2-(6-methoxy-[l,5]naph.thyridin-4-yl)-ethyl]- tetrahydro-pyran-3-yl} -arnide;
• 6-((2JR,3i?,6i?)-{2-(2-hydroxy-ethyl)-6-[2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]- tetrahydro-pyran-3 -ylamino } -methy l)-4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one; • /ra^-3-(2,5-difluoro-phenyl)-N-{(2i?,3i?,6i?)-2-(2-hydroxy-ethyl)-6-[2-(6-methoxy- [l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}-acrylaniide;
• trαrø-3-(2,5-difluoro-phenyl)-N-{(2i2,3i?,6i?)-6-[2-(6-metho?cy-quinolin-4-yl)-ethyl]- tetrahydro-pyran-3 -yl} -acrylamide;
• 6-({(3i?,65)-6-[(2i?)-2-(3-fluoro-6-methoxy-quinolin-4-yl)-2-hydroxy-ethyl]-tetrahydro- pyran-3 -ylamino } -methy l)-4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one;
• 6-({(3i?,65)-6-[(25)-2-(3-fluoro-6-methoxy-quinolin-4-yl)-2-hydroxy-ethyl]-tetrahydro- pyran-3 -ylamino } -methy l)-4H-pyrido [3 ,2-b] [ 1 ,4]thiazin-3 -one; • N-(2,5-difluoro-phenyl)-2-{(3i?,6JR)-6-[2-(6-methoxy-quinolin-4-yl)-ethyl]-tetrahydro- pyran-3-ylamino} -acetamide; and the salts of these compounds.
11. A compound according to claim 1, wherein M is M3.
12. A compound according to claim 11, wherein M3 is selected from the following groups:
Figure imgf000278_0001
13. A compound according to claim 11, which is selected from the following compounds:
• mc-4-{3-[l-(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-piperidin-3-yl]-propoxy}- 6-methoxy-quinoline;
• 6-methoxy-4-{3-[l-(traπ5-3-phenyl-allyl)-piperidin-3-yl]-propoxy}-quinoline; • 4-[3-(l-benzofuran-2-ylmethyl-piperidin-3-yl)-propoxy]-6-methoxy-quinoline;
• rαc-3-[l-(2,3-dihydro-benzo[l,4]dioxin.-6-ylmethyl)-piperidin-3-yl]-N-(6-methoxy- [l,5]naphthyridin-4-yl)-propionamide;
• rac-N-(6-methoxy-[l,5]naphthyridin-4-yl)-3-[l-(3-phenyl-allyl)-piperidin-3-yl]- propionamide; • rac-N-(6-methoxy-[ 1 ,5]naphthyridin-4-y l)-3- { 1 -[2-(thiophen-2-ylsulfanyl)-ethyl]- piperidin-3-yl}-propionamide; • ;"αc-N-(6-methoxy-[l,5]naphthyridirL-4-yl)-3-[l-(3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin- 6-ylmethyl)-piperidin-3-yl]-propionarnide;
• rαc-N-(6-methoxy-[l,5]naphthyridin.-4-yl)-3-[l-(3-oxo-3,4-dihydro- 2H-pyrido[3,2-ό][l,4]thiazin-6-ylmethyl)-piperidin-3-yl]-propionamide; • rαc-3-[l-(2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)-piperidin-3-yl]- N-(6-methoxy-[l,5]naphthyridin-4-yrl)-propionamide;
• rac-3-{ 1 -[2-(2,3-dihydro-benzo[l ,4] dioxin-6-yl)-ethyl]-piperidin-3-yl}-7V-(6-methoxy- [ 1 , 5 ]naphthyridin-4-yl)-prop ionamide ;
• rαc-N-(2-cyano-quinolin-8-yl)-3-[l-(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-piperidin- 3-yl]-propionamide;
• rαc-N-(2-cyano-quinolin-8-yl)-3-[/r«_3«5-l-(3-phenyl-allyl)-piperidin-3-yl]-propionamide;
• rαc-N-(2-cyano-quinolin-8-yl)-3-[l-(3-oxo-3,4-dihydro-2H-benzo[l,4]thιiazin- 6-ylmethyl)-piperidin-3-yl]-propioti amide;
• rαc-2-[l-(2,3-dihydro-benzo[l)4]dioxin-6-ylmethyl)-piperidin-3-yloxy]-iV-(6-methoxy- [ 1 ,5]naphthyridin-4-yl)-acetamide;
• (2,3 -dihydro-benzo [1,4] dioxin-6-y lrnethy I)- [3 -(6-methoxy-quinolin-4-yl oxymethy I)- cyclohexylmethyl]-amine;
• (2,3-dihydro-benzo[l,4]dioxin-6-ylrnethyl)-[(li?,35)-3-(6-methoxy-quiαolin- 4-yloxymethyl)-cyclohexylmethyl]-amine; • rαc-3-{[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-methyl}- cyclohexanecarboxylic acid (2-methyl-quinolin-8-yl)-arnide;
• rαc-3-[troπ5-(3-phenyl-allylamino)— niethyl]-cyclohexanecarboxylic acid (2-methyl- quinolin-8-yl)-amide;
• rac-3 -{[(2,3 -dihydro-benzo [ 1 ,4]dioxin-6-y lmethyl)-amino] -methy 1} - cyclohexanecarboxylic acid (6-metlioxy-[l,5]naphthyridin-4-yl)-amide;
• rαc-3-{[(3-oxo-3,4-dihydro-2//-benzo[l,4]oxazin-6-ylmethyl)-amino]-methyl}- cyclohexanecarboxylic acid (6-metlioxy-[ 1 ,5]naphthyridin-4-yl)-amide;
• c/5-3-{[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-methyl}- cyclohexanecarboxylic acid (6-metlioxy-[ 1 ,5]naphthyridin-4-yl)-amide; • c/5-3-{[(3-oxo-3,4-dihydro-2//-beixzo[l,4]thiazin-6-ylmethyl)-aniino]-methyl}- cyclohexanecarboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide;
• cw-3-{[(2,3-dihydro-[l,4]dioxino[2,3-έ]pyridin-6-ylmethyl)-amino]-methyl}- cyclohexanecarboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide; • cω-3-{[(2,3-dihydro-benzo[l,4]dϊoxin-6-ylmethyl)-amino]-methyl^- cyclohexanecarboxylic acid (2-cyano-quinolin-8-yl)-amide;
• cw-3-{[(3-oxo-3,4-dihydro-2H-benzo[l,4]thiazin-6-ylmethyl)-amino]-methyl}- cyclohexanecarboxylic acid (2-cyano-quinolin-8-yl)-amide; • cώ-3-{[(benzo[l,2,5]thiadiazol-5 -ylmethyl)-amino]-methyl}-cyclohexanecarboxylic acid (2-cyano-quinolin-8-yl)-amide;
• cis-3-{ [(3-oxo-3,4-dihydro-2H-pyrido[3,2-b] [ 1 ,4]thiazin-6-ylmetlryl)-amino]-methyl} - cyclohexanecarboxylic acid (2-cyano-quinolin-8-yl)-amide;
• cw-3-[(tra«5-3-phenyl-allylamino)-methyl]-cyclohexanecarboxylic acid (2-cyano- quinolin-8-yl)-amide;
• c/5-3-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-&][l,4]thiazin-6-ylmethyl)-amino]-methyl}- cyclohexanecarboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-arnide;
• 3-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-ό][l,4]oxazin-6-ylmethyl)-amino]-methyl}- cyclohexanecarboxylic acid (6-rnethoxy-[l,5]naphthyridin-4-yl)-arnide; and the salts of these compounds .
14. A compound according to claim 1, wherein M is M4.
15. A compound according to claim 14, wherein M4 is selected from the following groups:
Figure imgf000280_0001
16. A compound according to claim. 14, which is selected from the following compounds:
• rαc-trα«5-(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-[6-(6-niethoxy-quinolin- 4-yloxymethyl)-piperidin-3-yl]-amine;
• rαc-trαrø-6-{[6-(6-methoxy-quinazolin-4-yloxymethyl)-piperidin-3-ylamino]-methyl}- 4H-pyrido[3,2-δ][l,4]thiazin-3-one;
• rac-tra«5-(2,3-dihydro-benzo[l , 4]dioxin-6-ylmethyl)-[6-(6-methoxy-quinazolin- 4-yloxymethyl)-piperidin-3-yl]-amine; • rαc-trα«5-{2-(6-methoxy-quinazolin-4-yloxymethyl)-5-[(3-oxo-3-,4-dihydro-
2H-pyrido[3,2-6][l,4]thiazin-6-ylmethyl)-amino]-piperidin-l-yl}-acetic acid tert-butyl ester; • rfirc-trα«Λr-{2-(6-methoxy-quinazolin-4-yloxymethyl)-5-[(3-oxo-3,4-dihydro- 2H-pyrido [3 ,2-b] [ 1 ,4]thiazin-6-ylmethyl)-amino] -p iperidin- 1 -yl } -acetic acid;
• rαc-Λ"flR5-6-({6-[2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-piperidin-3-ylamino}- methyl)-4H-pyrido[3,2-6][l,4]thiazin-3-one; • rαc-trα»5-5-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-Z>][ l,4]thiazin-6-ylmethyl)-amino]- piperidine-2-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide;
• rαc-trα??5-5-[(3-oxo-3,4-dihydro-2H-benzo[ 1 ,4]thiazbn-6-ylrnethyl)-amino]-piperidine- 2-carboxylic acid (6-methoxy-[l,5]naphthyridin-4-yl)-amide;
• rαc-trα«5-5-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmeth.yl)-amino]-piperidine-2-carboxylic acid (6-methoxy-[ls5]naphthyridin-4-yl)-amide; and the salts of these compounds.
17. As a medicament, a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition containing, as active principle, a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.
19. Use of a compound according to claim 1 for the manufacture of a medicament for the prevention or treatment of infection(s).
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