JP2009529525A - Antibacterial compounds - Google Patents

Abstract

式中R¹は、アルキル、アルコキシ、ハロアルコキシ、ハロゲンまたはシアノを表す；U、V、WおよびXの1つまたは2つは、Nを表し、残りのものはCHを表すか、またはUの場合には、Vおよび／またはWは、CR^aを表してもよく、およびXの場合、CR^bをまた表してもよく、R^aは、ハロゲンを表し、かつR^bは、ハロゲンまたはアルコキシを表し；、A³は、NHCO、CH₂CH₂、CH=CH、COCH₂CH（OH）CH₂、CH₂CH（OH）CH（OH）CH（OH）またはOCH₂を表し；A⁴は、CH₂、CO、CH₂CH=CH、COCH=CHまたはCH₂CONHを表し；R²は、水素、アルキル、ヒドロキシアルキル、アルキルカルボニルオキシアルキル、カルバモイルオキシアルキル、カルボキシアルキルまたはカルバモイルアルキルを表し；R³およびR⁴は、それぞれ独立して、水素、ヒドロキシまたはアルキルカルボニルオキシを表すか；またはR³およびR⁴は、共にR³およびR⁴を有する炭素に付着された架橋されたジメチルメチレンジオキシ鎖を表し；R⁵は、水素、アルキルまたはヒドロキシアルキルを表し；並びに点線は単結合を表すか、またはR³およびR⁴が水素のときは、また二重結合を表し；並びにDは、アルキル、アリールまたはヘテロアリールを表す。このような抗生物質の例は、（E)-2-{(2R,3R,6R)-(3-[3-(2,5-ジフルオロ-フェニル)-アリルアミノ]-6-[2-(6-メトキシ-[1,5]ナフチリジン-4-イル)-エチル]-テトラヒドロ-ピラン-2-イル}-エタノールである。
【選択図】 なしThe present invention relates to selected antibiotics of formula (A1):

In which R ¹ represents alkyl, alkoxy, haloalkoxy, halogen or cyano; one or two of U, V, W and X represent N and the rest represent CH or In some cases, V and / or W may represent CR ^a , and in the case of X, CR ^b may also represent, R ^a represents halogen, and R ^b represents halogen or alkoxy. represents;, a ³ _{is, NHCO, CH 2 CH 2,} CH = CH, represents a _{COCH 2 CH (OH) CH 2} , CH 2 CH (OH) CH (OH) CH (OH) or OCH _2; a ⁴ is CH ₂ , CO, CH ₂ CH═CH, COCH═CH or CH ₂ CONH; R ² represents hydrogen, alkyl, hydroxyalkyl, alkylcarbonyloxyalkyl, carbamoyloxyalkyl, carboxyalkyl or carbamoylalkyl; R ³ and R ⁴ are each independently hydrogen, hydroxy or alkylcarbonyloxy Table Or; or R ³ and R ^4, dimethylmethylenedioxy chain represents a cross-linked are attached to a carbon having both R ³ and R ^4; is R ^5, hydrogen, alkyl or hydroxyalkyl; and the dotted line It represents a single bond, or when R ³ and R ⁴ are hydrogen, it also represents a double bond; and D represents alkyl, aryl or heteroaryl. Examples of such antibiotics are (E) -2-{(2R, 3R, 6R)-(3- [3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6 -Methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -ethanol.
[Selection figure] None

Description

  The present invention relates to novel antibiotics, pharmaceutical antibacterial compositions containing them and their use in the manufacture of a medicament for the treatment of infections (eg bacterial infections). These compounds are useful antibacterial agents effective against various human and animal pathogens and include, among others, gram positive and gram negative aerobic and anaerobic bacteria and mycobacteria.

  The high utilization of antibiotics has exerted selective evolutionary pressures on microorganisms, resulting in gene-based resistance mechanisms. The problem of resistance development by modern medical and socioeconomic behavior, by creating a situation in which pathogenic microorganisms multiply slowly, for example in artificial joints, and by assisting long-term host storage, for example in immunocompromised patients Has made it worse.

In the hospital environment, there are many strains of Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus spp. And Pseudomonas aeruginosa, the main sources of infection. It is becoming drug resistant and therefore difficult if not impossible to treat:
-S. aureus is resistant to β-lactams, quinolones, and now even vancomycin;
-S. pneumoniae is resistant to penicillins, quinolones, and even new macrolides;
-Enterococci is resistant to quinolone and vancomycin, β-lactam has no effect on these strains;
-Enterobacteriacea is resistant to cephalosporins and quinolones;
-Pseudomonas aeruginosa is resistant to β-lactams and quinolones.

  In addition, emerging organisms such as Acinetobacter or C. difficile that were selected during therapy with currently used antibiotics have become a real problem in hospital settings. It has become.

  In addition, microorganisms that cause persistent infection are increasingly recognized as causative factors or cofactors of severe chronic diseases such as peptic ulcers or heart diseases.

  New types of quinoline or naphthyridine derivatives that have antibacterial activity and are therefore useful for treating infections in mammals, particularly in humans, have been reported in the past few years.

  International Publication No. 99/37635, International Publication No. 00/21948, International Publication No. 00/21952, International Publication No. 00/43383, International Publication No. 03/101138, International Publication No. 01/025227, International Publication WO 02/040474 and WO 2004/011454 disclose quinoline, naphthyridine and quinazoline derivatives containing 4-methylpiperidinyl spacers.

  WO 00/78748, WO 02/50040 and WO 02/050061 disclose quinoline and naphthyridine derivatives containing piperazinyl spacers.

  International Publication No. 01/07432, International Publication No. 01/07433, International Publication No. 02/08224, International Publication No. 02/056882, International Publication No. 03/064421, International Publication No. 03/064431, International Publication 2004/02490 and WO2004 / 058144 disclose quinoline, quinoxaline and naphthyridine derivatives containing 4-aminopiperidinyl spacers.

  WO 04/035569 and WO 2006/014580 disclose quinoline and naphthyridine derivatives containing 3-aminomethylpiperidinyl spacers.

  WO 2004/002992, WO 03/087098, WO 2004/014361 and WO 2004/035569 disclose quinoline, quinoxaline and naphthyridine derivatives containing 4-aminocyclohexyl spacers.

  In addition, PCT application number PCT / EP2005 / 010154 (published as International Publication No. 2006/032466) provides certain bicyclic derivatives as useful antibacterial agents that are effective against various multi-drug resistant bacteria. Describe. The bicyclic derivative has the formula (A1)

を有し
式中、R¹は、アルキル、アルコキシ、ハロアルコキシ、ハロゲンまたはシアノを表し；
U、V、WおよびXの1つまたは2つは、Nを表し、残りは、CHを表すか、またはUの場合、Vおよび／またはWは、またCR^aを表してもよく、およびXの場合、またCR^bを表してもよく；
R^aは、ハロゲンを表し；
R^bは、ハロゲンまたはアルコキシを表し；
Dは、アルキル、アリールまたはヘテロアリールを表し；
Mは、特に基M²であり：

In which R ¹ represents alkyl, alkoxy, haloalkoxy, halogen or cyano;
One or two of U, V, W and X represent N and the rest represent CH, or in the case of U, V and / or W may also represent CR ^a and X And may also represent CR ^b ;
R ^a represents halogen;
R ^b represents halogen or alkoxy;
D represents alkyl, aryl or heteroaryl;
M is in particular the group M ² :

式中、A³は、NHCO、CH₂CH₂、CH=CH、COCH₂、CH（OH）CH₂、CH₂CH（OH）CH（OH）CH（OH）またはOCH₂を表し；
A⁴は、CH₂、CO、CH₂CH=CH、COCH=CHまたはCH₂CONHを表し；
R²は、水素、アルキル、ヒドロキシアルキル、アルキルカルボニルオキシアルキル、カルバモイルオキシアルキル、カルボキシアルキルまたはカルバモイルアルキルを表し；
R₃およびR₄は、それぞれ独立して、水素、ヒドロキシまたはアルキルカルボニルオキシを表すか；またはR³およびR⁴は共に、R³およびR⁴を有する炭素に付着された、架橋されたジメチルメチレンジオキシ鎖を表し；
R⁵は、水素、アルキルまたはヒドロキシアルキルを表し；並びに、
点線は、単結合を表すか、またはR³およびR⁴が水素のときは、また二重結合を表す。
本発明は、上記の通りの式（A1）およびその塩の選択化合物に関連する。

In which A ³ represents NHCO, CH ₂ CH ₂ , CH═CH, COCH ₂ , CH (OH) CH ₂ , CH ₂ CH (OH) CH (OH) CH (OH) or OCH ₂ ;
A ⁴ represents CH ₂ , CO, CH ₂ CH═CH, COCH═CH or CH ₂ CONH;
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 are both bridged dimethylmethylene attached to the carbon having R ³ and R ⁴ Represents a dioxy chain;
R ⁵ represents hydrogen, alkyl or hydroxyalkyl; and
The dotted line represents a single bond or, when R ³ and R ⁴ are hydrogen, also represents a double bond.
The present invention relates to selected compounds of formula (A1) and salts thereof as described above.

Accordingly, the compounds of the invention are selected from the following and their salts:
-(E) -2-{(2R, 3R, 6R)-(3- [3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy- [1,5] Naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -ethanol;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -acryloylamino] -6- [2- (3-methoxy-quinolin-5-yl)- Ethyl] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6R) -6- [2- (3-methoxy-quinolin-5-yl) -ethyl] -3-[(3-oxo-3,4-dihydro-2H-pyrido [3, 2-b] [1,4] thiazine-6-carbonyl) -amino] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6R) -6- [2- (6-Methoxy- [1,5] naphthyridin-4-yl) -ethyl] -3-[(3-oxo-3,4-dihydro-2H -Pyrido [3,2-b] [1,4] thiazin-6-ylmethyl) -amino] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy- [1,5] naphthyridine-4 -Yl) -ethyl] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(1S) -1-hydroxy-2- (6-methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetic acid;
-(1R) -2-{(2S, 5R, 6S) -5- [trans-3- (2,5-difluoro-phenyl) -allylamino] -6-hydroxymethyl-tetrahydro-pyran-2-yl}- 1- (3-fluoro-6-methoxy-quinolin-4-yl) -ethanol;
-(1S) -2-{(2S, 5R, 6S) -5- [trans-3- (2,5-difluoro-phenyl) -allylamino] -6-hydroxymethyl-tetrahydro-pyran-2-yl}- 1- (3-fluoro-6-methoxy-quinolin-4-yl) -ethanol;
-2-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy- [1,5] naphthyridine -4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(1R, 2R) -1,2-dihydroxy-2 -(3-methoxy-quinoxalin-5-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy-quinolin-4-yl) -ethyl ] -Tetrahydro-pyran-2-yl} -acetic acid;
-2-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy-quinolin-4-yl) -Ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(S) -1-hydroxy-2- (6- Methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2R) -2- (3-fluoro-6-methoxy-quinolin-4-yl) -2 -Hydroxy-ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2S) -2- (3-fluoro-6-methoxy-quinolin-4-yl) -2 -Hydroxy-ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2S, 3R, 6S) -6-[(2R) -2- (3-Fluoro-6-methoxy-quinolin-4-yl) -2-hydroxy-ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl} -amide;
-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2S, 3R, 6S) -6-[(2S) -2- (3-Fluoro-6-methoxy-quinolin-4-yl) -2-hydroxy-ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl} -amide;
-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2S, 3R, 6S) -6-[(2R) -2- Hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl} -amide;
-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2S, 3R, 6S) -6-[(2S) -2- Hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl} -amide;
-3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2R) -2-hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl ] -2-Hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2S) -2-hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl ] -2-Hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (3-fluoro-6- Methoxy- [1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetamide;
-(2S, 5R, 6R)-(5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- (2-hydroxy-ethyl))-tetrahydro-pyran-2-carboxylic Acid (6-methoxy- [1,5] naphthyridin-4-yl) -amide;
-(2S, 5R) -5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -tetrahydro-pyran-2-carboxylic acid (6-methoxy- [1,5] naphthyridine-4 -Yl) -amide;
-(1S) -1-{(2S, 5R) -5-[(E) -3- (3-Fluoro-phenyl) -allylamino] -tetrahydro-pyran-2-yl} -2- (6-methoxy- Quinolin-4-yl) -ethanol;
-7-fluoro-6-({(3R, 6S) -6-[(1S) -1-hydroxy-2- (6-methoxy-quinolin-4-yl) -ethyl] -tetrahydro-pyran-3-ylamino } -Methyl) -4H-benzo [1,4] thiazin-3-one;
-3- (2-Fluoro-phenyl) -N-{(3R, 6S) -6-[(1S) -1-hydroxy-2- (6-methoxy-quinolin-4-yl) -ethyl] -tetrahydro- Pyran-3-yl}-(E) -acrylamide;
-3- (3-Fluoro-phenyl) -N-{(3R, 6S) -6-[(1S) -1-hydroxy-2- (6-methoxy-quinolin-4-yl) -ethyl] -tetrahydro- Pyran-3-yl}-(E) -acrylamide;
-8-((1R, 2R) -2-{(2S, 5R) -5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -tetrahydro-pyran-2-yl}- 1,2-dihydroxy-ethyl) -quinoline-2-carbonitrile;
-[(E) -3- (2,5-difluoro-phenyl) -allyl]-{3R, 6S) -6-[(E) -2- (3-fluoro-6-methoxy-quinolin-5-yl ) -Vinyl] -tetrahydro-pyran-3-yl} -amine;
-[(E) -3- (2,5-difluoro-phenyl) -allyl]-{(3R, 6S) -6- [2- (6-fluoro-3-methoxy-quinolin-4-yl) -ethyl ] -Tetrahydro-pyran-3-yl} -amine;
-6-({(3R, 6S) -6- [2- (6-Fluoro-3-methoxy-quinolin-4-yl) -ethyl] -tetrahydro-pyran-3-ylamino} -methyl) -4H-pyrido [3,2-b] [1,4] thiazin-3-one;
-(1R, 2R) -1-{(2R, 5S) -5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -tetrahydro-pyran-2-yl} -2- ( 6-Fluoro-quinolin-4-yl) -ethane-1,2-diol;
-[(E) -3- (2,5-Difluoro-phenyl) -allyl]-{(3S, 6R)-(E) -6- [2- (6-Fluoro-quinolin-4-yl) -vinyl ] -Tetrahydro-pyran-3-yl} -amine;
-[(E) -3- (2,5-Difluoro-phenyl) -allyl]-{(3S, 6R) -6- [2- (6-Fluoro-quinolin-4-yl) -ethyl] -tetrahydro- Pyran-3-yl} -amine;
-6-({3S, 6R) -6- [2- (6-Fluoro-quinolin-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 {(2R, 3R, 6S) -2- (2-hydroxy-ethyl) -6-[(E) -2- (6-methoxy- [1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-3-yl} -amide;
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (6-methoxy- [1 , 5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetamide;
-(2R, 3R, 6S)-{3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (3-fluoro-6-methoxy- Quinolin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (6-methoxy- [1,5 ] Naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetic acid;
-[(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- (6-methoxy- [1,5] naphthyridin-4-ylcarbamoyl ) -Tetrahydro-pyran-2-yl] -acetic acid.

The invention relates in particular to compounds selected from: and salts thereof:
-(E) -2-{(2R, 3R, 6R)-(3- [3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy- [1,5] Naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -ethanol;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -acryloylamino] -6- [2- (3-methoxy-quinolin-5-yl)- Ethyl] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6R) -6- [2- (3-methoxy-quinolin-5-yl) -ethyl] -3-[(3-oxo-3,4-dihydro-2H-pyrido [3, 2-b] [1,4] thiazine-6-carbonyl) -amino] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6R) -6- [2- (6-Methoxy- [1,5] naphthyridin-4-yl) -ethyl] -3-[(3-oxo-3,4-dihydro-2H -Pyrido [3,2-b] [1,4] thiazin-6-ylmethyl) -amino] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy- [1,5] naphthyridine-4 -Yl) -ethyl] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(1S) -1-hydroxy-2- (6-methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetic acid;
-(1R) -2-{(2S, 5R, 6S) -5- [trans-3- (2,5-difluoro-phenyl) -allylamino] -6-hydroxymethyl-tetrahydro-pyran-2-yl}- 1- (3-fluoro-6-methoxy-quinolin-4-yl) -ethanol;
-(1S) -2-{(2S, 5R, 6S) -5- [trans-3- (2,5-difluoro-phenyl) -allylamino] -6-hydroxymethyl-tetrahydro-pyran-2-yl}- 1- (3-fluoro-6-methoxy-quinolin-4-yl) -ethanol;
-2-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy- [1,5] naphthyridine -4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(1R, 2R) -1,2-dihydroxy-2 -(3-methoxy-quinoxalin-5-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy-quinolin-4-yl) -ethyl ] -Tetrahydro-pyran-2-yl} -acetic acid;
-2-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy-quinolin-4-yl) -Ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(S) -1-hydroxy-2- (6- Methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2R) -2- (3-fluoro-6-methoxy-quinolin-4-yl) -2 -Hydroxy-ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2S) -2- (3-fluoro-6-methoxy-quinolin-4-yl) -2 -Hydroxy-ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2S, 3R, 6S) -6-[(2R) -2- (3-Fluoro-6-methoxy-quinolin-4-yl) -2-hydroxy-ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl} -amide;
-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2S, 3R, 6S) -6-[(2S) -2- (3-Fluoro-6-methoxy-quinolin-4-yl) -2-hydroxy-ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl} -amide;
-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2S, 3R, 6S) -6-[(2R) -2- Hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl} -amide;
-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2S, 3R, 6S) -6-[(2S) -2- Hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl} -amide;
-3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2R) -2-hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl ] -2-Hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2S) -2-hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl ] -2-Hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (3-fluoro-6- Methoxy- [1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetamide;
-(2S, 5R, 6R)-(5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- (2-hydroxy-ethyl))-tetrahydro-pyran-2-carboxylic Acid (6-methoxy- [1,5] naphthyridin-4-yl) -amide;
-(2S, 5R) -5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -tetrahydro-pyran-2-carboxylic acid (6-methoxy- [1,5] naphthyridine-4 -Yl) -amide;
-(1S) -1-{(2S, 5R) -5-[(E) -3- (3-Fluoro-phenyl) -allylamino] -tetrahydro-pyran-2-yl} -2- (6-methoxy- Quinolin-4-yl) -ethanol;
-7-fluoro-6-({(3R, 6S) -6-[(1S) -1-hydroxy-2- (6-methoxy-quinolin-4-yl) -ethyl] -tetrahydro-pyran-3-ylamino } -Methyl) -4H-benzo [1,4] thiazin-3-one;
-3- (2-Fluoro-phenyl) -N-{(3R, 6S) -6-[(1S) -1-hydroxy-2- (6-methoxy-quinolin-4-yl) -ethyl] -tetrahydro- Pyran-3-yl}-(E) -acrylamide;
-3- (3-Fluoro-phenyl) -N-{(3R, 6S) -6-[(1S) -1-hydroxy-2- (6-methoxy-quinolin-4-yl) -ethyl] -tetrahydro- Pyran-3-yl}-(E) -acrylamide;
-8-((1R, 2R) -2-{(2S, 5R) -5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -tetrahydro-pyran-2-yl}- 1,2-dihydroxy-ethyl) -quinoline-2-carbonitrile;
-[(E) -3- (2,5-difluoro-phenyl) -allyl]-{3R, 6S) -6-[(E) -2- (3-fluoro-6-methoxy-quinolin-5-yl ) -Vinyl] -tetrahydro-pyran-3-yl} -amine;
-[(E) -3- (2,5-difluoro-phenyl) -allyl]-{(3R, 6S) -6- [2- (6-fluoro-3-methoxy-quinolin-4-yl) -ethyl ] -Tetrahydro-pyran-3-yl} -amine;
-6-({(3R, 6S) -6- [2- (6-Fluoro-3-methoxy-quinolin-4-yl) -ethyl] -tetrahydro-pyran-3-ylamino} -methyl) -4H-pyrido [3,2-b] [1,4] thiazin-3-one;
-(1R, 2R) -1-{(2R, 5S) -5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -tetrahydro-pyran-2-yl} -2- ( 6-Fluoro-quinolin-4-yl) -ethane-1,2-diol;
-[(E) -3- (2,5-Difluoro-phenyl) -allyl]-{(3S, 6R)-(E) -6- [2- (6-Fluoro-quinolin-4-yl) -vinyl ] -Tetrahydro-pyran-3-yl} -amine;
-[(E) -3- (2,5-Difluoro-phenyl) -allyl]-{(3S, 6R) -6- [2- (6-Fluoro-quinolin-4-yl) -ethyl] -tetrahydro- Pyran-3-yl} -amine;
-6-({3S, 6R) -6- [2- (6-Fluoro-quinolin-4-yl) -ethyl] -tetrahydro-pyran-3-ylamino} -methyl) -4H-pyrido [3,2- b] [1,4] thiazin-3-one.

The following compounds of the invention are preferred:
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (6-methoxy- [1 , 5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetamide;
-(2R, 3R, 6S)-{3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (3-fluoro-6-methoxy- Quinolin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (6-methoxy- [1,5 ] Naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetic acid;
As well as their salts.

According to a first aspect, the compounds of the invention will be selected from:
-(E) -2-{(2R, 3R, 6R)-(3- [3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy- [1,5] Naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -ethanol;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -acryloylamino] -6- [2- (3-methoxy-quinolin-5-yl)- Ethyl] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy- [1,5] naphthyridine-4 -Yl) -ethyl] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(1S) -1-hydroxy-2- (6-methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetic acid;
-(1R) -2-{(2S, 5R, 6S) -5- [trans-3- (2,5-difluoro-phenyl) -allylamino] -6-hydroxymethyl-tetrahydro-pyran-2-yl}- 1- (3-fluoro-6-methoxy-quinolin-4-yl) -ethanol;
-(1S) -2-{(2S, 5R, 6S) -5- [trans-3- (2,5-difluoro-phenyl) -allylamino] -6-hydroxymethyl-tetrahydro-pyran-2-yl}- 1- (3-fluoro-6-methoxy-quinolin-4-yl) -ethanol;
-2-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy- [1,5] naphthyridine -4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(1R, 2R) -1,2-dihydroxy-2 -(3-methoxy-quinoxalin-5-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy-quinolin-4-yl) -ethyl ] -Tetrahydro-pyran-2-yl} -acetic acid;
-2-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy-quinolin-4-yl) -Ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(S) -1-hydroxy-2- (6- Methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2R) -2- (3-fluoro-6-methoxy-quinolin-4-yl) -2 -Hydroxy-ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2S) -2- (3-fluoro-6-methoxy-quinolin-4-yl) -2 -Hydroxy-ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2R) -2-hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl ] -2-Hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2S) -2-hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl ] -2-Hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (3-fluoro-6- Methoxy- [1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetamide;
-(2S, 5R, 6R)-(5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- (2-hydroxy-ethyl))-tetrahydro-pyran-2-carboxylic Acid (6-methoxy- [1,5] naphthyridin-4-yl) -amide;
-(2S, 5R) -5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -tetrahydro-pyran-2-carboxylic acid (6-methoxy- [1,5] naphthyridine-4 -Yl) -amide;
-(1S) -1-{(2S, 5R) -5-[(E) -3- (3-Fluoro-phenyl) -allylamino] -tetrahydro-pyran-2-yl} -2- (6-methoxy- Quinolin-4-yl) -ethanol;
-3- (2-Fluoro-phenyl) -N-{(3R, 6S) -6-[(1S) -1-hydroxy-2- (6-methoxy-quinolin-4-yl) -ethyl] -tetrahydro- Pyran-3-yl}-(E) -acrylamide;
-3- (3-Fluoro-phenyl) -N-{(3R, 6S) -6-[(1S) -1-hydroxy-2- (6-methoxy-quinolin-4-yl) -ethyl] -tetrahydro- Pyran-3-yl}-(E) -acrylamide;
-8-((1R, 2R) -2-{(2S, 5R) -5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -tetrahydro-pyran-2-yl}- 1,2-dihydroxy-ethyl) -quinoline-2-carbonitrile;
-[(E) -3- (2,5-difluoro-phenyl) -allyl]-{3R, 6S) -6-[(E) -2- (3-fluoro-6-methoxy-quinolin-5-yl ) -Vinyl] -tetrahydro-pyran-3-yl} -amine;
-[(E) -3- (2,5-difluoro-phenyl) -allyl]-{(3R, 6S) -6- [2- (6-fluoro-3-methoxy-quinolin-4-yl) -ethyl ] -Tetrahydro-pyran-3-yl} -amine;
-(1R, 2R) -1-{(2R, 5S) -5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -tetrahydro-pyran-2-yl} -2- ( 6-Fluoro-quinolin-4-yl) -ethane-1,2-diol;
-[(E) -3- (2,5-Difluoro-phenyl) -allyl]-{(3S, 6R)-(E) -6- [2- (6-Fluoro-quinolin-4-yl) -vinyl ] -Tetrahydro-pyran-3-yl} -amine;
-[(E) -3- (2,5-Difluoro-phenyl) -allyl]-{(3S, 6R) -6- [2- (6-Fluoro-quinolin-4-yl) -ethyl] -tetrahydro- Pyran-3-yl} -amine;
-6-({3S, 6R) -6- [2- (6-Fluoro-quinolin-4-yl) -ethyl] -tetrahydro-pyran-3-ylamino} -methyl) -4H-pyrido [3,2- b] [1,4] thiazin-3-one;
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (6-methoxy- [1 , 5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetamide;
-(2R, 3R, 6S)-{3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (3-fluoro-6-methoxy- Quinolin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (6-methoxy- [1,5 ] Naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetic acid;
Or a salt of these compounds.

According to said first aspect, the compounds of the invention will in particular be selected from:
-(E) -2-{(2R, 3R, 6R)-(3- [3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy- [1,5] Naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -ethanol;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -acryloylamino] -6- [2- (3-methoxy-quinolin-5-yl)- Ethyl] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy- [1,5] naphthyridine-4 -Yl) -ethyl] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(1S) -1-hydroxy-2- (6-methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetic acid;
-(1R) -2-{(2S, 5R, 6S) -5- [trans-3- (2,5-difluoro-phenyl) -allylamino] -6-hydroxymethyl-tetrahydro-pyran-2-yl}- 1- (3-fluoro-6-methoxy-quinolin-4-yl) -ethanol;
-(1S) -2-{(2S, 5R, 6S) -5- [trans-3- (2,5-difluoro-phenyl) -allylamino] -6-hydroxymethyl-tetrahydro-pyran-2-yl}- 1- (3-fluoro-6-methoxy-quinolin-4-yl) -ethanol;
-2-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy- [1,5] naphthyridine -4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(1R, 2R) -1,2-dihydroxy-2 -(3-methoxy-quinoxalin-5-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy-quinolin-4-yl) -ethyl ] -Tetrahydro-pyran-2-yl} -acetic acid;
-2-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy-quinolin-4-yl) -Ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(S) -1-hydroxy-2- (6- Methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2R) -2- (3-fluoro-6-methoxy-quinolin-4-yl) -2 -Hydroxy-ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2S) -2- (3-fluoro-6-methoxy-quinolin-4-yl) -2 -Hydroxy-ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2R) -2-hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl ] -2-Hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2S) -2-hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl ] -2-Hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (3-fluoro-6- Methoxy- [1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetamide;
-(2S, 5R, 6R)-(5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- (2-hydroxy-ethyl))-tetrahydro-pyran-2-carboxylic Acid (6-methoxy- [1,5] naphthyridin-4-yl) -amide;
-(2S, 5R) -5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -tetrahydro-pyran-2-carboxylic acid (6-methoxy- [1,5] naphthyridine-4 -Yl) -amide;
-(1S) -1-{(2S, 5R) -5-[(E) -3- (3-Fluoro-phenyl) -allylamino] -tetrahydro-pyran-2-yl} -2- (6-methoxy- Quinolin-4-yl) -ethanol;
-3- (2-Fluoro-phenyl) -N-{(3R, 6S) -6-[(1S) -1-hydroxy-2- (6-methoxy-quinolin-4-yl) -ethyl] -tetrahydro- Pyran-3-yl}-(E) -acrylamide;
-3- (3-Fluoro-phenyl) -N-{(3R, 6S) -6-[(1S) -1-hydroxy-2- (6-methoxy-quinolin-4-yl) -ethyl] -tetrahydro- Pyran-3-yl}-(E) -acrylamide;
-8-((1R, 2R) -2-{(2S, 5R) -5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -tetrahydro-pyran-2-yl}- 1,2-dihydroxy-ethyl) -quinoline-2-carbonitrile;
-[(E) -3- (2,5-difluoro-phenyl) -allyl]-{3R, 6S) -6-[(E) -2- (3-fluoro-6-methoxy-quinolin-5-yl ) -Vinyl] -tetrahydro-pyran-3-yl} -amine;
-[(E) -3- (2,5-difluoro-phenyl) -allyl]-{(3R, 6S) -6- [2- (6-fluoro-3-methoxy-quinolin-4-yl) -ethyl ] -Tetrahydro-pyran-3-yl} -amine;
-(1R, 2R) -1-{(2R, 5S) -5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -tetrahydro-pyran-2-yl} -2- ( 6-Fluoro-quinolin-4-yl) -ethane-1,2-diol;
-[(E) -3- (2,5-Difluoro-phenyl) -allyl]-{(3S, 6R)-(E) -6- [2- (6-Fluoro-quinolin-4-yl) -vinyl ] -Tetrahydro-pyran-3-yl} -amine;
-[(E) -3- (2,5-Difluoro-phenyl) -allyl]-{(3S, 6R) -6- [2- (6-Fluoro-quinolin-4-yl) -ethyl] -tetrahydro- Pyran-3-yl} -amine;
Or a salt of these compounds.

According to said first aspect, the compounds of the invention can also be selected from:
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (3-fluoro-6- Methoxy- [1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetamide;
-[(E) -3- (2,5-difluoro-phenyl) -allyl]-{3R, 6S) -6-[(E) -2- (3-fluoro-6-methoxy-quinolin-5-yl ) -Vinyl] -tetrahydro-pyran-3-yl} -amine;
-[(E) -3- (2,5-Difluoro-phenyl) -allyl]-{(3S, 6R)-(E) -6- [2- (6-Fluoro-quinolin-4-yl) -vinyl ] -Tetrahydro-pyran-3-yl} -amine;
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (6-methoxy- [1 , 5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetamide;
-(2R, 3R, 6S)-{3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (3-fluoro-6-methoxy- Quinolin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (6-methoxy- [1,5 ] Naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetic acid;
Or it can also be a salt of these compounds.

According to one variation of this first aspect, the compounds of the invention will be selected from:
-(E) -2-{(2R, 3R, 6R)-(3- [3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy- [1,5] Naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -ethanol;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -acryloylamino] -6- [2- (3-methoxy-quinolin-5-yl)- Ethyl] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy- [1,5] naphthyridine-4 -Yl) -ethyl] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(1S) -1-hydroxy-2- (6-methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetic acid;
-(1R) -2-{(2S, 5R, 6S) -5- [trans-3- (2,5-difluoro-phenyl) -allylamino] -6-hydroxymethyl-tetrahydro-pyran-2-yl}- 1- (3-fluoro-6-methoxy-quinolin-4-yl) -ethanol;
-(1S) -2-{(2S, 5R, 6S) -5- [trans-3- (2,5-difluoro-phenyl) -allylamino] -6-hydroxymethyl-tetrahydro-pyran-2-yl}- 1- (3-fluoro-6-methoxy-quinolin-4-yl) -ethanol;
-2-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy- [1,5] naphthyridine -4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(1R, 2R) -1,2-dihydroxy-2 -(3-methoxy-quinoxalin-5-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy-quinolin-4-yl) -ethyl ] -Tetrahydro-pyran-2-yl} -acetic acid;
-2-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy-quinolin-4-yl) -Ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(S) -1-hydroxy-2- (6- Methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2R) -2- (3-fluoro-6-methoxy-quinolin-4-yl) -2 -Hydroxy-ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2S) -2- (3-fluoro-6-methoxy-quinolin-4-yl) -2 -Hydroxy-ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2R) -2-hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl ] -2-Hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2S) -2-hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl ] -2-Hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (3-fluoro-6- Methoxy- [1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetamide;
-(2S, 5R, 6R)-(5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- (2-hydroxy-ethyl))-tetrahydro-pyran-2-carboxylic Acid (6-methoxy- [1,5] naphthyridin-4-yl) -amide;
-(2S, 5R) -5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -tetrahydro-pyran-2-carboxylic acid (6-methoxy- [1,5] naphthyridine-4 -Yl) -amide;
-8-((1R, 2R) -2-{(2S, 5R) -5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -tetrahydro-pyran-2-yl}- 1,2-dihydroxy-ethyl) -quinoline-2-carbonitrile;
-[(E) -3- (2,5-difluoro-phenyl) -allyl]-{3R, 6S) -6-[(E) -2- (3-fluoro-6-methoxy-quinolin-5-yl ) -Vinyl] -tetrahydro-pyran-3-yl} -amine;
-[(E) -3- (2,5-difluoro-phenyl) -allyl]-{(3R, 6S) -6- [2- (6-fluoro-3-methoxy-quinolin-4-yl) -ethyl ] -Tetrahydro-pyran-3-yl} -amine;
-(1R, 2R) -1-{(2R, 5S) -5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -tetrahydro-pyran-2-yl} -2- ( 6-Fluoro-quinolin-4-yl) -ethane-1,2-diol;
-[(E) -3- (2,5-Difluoro-phenyl) -allyl]-{(3S, 6R)-(E) -6- [2- (6-Fluoro-quinolin-4-yl) -vinyl ] -Tetrahydro-pyran-3-yl} -amine;
-[(E) -3- (2,5-Difluoro-phenyl) -allyl]-{(3S, 6R) -6- [2- (6-Fluoro-quinolin-4-yl) -ethyl] -tetrahydro- Pyran-3-yl} -amine;
Or a salt of these compounds.

According to said variant of this first aspect, the compounds of the invention will in particular be selected from:
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (3-fluoro-6- Methoxy- [1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetamide;
-[(E) -3- (2,5-difluoro-phenyl) -allyl]-{3R, 6S) -6-[(E) -2- (3-fluoro-6-methoxy-quinolin-5-yl ) -Vinyl] -tetrahydro-pyran-3-yl} -amine;
-[(E) -3- (2,5-Difluoro-phenyl) -allyl]-{(3S, 6R)-(E) -6- [2- (6-Fluoro-quinolin-4-yl) -vinyl ] -Tetrahydro-pyran-3-yl} -amine;
Or a salt of these compounds.

According to another variant of this first aspect, the compounds of the invention will be selected from:
-(1S) -1-{(2S, 5R) -5-[(E) -3- (3-Fluoro-phenyl) -allylamino] -tetrahydro-pyran-2-yl} -2- (6-methoxy- Quinolin-4-yl) -ethanol;
-3- (2-Fluoro-phenyl) -N-{(3R, 6S) -6-[(1S) -1-hydroxy-2- (6-methoxy-quinolin-4-yl) -ethyl] -tetrahydro- Pyran-3-yl}-(E) -acrylamide;
-3- (3-Fluoro-phenyl) -N-{(3R, 6S) -6-[(1S) -1-hydroxy-2- (6-methoxy-quinolin-4-yl) -ethyl] -tetrahydro- Pyran-3-yl}-(E) -acrylamide;
Or a salt of these compounds.

According to a second embodiment, the compounds of the invention will be selected from:
-{(2R, 3R, 6R) -6- [2- (3-methoxy-quinolin-5-yl) -ethyl] -3-[(3-oxo-3,4-dihydro-2H-pyrido [3, 2-b] [1,4] thiazine-6-carbonyl) -amino] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6R) -6- [2- (6-Methoxy- [1,5] naphthyridin-4-yl) -ethyl] -3-[(3-oxo-3,4-dihydro-2H -Pyrido [3,2-b] [1,4] thiazin-6-ylmethyl) -amino] -tetrahydro-pyran-2-yl} -acetic acid;
-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2S, 3R, 6S) -6-[(2R) -2- (3-Fluoro-6-methoxy-quinolin-4-yl) -2-hydroxy-ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl} -amide;
-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2S, 3R, 6S) -6-[(2S) -2- (3-Fluoro-6-methoxy-quinolin-4-yl) -2-hydroxy-ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl} -amide;
-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2S, 3R, 6S) -6-[(2R) -2- Hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl} -amide;
-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2S, 3R, 6S) -6-[(2S) -2- Hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl} -amide;
-7-fluoro-6-({(3R, 6S) -6-[(1S) -1-hydroxy-2- (6-methoxy-quinolin-4-yl) -ethyl] -tetrahydro-pyran-3-ylamino } -Methyl) -4H-benzo [1,4] thiazin-3-one;
-6-({(3R, 6S) -6- [2- (6-Fluoro-3-methoxy-quinolin-4-yl) -ethyl] -tetrahydro-pyran-3-ylamino} -methyl) -4H-pyrido [3,2-b] [1,4] thiazin-3-one;
-6-({3S, 6R) -6- [2- (6-Fluoro-quinolin-4-yl) -ethyl] -tetrahydro-pyran-3-ylamino} -methyl) -4H-pyrido [3,2- b] [1,4] thiazin-3-one;
Or a salt of these compounds.

  The compounds of the present invention are stored as chemotherapeutic active compounds in human and veterinary medicine, and in inorganic and organic materials, especially all types of organic materials such as polymers, lubricants, paints, fibers, leather, paper and wood Suitable for use as a substance to do.

  The compounds according to the invention are particularly active against bacteria and bacteria-like organisms. Thus, these include local and systemic infections caused by these pathogens, as well as Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus ), Enterococcus faecalis, E. faecium, E. casselflavus, S. epidermidis, S. haemolyticus or Peptostreptococcus species (Peptostreptococcus spp.)-Associated pneumonia, otitis media, sinusitis, bronchitis, tonsillitis and mastoiditis; Streptococcus pyogenes, group C and G streptococci, Corynebaterium diphtheriae Or Actinobacillus haemolyticum Pharyngitis, rheumatic fever and glomerulonephritis associated with infections; Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae or Chlamydia pneumoniae Respiratory tract infection associated with infection by Chlamydia pneumoniae; resistant to known antibacterials such as (but not limited to) β-lactams, vancomycin, aminoglycosides, quinolones, chloramphenicol, tetracyclines and macrolides Hearts caused by S. aureus, S. haemolyticus, E. faecalis, E. faecium, E. durans, including Blood and tissue infections, including endocarditis and osteomyelitis; Staphylococc us aureus), coagulase negative staphylococci (ie S. epidermidis, S. haemolyticus, others), Streptococcus pyogenes, Streptococcus agalactiae, streptococci group None associated with infection by CF (microcolony streptococci), viridans streptococci, Corynebacterium minutissimum, Closfridium spp. Or Bartonella henselae Concomitant skin and soft tissue infections and abscesses and postpartum fever; uncomplicated acute urinary tract infections associated with infections with Staphylococcus aureus, coagulase-negative staphylococcal species or Enterococcus spp .; Urethritis and cervicitis; Sexually transmitted infections associated with infection by Chlamydia trachomatis, Haemophilus ducreyi, Syphilis treponema, Ureaplasma urealyticum or Neisserria gonorrhoeae; S. aureus ) (Food poisoning and toxic shock syndrome) or Toxic diseases associated with infection by group A, B and C streptococci; Ulcers associated with infection by Helicobacter pylori; Associated with infection by recurrent fever Borrelia (Borrelia recurrentis) Systemic febrile phase syndrome; Lyme disease associated with infection by Borrelia burgdorferi; Chlamydia trachomatis, Neisseria gonorrhoeae, S. aureus, S. pneumoniae ), S. pyogenes, H. influenzae (H. in Conjunctivitis, keratitis and dacrocystitis associated with infection by fluenzae or Listeria species; dissemination associated with infection by Mycobacterium avium or Mycobacterium intracellulare Atypical mycobacterial complex (MAC) disease; Mycobacterium tuberculosis, M. leprae, M. paratuberculosis, M. kansasii or M. keronei infection caused by chelonei; gastroenteritis associated with infection by Campylobacter jejuni; gut protozoa associated with infection by Cryptosporidium species; teeth associated with infection by viridans streptococci Sexually transmitted infection; persistent cough associated with infection by Bordetella pertussis; Clostridium perfringens (C Gas gangrene associated with infection by lostridium perfringens or Bacteroides spp .; and atherosclerosis or cardiovascular disease associated with infection by Helicobacter pylori or Chlamydia pneumoniae Particularly suitable for human and veterinary medicine for the prevention and chemotherapy of disorders associated with bacterial infections.

  In accordance with the present invention, the compounds include E. coli, Klebsiella pneumoniae and other enterobacteriaceae, Acinetobacter spp., Stenotrophomonas maltophilia, Bacteria such as Neisseria meningitidis, Bacillus cereus, Bacillus anthracis, Corynebacterium spp., Propionibacterium acnes and bacteroide spp. Further useful for the manufacture of a medicament for the treatment of infections mediated by.

  In accordance with the present invention, the compounds include Plasmodium malaria, Plasmodium falciparum, Toxoplasma gondii, Pneumocystis carinii, Trypanosoma brucei and Leish. It is further useful for treating protozoal infections caused by mania species (Leishmania spp.).

  This list of pathogens is to be construed as an example only and not as a limitation.

  Similar to humans, bacterial infections can be treated in other species such as pigs, ruminants, horses, dogs, cats and poultry.

  The invention also relates to pharmaceutically acceptable salts or solvates and hydrates of the aforementioned compounds, respectively, and to compositions and formulations.

  Examples of pharmaceutically acceptable salts of fully basic compounds of the invention include salts of physiologically acceptable mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; or methane It is selected from the group consisting of salts of organic acids such as sulfonic acid, ptoluenesulfonic acid, lactic acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid and salicylic acid. Furthermore, fully acidic compounds of the present invention include alkali or earth alkali metal salts such as sodium, potassium, lithium, calcium or magnesium salts; ammonium salts; or organic base salts such as methylamine, dimethylamine, trimethylamine, triethylamine, Ethylenediamine, ethanolamine, choline hydroxide, meglumin, piperidine, morpholine, tris- (2-hydroxyethyl) amine, lysine or arginine salts may be formed. The compounds of the invention may be solvated and in particular hydrated. Hydration can occur during the manufacturing process or as a result of the hygroscopic nature of the compounds of the present invention which are initially free of water.

  The pharmaceutical composition according to the present invention comprises at least one compound from the above list of compounds (or pharmaceutically acceptable salts thereof) as an active agent, optionally a carrier and / or diluent and / or It contains an adjuvant and may contain further known antibiotics.

  As stated above, therapeutically useful agents including the compounds described herein, their solvates, salts or formulations are also within the scope of the present invention. In general, the compounds according to the invention will be administered by using 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: orally, such as tablets, dragees, coated tablets, pills, semisolid, soft or hard capsules, such as soft and hard Gelatin capsules, aqueous or oily solutions, emulsions, suspensions or syrups, parenteral, including intravenous, intramuscular and subcutaneous injections, for example as injection solutions or suspensions, rectal as suppositories, inhalation or By gas injection, for example as a powder formulation, as a microcrystal or as a spray (eg a liquid aerosol), transdermally, eg via a transdermal delivery system (TDS) such as a plaster containing the active ingredient, topically or nasally Inside. The materials of the present invention can also be used in impregnation or coating devices envisaged for implantation such as catheters or artificial joints. Also, pharmaceutically useful agents include storage, stabilization, eg UV stabilizers, emulsifiers, sweeteners, aromatisers, salts for changing osmotic pressure, buffers, paint additives and antioxidants Additives may be included for the agent.

  Another aspect of the invention relates to a method for treating a disease comprising administering to a patient a pharmaceutically active amount of a compound according to the invention (or a pharmaceutically acceptable salt thereof).

  Furthermore, the compounds according to the invention may be used for cleaning purposes, for example to remove pathogenic microorganisms and bacteria from surgical instruments or to sterilize a room or site. For such purposes, the compounds according to the invention can be included in solution or in spray formulations.

Preparation of the compounds of the invention Abbreviations:
The following abbreviations are used:
AcOH acetic acid
AD-mixα 1,4- bis (dihydro-quinine) _{phthalazine, K 3 Fe (CN) 6} , K 2 CO 3 and _{K 2 OsO 4 .2H 2 O,} AD - mixβ 1,4- bis (dihydro-quinidine ) _{phthalazine, K 3 Fe (CN) 6} , K 2 CO 3, and K ₂ OsO ₄ .2H ₂ O
AIBN 2,2'-azoisobutyronitrile
aq. Aqueous solution
BINAP 2,2'-bis- (diphenylphosphino) -1,1'-binaphthyl
Boc ₂ O di-tert-butyl dicarbonate
dba dibenzylideneacetone
DCC dicyclohexylcarbodiimide
1,2-DCE 1,2-dichloroethane
DCM Dichloromethane (DHQ) ₂ PHAL 1,4-bis (dihydroquinine) phthalazine (DHQD) ₂ PHAL 1,4-bis (dihydroquinidine) phthalazine
DIAD diisopropyl azodicarboxylate
DIBAH diisobutylaluminum hydride
DIPA Diisopropylamine
DIPEA N, N-Diisopropylethylamine
DMAP 4-Dimethylaminopyridine
1,2-DME 1,2-dimethoxyethane
DMF N, N-dimethylformamide
DMSO Dimethyl sulfoxide
DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidone
EA ethyl acetate
ESI Electrospray ionization
ether or Et ₂ O ether or diethyl ether
EtOH ethanol
h hours
HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate
Hept heptane
Hex Hexane
HV High vacuum state
KHMDS potassium hexamethyldisilazide
MeOH methanol
min minutes
MCPBA metachloroperbenzoic acid
MeCN Acetonitrile
MeOH methanol
MS mass spectrometry
NBS N-bromosuccinimide
NHS N-hydroxysuccinimide
n-BuLi n-Butyllithium
org. organic
Pd / C palladium on carbon
PPh ₃ Triphenylphosphine
PTSA para-toluenesulfonic acid
quant. Quantitative
rac racemic
Rf retention factor
sat. saturated
SiO ₂ silica gel
rt room temperature
TBAF Tetrabutylammonium fluoride
TEA Triethylamine
TFA trifluoroacetic acid
THF tetrahydrofuran
TsCl para-toluenesulfonyl chloride
wt% Weight percent.

Production method:
The compounds of the present invention can be prepared according to the procedures described in the examples, which in the future will illustrate but not limit the production of the pharmacologically active compounds of the present invention.

  Whenever the compounds of the invention are obtained in the form of a mixture of enantiomers, the enantiomers can be obtained using methods known to those skilled in the art (for example by formation and separation of diastereomeric salts or by chromatography on chiral stationary phases). Can be separated). Whenever the compounds of the present invention are obtained in the form of a mixture of diastereomers, they may be separated by an appropriate combination of silica gel chromatography, high performance liquid chromatography (HPLC) and crystallization techniques.

Examples All temperatures are given in ° C. Analytical and preparative HPLC studies on all non-chiral phases are performed using RP-C18 based columns. Analytical HPLC studies have been performed on two different instruments with cycle times of ~ 2.5 minutes and ~ 3.5 minutes, respectively.

Production A: 3-methoxy-quinoline-5-carbaldehyde:
Ai 3,5-Dibromoquinoline:
To the concentrated H ₂ SO ₄ (130 ml), 3-bromoquinoline (50 g) was added dropwise at a rate that allowed the internal temperature to be maintained between 0 ° C. and 10 ° C. over 80 minutes at 0 ° C. . After the addition was complete, NBS (48 g) was partially added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was poured onto ice (2 l) and the resulting solid was dissolved in DCM (600 ml). The aqueous layer was further extracted with DCM (600 ml) and the combined extracts were washed with 1M NaOH (300 mL) and concentrated in vacuo. The residue was dispersed in SiO _2, the resulting dispersion was filled in a column, eluting with DCM-Hex (1-1,3l), then DCM (3l) and finally DCM- ether (1-1,2l) I let you. The title compound was collected from the last fraction after evaporation to give 40 g of a white solid.
¹ H NMR (CDCl ₃ ) δ: 8.94 (d, J = 2.2 Hz, 1H); 8.73 (d, J = 2.2 Hz, 1H); 8.08 (d, J = 8.5 Hz, 1H); 7.88 (d, J = 7.5 Hz, 1H); 7.62 (dd, J = 7.5, 8.5 Hz, 1H).

A.ii. 5-Bromo-3-methoxyquinoline:
To a mixture of sodium methoxide (14.5 g) heated to 125 ° C. in DMPU (350 ml), intermediate Ai (34.5 g) was added in portions. The reaction was then heated at the same temperature for 1 hour. The reaction mixture was then cooled to room temperature and poured onto ice (300 g). After ice melting, the solid was filtered and dried under vacuum. The filtrate was extracted with ether (4 × 150 ml). The combined extracts were washed with brine and dried over Na ₂ SO ₄ . After filtration, the solvent was evaporated and the residue was purified through SiO ₂ (Hex-EA 4-1) to give the material pooled with solids. The material was dissolved in DCM and dried over Na ₂ SO ₄ . After filtration and evaporation, the solid was further dried under HV to give the title compound (24.5 g) as a beige solid.
¹ H NMR (CDCl ₃ ) δ: 8.68 (d, J = 2.8 Hz, 1H); 8.03 (d, J = 8.3 Hz, 1H); 7.80 (d, J = 7.5 Hz, 1H); 7.72 (d, J = 2.8 Hz, 1H); 7.42 (dd, J = 7.5, 8.3 Hz, 1H); 4.02 (s, 3H).
MS (ESI, m / z): 239.7 [M + H ^<+ >].

A.iii. 3-Methoxy-5-quinoline-carbaldehyde:
To a solution of intermediate A.ii (10 g) in THF (250 ml) cooled to −78 ° C. was added n-BuLi (22 ml). After 15 minutes, a solution of DMF (10 ml) in ether (20 ml) was added rapidly. The solution was stirred for 15 minutes and EtOH (5 ml) was added followed by 1M NaHSO ₄ (40 ml). After warming to room temperature, the organic layer was diluted with EA (100 ml). The two layers were separated and the aqueous layer was extracted once with EA (100 ml). The combined organic layers were washed with brine and concentrated to dryness. The residue was chromatographed on SiO ₂ (EA-Hex1-2, then 1-1) to give the title compound (4.75 g) as a yellowish solid.
¹ H NMR (CDCl ₃ ) δ: 10.32 (s, 1H); 9.02 (d, J = 2.9 Hz, 1H); 8.75 (d, J = 2.9 Hz, 1H); 8.31 (d, J = 8.3 Hz, 1H ); 8.02 (d, J = 7.1 Hz, 1H); 7.72 (dd, J = 7.1, 8.3 Hz, 1H); 4.02 (s, 3H).
MS (ESI, m / z): 187.9 [M + H ^<+ >].

Production B: 6-methoxy- [1,5] naphthyridine-4-carbaldehyde:
Bi 2-methoxy-8-styryl- [1,5] naphthyridine:
Trifluoromethanesulfonic acid 6-methoxy- [1,5] naphthyridin-4-yl ester (1.5 g, 4.86 mmol), trans-phenylvinylboronic acid (0.8 g, 5.35 mmol) and K ₂ CO ₃ (0.9 g, 6.32) mmol) was introduced into a two-necked flask. The atmosphere was cleaned with nitrogen. Dioxane (20 ml) and water (5 ml) were added. The mixture was stirred at room temperature for 5 minutes and (P (Ph) ₃ ) ₄ Pd (0.28 g, 0.24 mmol) was added. The mixture was heated at reflux for 5 hours. After cooling, the reaction mixture was diluted with EA (10 ml) and water (50 ml). The aqueous layer was extracted with EA (2 × 100 ml). The combined extracts were concentrated to dryness. The residue was chromatographed on SiO ₂ (Hex-EA 1-1) to give the title alkene (1.26 g, 4.8 mmol) as an oil that crystallized upon standing.
¹ H NMR (d6-DMSO) δ: 8.77 (d, J = 4.7 Hz, 1H); 8.28 (d, J = 9.0 Hz, 1H); 8.19 (d, J = 16.7 Hz, 1H); 8.01 (d, J = 4.7 Hz, 1H); 7.91 (d, J = 16.7 Hz, 1H); 7.74 (m, 2H); 7.40-7.34 (m, 3H); 7.30 (d, J = 9.0 Hz, 1H); 4.12 ( s, 3H).

B.ii. 1- (6-Methoxy- [1,5] naphthyridin-4-yl) -2-phenyl-ethane-1,2-diol:
To a mixture of intermediate Bi (1.26 g, 4.8 mmol) in 2-methyl-2-propanol (24 ml) and water (24 ml) was added methanesulfonamide (0.52 g) and ADmixβ® (7 g). . The mixture was stirred at room temperature for 12 hours. Sodium bisulfite (7.5 g) was carefully added and stirring was continued for 20 minutes. The two layers were decanted and the aqueous layer was extracted with EA (2 × 100 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was triturated with Hex-EA (1-3, 30 ml) and the resulting solid was filtered and dried in vacuo to give the title diol (1.3 g) as a white solid.
MS (ESI, m / z): 297.1 [M + H ^<+ >].

B.iii. 6-Methoxy- [1,5] naphthyridine-4-carbaldehyde:
To a solution of intermediate B.ii (1.3 g, 4.4 mmol) in acetone (15 ml) was added a solution of NaIO ₄ (2.35 g, 10.96 mmol) in water (5 ml). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with THF (100 ml) and the solid was filtered. 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 room temperature for 15 minutes and filtered. The solid was washed with water and Hex. After drying, the title aldehyde (0.42g) was recovered as a white solid.
¹ H NMR (d ₆ -DMSO) δ: 11.25 (s, 1H); 9.02 (d, J = 4.4 Hz, 1H); 8.42 (d, J = 9.1 Hz, 1H); 7.92 (d, J = 4.4 Hz , 1H); 7.40 (d, J = 9.1 Hz, 1H); 4.11 (s, 3H).

Production C: (E) -3- (2,5-difluoro-phenyl) -propenal:
Ci (E) -3- (2,5-difluoro-phenyl) -acrylic acid ethyl ester:
To a suspension of NaH (1.13 g, 60% in oil dispersion, 28.2 mmol) in ice-cold THF (32 ml) was added triethylphosphonoacetate (5.6 ml, 28.2 mmol). The reaction mixture was stirred at room temperature for 20 minutes. 2,5-Difluoro-benzaldehyde (3.34 g, 23.5 mol) was added dropwise. After 30 minutes, 10% water NaHSO ₄ (100 ml) was added and the mixture was diluted with EA (150 ml). The two phases were separated and the aqueous layer was extracted twice (2 × 100 ml). The combined organic layers were washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was chromatographed on SiO ₂ (Hex-EA 19-1) to give the title unsaturated ester (5.0 g, 100%) as a colorless oil.
¹ H NMR (CDCl ₃ ): 7.76 (dd, J = 1, 16.1 Hz, 1H); 7.26-7.21 (m, 1H); 7.13-7.03 (m, 2H); 6.52 (d, J = 16.1 Hz, 1H ); 4.29 (q, J = 7.1 Hz, 2H); 1.36 (t, J = 7.1 Hz, 3H).

C.ii. (E) -3- (2,5-Difluoro-phenyl) -prop-2-en-1-ol:
To a solution of intermediate Ci (5.0 g, 23.5 mmol) in ether (100 ml) was cooled to 0 ° C. and DIBAH (1M Hex solution, 60 ml, 60 mmol) was added. The mixture was stirred at the same temperature for 40 minutes. Water (6 ml) was added and the mixture was stirred for 30 minutes. The solid was filtered and washed thoroughly with ether. The filtrate was concentrated to dryness to give the title alcohol (4.0 g, 98% yield) as a colorless oil.
¹ H NMR (CDCl ₃ ): 7.15 (ddd, J = 3.1, 5.9, 9.0 Hz, 1H); 7.00 (td, J = 4.6, 9.0 Hz, 1H); 6.95-6.87 (m, 1H); 6.75 (dd J = 1.3, 16.1 Hz, 1H); 6.45 (td, J = 5.3, 16.1 Hz, 1H); 4.38 (br d, J = 5.3 Hz, 2H); 1.63 (s, 1H).

C.iii. (E) -3- (2,5-Difluoro-phenyl) -propenal:
To a solution of intermediate C.ii (1.70 g, 10 mmol) in DCM (20 ml) at room temperature was added a solution of Dess-Martin periodinane (15 wt% DCM (20 ml) solution). The mixture was stirred at room temperature for 3 hours. After concentration to dryness, the residue was chromatographed on SiO ₂ (Hex-EA 9-1) to give the title aldehyde (1.06 g, 63% yield) as a white solid.
¹ H NMR (d6-DMSO): 9.74 (d, J = 7.6Hz, 1H); 7.88-7.81 (m, 1H); 7.79 (overlapped dd, J = 1.4, 16.0 Hz, 1H); 7.46-7.37 (m , 2H); 6.67 (dd, J = 7.6, 16.0 Hz, 1H).

Production D: 3-methoxy-quinoxaline-5-carbaldehyde:
Di 2-cyano-N- (2-methyl-6-nitro-phenyl) -acetamide:
To a solution of 2-methyl-6-nitroaniline (25 g, 164.3 mmol) in benzene (200 ml) was added cyanoacetic acid (14.5 g, 170.46 mmol) and PCl ₅ (35 g, 168 mmol). The reaction mixture was heated at 60 ° C. for 7 hours. After cooling to room temperature, the reaction mixture was filtered and the solid was washed with benzene and water. The solid was dried under reduced pressure to give the title acetamide (24 g, 109 mmol) as a solid yellow.
¹ H NMR (d6-DMSO) δ: 10.2 (s, 1H); 7.78 (d, J = 8.3 Hz, 1H); 7.65 (d, J = 8.3 Hz, 1H); 7.43 (t, J = 8.3 Hz, 1H); 3.95 (s, 2H); 2.30 (s, 3H).

D.ii. 3-Hydroxy-5-methyl-1-oxy-quinoxaline-2-carbonitrile:
To a mixture of intermediate Di (24 g, 109.5 mmol) in 1M aqueous NaOH (100 ml) was added pyridine (100 ml). The reaction mixture was stirred at room temperature for 4 hours. The pH was adjusted to 6 by addition of 1M aqueous HCl. The solid was filtered 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 solid yellow.
MS (ESI, m / z): 202.1 [M + H] ^< +>.

D.iii. 8-Methyl-quinoxalin-2-ol:
To a solution of intermediate D.ii (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 hour. The reaction mixture was filtered warm and the pH of the filtrate was adjusted to 2 by adding 1M aqueous HCl. The pH of the solution was then made basic by adding solid NaOH (10 g). EA (150 ml) was added. The aqueous layer was extracted twice more with EA (2 × 150 ml). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was dried under HV to give the title intermediate (11.1 g, 69 mmol) as a solid yellow.
¹ H NMR (d6-DMSO) δ: 11.75 (br s, 1H); 8.17 (s, 1H); 7.62 (d, J = 8.4 Hz, 1H); 7.40 (d, J = 8.4 Hz, 1H); 7.21 (t, J = 8.4 Hz, 1H); 2.42 (s, 3H).
MS (ESI, m / z): 161.1 [M + H] ^< +>.

D.iv. 2-Chloro-8-methyl-quinoxaline:
A solution of intermediate D.iii (11.1 g, 69.5 mmol) in phosphorus oxychloride (80 ml) was heated at 110 ° C. for 2 hours. After cooling to room temperature, the reaction mixture was poured onto ice (200 g). The aqueous layer was extracted with EA (2 × 200 ml). The combined extracts were washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was chromatographed on silica gel (Hex-EA 1-1) to give the title intermediate (12.5 g, 69.5 mmol) as a red solid.
¹ H NMR (d6-DMSO) δ: 8.99 (s, 1H); 7.97 (m, 1H); 7.80 (m, 2H); 2.68 (s, 3H).
MS (ESI, m / z): 179.2 [M + H] ^< +>.

Dv 2-Methoxy-8-methyl-quinoxaline:
To a solution of intermediate D.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 4 hours. After cooling to room temperature, the reaction mixture was partitioned between water (10 ml) and EA (200 ml). The organic layer was washed once with water (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was chromatographed on silica gel (Hex-EA 1-4) to give the title intermediate (10.2 g, 58.55 mmol) as a solid yellow.
¹ H NMR (CDCl ₃ ) δ: 8.48 (s, 1H); 7.88 (d, J = 7.9 Hz, 1H); 7.55 (d, J = 7.9 Hz, 1H); 7.47 (t, J = 7.9 Hz, 1H ); 4.12 (s, 3H); 2.69 (s, 3H).
MS (ESI, m / z): 175.4 [M + H] ^< +>.

D.vi. 8-Dibromomethyl-2-methoxy-quinoxaline:
To a solution of intermediate Dv (10.2 g) in CCl ₄ (560 ml) was added AIBN (0.96 g) and NBS (25.9 g, 145.5 mmol). The reaction mixture was heated at 80 ° C. for 3 hours. After cooling to room temperature, the reaction mixture was washed with water (200 ml) and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was triturated with MeOH to give the title dibromide (14.4 g, 43.3 mmol) as a slightly beige solid after drying under HV.
¹ H NMR (d6-DMSO) δ: 8.69 (s, 1H); 8.25 (dd, J = 1.3, 7.5 Hz, 1H); 8.07 (dd, J = 1.3, 8.3 Hz, 1H); 8.02 (s, 1H ); 7.74 (dd, J = 7.5, 8.3 Hz, 1H); 4.14 (s, 3H).
MS (ESI, m / z): 332.8 [M + H] ^< +>.

D.vii. 3-Methoxy-5-quinoxaline-carbaldehyde:
To a solution of intermediate D.vi (10.7 g, 32.2 mmol) in EtOH (330 ml) at room temperature was added an aqueous solution (70 ml) of silver nitrate (15 g). The reaction was stirred at room temperature for 1 hour. The reaction mixture was diluted with MeCN (200 ml), the solid was filtered and the filtrate was concentrated in vacuo. The residue was filtered over a silica gel pad (eluent: EA) to give the title aldehyde (6.2 g, 32.2 mmol) as a slightly yellow solid.
¹ H NMR (d6-DMSO) δ: 11.15 (s, 1H); 8.74 (s, 1H); 8.36 (dd, J = 1.3, 8.1 Hz, 1H); 8.21 (dd, J = 1.3, 7.9 Hz, 1H ); 7.80 (dd, J = 7.9, 8.1 Hz, 1H); 4.14 (s, 3H).
MS (ESI, m / z): 189.2 [M + H] ^< +>.

Production E: 3-Fluoro-6-methoxy- [1,5] naphthyridine-4-carbaldehyde:
Ei trans-7-fluoro-2-methoxy-8-styryl- [1,5] naphthyridine:
8-Bromo-7-fluoro-2-methoxy- [1,5] naphthyridine (prepared as in WO 2004/058144; 7 g, 27.2 mmol), trans-phenylvinylboronic acid (4.23 g, 1.05 Eq.) And K ₂ CO ₃ (4.9 g) were introduced into a two-necked flask. The atmosphere was washed with nitrogen and dioxane (40 ml) and water (10 ml) was added. The mixture was stirred at room temperature for 5 minutes and Pd (PPh ₃ ) ₄ (1.56 g, 5 mol%) was added. The mixture was heated at reflux overnight. After cooling, the solvent was evaporated in vacuo and the residue was extracted with EA (2 × 150 ml). The combined extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was chromatographed (Hept-EA 2-1) to give the title compound (7.2 g, 94% yield) as a white solid.
MS (ESI, m / z): 281.0 [M + H] ^< +>.

E.ii. 1- (3-Fluoro-6-methoxy- [1,5] naphthyridin-4-yl) -2-phenyl-ethane-1,2-diol:
The title diol (7.6 g, 94% yield) was obtained as a white foam starting from intermediate Ei (7.2 g, 8.9 mmol) and using the procedure of Example 2, Step 2.iv. . The compound was purified by chromatography using EA as eluent.
¹ H NMR (CDCl ₃ ) δ: 8.42 (d, J = 0.7 Hz, 1H); 8.28 (d, J = 9.1 Hz, 1H); 7.24-7.15 (m, 4H); 7.08 (m, 2H); 6.70 (br s, 1H); 5.28 (br s, 1H); 5.10 (d, J = 7.9 Hz, 1H); 4.11 (s, 3H); 3.85 (br s, 1H).

E.iii. 3-Fluoro-6-methoxy- [1,5] naphthyridine-4-carbaldehyde:
To a solution of intermediate E.ii (7.6 g, 23.95 mmol) in acetone (150 ml) was added an aqueous solution (30 ml) of NaIO ₄ (12.8 g). The mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residue was diluted with water (500 ml). The resulting solid was filtered, washed thoroughly with water, collected and dried under HV to give the title aldehyde (4.0 g) as a solid light beige.
¹ H NMR (d6-DMSO) δ: 11.08 (s, 1H); 9.01 (d, J = 1.3 Hz, 1H); 8.41 (d, J = 9.1 Hz, 1H); 7.37 (d, J = 9.1 Hz, 1H); 4.09 (s, 3H).
MS (ESI, m / z): 206.9 [M + H] ^< +>.

Production F: -Fluoro-6-methoxy-quinoline-5-carbaldehyde:
Fi 5-bromo-3-fluoro-6-methoxyquinoline:
NBS (1 g) was added to a MeCN (9 ml) solution of 3-fluoro-6-methoxyquinoline (0.89 g) cooled to 0 ° C. The mixture was stirred at this temperature for 2 hours. The reaction mixture was allowed to warm to room temperature and proceed overnight. 10% water NaHSO ₃ (20 ml) was added. The mixture was further diluted with water (100 ml) and the resulting solid was filtered, washed with water and dried in vacuo to give the title compound (1.03 g, 80% yield) as a white solid.
¹ H NMR (d ₆ -DMSO) δ: 8.85 (d, J = 2.7 Hz, 1H); 8.18 (dd, J = 2.7, 10.2 Hz, 1H); 8.14 (d, J = 9.0 Hz, 1H); 7.77 (d, J = 9.0 Hz, 1H); 4.04 (s, 3H).
MS (ESI, m / z): 255.7 [MH ^<+ >].

F.ii. 3-Fluoro-6-methoxy-quinoline-5-carbaldehyde:
This aldehyde (0.68 g, 3.31 mmol) is obtained starting from intermediate Fi (1.0 g (3.9 mmol) and using the procedure described in Preparation E, steps Ei, E.ii and E.iii. Obtained as a white solid.
¹ H NMR (d ₆ -DMSO) δ: 10.69 (s, 1H); 9.16 (dd, J = 2.9, 11.7 Hz, 1H); 8.88 (d, J = 2.9 Hz, 1H); 8.38 (d, J = 9.0 Hz, 1H); 7.83 (d, J = 9.0 Hz, 1H); 4.12 (s, 3H).

Preparation G: (3R, 6S)-[6- (1-Phenyl-1H-tetrazol-5-sulfonylmethyl) -tetrahydro-pyran-3-yl] -carbamic acid tert-butyl ester:
Gi Toluene-4-sulfonic acid (2S, 5R) -5-tert-butoxycarbonylamino-tetrahydro-pyran-2-ylmethyl ester:
(3R, 6S)-(6-hydroxymethyl-tetrahydro-pyran-3-yl) -carbamic acid tert-butyl ester (obtained as described in Eur. J. Org. Chem. (2003); 25 g , 108 mmol) to an ice cold solution in DCM (650 ml) was added TEA (30 ml), DMAP (1.8 g) and TsCl (22.6 g). The reaction was stirred at room temperature for 4 hours. Saturated NaHCO ₃ (100 ml) was added. Volatiles were removed under reduced pressure and the residue was taken up in EA (400 ml). The organic layer was washed with saturated CuSO ₄ (2 × 150 ml) water (3 × 150 ml) and brine (100 ml). The organic layer was dried over Na ₂ SO ₄ , filtered, filtered to dryness and concentrated to give a white solid (41.8 g) after drying, which was continued without further purification.

G.ii. (3R, 6S)-(6-Iodomethyl-tetrahydro-pyran-3-yl) -carbamic acid tert-butyl ester:
To a solution of intermediate Gi (18 g, 46.7 mmol) in acetone (200 ml) was added NaI (20 g). The reaction mixture was heated at reflux for 24 hours. After cooling to room temperature, water (200 ml) was added and volatiles were removed in vacuo. The residue was filtered, washed thoroughly with water and Hex and dried under HV to give iodide (12.2 g, 76% yield) as a beige solid.
MS (ESI, m / z): 342.2 [M + H ^<+ >].

G.iii. (3R, 6S)-[6- (1-Phenyl-1H-tetrazol-5-ylsulfanylmethyl) -tetrahydro-pyran-3-yl] -carbamic acid tert-butyl ester:
To a solution of 1-phenyl-1H-tetrazole-5-thiol (7 g, 39 mmol) in EtOH (100 ml) was added KOH (3.0 g). The reaction mixture was refluxed for 1 h and intermediate G.ii (11.6 g, 34 mmol) was added. The mixture was refluxed overnight. Water (150 ml) was added and volatiles were removed under reduced pressure. The solid was filtered, washed thoroughly with water and dried under HV to give sulfide (13.3 g, quantitative) as a white solid.
MS (ESI, m / z): 392.5 [M + H ^<+ >].

G.iv. (3R, 6S)-[6- (1-Phenyl-1H-tetrazol-5-sulfonylmethyl) -tetrahydro-pyran-3-yl] -carbamic acid tert-butyl ester:
To a solution of intermediate G.iii (13.3 g, 34 mmol) in EtOH (150 ml) and THF (150 ml) was added ammonium molybdate tetrahydrate (11 g, 8.9 mmol) and then 30% H ₂ O ₂ (50 ml). Added. The mixture was heated at 60 ° C. overnight. The reaction mixture was cooled to room temperature, diluted with water (200 ml) and volatiles were removed under reduced pressure. The residue was partitioned between EA (300 ml) and water (100 ml) and the aqueous layer was extracted with EA (2 × 300 ml). The combined extracts were concentrated to dryness. The residue was resuspended in ether. The solid was filtered and washed with water and Hex to give the title sulfone (11.8 g, 81% yield) as a white solid.
¹ H NMR (CDCl ₃ ) δ: 7.69-7.60 (m, 5H); 4.23 (m, 1H); 3.95-3.80 (m, 2H); 3.68-3.52 (m, 2H); 2.86 (t, J = 10.7 Hz, 1H); 2.11 (m, 1H); 1.79 (m, 1H); 1.60-45 (m, 2H); 1.43 (s, 9H); 1.37 (m, 1H).
MS (ESI, m / z): 424.5 [M + H ^<+ >].

Production H: 6-Fluoro-quinoline-4-carbaldehyde:
Starting from 4-bromo-6-fluoro-quinoline (for production see WO 2004/014361; 6 g, 26.5 mmol), the title aldehyde (4.3 g, 24.5 mmol) Prepared as a solid beige using the procedures described in steps Ei, E.ii and E.iii.
¹ H NMR (d6-DMSO) δ: 10.50 (s, 1H); 9.23 (d, J = 4.2 Hz, 1H); 8.68 (dd, J = 2.9, 10.8 Hz, 1H); 8.25 (dd, J = 5.8 8.11 (d, J = 4.2 Hz, 1H); 7.83 (ddd, J = 2.9, 9.3, 10.8 Hz, 1H).

Preparation I: (3S, 6R)-[6- (1-Phenyl-1H-tetrazol-5-sulfonylmethyl) -tetrahydro-pyran-3-yl] -carbamic acid tert-butyl ester:
Ii (S)-(1-Hydroxymethyl-pent-4-enyl) -carbamic acid tert-butyl ester:
To a suspension of LiBH ₄ (1.15 g, 53 mmol) in THF (300 ml), (S) -2-tert-butoxycarbonylamino-hex-5-enoic acid methyl ester (12.9 g, 53 mmol, J Org. Chem. (1995), 60, 2210) was added in THF (100 ml). The mixture was stirred at room temperature for 4 hours, poured into water and extracted with EA. The organic layer was washed with brine, dried over MgSO ₄ and concentrated to give the title alcohol (11.4 g, 99% yield) as a colorless oil.
¹ H NMR (CDCl ₃ ) δ: 5.75-5.65 (m, 1H), 5.00-4.90 (m, 2H), 4.5 (br, 1H, OH), 3.70-3.45 (m, 3H), 2.10-2.00 (m , 2H), 1.60-1.35 (m, 2H), 1.38 (s, 9H).

I.ii. ((1S, 3RS, 4RS)-(1-hydroxymethyl-3-oxiranyl-propyl) -carbamic acid tert-butyl ester:
Intermediate Ii (11.4 g, 53 mmol) was dissolved in 1,2-DCE (300 ml) and water (250 ml) and 1M phosphate buffer pH 8 (150 ml) was added. MCPBA (14.3 g, 1.1 eq, 70%) was added and the mixture was stirred vigorously overnight. The two phases were separated and the aqueous phase was extracted once more with DCM. The combined organic layers were washed with saturated NaHCO ₃ solution, dried over MgSO ₄ , filtered and concentrated to dryness. The residue was purified by chromatography on SiO ₂ (Hex: 1: 1 EA, then EA) to give the title epoxide (7.74 g, 63% yield, mixture of diastereomers) as a colorless oil.
¹ H NMR (CDCl ₃ ) δ: 4.90-4.85 (m, 1H), 3.75-3.50 (m, 3H), 3.00-2.90 (m, 1H), 2.80-2.51 (m, 1H), 2.6 (br, 1H , OH), 2.55-2.50 (m, 1H), 1.80-1.40 (m, 4H), 1.42 (s, 9H).

I.iii. (3S, 6R)-(6-Hydroxymethyl-tetrahydro-pyran-3-yl) -carbamic acid tert-butyl ester:
A solution of intermediate I.ii (2.3 g, 10 mmol) in DCM (50 ml) was treated with D, L-10-camphorsulfonic acid (0.1 eq). The reaction was slightly exothermic. The mixture was stirred at room temperature for 3 hours, concentrated and purified by chromatography on SiO ₂ (EA) to give the title tetrahydropyran derivative (0.874 g, 37% yield) as a colorless solid.
¹ H NMR (CDCl ₃ ) δ: 4.28 (br, 1H), 4.20-10 (m, 1H), 3.70-3.30 (m, 5H), 3.04 (t, 1H, J = 10.6 Hz), 2.20-2.00 ( m, 2H, 1.75-1.20 (m, 11H).

I.iv. (3R, 6S)-[6- (1-Phenyl-1H-tetrazol-5-sulfonylmethyl) -tetrahydro-pyran-3-yl] -carbamic acid tert-butyl ester:
This sulfone (5.9 g, 13.9 mmol) was obtained as a white solid starting from intermediate I.iii (8.2 g, 35.4 mmol) and using the procedure described in Preparation G.

Example 1: (E) -2-{(2R, 3R, 6R)-(3- [3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy- [1 , 5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -ethanol:
1.i. ((2R, 3R, 6S) -6- (tert-butyl-dimethyl-silanyloxymethyl) -2-((2RS) -2,3-dihydroxy-propyl) -3,6-dihydro- 2H-pyran-3-yl] -carbamic acid tert-butyl ester:
(2R, 3R, 6S)-[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; 60.7 g, 158.2 mmol) mixture in 2-methyl-2-propanol (750 ml) and water (750 ml) To was added potassium ferricyanide (182.4 g, 553.8 mmol), potassium carbonate (65.8 g, 476.0 mmol), (DHQ) ₂ PHAL (1.12 g, 1.4 mmol) and potassium osmart dihydrate (0.118 g). The reaction mixture was mechanically stirred at room temperature for 24 hours. Sodium bisulfite (316 g) was added slowly. The two layers were decanted and the aqueous layer was extracted once more with EA (500 ml). The combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and concentrated to dryness. The residue was filtered through a pad of SiO ₂ (Hex-EA 1-4) to give the title diol as a yellow oil (61.0 g, 146.0 mmol). The compound was obtained as a 2-1 mixture of epimers.
MS (ESI, m / z): 418.0 [M + H ^<+ >].

1.ii. [(2R, 3R, 6S) -2-((4RS) -2,2-Dimethyl- [1,3] dioxolan-4-ylmethyl) -6-hydroxymethyl-tetrahydro-pyran-3-yl ] -Carbamic acid tert-butyl ester:
To a mixture of intermediate 1.i (61 g, 146.0 mmol) in THF (710 ml) was added PTSA (1.38 g, 7.3 mmol) and 2,2-dimethoxypropane (54.0 ml, 439.1 mmol). The reaction mixture was stirred at room temperature for 90 minutes. TBAF (1M THF (230 ml) solution) was added. The reaction was allowed to proceed for 90 minutes. The reaction mixture was concentrated to dryness and the residue was chromatographed on SiO ₂ (Hex-EA 1-4) to give the title compound as a thick oil (44.7 g, 130.1 mmol). The compound was obtained as a 2-1 mixture of epimers.
MS (ESI, m / z): 344.2 [M + H ^<+ >].

1.iii. [(2R, 3R, 6S) -2-((4RS) -2,2-Dimethyl- [1,3] dioxolan-4-ylmethyl) -6-hydroxymethyl-tetrahydro-pyran-3-yl ] -Carbamic acid tert-butyl ester:
To a solution of intermediate 1.ii (19.7 g, 57.3 mmol) in EA (230 ml) was added platinum oxide (0.7 g). The resulting suspension was stirred under hydrogen for 5 hours. The catalyst was removed by filtration through celite and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography SiO ₂ (EA-Hex4-1~1-0), to give the title compound as a white solid (19.43 g). The compound was obtained as a 2-1 mixture of epimers.
MS (ESI, m / z): 346.1 [M + H ^<+ >].

1.iv. [(2R, 3R, 6S) -2-((4R) -2,2-dimethyl- [1,3] dioxolan-4-ylmethyl) -6- (1-phenyl-1H-tetrazole-5 -Ylsulfanylmethyl) -tetrahydro-pyran-3-yl] -carbamic acid tert-butyl ester:
To an ice-cold THF (500 ml) solution of intermediate 1.iii (19.4 g, 56.1 mmol), PPh ₃ (29 g), phenyltetrazole thiol (14 g) and DIAD (16.7 ml) were added dropwise. The resulting solution was stirred overnight at room temperature. The reaction mixture was dried and concentrated, and the residue was purified by column chromatography on SiO ₂ (EA-Hex1-3 to 1-0) to give the title sulfide as a colorless solid (28.85 g, 99% yield). . The compound was obtained as a 2-1 mixture of epimers.
MS (ESI, m / z): 506.0 [M + H ^<+ >].

1.v. [(2R, 3R, 6S) -2-((4RS) -2,2-dimethyl- [1,3] dioxolan-4-ylmethyl) -6- (1-phenyl-1H-tetrazole-5 -Sulfonylmethyl) -tetrahydro-pyran-3-yl] -carbamic acid tert-butyl ester:
To a solution of intermediate 1.iv (28.4 g) in EtOH (240 ml) and THF (240 ml) was added ammonium molybdate heptahydrate (17.73 g) and 50% aqueous H ₂ O ₂ (82.5 ml). The mixture was heated at 60 ° C. overnight. After cooling to room temperature, the reaction mixture was diluted with water (250 ml) and volatiles were removed under reduced pressure. EA (150 ml) was added to the aqueous residue and the phases were separated. The aqueous layer was extracted 3 times with EA. The combined organic layers were dried over MgSO ₄ , filtered and evaporated under reduced pressure. The residue was purified by column chromatography on SiO ₂ (DCM-MeOH 19-1 to 9-1) to give the first desired sulfone as a colorless thick oil (4.9 g) and then as a white foam (9.4 g) [(2R, 3R, 6S) -2-((2RS) -2,3-dihydroxy-propyl) -6- (1-phenyl-1H-tetrazole-5-sulfonylmethyl) -tetrahydro-pyran-3-yl] -Carbamic acid tert-butyl ester was obtained. The latter was taken up in THF (90 ml) and treated with PTSA (0.187 g) and 2,2-dimethoxypropane (6.95 ml). The reaction mixture was stirred at room temperature for 2.5 hours. Water (8 ml) and aqueous NaHCO ₃ solution were added and then concentrated to dryness. The residue was partitioned between water and EA and the phases were separated. The organic layer was washed with brine, dried over MgSO ₄ , filtered and evaporated under reduced pressure. The residue was further dried under HV to give more title sulfone (9.94 g).
MS (ESI, m / z): 538.0 [M + H ^<+ >].

1.vi. {(2R, 3R, 6S) -2-((4RS) -2,2-dimethyl- [1,3] dioxolan-4-ylmethyl) -6-trans- [2- (6-methoxy- [1,5] Naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-3-yl} -carbamic acid tert-butyl ester:
6-methoxy- [1,5] naphthyridine-4-carbaldehyde (see Preparation B; 1.7 g, 9.03 mmol) and intermediate 1.v (4 g, 7.45 mmol) cooled to −78 ° C. To the 1,2-DME (40 ml) solution, KHMDS (0.5 M toluene (24 ml) solution) was added dropwise over 10 minutes. The mixture was stirred at this temperature for 30 minutes. The reaction was then warmed to room temperature over 30 minutes, at which time water (50 ml) was added. The two layers were decanted and the aqueous layer was extracted twice with EA (2 × 150 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was chromatographed on SiO ₂ (Hex-EA 1-1, then 1-4) to give the title alkene (2.8 g, 62% yield) as a colorless foam.
MS (ESI, m / z): 500.4 [M + H ^<+ >].

1.vii.a. {(2R, 3R, 6S) -2- (2-hydroxy-ethyl) -6-trans- [2- (6-methoxy- [1,5] naphthyridin-4-yl) -vinyl ] -Tetrahydro-pyran-3-yl} -carbamic acid tert-butyl ester: and
1.vii.b. {(2R, 3R, 6R) -2- (2-hydroxy-ethyl) -6- [2- (6-methoxy- [1,5] naphthyridin-4-yl) -ethyl]- Tetrahydro-pyran-3-yl} -carbamic acid tert-butyl ester:
A mixture of Intermediate 1.vi (2.8 g, 5.6 mmol) in THF-AcOH-water (1-3-1, 50 ml) was heated at 60 ° C. for 6 hours. The reaction mixture was concentrated to dryness and the residue was partitioned between EA and saturated NaHCO ₃ . The pH was adjusted to 7 by adding solid NaHCO ₃ . The aqueous layer was extracted once with EA and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was taken up in acetone (100 ml) and a solution of NaIO ₄ (3 g) in warm water (10 ml) was added. The mixture was stirred for 1 hour. The reaction mixture was filtered through a pad of celite and the solvent was removed in vacuo. The residue was extracted twice with EA. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was taken up in MeOH (30 ml) and NaBH ₄ (0.7 g) was added. The reaction was allowed to proceed for 15 minutes. 10% NaHSO ₄ aqueous solution (100 ml) was added. Volatiles were removed in vacuo and the water residue was extracted 3 times with EA (3 × 100 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was chromatographed on SiO ₂ (DCM-MeOH 19-1) to give a colorless foam (1.76 g), which was characterized as a mixture of the two title compounds.
MS (ESI, m / z): 430.1 [M + H ^<+ >].

1.viii.a. {(2R, 3R, 6R) -2- (2-hydroxy-ethyl) -6- [2- (6-methoxy- [1,5] naphthyridin-4-yl) -ethyl]- Tetrahydro-pyran-3-yl} -carbamic acid tert-butyl ester: and
1.viii.b. [(2R, 3R, 6S) -6-[(1R, 2R) -1,2-dihydroxy-2- (6-methoxy- [1,5] naphthyridin-4-yl) -ethyl ] -2- (2-Hydroxy-ethyl) -tetrahydro-pyran-3-yl] -carbamic acid tert-butyl ester:
To a solution of intermediate 1.vii (1.76 g, mixture of compounds), potassium ferricyanide (4.04 g) K ₂ CO ₃ (1.7 g) methanesulfonamide (0.47 g), (DHDQ) ₂ PHAL (0.035 g) and potassium Osmart dihydrate (0.005 g) was added. The mixture was stirred at room temperature for 40 hours. Sodium bisulfite (6 g) was added. The two layers were decanted and the aqueous layer was extracted twice with EA (2 × 150 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was chromatographed on SiO ₂ (DCM-MeOH 19-1) to initially give the title alkane 1.viii.a (1.34 g, 3.1 mmol) as a colorless foam.
MS (ESI, m / z): 432.0 [M + H ^<+ >].
Elution was performed with DCM-MeOH 6-1 to give the title diol 1.viii.b (0.4 g, 0.86 mmol) as a colorless foam.
MS (ESI, m / z): 464.3 [M + H ^<+ >].

1.ix. (2R, 3R, 6R) -2- {3-Amino-6- [2- (6-methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2- Il} -ethanol:
A solution of intermediate 1.viii.a (1.34 g, 3.1 mmol) in TFA (10 ml) was stirred at room temperature for 15 minutes. After evaporation to dryness, the residue was dissolved in water (50 ml) and washed once with EA (50 ml). The pH of the aqueous layer was adjusted to 12 with the addition of 3M aqueous NaOH and the aqueous layer was extracted four times with a DCM-MeOH 9-1 mixture (4 × 100 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. After further drying under HV, the residue was purified by chromatography on SiO ₂ (DCM-MeOH 6-1 with 1% aqueous NH ₄ OH) and the title amine (0.65 g, 63 % Yield).
MS (ESI, m / z): 332.3 [M + H ^<+ >].

1.x. (E) -2-{(2R, 3R, 6R) -3- [3- (2,5-Difluoro-phenyl) -allylamino] -6- [2- (6-methoxy- [1, 5] Naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -ethanol:
To a solution of intermediate 1.ix (0.1 g, 0.3 mmol) in 1,2-DCE (4.5 ml) and MeOH (1.5 ml), (E) -3- (2,5-difluoro-phenyl) -propenal (preparation) See C, 0.055 g, 1.1 eq) and 3M molecular sieves (1 g) were added. The mixture was heated at 50 ° C. overnight. After cooling to room temperature, NaBH ₄ (0.1 g) was added. The reaction was allowed to proceed for 2 hours and then filtered through a pad of Hydromatrix® (treated with saturated aqueous NaHCO ₃ solution). The filtrate was concentrated to dryness. The residue was chromatographed on SiO ₂ (DCM-MeOH 19-1 containing 0.5% aqueous NH ₄ OH) (0.09 g, 61% yield) to give as a colorless oil.
MS (ESI, m / z): 484.1 [M + H ^<+ >].

Example 2: {(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -acryloylamino] -6- [2- (3-methoxy-quinoline-5- Yl) -ethyl] -tetrahydro-pyran-2-yl} -acetic acid:
2.i. {(2R, 3R, 6S) -2-((4RS) -2,2-Dimethyl- [1,3] dioxolan-4-ylmethyl) -6-[(E) -2- (3- Methoxy-quinolin-5-yl) -vinyl] -tetrahydro-pyran-3-yl} -carbamic acid tert-butyl ester:
The Julia coupling was performed as described in Example 1 (Step 1.vi) with intermediate 1.v (1.99 g, 3.7 mmol) and 3-methoxy-5-quinoline-carbaldehyde (see Preparation A). Starting from 0.67 g), the title compound was obtained as a white foam (1.07 g, 2.14 mmol). The compound was purified by column chromatography on SiO ₂ (EA-Hex1-1). The compound was obtained as a 2-1 mixture of epimers.
MS (ESI, m / z): 499.2 [M + H ^<+ >].

2.ii. {(2R, 3R, 6R) -2-((4RS) -2,2-dimethyl- [1,3] dioxolan-4-ylmethyl) -6- [2- (3-methoxy-quinoline- 5-yl) -ethyl] -tetrahydro-pyran-3-yl} -carbamic acid tert-butyl ester:
To a solution of intermediate 2.i (1.07 g, 2.14 mmol) in EA (35 ml) was added 10% Pd / C (0.23 g). The resulting suspension was stirred under hydrogen for 1 hour. The catalyst was removed by filtration. The filtrate was further dried under HV and evaporated under reduced pressure to give the title compound as a white foam (1.03 g, 2.05 mmol). The compound was obtained as a 2-1 mixture of epimers.
MS (ESI, m / z): 501.1 [M + H ^<+ >].

2.iii. 3- (2RS)-{(2R, 3R, 6R) -3-Amino-6- [2- (3-methoxy-quinolin-5-yl) -ethyl] -tetrahydro-pyran-2-yl } -Propane-1,2-diol:
A solution of intermediate 2.ii (1.03 g) in TFA (21 ml) was stirred for 10 minutes. Water (7 ml) was added. The resulting mixture was stirred for 1 hour and concentrated to dryness. The residue was basified with 1M aqueous NaOH. DCM-MeOH 9-1 was added and the phases were separated. The aqueous layer was extracted 6 times with DCM-MeOH 9-1 and the combined extracts were dried over MgSO ₄ , filtered and evaporated under reduced pressure. The title compound (0.69 g, 1.91 mmol) was obtained as a white foam. This was obtained as a 2-1 mixture of epimers.
¹ H NMR (CDCl ₃ ) main signal δ: 8.65 (d, J = 2.8 Hz, 1H); 7.89 (d, J = 8.4 Hz, 1H); 7.56 (m, 1H); 7.45 (m, 1H); 7.31 (m, 1H); 4.03 (m, 1H); 3.94 (s, 3H); 3.79 (m, 1H); 3.63 (m, 2H); 3.47 (m, 1H); 3.14 (m, 2H); 2.95 ( m, 1H); 2.25-2.05 (m, 5H); 2.03-1.87 (m, 3H); 1.85-1.67 (m, 3H); 1.59 (m, 1H); 1.23 (m, 1H).
MS (ESI, m / z): 361.1 [M + H ^<+ >].

2.iv. (E) -3- (2,5-Difluoro-phenyl) -N-{(2R, 3R, 6R) -2-((2RS) -2,3-dihydroxy-propyl) -6- [ 2- (3-Methoxy-quinolin-5-yl) -ethyl] -tetrahydro-pyran-3-yl} -acrylamide:
To a solution of intermediate 2.iii (0.360 g, 1 mmol) and 3- (2,5-difluoro-phenyl) -acrylic acid (0.203 g, 1.1 mmol) in DMF (15 ml), DIPEA (0.514 ml, 3 mmol) and HATU (0.456 g, 1.2 mmol) was added. The reaction mixture was stirred at room temperature for 90 minutes and concentrated to dryness. The residue was washed with saturated NaHCO ₃ (20 ml) and dissolved in DCM-MeOH 9-1 (50 ml). The aqueous layer was extracted twice with DCM-MeOH 9-1 (2 × 20 ml) and the combined organic layers were dried over MgSO ₄ , filtered and evaporated under reduced pressure. The residue was purified by column chromatography on SiO ₂ (DCM-MeOH 9-1 containing aqueous NH ₄ OH DCM-MeOH 19-1~1% containing 1% aqueous NH ₄ OH) to afford the title amide as an orange solid (0.331 g, 62% yield) was obtained.
¹ H NMR (d ₆ -DMSO) Main signal δ: 8.69 (d, J = 2.7 Hz, 1H); 8.30 (d, J = 8.6 Hz, 1H); 7.87-7.79 (m, 2H); 7.56-7.50 ( m, 4H); 7.40-7.27 (m, 2H); 7.02 (dd, J = 5.1, 15.9 Hz, 1H); 4.58 (m, 2H); 4.23 (m, 1H); 4.06 (overlapped m, 2H); 4.02 (overlapped s, 3H); 3.86-3.76 (m, 2H); 3.45-3.24 (overlapped m, 2H); 3.09-2.99 (m, 1H); 2.16 (m, 1H); 2.00 (m, 3H); 1.67 (m, 2H); 1.37 (m, 1H); 1.21 (m, 1H).
MS (ESI, m / z): 527.0 [M + H ^<+ >].

2.v. (E) -3- (2,5-Difluoro-phenyl) -1-{(2RS, 5R) -2-hydroxy-5- [2- (3-methoxy-quinolin-5-yl)- Ethyl] -hexahydro-pyrano [3,2-b] pyrrol-1-yl} -propenone:
An aqueous solution (0.5 ml) of NaIO ₄ (0.156 g) was added to a solution of intermediate 2.iv (0.153 g) in acetone (1.7 ml) at room temperature. The reaction mixture was stirred for 30 minutes and concentrated to dryness. The residue was purified on SiO ₂ (EA-Hex2-1) to give a colorless gum (0.118 g, 82% yield).
MS (ESI, m / z): 495.1 [M + H ^<+ >].

2.vi. {(2R, 3R, 6R) -3-[(E) -3- (2,5-Difluoro-phenyl) -acryloylamino] -6- [2- (3-methoxy-quinoline-5- Yl) -ethyl] -tetrahydro-pyran-2-yl} -acetic acid:
To a solution of intermediate 2.v (0.114 g, 0.23 mmol) in 2-methyl-2-propanol (5 ml) and 2-methyl-2-butene (1.2 ml), sodium zinc borate (0.193 g) and diphosphate An aqueous solution (2 ml) of sodium hydride (0.193 g) was added dropwise. The resulting solution was stirred overnight at room temperature and volatiles were removed under HV. The residue was diluted with water and Hex. The phases were separated and the organic layer was extracted once with Hex. The aqueous layer was acidified to pH 3 and extracted 3 times with EA. The combined extracts were washed with cold water and evaporated under reduced pressure. The resulting colorless olibanum was triturated in ether, filtered and dried under reduced pressure to give the title compound as a white solid (0.069 g, 58% yield).
¹ H NMR (d ₆ -DMSO) δ: 12.32 (br.s, 1H); 8.82 (m, 1H); 8.58 (m, 1H); 8.05 (m, 2H); 7.51 (m, 4H); 7.37 ( m, 2H); 7.03 (m, 1H); 4.36 (m, 1H); 4.02 (overlapped s, 3H); 4.01 (overlapped m, 1H); 3.86 (m, 1H); 3.39 (m, 1H); 3.10 (m, 1H); 2.44 (overlapped m, 2H); 2.25 (m, 1H); 1.92 (m, 2H); 1.65 (m, 2H); 1.37 (m, 1H).
MS (ESI, m / z): 511.0 [M + H ^<+ >].

Example 3: {(2R, 3R, 6R) -6- [2- (3-Methoxy-quinolin-5-yl) -ethyl] -3-[(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carbonyl) -amino] -tetrahydro-pyran-2-yl} -acetic acid:
3.i. -Oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2R, 3R, 6R) -2-((2RS)- 2,3-dihydroxy-propyl) -6- [2- (3-methoxy-quinolin-5-yl) -ethyl] -tetrahydro-pyran-3-yl} -amide:
Intermediate 2.iii (0.270 g, 0.75 mmol) and 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid (0.174 g, 1.1 eq. The title compound (0.187 g, 0.32 mmol) was obtained as a pale brown orange foam using the procedure of Example 2, Step 2.iv. The compound was obtained as a 2-1 mixture of epimers.
¹ H NMR (d ₆ -DMSO) Main signal δ: 11.29 (s, 1H); 8.69 (dd, J = 1.7, 2.7 Hz, 1H); 8.36 (d, J = 9.3 Hz, 1H); 8.01 (d, J = 7.9 Hz, 1H); 7.88-7.79 (m, 2H); 7.66 (dd, J = 1.3, 7.9 Hz, 1H); 7.51 (m, 1H); 4.64 (d, J = 5.2 Hz, 2H); 4.58 (m, 1H); 4.25 (m, 1H); 4.08 (overlapped m, 1H); 4.03 (overlapped s, 3H); 3.95 (m, 1H); 3.77 (m, 1H); 3.69 (d, J = 5.1 Hz, 2H); 3.39-3.25 (overlapped m, 4H); 3.07 (m, 1H); 2.28 (m, 1H); 1.98 (m, 2H); 1.83-1.58 (m, 3H); 1.27 (m, 1H); 1.20 (m, 1H).

3.ii. 3-Oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid [(2R, 3R, 6R) -6- [2- ( 3-methoxy-quinolin-5-yl) -ethyl] -2- (2-oxo-ethyl) -tetrahydro-pyran-3-yl] -amide:
Starting from Intermediate 3.i (0.148 g, 0.27 mmol) and using the procedure of Example 2, Step 2.v, the title aldehyde (0.078 g, 56% yield) was obtained as a colorless foam. Obtained.
MS (ESI, m / z): 521.1 [M + H ^<+ >].

3.iii. {(2R, 3R, 6R) -6- [2- (3-Methoxy-quinolin-5-yl) -ethyl] -3-[(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carbonyl) -amino] -tetrahydro-pyran-2-yl} -acetic acid:
Starting from Intermediate 3.ii (0.073 g, 0.14 mmol), the title acid (0.032 g, 42% yield) was obtained using the procedure described in Example 2, Step 2.vi. As obtained. The compound was purified by trituration with ether.
¹ H NMR (d ₆ -DMSO) δ: 11.29 (s, 1H); 8.76 (m, 1H); 8.55 (m, 1H); 8.12-7.87 (m, 3H); 7.67-7.47 (m, 3H); 4.45 (m, 1H); 4.14 (overlapped m, 1H); 4.04 (overlapped s, 3H); 3.96 (overlapped m, 1H); 3.76 (m, 1H); 3.46-3.25 (m, 2H); 3.04 (m , 1H); 2.53-2.20 (m, 4H); 2.01 (m, 2H); 1.69 (m, 2H); 1.30 (m, 1H).
MS (ESI, m / z): 537.0 [M + H ^<+ >].

Example 4: {(2R, 3R, 6R) -6- [2- (6-Methoxy- [1,5] naphthyridin-4-yl) -ethyl] -3-[(3-oxo-3,4- Dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-ylmethyl) -amino] -tetrahydro-pyran-2-yl} -acetic acid trihydrochloride:
4.i. (2RS) -3-{(2R, 3R, 6R) -3-Amino-6- [2- (6-methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro- Pyran-2-yl} -propane-1,2-diol:
The title compound (1.30 g, 94% yield) is obtained in white starting from intermediate 1.vi (1.98 g, 3.98 mmol) using the procedure of Example 2, Steps 2.ii and 2.iii. Obtained as a solid.
MS (ESI, m / z): 362.1 [M + H ^<+ >].

4.ii. 6-({(2R, 3R, 6R) -2-((2RS) -2,3-dihydroxy-propyl) -6- [2- (6-methoxy- [1,5] naphthyridine-4 -Yl) -ethyl] -tetrahydro-pyran-3-ylamino} -methyl) -4H-pyrido [3,2-b] [1,4] thiazin-3-one:
Intermediate 4.i (0.644 g, 1.78 mmol) and 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carbaldehyde (0.380 g, 1.1 eq) The title compound (0.583 g, 60% yield) was obtained as a white foam using the procedure of Example 1, Step 1.x.
¹ H NMR (d ₆ -DMSO) δ: 10.93 (s, 1H); 8.69 (dd, J = 1.1, 4.4 Hz, 1H); 8.27 (d, J = 9.0 Hz, 1H); 7.78 (dd, J = 1.36, 7.9 Hz, 1H); 7.56 (t, J = 4.4 Hz, 1H); 7.28 (d, J = 9.0 Hz, 1H); 7.12 (d, J = 7.9 Hz, 1H); 4.65-4.46 (m, 2H); 4.20-4.05 (overlapped m, 1H); 4.05 (overlapped s, 3H); 3.70 (overlapped s, 2H); 3.70-3.56 (overlapped m, 2H); 3.56 (overlapped s, 2H); 3.41-3.19 (overlapped m, 3H); 3.17-3.07 (m, 1H); 2.74 (m, 1H); 2.09 (m, 1H); 1.92-1.70 (m, 5H); 1.51 (m, 1H); 1.37 (m, 1H); 1.25 (m, 1H).
MS (ESI, m / z): 540.0 [M + H ^<+ >].

4.iii. {(2R, 3R, 6R) -2-((2RS) -2,3-dihydroxy-propyl) -6- [2- (6-methoxy- [1,5] naphthyridin-4-yl) -Ethyl] -tetrahydro-pyran-3-yl}-(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-ylmethyl) -carbamic acid tert- Butyl ester:
To a solution of intermediate 4.ii (0.5 g, 0.92 mmol) in dioxane (4.5 ml) and water (0.6 ml) was added 1M aqueous NaOH (1 ml). The solution was cooled to 0 ° C. and Boc ₂ O (0.303 g) was added. After stirring overnight, 1M aqueous NaOH (0.5 ml) and Boc ₂ O (0.3 g) were added. After 4 hours, 1M aqueous NaOH (1 ml) and Boc ₂ O (0.3 g) were added again and the reaction mixture was stirred for 16 hours. EA was added and the phases were separated. The aqueous layer was extracted twice with EA and the combined organic layers were washed with brine, dried over MgSO ₄ , filtered and evaporated under reduced pressure. The residue was purified by column chromatography on SiO ₂ (DCM-MeOH 19-1 containing 1% aqueous NH ₄ OH, then DCM-MeOH 9-1 containing 1% aqueous NH ₄ OH), a pale yellow foam The title compound was obtained as (0.449 g, 76% yield).
¹ H NMR (CDCl ₃ ) Main signal δ: 9.27 (br.s, 1H); 8.64 (dd, J = 1.3, 4.5 Hz, 1H); 8.19 (dd, J = 1.2, 9.0 Hz, 1H); 7.56 ( m, 1H); 7.36 (m, 1H); 7.10 (dd, J = 1.8, 9.0 Hz, 1H); 6.84 (br.d, J = 5.4 Hz, 1H); 4.66-4.53 (m, 2H); 4.39 -4.09 (m, 2H); 4.04 (overlapped s, 3H); 4.00 (overlapped m, 1H); 3.73-3.51 (m, 3H); 3.47 (d, J = 5.4 Hz, 2H); 3.23-3.09 (m , 2H); 2.12-1.13 (m, 19H).
MS (ESI, m / z): 640.0 [M + H ^<+ >].

4.iv. [(2R, 3R, 6R) -6- [2- (6-Methoxy- [1,5] naphthyridin-4-yl) -ethyl] -2- (2-oxo-ethyl) -tetrahydro- Pyran-3-yl]-(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-ylmethyl) -carbamic acid tert-butyl ester:
Starting from intermediate 4.iii (0.444 g, 0.69 mmol) and using the procedure of Example 2, Step 2.v, the title aldehyde (0.372 g, 88% yield) was obtained as a colorless thick oil. As obtained. The compound was purified by column chromatography on SiO ₂ using DCM-MeOH 19-1 as eluent.
¹ H NMR (CDCl ₃ ) δ: 9.77 (br.s, 1H); 8.65 (d, J = 4.5 Hz, 1H); 8.37 (br.s, 1H); 8.19 (d, J = 9.0 Hz, 1H) 7.57 (d, J = 8.0 Hz, 1H); 7.36 (d, J = 4.5 Hz, 1H); 7.10 (d, J = 9.0 Hz, 1H); 6.84 (d, J = 7.7 Hz, 1H); 4.83 (m, 1H); 4.20-4.13 (m, 2H); 4.06 (s, 3H); 3.60 (m, 1H); 3.48 (d, J = 2.3 Hz, 2H); 3.23 (m, 1H); 3.07 ( m, 1H); 2.90 (m, 1H); 2.59 (m, 1H); 1.90 (m, 2H); 1.75 (m, 3H); 1.34 (m, 11H).
MS (ESI, m / z): 608.0 [M + H ^<+ >].

4.v. {(2R, 3R, 6R) -3- [tert-butoxycarbonyl- (3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6 -Ylmethyl) -amino] -6- [2- (6-methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetic acid:
Starting from intermediate 4.iv (0.365 g, 0.6 mmol), the title acid (0.258 g, 69% yield) is obtained in solid yellow using the procedure of Example 2, Step 2.vi. As obtained. The compound was purified by trituration with ether.
¹ H NMR (d ₆ -DMSO) δ: 12.28 (s, 1H); 10.92 (s, 1H); 8.68 (d, J = 4.4 Hz, 1H); 8.26 (d, J = 9.0 Hz, 1H); 7.76 (d, J = 8.0 Hz, 1H); 7.56 (d, J = 4.4 Hz, 1H); 7.27 (d, J = 9.0 Hz, 1H); 6.82 (d, J = 8.0 Hz, 1H); 4.50 (m , 2H); 4.19 (m, 2H); 4.05 (s, 3H); 3.64 (m, 1H); 3.56 (d, J = 3.4 Hz, 2H); 3.22 (m, 1H); 3.07 (m, 1H) 2.79 (m, 1H); 2.37 (m, 1H); 1.93 (m, 1H); 1.87-1.73 (m, 4H); 1.46-1.37 (m, 6H); 1.26 (m, 4H).
MS (ESI, m / z): 624.0 [M + H ^<+ >].

4.vi. {(2R, 3R, 6R) -6- [2- (6-Methoxy- [1,5] naphthyridin-4-yl) -ethyl] -3-[(3-oxo-3,4- Dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-ylmethyl) -amino] -tetrahydro-pyran-2-yl} -acetic acid trihydrochloride:
To a suspension of intermediate 4.v (0.256 g, 0.41 mmol) in dioxane (1 ml) was added a solution of anhydrous HCl in dioxane (5N, 0.86 ml). The resulting solution was stirred at room temperature for 3 hours. The mixture was concentrated to dryness. The residual solid was diluted with ether and evaporated under reduced pressure. The solid thus obtained was triturated in ether and filtered. After drying under HV, the trihydrochloride salt was collected as a white solid (0.260 g).
¹ H NMR (d ₆ -DMSO) δ: 11.16 (s, 1H); 9.53 (br.s, 1H); 9.18 (br.s, 1H); 8.95 (d, J = 5.1 Hz, 1H); 8.56 ( d, J = 9.0 Hz, 1H); 7.92 (m, 2H); 7.53 (d, J = 9.2 Hz, 1H); 7.30 (d, J = 7.9 Hz, 1H); 4.65 (m, 1H); 4.28 ( br.s, 2H); 4.11 (s, 3H); 3.82 (m, 1H); 3.64 (overlapped s, 2H); 3.60 (overlapped m, 1H); 3.26 (m, 2H); 2.86-2.66 (m, 2H); 2.09 (m, 1H); 1.96 (m, 4H); 1.34 (m, 1H).
MS (ESI, m / z): 524.7 [M + H ^<+ >].

Example 5: {(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy- [1,5] Naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetic acid dihydrochloride:
5.i. (2RS) -3-{(2R, 3R, 6R) -3-[(E) -3- (2,5-Difluoro-phenyl) -allylamino] -6- [2- (6-methoxy -[1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -propane-1,2-diol:
Starting from intermediate 4.i (0.470 g, 1.3 mmol) and (E) -3- (2,5-difluoro-phenyl) -propenal (0.240 g; 1.1 eq), the title compound (0.450 g, 67% Yield) was obtained as a white foam according to the procedure of Example 1, Step 1.x.
¹ H NMR (d ₆ -DMSO) δ: 8.69 (dd, J = 1.1, 4.4 Hz, 1H); 8.27 (d, J = 9.0 Hz, 1H); 7.58-7.48 (m, 2H); 7.31-7.22 ( m, 2H); 7.18-7.10 (m, 1H); 6.62 (t, J = 16.1 Hz, 1H); 6.52 (m, 1H); 4.73 (br.s, 1H); 4.55-4.44 (m, 2H) ; 4.17 (m, 1H); 4.05 (s, 3H); 3.69-3.58 (m, 2H); 3.38 (overlapped m, 2H); 3.28 (overlapped m, 2H); 3.12 (m, 1H); 2.77 (m , 1H); 1.99-1.72 (m, 6H); 1.54-1.23 (m, 3H).
MS (ESI, m / z): 514.0 [M + H ^<+ >].

5.ii. [(E) -3- (2,5-Difluoro-phenyl) -allyl]-{(2R, 3R, 6R) -2-((2RS) -2,3-dihydroxy-propyl) -6 -[2- (6-Methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-3-yl} -carbamic acid tert-butyl ester:
Starting from intermediate 5.i (0.73 g, 1.42 mmol), the title compound (0.65 g, 74% yield) was obtained as a white foam using the procedure of Example 4, step 4.iii. . The compound was purified by column chromatography on SiO ₂ (DCM-MeOH 19-1, then 9-1). This was obtained as a 2-1 mixture of epimers.
¹ H NMR (CDCl ₃ ) Main signal δ: 8.66 (d, J = 3.7 Hz, 1H); 8.30 (dd, J = 6.3, 9.0 Hz, 1H); 7.42 (m, 1H); 7.14 (overlapped d, J = 9.1 Hz, 1H); 7.09 (overlapped m, 1H); 7.01-6.93 (m, 1H); 6.90-6.84 (m, 1H); 6.52 (d, J = 16.0 Hz, 1H); 6.24 (m, 1H ); 4.35-4.20 (m, 3H); 4.06 (s, 3H); 3.96-3.89 (m, 1H); 3.83 (dd, J = 5.2, 16.9 Hz, 1H); 3.66 (m, 2H); 3.50 ( m, 1H); 3.26-3.14 (m, 3H); 2.27-2.20 (br. m, 2H); 2.10-1.84 (m, 6H); 1.47 (overlapped s, 9H); 1.46 (overlapped m, 1H).
MS (ESI, m / z): 614.1 [M + H ^<+ >].

5.iii. [(E) -3- (2,5-Difluoro-phenyl) -allyl]-[(2R, 3R, 6R) -6- [2- (6-methoxy- [1,5] naphthyridine- 4-yl) -ethyl] -2- (2-oxo-ethyl) -tetrahydro-pyran-3-yl] -carbamic acid tert-butyl ester:
Starting from Intermediate 5.ii (0.645 g, 1.05 mmol), the title aldehyde (0.557 g, 91% yield) was obtained as a white foam using the procedure of Example 2, Step 2.v. . The residue was purified by column chromatography on _{SiO 2 (DCM-MeOH 97-3~19-1)} .
¹ H NMR (CDCl ₃ ) δ: 9.75 (m, 1H); 8.65 (d, J = 4.6 Hz, 1H); 8.29 (d, J = 9.1 Hz, 1H); 7.43 (d, J = 4.6 Hz, 1H ); 7.14 (overlapped d, J = 9.1 Hz, 1H); 7.08 (overlapped m, 1H); 7.02-6.95 (m, 1H); 6.92-6.85 (m, 1H); 6.52 (d, J = 16.1 Hz, 6.22 (td, J = 5.2, 15.8 Hz, 1H); 4.79 (m, 1H); 4.24 (m, 1H); 4.08 (s, 3H); 3.76 (dd, J = 4.5, 16.8Hz, 1H ); 3.66-3.58 (m, 1H); 3.31-3.21 (m, 1H); 3.14-3.04 (m, 1H); 2.89-2.80 (m, 1H); 2.54 (dd, J = 4.7, 15.3 Hz, 1H ); 1.93-1.89 (m, 4H); 1.86-1.79 (m, 1H); 1.48 (overlapped s, 9H); 1.47 (overlapped m, 2H).
MS (ESI, m / z): 582.0 [M + H ^<+ >].

5.iv. {(2R, 3R, 6R) -3- {tert-butoxycarbonyl-[(E) -3- (2,5-difluoro-phenyl) -allyl] -amino} -6- [2- ( 6-methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetic acid:
Starting from intermediate 5.iii (0.557 g, 0.96 mmol), the title acid (0.58 g, 99% yield) is obtained as a colorless foam using the procedure of Example 2, Step 2.vi. It was. The compound was purified by trituration with ether.
¹ H NMR (CDCl ₃ ) δ: 8.52 (d, J = 4.6 Hz, 1H); 8.36 (d, J = 9.1 Hz, 1H); 7.27 (overlapped m, 1H); 7.12-6.86 (m, 4H); 6.53 (d, J = 15.8 Hz, 1H); 6.27 (m, 1H); 4.60 (m, 1H); 4.30-4.07 (m, 2H); 3.99 (s, 3H); 3.85-3.70 (m, 2H) 3.02 (m, 2H); 2.79 (m, 1H); 2.49 (dd, J = 3.7, 14.2 Hz, 1H); 1.94-1.90 (m, 3H); 1.84-1.77 (m, 3H); 1.52-1.40 (overlapped m, 3H); 1.27 (s, 9H).
MS (ESI, m / z): 598.1 [M + H ^<+ >].

5.v. {(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy- [1,5] Naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetic acid dihydrochloride:
Starting from intermediate 5.iv (0.100 g, 0.167 mml), the title compound (0.074 g, 78% yield) is obtained as a white solid using the procedure of Example 4, step 4.vi. It was.
¹ H NMR (D ₂ O) δ: 8.80 (d, J = 9.2 Hz, 1H); 8.36 (d, J = 9.2 Hz, 1H); 8.03 (d, J = 6.0 Hz, 1H); 7.51 (d, J = 9.3 Hz, 1H); 7.31 (m, 1H); 7.15 (m, 2H); 6.97 (d, J = 16.3 Hz, 1H); 6.35 (m, 1H); 4.79 (overlapped s, 1H); 4.61 (m, 1H); 4.14 (s, 3H); 4.06-3.84 (m, 3H); 3.58 (m, 1H); 3.45 (m, 2H); 2.90-2.79 (m, 1H); 2.59 (dd, J = 3.6, 15.0 Hz, 1H); 2.25-2.00 (m, 3H); 1.96-1.79 (m, 3H); 1.54-1.40 (m, 1H).
MS (ESI, m / z): 498.0 [M + H ^<+ >].

Example 6: {(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(1S) -1-hydroxy-2- (6 -Methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetic acid dihydrochloride:
6.i. [(2R, 3R, 6S) -6-[(1R, 2R) -1,2-dihydroxy-2- (6-methoxy- [1,5] naphthyridin-4-yl) -ethyl]- 2-((4RS) -2,2-dimethyl- [1,3] dioxolan-4-ylmethyl) -tetrahydro-pyran-3-yl] -carbamic acid tert-butyl ester:
To a suspension of intermediate 1.vi (1.274 g, 2.55 mmol) and methanesulfonamide (0.291 g, 3.06 mmol) in 2-methyl-2-propanol (13 ml), water (13 ml) and EA (4 ml) AD-mixβ (4.5 g) was added. The reaction mixture was stirred at room temperature for 24 hours. Sodium metabisulfite (10 g) and EA (50 ml) were added. The two layers were decanted and the aqueous layer was extracted twice with EA. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on SiO ₂ (DCM-MeOH 9-1) to give the desired diol as a white foam (1.2 g). The compound was obtained as a 2-1 mixture of epimers.
MS (ESI, m / z): 534.0 [M + H ^<+ >].

6.ii. {(2R, 3R, 6S) -2-((4RS) -2,2-Dimethyl- [1,3] dioxolan-4-ylmethyl) -6-[(4R, 5R) -5- ( 6-methoxy- [1,5] naphthyridin-4-yl) -2-oxo- [1,3] dioxolan-4-yl] -tetrahydro-pyran-3-yl} -carbamic acid tert-butyl ester:
To an ice-cold DCM (12 ml) solution of intermediate 6.i (1.22 g, 2.30 mmol), pyridine (1.12 ml, 13.80 mmol) and triphosgene (0.341 g, 1.15 mmol) were added. The reaction was stirred at 0 ° C. for 30 minutes and then at room temperature for 1 hour. The reaction mixture was diluted with saturated NaHCO ₃ and the two layers were decanted. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was chromatographed on SiO ₂ (DCM-MeOH 19-1) to give the title cyclic carbonate (1.18 g, 92% yield) as a white foam. The compound was obtained as a 2-1 mixture of epimers.
MS (ESI, m / z): 560.0 [M + H ^<+ >].

6.iii. {(2R, 3R, 6S) -2-((4RS) -2,2-Dimethyl- [1,3] dioxolan-4-ylmethyl) -6-[(1S) -1-hydroxy-2 -(6-Methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-3-yl} -carbamic acid tert-butyl ester:
To a solution of intermediate 6.ii (1.178 g, 2.11 mmol) in EA (80 ml) was added 20% Pd (OH) ₂ on carbon (wet, 0.443 g) and the suspension was hydrogenated Stir for 2 hours under. The catalyst was filtered and the filtrate was concentrated to dryness. The residue was purified by column chromatography on SiO ₂ (DCM-MeOH 9-1) to give the title compound (0.973 g, 89% yield) as a white foam.
MS (ESI, m / z): 518.0 [M + H ^<+ >].

6.iv. (2RS) -3-{(2R, 3R, 6S) -3-Amino-6-[(1S) -1-hydroxy-2- (6-methoxy- [1,5] naphthyridine-4- Yl) -ethyl] -tetrahydro-pyran-2-yl} -propane-1,2-diol:
Starting from intermediate 6.iii (0.97 g, 1.87 mmol) and using the procedure of Example 2, Step 2.iii, the title amine (0.57 g, 80% yield) was obtained as a brown foam. Obtained. The compound was obtained as a 2-1 mixture of epimers.
¹ H NMR (d6-DMSO) Main signal δ: 8.69 (d, J = 4.4 Hz, 1H); 8.27 (d, J = 9.0 Hz, 1H); 7.59 (d, J = 4.5 Hz, 1H); 7.27 ( d, J = 9.0 Hz, 1H); 4.57-4.42 (m, 2H); 4.06 (overlapped s, 3H); 4.05-3.89 (overlapped m, 2H); 3.68 (m, 1H); 3.59-3.45 (m, 2H); 3.28 (m, 3H); 2.93-2.82 (m, 2H); 1.87-1.69 (m, 1H); 1.62-1.57 (m, 3H); 1.54-1.27 (m, 4H).
MS (ESI, m / z): 378.2 [M + H ^<+ >].

6.v. (2RS) -3-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(1S) -1- Hydroxy-2- (6-methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -propane-1,2-diol:
Starting from intermediate 6.iv (0.570 g, 1.51 mmol) and (E) -3- (2,5-difluoro-phenyl) -propenal (0.279 g, 1.1 eq), the title compound (0.420 g. 52% Yield) was obtained as a white solid following the procedure described in Example 1 (Step 1.x).
¹ H NMR (d ₆ -DMSO) Main signal δ: 8.69 (d, J = 4.4 Hz, 1H); 8.27 (d, J = 9.0 Hz, 1H); 7.59 (d, J = 4.5 Hz, 1H); 7.52 (m, 2H); 7.32-7.23 (m, 2H); 7.22-7.10 (m, 1H); 6.62 (overlapped t, J = 16.3 Hz, 1H); 6.53 (overlapped m, 1H); 4.58 (m, 1H ); 4.48 (d, J = 6.5 Hz, 1H); 4.26-4.09 (m, 1H); 4.04 (s, 3H); 3.91 (m, 1H); 3.72 (m, 1H); 3.53 (m, 2H) 3.40-3.29 (m, 4H); 2.92 (m, 1H); 2.76 (m, 1H); 1.96 (m, 1H); 1.82-1.68 (m, 4H); 1.62-1.37 (m, 3H).
Rf = 0.38 (DCM-MeOH 9-1 with 1% NH ₄ OH solution).
MS (ESI, m / z): 529.8.

6.vi. [(E) -3- (2,5-Difluoro-phenyl) -allyl]-{(2R, 3R, 6S) -2-((2RS) -2,3-dihydroxy-propyl) -6 -[(1S) -1-hydroxy-2- (6-methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-3-yl} -carbamic acid tert-butyl ester:
Starting from intermediate 6.v (0.363 g, 0.69 mmol) and using the procedure of Example 4, step 4.iii, the title N-protected amine (0.279 g, 64% yield) was obtained. Obtained as a white foam. The compound was obtained as a 2-1 mixture of epimers.
MS (ESI, m / z): 629.9 [M + H ^<+ >].

6.vii. {(2R, 3R, 6S) -3- {tert-butoxycarbonyl-[(E) -3- (2,5-difluoro-phenyl) -allyl] -amino} -6-[(1S) -1-hydroxy-2- (6-methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetic acid:
Starting from intermediate 6.vi (0.275 g, 0.43 mmol), the title acid (0.257 g, 99% yield) was obtained using the procedure described in Example 2, Steps 2.v and vi. Obtained as a colorless foam.
MS (ESI, m / z): 614.0 [M ⁺ ].

6.viii. {(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(1S) -1-hydroxy-2- (6 -Methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetic acid dihydrochloride:
Starting from intermediate 6.vii (0.252 g, 0.41 mmol), the title acid (0.24 g, 99% yield) is obtained in yellow using the procedure described in Example 4, step 4.vi. Obtained as a gummy solid. The compound was triturated in ether.
¹ H NMR (d ₆ -DMSO) δ: 8.69 (d, J = 4.4 Hz, 1H); 8.27 (d, J = 9.0 Hz, 1H); 7.59 (d, J = 4.5 Hz, 1H); 7.52 (m , 2H); 7.32-7.23 (m, 2H); 7.22-7.10 (m, 1H); 6.62 (overlapped t, J = 16.3 Hz, 1H); 6.53 (overlapped m, 1H); 4.58 (m, 1H); 4.48 (d, J = 6.5 Hz, 1H); 4.26-4.09 (m, 1H); 4.04 (s, 3H); 3.91 (m, 1H); 3.72 (m, 1H); 3.53 (m, 2H); 3.40 -3.29 (m, 4H); 2.92 (m, 1H); 2.76 (m, 1H); 1.96 (m, 1H); 1.82-1.68 (m, 4H); 1.62-1.37 (m, 3H).
MS (ESI, m / z): 514.0 [M + H ^<+ >].

Example 7: (1RS) -2-{(2S, 5R, 6S) -5- [trans-3- (2,5-difluoro-phenyl) -allylamino] -6-hydroxymethyl-tetrahydro-pyran-2- Yl} -1- (3-fluoro-6-methoxy-quinolin-4-yl) -ethanol:
7.i. (2R, 3S, 6R) -6-allyl-2- (tert-butyl-diphenyl-silanyloxymethyl) -3,6-dihydro-2H-pyran-3-ol:
Ice-cooled (2R, 3S, 6R) -6-allyl-2-hydroxymethyl-3,6-dihydro-2H-pyran-3-ol (Eur. J. Org. Chem. (2003), 2418-2427; To the solution of 31.55 g (185.4 mmol) in DCM (650 ml) was added imidazole (24.96 g, 2 eq). A solution of tert-butylchlorodiphenylsaline (50.45 g, 210.7 mmol) in DCM (130 ml) was added dropwise over 90 minutes. After 2 hours, saturated aqueous NaHCO ₃ solution (250 ml) was added. The two layers were separated and the organic layer was washed twice with brine, dried over MgSO ₄ , filtered and concentrated to dryness. The residue was chromatographed on SiO ₂ (Hex-EA 5-1) to give the title compound as a yellow oil (51.52 g, 68% yield).
¹ H NMR (CDCl ₃ ) δ: 7.74-7.68 (m, 4H); 7.47-7.38 (6H); 5.87-5.76 (m, 3H); 5.10-5.04 (m, 2H); 4.19-4.15 (m, 2H ); 3.89 (dd, J = 5.3, 10.0 Hz, 1H); 3.79 (dd, J = 7.3, 10.0 Hz, 1H); 3.68 (m, 1H); 2.70 (br s, 1H); 2.38 (m, 1H ); 2.28 (m, 1H); 1.09 (s, 9H).

7.ii. (2RS) -3-[(2R, 5S, 6R) -6- (tert-butyl-diphenyl-silanyloxymethyl) -5-hydroxy-5,6-dihydro-2H-pyran-2- Yl] -propane-1,2-diol:
A solution of intermediate 7.i (51.52 g, 126.1 mmol) in 2-methyl-2-propanol (560 ml), EA (15 ml) and water (560 ml) was added potassium ferricyanide (189.48 g, 3 eq), K ₂ CO ₃ (67.10 g, 3 eq), (DHQD) ₂ PHAL (1.5121 g, 0.015 eq) and potassium osmart dihydrate (0.1907 g, 0.004 eq) were added. The reaction mixture was stirred for 2 days and sodium bisulfite (150.92 g) was added. The two layers were decanted and the aqueous layer was extracted twice with EA (2 × 350 ml). The combined organic layers were washed with brine (500 ml), dried over MgSO ₄ , filtered and concentrated to dryness. The residue was filtered through SiO ₂ (Hex-EA 1-1, then EA) to give the title product as a yellow oil (36.33 g, 65% yield). The compound was obtained as a 2-1 mixture of epimers.
¹ H NMR (d ₆ -DMSO) δ: 7.71-7.65 (m, 4H); 7.47-7.40 (m, 6H); 5.80-5.65 (m, 2H); 4.95 (m, 1H); 4.50-4.35 (m 3.92-3.28 (m, 7H); 1.80-1.65 (m, 1.33H); 1.17 (m, 0.67H); 0.99 (s, 9H).

7.iii. (2R, 3S, 6R) -2- (tert-butyl-diphenyl-silanyloxymethyl) -6-((4RS) -2,2-dimethyl- [1,3] dioxolan-4-ylmethyl ) -3,6-Dihydro-2H-pyran-3-ol:
To a solution of intermediate 7.ii (34.83 g, 78.7 mmol) in DCM (575 ml) at room temperature was added PTSA (0.90 g, 4.7 mmol) and 2,2-dimethoxypropane (24 ml, 195.2 mmol). After 2 hours, water (100 mL) and saturated NaHCO ₃ (200 ml) were added and the two phases were separated. The aqueous layer was extracted with DCM (260 ml). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated to dryness. The residue was chromatographed on SiO ₂ (Hex-EA 1-1) to give the title compound as a yellow oil (36.19 g (74.9 mmol). The compound was obtained as a 2-1 mixture of epimers.
¹ H NMR (CDCl ₃ ) δ: 7.72-7.67 (m, 4H); 7.50-7.39 (m, 6H); 5.85-5.77 (m, 2H); 4.23-3.41 (m, 8H); 2.80 (br s, 2.06 (m, 0.33H); 1.80-1.65 (1.67H); 1.40 (s, 3H); 1.33 (s, 3H); 1.09 (s, 9H).

7.iv. (2R, 3S, 6R) -2- (tert-butyl-diphenyl-silanyloxymethyl) -6-((4RS) -2,2-dimethyl- [1,3] dioxolan-4-ylmethyl ) -Tetrahydro-pyran-3-ol:
To a solution of intermediate 7.iii (36.16 g, 74.9 mmol) in EA (600 ml) was added platinum oxide hydrate (1.1 g, 4.8 mmol). The reaction mixture was stirred under hydrogen for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated to dryness to give the title alcohol (36.18 g, 99% yield) as a thick oil. The compound was obtained as a 2-1 mixture of epimers.
MS (ESI, m / z): 485.2 [M + H ^<+ >].

7.v. (2R, 6S) -2- (tert-butyl-diphenyl-silanyloxymethyl) -6-((4RS) -2,2-dimethyl- [1,3] dioxolan-4-ylmethyl)- Dihydro-pyran-3-one:
To a solution of intermediate 7.iv (12 g, 24.75 mmol) in DCM (100 ml) was added a solution of Dess-Martin periodinane (15 wt% DCM solution, 50 ml). The mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with DCM (30 ml) and washed with saturated NaHCO ₃ (30 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was chromatographed (Hex-EA 3-1) to give the title compound (10.9 g, 91% yield) as a colorless oil. The compound was obtained as a 2-1 mixture of epimers.
¹ H NMR (CDCl ₃ ) δ: 7.72-7.61 (m, 4H); 7.46-7.38 (m, 6H); 4.55 (m, 1H); 4.32 (m, 1H); 4.13-3.90 (m, 7H); 3.59 (m, 1H); 2.65-2.59 (m, 2H); 2.2-2.05 (m, 1.33H); 1.91-1.71 (m, 2.66H); 1.42 (s, 3H); 1.38 (s, 2H); 1.36 (s, 1H); 1.05 (s, 9H).

7.vi. (2S, 3RS, 6S) -Benzyl- [2- (tert-butyl-diphenyl-silanyloxymethyl) -6-((4RS) 2,2-dimethyl- [1,3] dioxolane-4 -Ilmethyl) -tetrahydro-pyran-3-yl] -amine:
To a solution of intermediate 7.v (10.9 g, 22.58 mmol) in 1,2-DCE (60 ml) was added benzylamine (2.5 ml, 1 eq) and sodium triacetoxyborohydride (6.7 g, 1.4 eq). The mixture was stirred overnight at room temperature. Saturated NaHCO ₃ (200 ml) was added. The two layers were decanted and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was chromatographed on SiO ₂ (Hex-EA 3-1) to give the title compound (9.7 g, 74% yield) as a yellowish oil. The compound was obtained as a mixture of four isomers.
MS (ESI, m / z): 574.8 [M + H ^<+ >].

7.vii. (2S, 3RS, 6S) -2- (tert-butyl-diphenyl-silanyloxymethyl) -6-((4RS) 2,2-dimethyl- [1,3] dioxolan-4-ylmethyl) -Tetrahydro-pyran-3-ylamine:
To a solution of intermediate 7.vi (9.7 g, 16.9 mmol) in EtOH (190 ml) was added AcOH (1.1 ml) and 10% Pd / C (4 g). The reaction mixture was then stirred under a hydrogen atmosphere for 8 hours. The reaction mixture was filtered and the catalyst was washed with EtOH and water. After concentration, the residue was diluted with saturated NaHCO ₃ (100 ml) and then extracted with EA (2 × 250 mL). The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was chromatographed on SiO ₂ (DCM-MeOH 97-3 containing 1% aqueous NH ₄ OH) to give the title amine (5.5 g, 67% yield) as a colorless oil.
MS (ESI, m / z): 484.1 [M + H ^<+ >].

7.viii. (2S, 3R, 6S)-[2- (tert-butyl-diphenyl-silanyloxymethyl) -6-((4RS) -2,2-dimethyl- [1,3] dioxolane-4- Ylmethyl) -tetrahydro-pyran-3-yl] -carbamic acid tert-butyl ester:
To a solution of intermediate 7.vii (5.5 g, 11.37 mmol) in DCM (65 ml) was added Boc ₂ O (3.0 g, 1.2 eq) and TEA (3.2 mL, 2.0 eq). The reaction mixture was stirred at room temperature overnight. After concentration to dryness, the residue is chromatographed on SiO ₂ (Hex-Toluene-DCM-EA 13-3-1-3) to give the first (2S, 3S, 6S) -isomer as a 2-1 mixture of epimers (1.98 g, 29% yield), followed by the desired isomer (4.0 g, 60% yield) as a 2-1 mixture of epimers.
¹ H NMR (CDCl ₃ ) δ: 7.71-7.67 (m, 4H); 7.48-7.38 (m, 6H); 5.39 (d, J = 7.5 Hz, 1H); 4.18-3.43 (m, 8H); 2.12 ( m, 0.33H); 1.89-1.49 (m, 5.67H); 1.43 (s, 9H); 1.37 (s, 3H); 1.31 (s, 1H); 1.28 (s, 2H); 1.07 (s, 9H) .

7.ix. ((2S, 3R, 6S) -2- (tert-butyl-diphenyl-silanyloxymethyl) -6-((2RS) -2,3-dihydroxy-propyl) -tetrahydro-pyran-3- Yl] -carbamic acid tert-butyl ester:
A solution of intermediate 7.viii (4.0 g, 6.85 mmol) in AcOH (30 ml), water (10 ml) and THF (10 ml) was heated at 50 ° C. for 3 hours. The reaction mixture was concentrated to dryness and the residue was partitioned between saturated NaHCO ₃ (40 ml) and EA (100 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was chromatographed on SiO ₂ (Hex-EA 1-3) to give the title diol (3.38 g, 90% yield) as a colorless oil.
MS (ESI, m / z): 544.2 [M + H ^<+ >].

7.x. [(2S, 3R, 6S) -2- (tert-butyl-diphenyl-silanyloxymethyl) -6- (2-oxo-ethyl) -tetrahydro-pyran-3-yl] -carbamic acid tert -Butyl ester:
To a solution of intermediate 7.ix (1.5 g, 2.75 mmol) in acetone (30 ml) was added an aqueous solution (10 ml) of NaIO ₄ (1.5 g, 2.5 eq) at room temperature. The reaction was stirred for 40 minutes, the solid was filtered and the filtrate was concentrated in vacuo. The residue was partitioned between water (50 ml) and EA (100 ml). The aqueous layer was extracted once with EA (100 ml) and the combined extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was chromatographed on SiO ₂ (Hex-EA 2-1) to give the title aldehyde (1.3 g) as a colorless foam.
¹ H NMR (CDCl ₃ ) δ: 9.74 (t, J = 1.9 Hz, 1H); 7.69-7.66 (m, 4H); 7.49-7.39 (m, 6H); 5.45 (d, J = 6.75 Hz, 1H) ; 4.26 (m, 1H); 3.96-3.61 (m, 4H); 2.68 (m, 1H); 2.44 (ddd, J = 1.8, 5.4, 16.3 Hz, 1H); 1.92-1.78 (m, 3H); 1.44 (s, 9H); 1.43 (m, 1H); 1.07 (s, 9H).

7xi. {(2S, 3R, 6S) -2- (tert-butyl-diphenyl-silanyloxymethyl) -6-[(2RS) -2- (3-fluoro-6-methoxy-quinolin-4-yl) -2-Hydroxy-ethyl] -tetrahydro-pyran-3-yl} -carbamic acid tert-butyl ester:
N-BuLi (2.5N hexane solution, 2.5 ml) was added to a solution of DIPA (0.9 ml, 2.5 eq) in THF (17 ml) at -78 ° C. The mixture was warmed to 0 ° C. and stirred at this temperature for 5 minutes. After 15 minutes, the solution was cooled to −78 ° C. and 3-fluoro-6-methoxy-quinoline (prepared as described in WO 2005/049575; 1.12 g, 2.5 eq) THF. (5 ml) solution was added. The reaction proceeded for 4 hours. A solution of intermediate 7.x (1.3 g, 2.54 mmol) in THF (5 ml) was added dropwise and the reaction proceeded for 10 minutes before rapidly warming to room temperature. The reaction was further stirred for 20 minutes and quenched with 10% aqueous NaHSO ₄ (30 ml). The organic layer was diluted with EA (100 ml). The two layers were decanted and the aqueous layer was extracted twice with EA. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was chromatographed on SiO ₂ (Hex-EA 2-, then 1-1) to give the title compound (0.98 g, 56% yield) as a colorless foam. The compound was obtained as a 1-1 mixture of epimers.
MS (ESI, m / z): 689.0 [M + H ^<+ >].

7.xii. {(2S, 3R, 6S) -6-[(2RS) -2- (3-Fluoro-6-methoxy-quinolin-4-yl) -2-hydroxy-ethyl] -2-hydroxymethyl- Tetrahydro-pyran-3-yl} -carbamic acid tert-butyl ester:
To a solution of intermediate 7.xi (0.98 g, 1.42 mmol) in THF (5 ml) was added TBAF (1M THF solution, 2.2 ml). The reaction proceeded for 1 hour at room temperature. After concentration to dryness, the residue was chromatographed on SiO ₂ (EA-Hex3-1) to give the title compound (0.57 g, 89% yield) as a colorless foam. The compound was obtained as a 1-1 mixture of isomers.
MS (ESI, m / z): 451.0 [M + H ^<+ >].

7.xiii. (1RS) -2-((2S, 5R, 6S) -5-amino-6-hydroxymethyl-tetrahydro-pyran-2-yl) -1- (3-fluoro-6-methoxy-quinoline- 4-yl) -ethanol:
To a solution of intermediate 7.xii (0.57 g, 1.26 mmol) in dioxane (3 ml) was added a solution of HCl in dioxane (5N, 3 ml). The mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo and the residue was dissolved in water (5 ml). The pH was adjusted to 7 with the addition of K ₂ CO ₃ . Water was evaporated and the residue was chromatographed on SiO ₂ (DCM-MeOH 6-1 1% aqueous NH ₄ OH) to give the title amine (0.4 g, 90% yield) as a colorless foam. The compound was obtained as a 1-1 mixture of isomers.
MS (ESI, m / z): 351.0 [M + H ^<+ >].

7.xiv. (1RS) -2-{(2S, 5R, 6S) -5- [trans-3- (2,5-difluoro-phenyl) -allylamino] -6-hydroxymethyl-tetrahydro-pyran-2- Yl} -1- (3-fluoro-6-methoxy-quinolin-4-yl) -ethanol:
Starting from intermediate 7.xiii (0.1 g, 0.285 mmol) and (E) -3- (2,5-difluoro-phenyl) -propenal (0.053 g, 1.1 eq), the title compound (0.135 g, 94% Yield) was obtained as a colorless foam using the procedure of Example 1, Step 1.x. The compound was purified by chromatography on SiO ₂ (DCM-MeOH 93-7 containing 1% aqueous NH ₄ OH). The compound was obtained as a mixture of 1-1 isomers.
MS (ESI, m / z): 503.2 [M + H ^<+ >].

Example 8: 2-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy- [1, 5] Naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamido dihydrochloride:
8.i. [(E) -3- (2,5-Difluoro-phenyl) -allyl]-{(2R, 3R, 6R) -2-hydroxycarbamoylmethyl-6- [2- (6-methoxy- [ 1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-3-yl} -carbamic acid tert-butyl ester and {(2R, 3R, 6R) -2-carbamoylmethyl-6- [2- ( 6-Methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-3-yl}-[(E) -3- (2,5-difluoro-phenyl) -allyl] -carbamic acid tert-butyl ester:
To a solution of intermediate 5.v (0.11 g, 0.19 mmol) in DMF (2.3 ml) was added DIPEA (0.16 ml, 0.93 mmol) and HATU (0.11 g, 0.28 mmol). The resulting solution was stirred at room temperature for 30 minutes. Hydroxylamine hydrochloride (0.019 g, 0.28 mmol) was added. After stirring at room temperature overnight, hydroxylamine hydrochloride (0.019 g, 0.28 mmol) was added and the reaction was further stirred at room temperature for 24 hours. The reaction mixture was concentrated to dryness. The residue was partitioned between water and DCM-MeOH 9-1 and the phases separated. The aqueous layer was extracted 5 times with DCM-MeOH. The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on SiO ₂ (DCM-MeOH 9-1 containing 1% aqueous NH ₄ OH) to give the title amide as a yellow oil (0.032 g, 29% yield) and then the title hydroxamic acid ( 0.045 g, 40% yield).
Amide: MS (ESI, m / z): 597.0 [M + H ⁺ ].
Hydroxamic acid: MS (ESI, m / z): 613.0 [M + H ⁺ ].

8.ii. 2-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy- [1, 5] Naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamido dihydrochloride:
{(2R, 3R, 6R) -2-carbamoylmethyl-6- [2- (6-methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-3-yl}-[( Starting from E) -3- (2,5-difluoro-phenyl) -allyl] -carbamic acid tert-butyl ester (0.030 g, 0.049 mmol), the title compound (0.017 g, 60% yield) was carried out. Obtained as a yellow solid using the procedure of Example 4, Step 4.vi. The compound was purified by trituration with ether.
MS (ESI, m / z): 497.0 [M + H ^<+ >].

Example 9: 2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(1R, 2R) -1,2- Dihydroxy-2- (3-methoxy-quinoxalin-5-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamide:
9.i. {(2R, 3R, 6S) -2-((4RS) -2,2-dimethyl- [1,3] dioxolan-4-ylmethyl) -6- [2- (3-methoxy-quinoxaline- 5-yl) -vinyl] -tetrahydro-pyran-3-yl} -carbamic acid tert-butyl ester:
The Julia coupling was performed as in Example 1, step 1.vi from intermediate 1.v (9.67 g, 18 mmol) and 3-methoxy-quinoxaline-5-carbaldehyde (see preparation D; 3.38 g). Initiated to give the title compound as a yellowish foam (3.72 g, 41% yield). The compound was purified by column chromatography on SiO ₂ (EA-Hex1-1). The compound was obtained as a 2-1 mixture of epimers.
MS (ESI, m / z): 500.1 [M + H ^<+ >].

9.ii. {(2R, 3R, 6S) -2-((2RS) -2,3-dihydroxy-propyl) -6-[(E) -2- (3-methoxy-quinoxalin-5-yl)- Vinyl] -tetrahydro-pyran-3-yl} -carbamic acid tert-butyl ester:
A solution of intermediate 9.i (3.72 g) in AcOH (60 ml), water (20 ml) and THF (20 ml) was heated at 60 ° C. for 5 hours. The reaction mixture was concentrated to dryness and the residue was partitioned between EA (200 ml) and saturated NaHCO ₃ (200 ml). The pH of the aqueous layer was adjusted to 8 by adding 1M NaOH aqueous solution. The precipitate was then extracted twice with EA (2 × 150 ml). The combined extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was chromatographed on SiO ₂ (EA-Hept 4-1) to give the title compound (2.45 g) as a colorless foam. The compound was obtained as a 2-1 mixture of epimers.
MS (ESI, m / z): 460.1.1 [M + H ^<+ >].

9.iii. {(2R, 3R, 6S) -3-tert-butoxycarbonylamino-6-[(E) -2- (3-methoxy-quinoxalin-5-yl) -vinyl] -tetrahydro-pyran-2 -Il} -acetic acid:
Starting from intermediate 9.ii (2.45 g, 5.3 mmol), the title acid (0.65 g, 1.46 mmol) was purified using the procedure of Example 2, Steps 2.v and 2.vi. Obtained as a foam. The compound was purified by chromatography on SiO ₂ using EA-Hex1-2 as eluent.
MS (ESI, m / z): 443.8 [M + H ^<+ >].

9.iv. {(2R, 3R, 6S) -2-carbamoylmethyl-6-[(E) -2- (3-methoxy-quinoxalin-5-yl) -vinyl] -tetrahydro-pyran-3-yl} -Carbamic acid tert-butyl ester:
To a solution of intermediate 9.iii (0.65 g, 1.46 mmol) in THF (10 ml) at 0 ° C. was added TEA (0.265 ml) and i-butyl chloroformate (0.24 g). The reaction was stirred at this temperature for 1 h, then aqueous NH ₄ OH (3 ml) was added. The reaction was stirred vigorously for 30 minutes. EA (50 ml) was added. The two layers were decanted and the aqueous layer was extracted once with EA (50 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was triturated (Hex) to give the title amide (0.47 g) as a solid light beige in 75% purity.
MS (ESI, m / z): 442.8 [M + H ^<+ >].

9.v. {2R, 3R, 6S) -2-carbamoylmethyl-6-[(1R, 2R) -1,2-dihydroxy-2- (3-methoxy-quinoxalin-5-yl) -ethyl] -tetrahydro -Pyran-3-yl} -carbamic acid tert-butyl ester:
Asymmetric dihydroxylation of intermediate 9.iv (0.47 g, 1.05 mmol) was performed using the procedure of Example 6, Step 6.i and the title diol (0.19 g, 38% yield) as a colorless foam. ) The compound was purified by chromatography on SiO ₂ using DCM-MeOH 9-1 as eluent.
¹ H NMR (d ₆ -DMSO) δ: 8.60 (s, 1H); 7.91-7.87 (m, 2H); 7.63 (dd, J = 7.3, 8.2 Hz, 1H); 7.39 (br s, 1H); 6.89 (br s, 1H); 6.82 (d, J = 8.8 Hz, 1H); 5.62 (d, J = 7.2 Hz, 1H); 5.11 (d, J = 7.2 Hz, 1H); 4.35 (d, J = 3.7 4.06 (m, 1H); 4.03 (overlapped s, 3H); 4.02-3.92 (m, 2H); 3.57 (m, 1H); 2.39 (dd, J = 10.4, 15.9 Hz, 1H); 2.10-2.04 (m, 2H); 1.85 (m, 1H); 1.68-1.57 (m, 2H); 1.40 (s, 9H).
MS (ESI, m / z): 477.0 [M + H ^<+ >].

9.vi. 2- {2R, 3R, 6S) -3-Amino-6-[(1R, 2R) -1,2-dihydroxy-2- (3-methoxy-quinoxalin-5-yl) -ethyl] tetrahydro -Pyran-2-yl} -acetamide:
The title amine (0.071 g, 47% yield) was obtained as a colorless foam starting from intermediate 9.v (0.19 g, 0.4 mmol) and using the procedure of Example 1, Step 1.ix. As obtained.
MS (ESI, m / z): 377.2 [M + H ^<+ >].

9.vii. 2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(1R, 2R) -1,2- Dihydroxy-2- (3-methoxy-quinoxalin-5-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamide:
Starting from intermediate 9.vi (0.071 g, 0.285 mmol) and (E) -3- (2,5-difluoro-phenyl) -propenal (0.031 g, 1.1 eq), Example 1, Step 1.x The title compound (0.020 g, 20% yield and 75% purity) was obtained as a colorless foam following the procedure described in. The compound was purified by chromatography on SiO ₂ (DCM-MeOH 9-1 containing 1% aqueous NH ₄ OH).
MS (ESI, m / z): 528.7 [M + H ^<+ >].

Example 10: {(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy-quinolin-4-yl ) -Ethyl] -tetrahydro-pyran-2-yl} -acetic acid dihydrochloride:
10.i. {(2R, 3R, 6R) -3- {tert-butoxycarbonyl-[(E) -3- (2,5-difluoro-phenyl) -allyl] -amino} -6- [2- ( 6-methoxy-quinolin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetic acid:
Starting from intermediate 1.v (5.68 g, 10.57 mmol) and 6-methoxy-4-quinoline-carbaldehyde (1.8 g, 9.6 mmol), the title compound (1.48 g, 2.41 mmol) was run continuously. Example 1 Step 1.vi (Julia coupling, 46% yield), Example 2, Step 2.ii (hydrogenation, 96% yield) and 2.iii (acetonide and Boc deprotection, 99% State ), Example 1, Step 1.x (reductive amination, 78% yield), Example 4, Step 4.iii (Boc formation, 68% yield) and Example 2, Step 2.v (periodic) Using a procedure of cleavage, 95% yield) and 2.vi (acid production, 99% yield), obtained as a colorless foam.
MS (ESI, m / z): 581.1 [M + H ^<+ >].

10.ii. {(2R, 3R, 6R) -3-[(E) -3- (2,5-Difluoro-phenyl) -allylamino] -6- [2- (6-methoxy-quinolin-4-yl ) -Ethyl] -tetrahydro-pyran-2-yl} -acetic acid dihydrochloride:
Starting from intermediate 10.i (0.283 g, 0.475 mmol), the title acid (0.267 g, 96% yield) was prepared using the procedure of Example 4, step 4.vi. As obtained. The compound was purified by trituration with ether.
MS (ESI, m / z): 497.0 [M + H ^<+ >].

Example 11: 2-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy-quinoline-4 -Yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamide dihydrochloride:
11.i. {(2R, 3R, 6R) -2-carbamoylmethyl-6- [2- (6-methoxy-quinolin-4-yl) -ethyl] -tetrahydro-pyran-3-yl}-[(E ) -3- (2,5-Difluoro-phenyl) -allyl] -carbamic acid tert-butyl ester:
Starting from intermediate 10.i (1.15 g, 1.93 mmol), the title acetamide (0.506 g, 44% yield) was prepared using the procedure of Example 9, step 9.iv. As obtained. The compound was purified by chromatography on SiO ₂ using DCM-MeOH 19-1 containing 0.5% aqueous NH ₄ OH as eluent.
MS (ESI, m / z): 596.0 [M + H ^<+ >].

11.ii. 2-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy-quinoline-4 -Yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamide:
Starting from intermediate 11.i (0.045 g, 0.076 mmol), the title compound (0.034 g, 80% yield) was obtained as a yellowish solid using the procedure of Example 4, Step 4.vi. As obtained. The compound was purified by trituration with ether.
MS (ESI, m / z): 496.0 [M + H ^<+ >].

Example 12: 2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(S) -1-hydroxy-2- (6-Methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamide:
12.i. {(2R, 3R, 6S) -2-carbamoylmethyl-6-[(S) -1-hydroxy-2- (6-methoxy- [1,5] naphthyridin-4-yl) -ethyl] -Tetrahydro-pyran-3-yl}-[(E) -3- (2,5-difluoro-phenyl) -allyl] -carbamic acid tert-butyl ester:
To a solution of intermediate 6.vii (0.724 g) in THF (8 ml) at 0 ° C. was added TEA (0.427 ml) and i-butyl chloroformate (0.367 ml). The reaction was stirred at this temperature for 1 hour and then aqueous ammonia (2.5 ml) was added. The reaction was vigorously stirred for 45 minutes. EA (20 ml) was added. The two layers were decanted and the aqueous layer was extracted once with EA (10 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 column chromatography on SiO ₂ (DCM-MeOH 19-1, containing 0.5% aqueous NH ₄ OH, then 9-1 containing 1% aqueous NH ₄ OH) and off-white foam (0.485 g The title amide was obtained as
MS (ESI, m / z): 613.0 [M + H ^<+ >].

12.ii. 2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-Difluoro-phenyl) -allylamino] -6-[(S) -1-hydroxy-2- (6-Methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamide:
5N HCl in dioxane (0.346 ml) was added to a solution of intermediate 12.i (0.1 g) in dioxane (0.311 ml). After evaporation to dryness, finally the residue was purified SiO ₂ (DCM-MeOH 19-1 containing 1% aqueous NH ₄ OH, then 9-1 containing 1% aqueous NH ₄ OH) by column chromatography on, The title compound was obtained as an off-white foam (0.032 g).
Rf = 0.33 in DCM-MeOH 9-1 containing 1% aqueous NH ₄ OH.
MS (ESI, m / z): 513.0 [M + H ^<+ >].

Example 13: 3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2RS) 2- (3-fluoro-6-methoxy-quinolin-4-yl) -2-hydroxy-ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide:
Using the procedure of Example 2, step 2.iv, starting from intermediate 7.xiii (0.100 g, 0.29 mmol) and (E) -3- (2,5-difluoro-phenyl) -acrylic acid The title amide (0.123 g, 83% yield) was obtained as a yellow foam. The compound was purified by chromatography on SiO ₂ (DCM-MeOH 19-1 containing 1% aqueous NH ₄ OH) and obtained as a 1-1 mixture of epimers.
Rf = 0.41 (DCM-MeOH 9-1 with 1% aqueous NH ₄ OH).
MS (ESI, m / z): 517.2 [M + H ^<+ >].

Example 14: 3-Oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2S, 3R, 6S) -6-[(2RS) 2- (3-Fluoro-6-methoxy-quinolin-4-yl) -2-hydroxy-ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl} -amide:
Intermediate 7.xiii (0.100 g, 0.29 mmol) and 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid (0.06 g, 1 equivalent) ) And using the procedure of Example 2, Step 2.iv, the title amide (0.072 g, 46% yield) was obtained as a solid beige. The compound was purified by chromatography on SiO ₂ (DCM-MeOH 19-1 containing 1% aqueous NH ₄ OH) and obtained as a 1-1 mixture of epimers.
Rf = 0.41 (DCM-MeOH 9-1 containing 1% aqueous NH ₄ OH).
¹ H NMR (d ₆ -DMSO) δ: 11.24 (s, 0.5H); 11.16 (s, 0.5H); 8.69 (d, J = 1.8 Hz, 0.5H); 8.68 (d, J = 1.8 Hz, 0.5 H); 8.32 (d, J = 8.9 Hz, 0.5H); 8.27 (d, J = 8.9 Hz, 0.5H); 7.98-7.90 (m, 3H); 7.62 (d, J = 4.4 Hz, 0.5H) 7.59 (d, J = 4.4 Hz, 0.5H); 7.40 (d, J = 2.2 Hz, 0.5H); 7.37 (d, J = 2.2 Hz, 0.5H); 5.79 (m, 1H); 5.62-5.50 (two overlapped m, 2 x 0.5H); 4.66 (t, J = 5.0 Hz, 0.5H); 4.61 (t, J = 5.5 Hz, 0.5H); 4.27 (m, 0.5H); 4.12-4.02 (m , 1H); 3.91 (s, 3H); 3.91 (overlapped m, 0.5H); 3.80 (m, 0.5H); 3.70-3.60 (m, 2.5H); 3.45-3.34 (m, 2H); 2.61 (m , 0.5H); 2.27 (m, 0.5H); 2.11 (m, 1H); 2.15-2.06 (m, 0.5H); 1.99-1.64 (m, 2.5H); 1.45-1.33 (m, 1H).
MS (ESI, m / z): 542.8 [M ⁺ ].

Example 15: -Oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2S, 3R, 6S) -6-[(2RS)- 2-Hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl} -amide:
15.i. 2- (tert-Butyl-diphenyl-silanyloxymethyl) -6-[(2RS) -2-hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl] -tetrahydro-pyran -3-yl} -carbamic acid tert-butyl ester:
To a solution of 5-bromo-3-methoxyquinoline (3.12 g) in THF (70 ml) was added n-BuLi (2.5N, 5.2 ml) cooled to -78 ° C. The mixture was stirred for 15 min at the same temperature and a solution of intermediate 7.x (1.6 g, 3.12 mmol) in THF (5 ml) was added rapidly. The reaction proceeded for 5 minutes before warming to room temperature. After 15 minutes, 10% aqueous NaHSO ₄ solution (100 ml) was added. The two layers were decanted and the aqueous layer was extracted with EA (100 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was chromatographed on SiO ₂ (hept-EA 3-1, then 1-1) to give the title compound (0.46 g) as a colorless foam. The compound was obtained as a 2-1 mixture of isomers.
MS (ESI, m / z): 671.0 [M + H ^<+ >].

15.ii. {(2S, 3R, 6S) -6-[(2RS) -2-hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl] -2-hydroxymethyl-tetrahydro-pyran- 3-yl} -carbamic acid tert-butyl ester:
This alcohol (0.26 g, 86% yield) was obtained from a colorless foam starting from intermediate 15.i (0.46 g, 0.68 mmol) and using the procedure of Example 7, step 7.xii. As obtained. The compound was purified by chromatography on SiO ₂ using EA as eluent. The compound was obtained as a 2-1 mixture of isomers.
MS (ESI, m / z): 432.9 [M ^<+ >].

15.iii. (2RS) -2-[(2S, 5R, 6S) -5-Amino-6-hydroxymethyl-tetrahydro-pyran-2-yl] -1- (3-methoxy-quinolin-5-yl) -ethanol:
This amine (0.15 g, 84% yield) was obtained from a colorless foam starting from intermediate 15.ii (0.23 g, 0.53 mmol) and using the procedure of Example 1, Step 1.ix. As obtained.
MS (ESI, m / z): 333.1 [M + H ^<+ >].

15.iv. 3-Oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2S, 3R, 6S) -6-[(2RS) -2-Hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl} -amide:
Intermediate 15.iii (0.05 g, 0.15 mmol) and 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid (0.032 g, 1 equivalent) ) And using the procedure of Example 2, Step 2.iv, the title amide (0.030 g, 38% yield) was obtained as an off-white solid. The compound was purified by chromatography on SiO ₂ (DCM-MeOH 9-1 containing 1% aqueous NH ₄ OH) to give a 2-1 mixture of epimers.
¹ H NMR (d ₆ -DMSO) δ: 11.24 (s, 0.34H); 11.18 (s, 0.66H); 8.66 (m, 1H); 8.34 (d, J = 9.0 Hz, 0.34H); 8.26 (d , J = 9.0 Hz, 0.66H); 7.99-7.94 (m, 1.66H); 7.74-7.69 (m, 1.34H); 7.71 (m, 1H); 7.63-7.55 (m, 2H); 5.48-5.35 ( m, 2H); 4.75 (t, J = 5.5 Hz, 0.34H); 4.67 (t, J = 5.1 Hz, 0.66H); 4.33 (m, 0.34H); 4.09 (m, 0.66H); 3.97 (s , 3 x 0.34H); 3.95 (s, 3 x 0.66H); 3.96 (overlapped m, 1H); 3.80 (m, 0.66H); 3.66-3.60 (m, 2H); 3.52 (m, 0.34H); 3.41 (t, J = 5.6Hz, 1H); 2.43-2.27 (two overlapped m, 1H); 2.03-1.83 (m, 3H); 1.69-1.59 (m, 2H); 1.51-1.41 (m, 1H).
MS (ESI, m / z): 525.6 [M + H ^<+ >].

Example 16: 3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2RS) -2-hydroxy-2- (3-methoxy-quinolin-5-yl ) -Ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide:
Starting from intermediate 15.iii (0.1 g, 0.3 mmol) and (E) -3- (2,5-difluoro-phenyl) -acrylic acid (0.055 g, 1 eq) and Example 2, step 2 Using the procedure of .iv, the title amide (0.095 g, 63% yield) was obtained as a colorless oil. The compound was purified by chromatography on SiO ₂ (DCM-MeOH 9-1 containing 1% aqueous NH ₄ OH) to give a 2-1 mixture of epimers.
MS (ESI, m / z): 498.9 [M + H ^<+ >].

Example 17: 2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (3-fluoro -6-Methoxy- [1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetamide:
17.i. {(2R, 3R, 6S) -2-((4RS) -2,2-Dimethyl- [1,3] dioxolan-4-ylmethyl) -6-[(E) -2- (3- Fluoro-6-methoxy- [1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-3-yl} -carbamic acid tert-butyl ester:
Starting from 3-fluoro-6-methoxy- [1,5] naphthyridine-4-carbaldehyde (see Preparation E; 3.17 g, 15.37 mmol) and intermediate 1.v (8.98 g, 16.71 mmol) Using the procedure of Example 1, Step 1.vi, the title alkene (4.02 g, 50% yield) was obtained as a pale yellow foam. The compound was purified by chromatography on SiO ₂ using Hept-EA 1-2 as the eluent. The compound was obtained as a 2-1 mixture of epimers.
MS (ESI, m / z): 500.4 [M + H ^<+ >].

17.ii. {2-Carbamoylmethyl-6- [2- (3-fluoro-6-methoxy- [1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-3-yl} -carbamic acid tert-butyl ester:
Starting from intermediate 17.i (3.85 g, 7.44 mmol), this amide (0.759 g, 1.65 mmol) was prepared according to Example 9, step 9.ii (deprotection, 80% yield), 9.iii Obtained as an off-white solid using procedures (aldehyde formation followed by oxidation, 93% and 62% yield, respectively) and 9.iv (amide formation, 51% yield).
¹ H NMR (d ₆ -DMSO) δ: 8.81 (d, J = 3.8 Hz, 1H); 8.29 (d, J = 9.0 Hz, 1H); 7.35 (br s, 1H); 7.28-7.20 (m, 3H ); 6.88 (br d, J = 8.4 Hz, 1H); 6.82 (br s, 1H); 4.52 (m, 1H); 4.33 (m, 1H); 4.05 (s, 3H); 3.66 (m, 1H) 2.58 (dd, J = 10.3, 14.8 Hz, 1H); 2.13-1.98 (m, 2H); 1.72-1.53 (m, 3H); 1.40 (s, 9H).
MS (ESI, m / z): 460.7 [M + H ^<+ >].

17.iii. 2-{(2R, 3R, 6S) -3-Amino-6- [2- (3-fluoro-6-methoxy- [1,5] naphthyridin-4-yl) -vinyl] -tetrahydro- Pyran-2-yl} -acetamide:
This amine (0.132 g, 65% yield) was obtained in solid beige starting from intermediate 17.ii (0.258 g, 0.56 mmol) and using the procedure of Example 1, Step 1.ix. As obtained.
MS (ESI, m / z): 361.0 [M + H ^<+ >].

17.iv. 2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) 2- (3-fluoro- 6-Methoxy- [1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetamide:
Starting from Intermediate 17.iii (0.126 g, 0.35 mmol) and (E) -3- (2,5-difluoro-phenyl) -propenal (0.065 g, 1.1 eq) and Example 1, Step 1. Using the x procedure, the title compound (0.060 g, 33% yield) was obtained as a white solid.
¹ H NMR (d ₆ -DMSO) δ: 8.82 (d, J = 2.1 Hz, 1H); 8.28 (d, J = 9.0 Hz, 1H); 7.49 (m, 1H); 7.35 (br s, 1H); 7.31-7.20 (m, 4H); 7.13 (m, 1H); 6.81 (br s, 1H); 6.62 (d, J = 16.0 Hz, 1H); 6.51 (td, J = 5.3, 16.0 Hz, 1H); 4.51-4.41 (m, 2H); 4.05 (s, 3H); 3.42-3.34 (m, 2H); 2.80 (m, 1H); 2.62 (dd, J = 9.7, 14.4 Hz, 1H); 2.35 (dd, J = 3.8, 14.4 Hz, 1H); 1.95-1.74 (m, 3H); 1.61-1.43 (m, 2H).
MS (ESI, m / z): 512.9 [M + H ^<+ >].

Example 18: (2S, 5R, 6R)-(5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- (2-hydroxy-ethyl))-tetrahydro-pyran- 2-Carboxylic acid (6-methoxy- [1,5] naphthyridin-4-yl) -amide:
18.i. (2S, 5R, 6R) -5-tert-Butoxycarbonylamino-6-[(4RS) 2,2-dimethyl- [1,3] dioxolan-4-ylmethyl] -tetrahydro-pyran-2- carboxylic acid:
Intermediate 1.ii (5 g, 14.48 mmol) in ice-cooled DCM (32 ml), MeCN (32 ml) and water (46 ml) in NaIO ₄ (14.6 g, 68.17 mmol) and RuCl ₃ (0.030 g, 0.15 mmol) Was added. The reaction mixture was stirred at the same temperature for 5 hours. The reaction mixture was diluted with EA (150 ml) and the solid was removed by filtration. MeOH (30 ml) was added and the resulting suspension was filtered. The filtrate was treated with 10% aqueous NaHSO ₃ solution (60 ml). The phases were separated and the aqueous layer was extracted 3 times with EA. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give a brown foam (quantitative). The compound was obtained as a 2-1 mixture of epimers.
MS (ESI, m / z): 360.1 [M + H ^<+ >].

18.ii. {(2S, 5R, 6R) -6-carbamoyl-2-[(4RS) -2,2-dimethyl- [1,3] dioxolan-4-ylmethyl] -tetrahydro-pyran-3-yl} -Carbamic acid tert-butyl ester:
Starting from intermediate 18.i (5.27 g, 14.6 mmol), the title amide (3.16 g, 60% yield) was obtained as a colorless foam using the procedure of Example 12, step 12.i. It was. The compound was purified by chromatography on SiO ₂ using EA-cyclohexane 4-1 as the eluent. The compound was obtained as a 2-1 mixture of epimers.
MS (ESI, m / z): 359.1 [M + H ^<+ >].

18.iii. {(2S, 5R, 6R) -2-[(4RS) -2,2-Dimethyl- [1,3] dioxolan-4-ylmethyl) -6- (6-methoxy- [1,5] Naphthyridin-4-ylcarbamoyl) -tetrahydro-pyran-3-yl] -carbamic acid tert-butyl ester:
Intermediate 18.ii (2.3 g, 6.42 mmol), rac-BINAP (0.288 g, 0.46 mmol), (dba) ₃ Pd ₂ .CHCl ₃ (0.120 g, 0.12 mmol) and cesium carbonate (2.56 g, 7.86 mmol) Dioxane (82 ml) was added to the mixture. The mixture was sonicated for 10 minutes, when trifluoro-methanesulfonic acid 6-methoxy- [1,5] naphthyridin-4-yl ester (as described in WO 03/064431). 2.10 g, 6.81 mmol) was partially added. The resulting mixture was heated at 100 ° C. for 4 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The residue was purified on SiO ₂ (DCM-MeOH 19-1) to give the title amide (3.27 g, 6.32 mmol) as a reddish foam. The compound was obtained as a 2-1 mixture of epimers.
MS (ESI, m / z): 477.0 [M + H ^<+ >].

18.iv. (2S, 5R, 6S) -5-Amino-6-[(2RS) -2,3-dihydroxy-propyl] -tetrahydro-pyran-2-carboxylic acid (6-methoxy- [1,5] Naphthyridin-4-yl) -amide:
Starting from intermediate 18.iii (2.72 g, 2.06 mmol), the title amine (1.27 g, 64% yield) was obtained as a reddish solid using the procedure of Example 1, Step 1.ix. Obtained. The compound was purified by chromatography on SiO ₂ using DCM-MeOH 6-1 with 1% aqueous NH ₄ OH as eluent. The compound was obtained as a 2-1 mixture of epimers.
¹ H NMR (d ₆ -DMSO) δ: 10.59 (s, 0.66H); 10.51 (s, 0.34H); 8.70 (d, J = 5.0 Hz, 1H); 8.45 (d, J = 5.0 Hz, 0.34H ); 8.39 (d, J = 5.0Hz, 0.66H); 8.28 (d, J = 9.0 Hz, 1H); 7.33 (d, J = 9.0 Hz, 1H); 4.50 (br s, 1H); 4.47 (dd , J = 4.3, 7.0 Hz, 0.34H); 4.31 (dd, J = 3.5, 9.0 Hz, 0.66H); 4.11 (m, 0.66H); 4.09 (s, 3 x 0.34H); 4.08 (s, 3 x 0.66H); 3.96 (m, 0.34H); 3.63 (m, 1H); 3.37-3.21 (m, 5H), 2.97 (m, 0.66H); 2.91 (m, 0.34H); 2.08 (m, 1H ); 1.96 (m, 0.66H); 1.82-1.42 (m, 4.34H).
MS (ESI, m / z): 377.0 [M + H ^<+ >].

18.v. (2S, 5R, 6R) -5-[(E) -3- (2,5-Difluoro-phenyl) -allylamino] -6-[(2RS) -2,3-dihydroxy-propyl]- Tetrahydro-pyran-2-carboxylic acid (6-methoxy- [1,5] naphthyridin-4-yl) -amide:
Starting from intermediate 18.iv (0.58 g, 1.55 mmol) and (E) -3- (2,5-difluoro-phenyl) -propenal (0.286 g, 1.1 eq), the title compound (0.393 g, 48% Yield) was obtained as a white solid using the procedure of Example 1, Step 1.x. The compound was purified by chromatography on SiO ₂ using DCM-MeOH 9-1 containing 1% aqueous NH ₄ OH as eluent. The compound was obtained as a 2-1 mixture of epimers.
¹ H NMR (d ₆ -DMSO) δ: 10.64 (s, 0.66H); 10.56 (s, 0.34H); 8.69 (d. J = 5.0 Hz, 1H); 8.42 (d, J = 5.0 Hz, 0.34H ); 8.37 (d, J = 5.0 Hz, 0.66H); 8.28 (d, J = 9.0 Hz, 1H); 7.49 (m, 1H); 7.32 (d, J = 9.0 Hz, 1H); 7.27 (m, 7.12 (m, 1H); 6.63 (d, J = 16.2 Hz, 1H); 6.49 (m, 1H); 4.52-4.42 (m, 3H); 4.26 (m, 1H); 4.06 (s, 3 4.04 (s, 3 x 0.66H); 3.65 (m, 1H); 3.44-3.24 (m, 4H); 2.81 (m, 1H); 2.12-1.41 (m, 7H).
MS (ESI, m / z): 529.0 [M + H ^<+ >].

18.vi. [(E) -3- (2,5-Difluoro-phenyl) -allyl]-{(2R, 3R, 6S) -2-[(2RS) -2,3-dihydroxy-propyl] -6 -(6-Methoxy- [1,5] naphthyridin-4-ylcarbamoyl) -tetrahydro-pyran-3-yl} -carbamic acid tert-butyl ester:
Starting from intermediate 18.v (0.351 g, 0.66 mmol), this diol (0.307 g, 73% yield) was obtained as a colorless foam using the procedure of Example 4, step 4.iii). Obtained. The compound was purified by chromatography on SiO ₂ using DCM containing 7.5% MeOH and recovered as a 2-1 mixture of epimers.
MS (ESI, m / z): 629.0 [M + H ^<+ >].

18.vii. [(E) -3- (2,5-Difluoro-phenyl) -allyl]-[(2R, 3R, 6S) -2- (2-hydroxy-ethyl) -6- (6-methoxy- [1,5] naphthyridin-4-ylcarbamoyl) -tetrahydro-pyran-3-yl] -carbamic acid tert-butyl ester:
To a solution of intermediate 18.vi (0.294 g, 0.47 mmol) in acetone (4 ml) was added an aqueous solution (0.9 ml) of NaIO ₄ (0.25 g, 1.17 mmol). The reaction was allowed to proceed for 1 hour. The solid was filtered and the filtrate was concentrated to dryness. The white remaining foam was taken up in MeOH (3 ml) and NaBH ₄ (0.042 g, 1.12 mmol) was partially added. The reaction was stirred at room temperature for 1 hour. Water was added and volatiles were evaporated under reduced pressure. DCM-MeOH was added and the phases were separated. The aqueous layer was extracted twice with DCM-MeOH 9-1 and the combined organic layers were dried over Na ₂ SO ₄ and evaporated under reduced pressure. After drying under HV, the title compound (0.272 g, 97% yield) was obtained as a yellow foam.
Rf = 0.30 in DCM-MeOH 19-1.
MS (ESI, m / z): 599.1 [M + H ^<+ >].

18.viii. (2S, 5R, 6R)-(5-[(E) -3- (2,5-Difluoro-phenyl) -allylamino] -6- (2-hydroxy-ethyl) -tetrahydro-pyran-2 -Carboxylic acid (6-methoxy- [1,5] naphthyridin-4-yl) -amide:
The title compound (0.271 g, 96% yield) was prepared off-white starting from intermediate 18.vii. (0.268 g, 0.45 mmol) and using the procedure of Example 2, Step 2.iii. Obtained as a foam.
¹ H NMR (d ₆ -DMSO) δ: 10.56 (s, 1H); 8.70 (d, J = 5.0 Hz, 1H); 8.39 (d, J = 5.0 Hz, 1H); 8.28 (d, J = 9.0 Hz , 1H); 7.48 (m, 1H); 7.32 (d, J = 9.0 Hz, 1H); 7.24 (m, 1H); 7.13 (m 1H); 6.65 (d, J = 16.1 Hz, 1H); 6.51 ( td, J = 5.6, 16.1 Hz, 1H); 4.40 (br s, 1H); 4.36 (m, 1H); 4.26 (m, 1H); 4.04 (s, 3H); 3.65-3.54 (m, 2H); 3.51-3.35 (m, 2H); 2.85 (m, 1H); 2.14 (m, 1H); 1.97 (m, 1H); 1.80-1.70 (m, 2H); 1.68-1.54 (m, 3H).
Example 19: (2S, 5R) -5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -tetrahydro-pyran-2-carboxylic acid (6-methoxy- [1,5] Naphthyridin-4-yl) -amide:
19.i. (3R, 6S)-(6-Carbamoyl-tetrahydro-pyran-3-yl) -carbamic acid tert-butyl ester:
(2S, 5R) -5-tert-Butoxycarbonylamino-tetrahydro-pyran-2-carboxylic acid (obtained as described in Eur. J. Org. Chem. (2003), 2418-2427; 3g) To a solution of EA (50 ml), NHS (1.5 g) and DCC (2.7 g) were added. The reaction was stirred overnight at room temperature. The solid was removed by filtration. The filtrate was concentrated in vacuo and the residue was taken up in THF (180 ml). NH ₃ was bubbled through the solution for 10 minutes and the resulting cloudy mixture was stirred at room temperature for 1 hour. SiO ₂ (20 g) was added to the mixture and volatiles were removed by rotary evaporation. The material was chromatographed on SiO ₂ (DCM-MeOH 19-1) to give the title compound (1.3 g) as a white solid.
MS (ESI, m / z): 245.3 [M + H ^<+ >].

19.ii. [(3R, 6S) -6- (6-Methoxy- [1,5] naphthyridin-4-ylcarbamoyl) -tetrahydro-pyran-3-yl] -carbamic acid tert-butyl ester:
Dioxane (41 ml) was added to a mixture of intermediate 19.i (0.8 g), cesium carbonate (1.3 g), rac-BINAP (0.145 g) and (dba) ₃ Pd ₂ .CHCl ₃ (0.057 g). The mixture was sonicated for 15 minutes and trifluoro-methanesulfonic acid 6-methoxy- [1,5] 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 on SiO ₂ (DCM-MeOH 19-1) to give the title amide (1.3 g) as a foam.
¹ H NMR (CDCl ₃ ) δ: 10.57 (s, 1H); 8.70 (d, J = 5.2 Hz, 1H); 8.51 (d, J = 5.2 Hz, 1H); 8.22 (d, J = 9.0 Hz, 1H ); 7.16 (d, J = 9.0 Hz, 1H); 4.32 (m, 2H); 4.12 (s, 3H); 4.01 (dd, J = 2.5, 11.4 Hz, 1H); 3.72 (m, 1H); 3.23 (t, J = 10.6 Hz, 1H); 2.39 (qd, J = 2.8, 10.2 Hz, 1H); 2.22 (m. 1H); 1.76 (m, 1H); 1.47 (overlapped m, 1H); 1.47 (s , 9H).
MS (ESI, m / z): 403.6 [M + H ^<+ >].

19.iii. (2S, 5R) -5-Amino-tetrahydro-pyran-2-carboxylic acid (6-methoxy- [1,5] naphthyridin-4-yl) -amide:
The title amine (0.5 g) was obtained as a white solid starting from intermediate 19.ii (1.3 g) and using the procedure of Example 1, Step 1.ix. The compound was purified by chromatography on SiO ₂ (DCM-MeOH 19-1 containing 1% concentrated aqueous NH ₄ OH).
MS (ESI, m / z): 303.2 [M + H ^<+ >].

19.iv. (2S, 5R) -5-[(E) -3- (2,5-Difluoro-phenyl) -allylamino] -tetrahydro-pyran-2-carboxylic acid (6-methoxy- [1,5] Naphthyridin-4-yl) -amide:
Starting from intermediate 19.iii (0.254 g, 0.84 mmol) and (E) -3- (2,5-difluoro-phenyl) -propenal (0.141 g, 1.0 eq), the title compound (0.12 g, 31% Yield) was obtained as a white solid using the procedure of Example 1, Step 1.x. The compound was purified by chromatography on SiO ₂ using DCM-MeOH 97-3 containing 0.5% aqueous NH ₄ OH as eluent.
¹ H NMR (d ₆ -DMSO) δ: 10.52 (s, 1H); 8.71 (d, J = 5.0 Hz, 1H); 8.38 (d, J = 5.0 Hz, 1H); 8.27 (d, J = 9.0 Hz , 1H); 7.48 (m, 1H); 7.32 (d, J = 9.0 Hz, 1H); 7.25 (m, 1H); 7.11 (m, 1H); 6.63 (d, J = 16.2 Hz, 1H); 6.50 (td, J = 5.3, 16.2 Hz, 1H); 4.21 (dd, J = 3.2, 10.7 Hz, 1H); 4.08 (dd, J = 2.1, 10.7 Hz, 1H); 4.02 (s, 3H); 3.48- 3.35 (m, 2H); 3.25 (t, J = 10.5 Hz, 1H); 2.69 (m, 1H); 2.18-2.14 (m, 2H); 1.99 (br s, 1H); 1.55 (m, 1H); 1.35 (m, 1H).
MS (ESI, m / z): 454.9 [M + H ^<+ >].

Example 20: (1S) -1-{(2S, 5R) -5-[(E) -3- (3-Fluoro-phenyl) -allylamino] -tetrahydro-pyran-2-yl} -2- (6 -Methoxy-quinolin-4-yl) -ethanol:
20.i. {(3R, 6S) -6- [2- (3-Methoxy-quinolin-5-yl) -vinyl] -tetrahydro-pyran-3-yl} -carbamic acid tert-butyl ester:
(3R, 6S)-[6- (1-Phenyl-1H-tetrazol-5-sulfonylmethyl) -tetrahydro-pyran-3-yl] -carbamic acid tert-butyl ester (see Preparation G; 15 g, 35.4 mmol) and 3-methoxy-quinoline-5-carbaldehyde (see Preparation F; 6.3 g, 33.7 mmol), the title alkene (9.9 g, 76% yield) was prepared in Example 1, step 1. Obtained as an unemployed solid using vi procedure. The compound was purified by trituration in a Hex-ether mixture.
¹ H NMR (CDCl ₃ ) δ: 8.72 (d, J = 4.5 Hz, 1H); 8.02 (d, J = 9.2 Hz, 1H); 7.36-7.25 (m, 3H); 7.26 (d, J = 15.8 Hz , 1H); 6.42 (dd, J = 5.2, 15.8 Hz, 1H); 4.27 (m, 1H); 4.08 (m, 1H); 3.98 (s, 3H); 3.74 (br s, 1H); 3.18 (t , J = 10.6 Hz, 1H); 2.22 (m, 1H); 1.98 (m, 1H); 1.75-1.60 (m, 2H); 1.48 (s, 9H), 1.47 (overlapped m, 1H).
MS (ESI, m / z): 385.3 [M + H ^<+ >].

20.ii. {(3R, 6S) -6-[(1S, 2S) -1,2-dihydroxy-2- (6-methoxy-quinolin-4-yl) -ethyl] -tetrahydro-pyran-3-yl } -Carbamate tert-butyl ester:
Starting from intermediate 20.i (9.9 g, 25.7 mmol), the title diol (10.5 g, 97% yield) is obtained as a colorless foam using the procedure of Example 6, step 6.i. It was. The compound was purified by chromatography on SiO ₂ using DCM-MeOH 9-1 as eluent.
¹ H NMR (d ₆ -DMSO) δ: 8.71 (d, J = 4.5 Hz, 1H); 7.93 (d, J = 9.0 Hz, 1H); 7.54 (d, J = 4.5 Hz, 1H); 7.44-7.38 (m, 2H); 6.851 (br s, 1H); 6.65 (d, J = 8.2 Hz, 1H); 5.43 (d, J = 5.4 Hz, 1H); 5.36 (m, 1H); 4.83 (d, J = 6.3 Hz, 1H); 3.89 (s, 3H); 3.79 (m, 1H); 3.56 (m, 1H); 3.37 (br s, 1H); 2.72 (t, J = 10.6 Hz, 1H); 1.85 ( m, 1H); 1.71-1.65 (m, 2H); 1.36 (s, 9H); 1.21 (m, 1H).

20.iii. (3R, 6S)-{6-[(4R, 5R) -5- (6-Methoxy-quinolin-4-yl) -2-oxo- [1,3] dioxolan-4-yl]- Tetrahydro-pyran-3-yl} -carbamic acid tert-butyl ester:
To an ice-cold DCM (130 ml) solution of intermediate 20.ii (10.2 g), pyridine (12 ml) and triphosgene (3.62 g) were added. The reaction was stirred at this temperature for 30 minutes and then at room temperature for 90 minutes. The reaction mixture was diluted with aqueous NaHCO ₃ and the two layers were decanted. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was chromatographed on SiO ₂ (DCM-MeOH 19-1) to give the title cyclic carbonate (10.5 g) as a colorless foam.
¹ H NMR (CDCl ₃ ) δ: 8.82 (d, J = 4.5 Hz, 1H); 8.10 (d, J = 9.3 Hz, 1H); 7.49-7.43 (m, 2H); 7.21 (br. S, 1H) 6.27 (d, J = 4.2 Hz, 1H); 4.61 (m, 1H); 4.28 (ddd, J = 2.0, 4.7, 10.6 Hz, 2H); 3.95 (s, 3H); 3.70 (m, 2H); 3.18 (t, J = 10.7 Hz, 1H); 2.27 (m, 1H); 1.84 (m, 2H); 1.46 (s, 9H); 1.45 (m overlapped, 1H).
MS (ESI, m / z): 445.0 [M + H ^<+ >].

20.iv. (3R, 6S)-{6-[(1S) -1-hydroxy-2- (6-methoxy-quinolin-4-yl) -ethyl] -tetrahydro-pyran-3-yl} -carbamic acid tert-butyl ester:
To a solution of intermediate 20.iii (2.75 g) in EA (250 ml) was added Pd / C (1.32 g) under argon. The resulting suspension was stirred under a hydrogen atmosphere. After 2.5 hours, more Pd / C (0.66 g) was added and the reaction was stirred overnight under a hydrogen atmosphere. The catalyst was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO ₂ (DCM-MeOH 19-1 containing 1% aqueous NH ₄ OH) to give the title compound as a white foam (1.23 g).
¹ H NMR (d ₆ -DMSO) δ: 8.62 (d, J = 4.4 Hz, 1H); 7.92 (d, J = 9.0 Hz, 1H); 7.42 (d, J = 2.5 Hz, 1H); 7.40 (dd , J = 2.7, 9.0 Hz, 1H); 7.33 (d, J = 4.4 Hz, 1H); 6.76 (br d, J = 8.0 Hz, 1H); 4.83 (d, J = 6.4 Hz, 1H); 3.91 ( s, 3H); 3.90 (overlapped m, 1H); 3.74 (m, 1H); 3.38 (br.s, 1H); 3.29 (overlapped dd, visible J = 3.8 Hz, 1H); 3.12 (d, J = 10.4 Hz, 1H); 2.98 (t, J = 10.3 Hz, 1H); 2.97 (m overlapped, 1H); 1.90 (d, J = 9.2 Hz, 1H); 1.60 (m, 2H); 1.39 (s, 9H) ; 1.38 (m overlapped, 1H).
MS (ESI, m / z): 403.0 [M + H ^<+ >].

20.v. (1S) -1-((2S, 5R)-(5-Amino-tetrahydro-pyran-2-yl) -2- (6-methoxy-quinolin-4-yl) -ethanol:
A solution of intermediate 20.iv (1.23 g) in TFA (15 ml) was stirred for 10 minutes. The solution was concentrated to dryness, basified with 2M aqueous NaOH, diluted with DCM-MeOH 9-1 and the phases separated. The aqueous layer was extracted 6 times with DCM-MeOH 9-1. The combined organic layers were dried over Na ₂ SO ₄ and filtered to give a white solid (0.768 g), concentrated to dryness.
¹ H NMR (DMSO) δ: 8.62 (d, J = 4.4 Hz, 1H); 7.92 (d, J = 9.1 Hz, 1H); 7.44 (d, J = 2.7 Hz, 1H); 7.39 (dd, J = 2.8, 9.1 Hz, 1H); 7.32 (d, J = 4.4 Hz, 1H); 4.79 (d, J = 6.3 Hz, 1H); 3.91 (s, 3H); 3.88 (ddd, J = 1.8, 4.4, 10.5 Hz, 1H); 3.73 (m, 1H); 3.31 (dd, J = 4.0, 13.6 Hz, 1H); 3.10 (dt, J = 3.4, 10.4 Hz, 1H); 2.93 (m overlapped, 1H); 2.87 ( t overlapped, J = 10.5 Hz, 1H); 2.61 (m, 1H); 1.92 (m, 1H); 1.56 (m, 2H); 1.39 (br s, 2H) 1.13 (m, 1H).
MS (ESI, m / z): 303.2 [M + H ^<+ >].

20.vi. (1S) -1-{(2S, 5R) -5-[(E) -3- (3-Fluoro-phenyl) -allylamino] -tetrahydro-pyran-2-yl} -2- (6 -Methoxy-quinolin-4-yl) -ethanol:
Starting from intermediate 20.v (0.1 g, 0.33 mmol) and (E) -3- (3-fluoro-phenyl) -propenal (0.050 g, 1.0 eq), the title compound (0.063 g, 43% yield) ) Was made as a white solid using the procedure of Example 1, Step 1.x. The compound was purified by chromatography on SiO ₂ using DCM-MeOH 97-3 containing 0.5% aqueous NH ₄ OH as eluent.
MS (ESI, m / z): 437.0 [M + H ^<+ >].

Example 21: 7-Fluoro-6-({(3R, 6S) -6-[(1S) -1-hydroxy-2- (6-methoxy-quinolin-4-yl) -ethyl] -tetrahydro-pyran -3-ylamino} -methyl) -4H-benzo [1,4] thiazin-3-one:
Intermediate 20.v (0.051 g, 0.17 mmol) and 7-fluoro-3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-6-carbaldehyde (in WO 02/056882) Starting from 0.036 g, 1.0 eq) obtained as described, the title compound (0.020 g, 23% yield) was obtained as a white solid using the procedure of Example 1, Step 1.x. As obtained. The compound was purified by chromatography on SiO ₂ using DCM-MeOH 19-1 containing 0.5% aqueous NH ₄ OH as eluent.
¹ H NMR (d ₆ -DMSO) δ: 10.55 (s, 1H); 8.62 (d, J = 4.4 Hz, 1H); 7.91 (d, J = 9.0 Hz, 1H); 7.42-7.40 (m, 2H) 7.32 (d, J = 4.4 Hz, 1H); 7.20 (d, J = 9.0 Hz, 1H); 7.09 (d, J = 6.8 Hz, 1H); 4.79 (d, J = 6.3 Hz, 1H); 4.04 (m, 1H); 3.90 (s, 3H); 3.77-3.71 (m, 3H); 3.46 (s, 2H); 3.30 (dd, J = 3.8, 13.1 Hz, 1H); 3.15 (m, 1H); 3.00-2.90 (m, 2H); 2.50 (overlapped m, 1H); 2.09-1.99 (m, 2H); 1.66-1.51 (m, 2H); 1.18 (m, 1H).
MS (ESI, m / z): 498.1 [M + H ^<+ >].

Example 22: 3- (2-Fluoro-phenyl) -N-{(3R, 6S) -6-[(1S) -1-hydroxy-2- (6-methoxy-quinolin-4-yl) -ethyl] -Tetrahydro-pyran-3-yl}-(E) -acrylamide:
Starting from intermediate 20.v (0.1 g, 0.33 mmol) and (E) -3- (2-fluoro-phenyl) -acrylic acid (0.055 g, 1.0 eq), the title compound (0.085 g, 57% yield) was obtained. Was obtained as a white solid using the procedure of Example 2, Step 2.iv. The compound was purified by chromatography on SiO ₂ using DCM-MeOH 97-3 containing 0.5% aqueous NH ₄ OH as eluent.
¹ H NMR (d ₆ -DMSO) δ: 8.63 (d, J = 4.2 Hz, 1H); 8.13 (d, J = 7.2 Hz, 1H); 7.95 (d, J = 9.0 Hz, 1H); 7.64 (t , J = 7.2 Hz, 1H); 7.62-7.19 (m, 7H); 6.70 (d, J = 15.8 Hz, 1H); 4.87 (d, J = 6.4 Hz, 1H); 4.02 (m, 1H); 3.92 (s, 3H); 3.92-3.78 (m, 2H); 3.35 (m, 1H); 3.21 (m, 1H); 3.08-2.93 (m, 2H); 1.98 (m, 1H); 1.80-1.60 (m , 2H); 1.43 (m, 1H).

Example 23: 3- (3-Fluoro-phenyl) -N-{(3R, 6S) -6-[(1S) -1-hydroxy-2- (6-methoxy-quinolin-4-yl) -ethyl] -Tetrahydro-pyran-3-yl}-(E) -acrylamide:
Starting from intermediate 20.v (0.1 g, 0.33 mmol) and (E) -3- (3-fluoro-phenyl) -acrylic acid (0.055 g, 1.0 eq), the title compound (0.030 g, 20% yield) Was obtained as a white solid using the procedure of Example 2, Step 2.iv. The compound was purified by chromatography on SiO ₂ using DCM-MeOH 97-3 containing 0.5% aqueous NH ₄ OH as eluent.
¹ H NMR (d ₆ -DMSO) δ: 8.63 (d, J = 4.2 Hz, 1H); 8.05 (d, J = 7.8 Hz, 1H); 7.92 (d, J = 9.0 Hz, 1H); 7.56-7.25 (m, 7H); 7.19 (m, 1H); 6.62 (d, J = 15.8 Hz, 1H); 4.87 (d, J = 6.5 Hz, 1H); 4.02 (m, 1H); 3.92 (s, 3H) ; 3.92-3.78 (m, 2H); 3.35 (m, 1H); 3.21 (m, 1H); 3.08-2.93 (m, 2H); 2.01 (m, 1H); 1.80-1.60 (m, 2H); 1.43 (m, 1H).

Example 24: 8-((1R, 2R) -2-{(2S, 5R) -5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -tetrahydro-pyran-2- Yl} -1,2-dihydroxy-ethyl) -quinoline-2-carbonitrile:
24.i. (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., a solution of DMSO (3.5 ml) in DCM (25 ml) was added dropwise. After stirring for 15 minutes, (3R, 6S)-(6-hydroxymethyl-tetrahydro-pyran-3-yl) -carbamic acid tert-butyl ester (described in Eur. J. Org. Chem. (2003), 2418-2427) (Prepared as described) in DCM (25 ml) was added dropwise. The reaction mixture was stirred for 1 h and a solution of TEA (15 ml) in DCM (15 ml) was added dropwise. The reaction is allowed to proceed for 1 hour and warmed to 0 ° C. Saturated NaHCO ₃ (50 ml) was added. The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on SiO ₂ (Hex-EA 1-2) to give the title aldehyde (2.5 g) as an unemployed solid.

24.ii. (3R, 6S)-(6-Ethynyl-tetrahydro-pyran-3-yl) -carbamic acid tert-butyl ester:
To a solution of p-toluenesulfonyl azide (3.08 g) in MeCN (200 ml) was added K ₂ CO ₃ (5.38 g) and dimethyl-2-oxophosphonate (2.13 ml). The mixture was stirred at room temperature for 2 hours and a solution of intermediate 24.i (2.5 g) in MeOH (30 ml) was added. After the mixture was stirred at room temperature overnight and concentrated to dryness, the residue was partitioned between water (50 ml) and EA (100 ml). The aqueous layer was extracted with EA (2 × 100 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was filtered through SiO ₂ (EA-Hex1-3) to give the title alkyne (1.9 g) as a white solid.
¹ H NMR (CDCl ₃ ) δ: 4.78 (m, 1H); 4.39 (m, 1H); 4.14 (dd, J = 3.0, 11.4 Hz, 1H); 3.71 (m, 1H); 3.34 (m, 1H) 2.50 (d, J = 2.2 Hz, 1H); 2.11-1.99 (m, 2H); 1.73 (m, 1H); 1.60 (m, 1H); 1.46 (s, 9H).
MS (ESI, m / z): 226.2 [M + H ^<+ >].

24.iii. Cis, trans-[(3R, 6S) -6- (2-Tributylstannanyl-vinyl) -tetrahydro-pyran-3-yl] -carbamic acid tert-butyl ester:
To a solution of intermediate 24.ii (1.95 g, 8.65 mmol) in THF (26 ml) is added bis (triphenylphosphine) palladium dichloride (0.12 g, 0.17 mmol) and then tributyltin hydride (2.75 ml, 10.38 mmol) did. The mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated to dryness and the residue was chromatographed on SiO ₂ (Hex, then Hex-EA 9-1) to give the title stannane (3.4 g) as an equimolar mixture of cis and trans isomers. .

24.iv. trans-{(3R, 6S) -6- [2- (6-Methoxy- [1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-3-yl} -carbamic acid tert -Butyl ester:
To a solution of intermediate 24.iii (5 g) in dioxane (freshly distilled, 50 ml) was added trifluoromethanesulfonic acid 2-cyano-quinolin-8-yl ester (2.0 g, 6.6 mmol), LiCl (0.936 g), 2 , 6-Di-tert-butyl-4-methylphenol (few seeds), (PPh ₃ ) ₄ Pd (0.153 g) was added. The mixture was heated at 100 ° C. overnight. After cooling, the solid was filtered and the filtrate was concentrated to dryness. The residue was chromatographed on SiO ₂ (Hex-EA 1-1) to give the title alkene (1.80 g, 71% yield) as a white solid.
¹ H NMR (d ₆ -DMSO) δ: 8.72 (d, J = 4.7 Hz, 1H); 8.25 (d, J = 9.0 Hz, 1H); 7.84 (d, J = 4.7 Hz, 1H); 7.55 (d , J = 16.5 Hz, 1H); 7.28 (d, J = 9.0 Hz, 1H); 6.93 (dd, J = 5.3 Hz, 16.5 Hz, 1H); 6.85 (d, J = 7.7 Hz, 1H); 4.04 ( s, 3H); 4.01 (partially overlapped m, 1H); 3.90 (m, 1H); 3.39 (br s, 1H); 3.10 (t, J = 10.6 Hz, 1H); 1.89 (m, 2H); 1.50 ( m, 2H); 1.39 (s, 9H).
MS (ESI, m / z): 386.1 [M + H ^<+ >].

24.v. (3R, 6S)-{6-[(1R, 2R) -2- (cyano-quinolin-8-yl) -1,2-dihydroxy-ethyl] -tetrahydro-pyran-3-yl}- Carbamic acid tert-butyl ester:
The title diol (1.60 g, 81% yield) was obtained as a white solid starting from intermediate 24.iv (1.80 g, 4.74 mmol) and using the procedure of Example 6, step 6.i. It was.
MS (ESI, m / z): 419.2 [M + H ^<+ >].

24.vi. 8-[(1R, 2R) -2-((2S, 5R) -5-Amino-tetrahydro-pyran-2-yl) -1,2-dihydroxy-ethyl] -quinoline-2-carbonitrile :
The title amine (0.62 g, 74% yield) was obtained starting from intermediate 24.v (1.1 g, 2.61 mmol) and using the procedure of Example 1, Step 1.ix. As obtained.
MS (ESI, m / z): 314.2 [M + H ^<+ >].

24.vii. 8-((1R, 2R) -2-{(2S, 5R) -5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -tetrahydro-pyran-2- Yl} -1,2-dihydroxy-ethyl) -quinoline-2-carbonitrile:
Starting from intermediate 24.vi (0.158 g, 0.5 mmol) and (E) -3- (2,5-difluoro-phenyl) -propenal (0.084 g, 1.0 equiv), the title compound (0.04 g, 17% Yield) was obtained as a white solid according to the procedure of Example 1, Step 1.x. The compound was purified by chromatography on SiO ₂ using DCM-MeOH 19-1 containing 0.5% aqueous NH ₄ OH as eluent.
¹ H NMR (d ₆ -DMSO) δ: 8.65 (d, J = 8.5 Hz, 1H); 8.07-7.99 (m, 3H); 7.80 (dd, J = 7.2, 8.3 Hz, 1H); 7.49 (m, 7.25 (m, 1H); 7.13 (m, 1H); 6.61 (d, J = 16.4 Hz, 1H); 6.48 (td, J = 5.4, 16.4 Hz, 1H); 5.77 (dd, J = 2.9 , 6.3 Hz, 1H); 5.16 (d, J = 7.6 Hz, 1H); 4.35 (d, J = 6.3 Hz, 1H); 3.91 (m, 1H); 3.60 (m, 1H); 3.42-3.32 (m , 2H), 3.24 (m, 1H); 2.81 (t, J = 10.3 Hz, 1H); 2.56 (overlapped m, 1H); 2.11 (m, 1H); 1.90 (m, 1H); 1.76 (br s, 1H); 1.56 (m, 1H); 1.24 (m, 1H).
MS (ESI, m / z): 465.6 [M + H ^<+ >].

Example 25: [(E) -3- (2,5-difluoro-phenyl) -allyl]-{3R, 6S) -6-[(E) -2- (3-fluoro-6-methoxy-quinoline- 5-yl) -vinyl] -tetrahydro-pyran-3-yl} -amine:
25.i. {(3R, 6S) -6-[(E) -2- (3-Fluoro-6-methoxy-quinolin-5-yl) -vinyl] -tetrahydro-pyran-3-yl} -carbamic acid tert-butyl ester:
(3R, 6S)-[6- (1-Phenyl-1H-tetrazol-5-sulfonylmethyl) -tetrahydro-pyran-3-yl] -carbamic acid tert-butyl ester (described in Preparation G; 1.43 g, 3.4 mmol) and 3-fluoro-6-methoxy-quinoline-5-carbaldehyde (0.462 g, 2.25 mmol), the title alkene (0.85 g, 62% yield) was prepared according to Example 1, Step 1.vi. Was obtained as a white solid using The compound was purified by chromatography on SiO ₂ using EA-Hex1-1as eluent.
¹ H NMR (d ₆ -DMSO) δ: 8.90 (d, J = 2.7 Hz, 1H); 8.32 (dd, J = 3.0, 11.4 Hz, 1H); 8.12 (d, J = 9.3 Hz, 1H); 7.78 (d, J = 9.3 Hz, 1H); 7.99 (d, J = 16.2 Hz, 1H); 6.93 (d, J = 8.1 Hz, 1H); 6.35 (dd, J = 5.7, 16.2 Hz, 1H); 4.12 -3.99 (m, 2H); 4.10 (s, 3H); 3.50 (br s, 1H); 3.21 (t, J = 10.5 Hz, 1H); 2.03-2.00 (m, 2H); 1.62 (m, 1H) 1.49 (m, 1H); 1.49 (s, 9H).

25.ii. 6-[(3R, 6S)-(E) -2- (3-Fluoro-6-methoxy-quinolin-5-yl) -vinyl] -tetrahydro-pyran-3-ylamine:
The title amine (0.16 g, 71% yield) was obtained as a white solid starting from intermediate 25.i (0.3 g, 0.745 mmol) and using the procedure of Example 1, Step 1.ix. Obtained. The compound was purified by chromatography on SiO ₂ using DCM-MeOH 9-1 containing 1% aqueous NH ₄ OH as eluent.
MS (ESI, m / z): 465.6 [M + H ^<+ >].

25.iii. [(E) -3- (2,5-Difluoro-phenyl) -allyl]-{3R, 6S) -6-[(E) -2- (3-Fluoro-6-methoxy-quinoline- 5-yl) -vinyl] -tetrahydro-pyran-3-yl} -amine:
Starting from intermediate 25.ii (0.1 g, 0.33 mmol) and (E) -3- (2,5-difluoro-phenyl) -propenal (0.055 g, 1.0 eq), the title compound (0.034 g, 22% Yield) was obtained as a colorless oil using the procedure of Example 1, Step 1.x. The compound was purified by chromatography on SiO ₂ using DCM-MeOH 19-1 containing 0.5% aqueous NH ₄ OH as eluent.
MS (ESI, m / z): 455.0 [M + H ^<+ >].

Example 26: [(E) -3- (2,5-difluoro-phenyl) -allyl]-{(3R, 6S) -6- [2- (6-fluoro-3-methoxy-quinolin-4-yl) ) -Ethyl] -tetrahydro-pyran-3-yl} -amine:
26.i. {(3R, 6S) -6- [2- (6-Fluoro-3-methoxy-quinolin-4-yl) -ethyl] -tetrahydro-pyran-3-yl} -carbamic acid tert-butyl ester :
To a solution of intermediate 25.i (0.55 g, 1.36 mmol) in EA (6 ml) and MeOH (20 ml) was added 10% Pd / C (0.25 g). The reaction was stirred for 2 hours under hydrogen atmosphere. The catalyst was removed by filtration and the filtrate was concentrated to dryness to give the title compound (0.55 g) as a white solid.
MS (ESI, m / z): 405.0 [M + H ^<+ >].

26.ii. (3R, 6S) -6- [2- (6-Fluoro-3-methoxy-quinolin-4-yl) -ethyl] -tetrahydro-pyran-3-ylamine:
The title amine (0.3 g, 72% yield) was obtained as a colorless oil starting from intermediate 26.i (0.55 g, 1.36 mmol) and using the procedure of Example 1 Step 1.ix. Obtained. The compound was purified by chromatography on SiO ₂ using DCM-MeOH 9-1 containing 1% aqueous NH ₄ OH as eluent.
MS (ESI, m / z): 305.1 [M + H ^<+ >].

26.iii. [(E) -3- (2,5-difluoro-phenyl) -allyl]-{(3R, 6S) -6- [2- (6-fluoro-3-methoxy-quinolin-4-yl ) -Ethyl] -tetrahydro-pyran-3-yl} -amine:
Starting from intermediate 26.ii (0.15 g, 0.49 mmol) and (E) -3- (2,5-difluoro-phenyl) -propenal (0.082 g, 1.0 eq), the title compound (0.17 g, 75% Yield) was obtained as a colorless oil using the procedure of Example 1, Step 1.x. The compound was purified by chromatography on SiO ₂ using DCM-MeOH 19-1 containing 0.5% aqueous NH ₄ OH as eluent.
¹ H NMR (d6-DMSO) δ: 8.77 (d, J = 2.7 Hz, 1H); 8.12 (dd, J = 3.2, 11.2 Hz, 1H); 7.97 (d, J = 9.2 Hz, 1H), 7.63 ( d, J = 9.2 Hz, 1H); 7.48 (m, 1H); 7.24 (m, 1H); 7.11 (m, 1H) 6.59 (d, J = 16.1 Hz, 1H); 6.48 (td, J = 5.2, 16.2 Hz, 1H); 4.02 (m 1H); 3.95 (s, 3H); 3.37 (m, 2H), 3.13-2.92 (m, 3H); 2.88 (t, J = 10.5 Hz, 1H); 2.55 (m 1.96 (m, 1H); 1.75 (br s, 1H); 1.66-1.55 (m, 3H); 1.26-1.10 (m, 2H).
MS (ESI, m / z): 456.9 [M + H ^<+ >].

Example 27: 6-({(3R, 6S) -6- [2- (6-Fluoro-3-methoxy-quinolin-4-yl) -ethyl] -tetrahydro-pyran-3-ylamino} -methyl)- 4H-pyrido [3,2-b] [1,4] thiazin-3-one:
Intermediate 26.ii (0.15 g, 0.49 mmol) and 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carbaldehyde (0.095 g, 1.0 eq) The title compound (0.035 g, 17% yield) was obtained as an off-white solid using the procedure of Example 1, Step 1.x. The compound was purified by chromatography on SiO ₂ using DCM-MeOH 9-1 containing 1% aqueous NH ₄ OH as eluent.
MS (ESI, m / z): 482.8 [M + H ^<+ >].

Example 28: (1R, 2R) -1-{(2R, 5S) -5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -tetrahydro-pyran-2-yl}- 2- (6-Fluoro-quinolin-4-yl) -ethane-1,2-diol:
28.i. {(3S, 6R) -6-[(E) -2- (6-Fluoro-quinolin-4-yl) -vinyl] -tetrahydro-pyran-3-yl} -carbamic acid tert-butyl ester :
(3S, 6R)-[6- (1-Phenyl-1H-tetrazol-5-sulfonylmethyl) -tetrahydro-pyran-3-yl] -carbamic acid tert-butyl ester (see Preparation I, 1.69 g, Starting from 4 mmol) and 3-methoxy-quinoline-5-carbaldehyde (see Preparation D, 0.7 g, 4 mmol), the title alkene (1.03 g, 69% yield) Obtained as a white solid using the procedure of .vi. The compound was then purified by chromatography on SiO ₂ using Hept-EA 1-1 with 1-4 as eluent.
MS (ESI, m / z): 373.1 [M + H ^<+ >].

28.ii. {(3S, 6R) -6-[(1R, 2R) -2- (6-Fluoro-quinolin-4-yl) -1,2-dihydroxy-ethyl] -tetrahydro-pyran-3-yl } -Carbamate tert-butyl ester:
Starting from intermediate 28.i (0.497 g, 1.33 mmol), the title diol (0.54 g, 99% yield) is obtained as a white solid using the procedure of Example 6, step 6.i. It was. The compound was purified by chromatography on SiO ₂ using DCM-MeOH 9-1 as eluent.
MS (ESI, m / z): 407.0 [M + H ^<+ >].

28.iii. (1R, 2R) -1-[(2R, 5S) -5-Amino-tetrahydro-pyran-2-yl] -2- (6-fluoro-quinolin-4-yl) -ethane-1, 2-diol:
The title amine (0.21 g, 51% yield) was obtained starting from intermediate 28.ii (0.54 g, 1.32 mmol) and using the procedure of Example 1, Step 1.ix. As obtained.
MS (ESI, m / z): 307.1 [M + H ^<+ >].

28.iv. (1R, 2R) -1-{(2R, 5S) -5-[(E) -3- (2,5-Difluoro-phenyl) -allylamino] -tetrahydro-pyran-2-yl}- 2- (6-Fluoro-quinolin-4-yl) -ethane-1,2-diol:
Starting from intermediate 28.iii (0.21 g, 0.68 mmol) and (E) -3- (2,5-difluoro-phenyl) -propenal (0.115 g, 1.0 eq), the title compound (0.095 g, 31% Yield) was obtained as a white foam using the procedure of Example 1, Step 1.x. The compound was purified by chromatography on SiO ₂ using DCM-MeOH 9-1 containing 1% aqueous NH ₄ OH as eluent.
MS (ESI, m / z): 458.9 [M + H ^<+ >].

Example 29: [(E) -3- (2,5-difluoro-phenyl) -allyl]-{(3S, 6R)-(E) -6- [2- (6-fluoro-quinolin-4-yl ) -Vinyl] -tetrahydro-pyran-3-yl} -amine:
29.i. (3S, 6R) -6-[(E) -2- (6-Fluoro-quinolin-4-yl) -vinyl] -tetrahydro-pyran-3-ylamine:
The title amine (0.135 g, 82% yield) was obtained starting from intermediate 28.i (0.226 g, 0.6 mmol) and using the procedure of Example 1, Step 1.ix. As obtained. The compound was purified by chromatography on SiO ₂ using DCM-MeOH 9-1 containing 1% aqueous NH ₄ OH as eluent.
MS (ESI, m / z): 273.2 [M + H ^<+ >].

29.ii. [(E) -3- (2,5-Difluoro-phenyl) -allyl]-{(3S, 6R)-(E) -6- [2- (6-Fluoro-quinolin-4-yl ) -Vinyl] -tetrahydro-pyran-3-yl} -amine:
Starting from intermediate 29.i (0.131 g, 0.48 mmol), the title compound (0.112 g, 54% yield) was obtained as a colorless oil according to the procedure of Example 1, Step 1.x. The compound was purified by chromatography on SiO ₂ using DCM-MeOH 97-3 containing 0.3% aqueous NH ₄ OH as eluent.
¹ H NMR (d ₆ -DMSO) δ: 8.82 (d, J = 4.6 Hz, 1H); 8.09 (dd, J = 5.7, 9.2 Hz, 1H); 7.97 (dd, J = 2.7, 10.6 Hz, 1H) 7.72-7.65 (M, 2H); 7.48 (m, 1H); 7.31 (d, J = 15.8 Hz, 1H); 7.24 (m, 1H); 7.11 (m, 1H); 6.63 (d, J = 15.8 Hz, 1H); 6.62 (d, J = 15.8 Hz, 1H); 6.51 (td, J = 5.5, 15.8 Hz, 1H); 4.11-4.03 (m, 2H); 3.48-3.35 (m, 2H); 3.10 (t, J = 10.5 Hz, 1H); 2.60 (m, 1H); 2.10 (m, 1H); 1.90-1.88 (m, 2H); 1.54-1.23 (m, 2H).
MS (ESI, m / z): 425.0 [M + H ^<+ >].

Example 30: [(E) -3- (2,5-difluoro-phenyl) -allyl]-{(3S, 6R) -6- [2- (6-fluoro-quinolin-4-yl) -ethyl] -Tetrahydro-pyran-3-yl} -amine:
30.i. {(3S, 6R) -6- [2- (6-Fluoro-quinolin-4-yl) -ethyl] -tetrahydro-pyran-3-yl} -carbamic acid tert-butyl ester:
This alkane (0.267 g, 95% yield) was obtained as a colorless foam starting from intermediate 28.i (0.277 g, 0.74 mmol) and using the procedure of Example 2, Step 2.ii. The compound obtained as was purified by chromatography on SiO ₂ using DCM-MeOH 9-1 containing 1% aqueous NH ₄ OH as eluent.
MS (ESI, m / z): 375.1 [M + H ^<+ >].

30.ii. (3S, 6R) -6- [2- (6-Fluoro-quinolin-4-yl) -ethyl] -tetrahydro-pyran-3-ylamine:
The title amine (0.155 g, 81% yield) was yellowish starting from intermediate 30.i (0.261 g, 0.7 mmol) and using the procedure of Example 1, Step 1.ix. Obtained as an oil. The compound was purified by chromatography on SiO ₂ using DCM-MeOH 9-1 containing 1% aqueous NH ₄ OH as eluent.
MS (ESI, m / z): 275.1 [M + H ^<+ >].

30.iii. [(E) -3- (2,5-Difluoro-phenyl) -allyl]-{(3S, 6R) -6- [2- (6-Fluoro-quinolin-4-yl) -ethyl] -Tetrahydro-pyran-3-yl} -amine:
Starting from intermediate 30.ii (0.08 g, 0.29 mmol) and (E) -3- (2,5-difluoro-phenyl) -propenal (0.054 g, 1.1 eq), the title compound (0.106 g, 85% Yield) was obtained as a colorless oil according to the procedure of Example, Step 1.x1. The compound was purified by chromatography on SiO ₂ using DCM-MeOH 19-1 containing 0.5% aqueous NH ₄ OH as eluent.
MS (ESI, m / z): 426.7 [M + H ^<+ >].

Example 31: 6-({3S, 6R) -6- [2- (6-Fluoro-quinolin-4-yl) -ethyl] -tetrahydro-pyran-3-ylamino} -methyl) -4H-pyrido [3 , 2-b] [1,4] thiazin-3-one:
Intermediate 30.ii (0.064 g, 0.24 mmol) and 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carbaldehyde (0.050 g, 1.0 eq) The title compound (0.063 g, 60% yield) was obtained as a white foam using the procedure of Example 1, Step 1.x. The compound was purified by chromatography on SiO ₂ using DCM-MeOH 9-1 containing 1% aqueous NH ₄ OH as eluent.
¹ H NMR (d ₆ -DMSO) δ: 10.87 (s, 1H); 8.77 (d, J = 4.4 Hz, 1H); 8.08 (dd, J = 5.7, 9.2 Hz, 1H); 7.85 (dd, J = 2.8, 10.7 Hz, 1H); 7.73 (d, J = 7.8 Hz, 1H); 7.66 (m, 1H); 7.39 (d, J = 4.4 Hz, 1H); 7.09 (d, J = 7.8 Hz, 1H) ; 4.00 (m, 1H); 3.78-3.68 (m, 2H); 3.53 (s, 2H); 3.17 (m, 1H); 3.10-3.00 (m, 2H); 2.94 (t, J = 10.5 Hz, 1H ); 2.50 (m, 1H); 2.11 (m, 1H); 1.99 (m, 1H); 1.79-1.65 (m, 3H); 1.32-1.11 (m, 2H).
MS (ESI, m / z): 452.8 [M + H ^<+ >].

Example 32: 3-Oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2R, 3R, 6S) -2- (2-hydroxy -Ethyl) -6-[(E) -2- (6-methoxy- [1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-3-yl} -amide:
32.i. 3- {3-Amino-6-[(E) -2- (6-methoxy- [1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -propane 1,2-diol:
Starting from intermediate 1.vi (2.19 g, 4.39 mmol), the title compound (1.35 g, 85% yield) is obtained as an off-white solid using the procedure of Example 2, Step 2.iii. As obtained. The compound was obtained as a 2-1 mixture of epimers.
MS (ESI, m / z): 360.3 [M + H ^<+ >].

32.ii. 3-Oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2R, 3R, 6S) -2-((2R) -2,3-dihydroxy-propyl) -6-[(E) -2- (6-methoxy- [1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-3-yl} -amide and 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2R, 3R, 6S) -2-((2S) -2,3 -Dihydroxy-propyl) -6-[(E) -2- (6-methoxy- [1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-3-yl} -amide:
Intermediate 32i (0.2 g, 0.55 mmol) and 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid (0.116 g, 1.1 eq. ) And using the procedure described in Example 1, Step 1.x., the title compound was obtained as a white solid. The isomers are partially separated by chromatography on SiO ₂ (DCM-MeOH 93-7 containing 0.7% aqueous NH ₄ OH) and eluting first (0.019 g, 6% yield), Fractions containing both the isomer (0.12 g, 39% yield) and the second eluting isomer (0.055 g, 18% yield) were obtained.
MS (ESI, m / z): 551.9 [M + H ^<+ >] (mixture of isomers).

32.iii. 3-Oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid [6- [2- (6-methoxy- [1,5 ] Naphthyridin-4-yl) -vinyl] -2- (2-oxo-ethyl) -tetrahydro-pyran-3-yl] -amide:
Starting from intermediate 32.ii (0.12 g (0.21 mmol)), the title aldehyde (0.09 g, 72% yield) was obtained as a white solid using the procedure of Example 2, step 2.v. It was.
¹ H NMR (d ₆ -DMSO) δ: 11.24 (s, 1H); 9.72 (s, 1H); 8.77 (d, J = 4.5 Hz, 1H); 8.34 (d, J = 9.0 Hz, 1H); 8.28 (d, J = 9.0 Hz, 1H); 8.02-7.94 (m, 2H); 7.68-7.57 (m, 2H); 7.30 (d, J = 9.0 Hz, 1H); 7.11 (dd, J = 4.0, 16.8 Hz, 1H); 4.76 (m, 1H); 4.65 (m, 1H); 4.05 (m, 1H); 4.03 (s, 3H); 3.72 (s, 2H); 2.57 (m, 2H); 2.18-1.90 (m, 2H); 1.94-1.89 (m, 2H).
MS (ESI, m / z): 520.1 [M + H ^<+ >].

32.iv. 3-Oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2R, 3R, 6S) -2- (2-hydroxy -Ethyl) -6-[(E) -2- (6-methoxy- [1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-3-yl} -amide:
To a solution of intermediate 32.iii. (0.07 g, 0.13 mmol) in MeOH (3 ml) and THF (1 ml) at 0 ° C. was added NaBH ₄ (0.02 g). The reaction was stirred at this temperature for 1 hour. Water (2 ml) was added. Volatiles were removed in vacuo and the residue was chromatographed (DCM-MeOH 19-1 with 0.5% aqueous NH ₄ OH) to give a solid that was further triturated in ether and filtered. And dried under HV. The title alcohol (0.025 g, 35% yield) was obtained as a white solid.
MS (ESI, m / z): 521.8 [M + H ^<+ >].

Example 33: 2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (6-methoxy -[1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetamide:
33.i. {(2R, 3R, 6S) -2-carbamoylmethyl-6-[(E) -2- (6-methoxy- [1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran -3-yl} -carbamic acid tert-butyl ester:
Starting from intermediate 1.vi (5.5 g, 11 mmol), the title amide (0.602 g, 1.36 mmol) was prepared according to Example 9, step 9.ii. (deprotection, 89% yield), Example 2. , 2.v (aldehyde formation, 99% yield) and step 2.vi (acid formation, 76% yield) and procedures described in Example 9, step 9.iv (30% yield), respectively. Was obtained as a yellowish solid.
MS (ESI, m / z): 521.8 [M + H ^<+ >].

33.ii.2- {3-Amino-6-[(E) -2- (6-methoxy- [1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetamide :
Starting from intermediate 33.i (0.6 g, 1.36 mmol), the title amine (0.33 g, 71% yield) was obtained as a solid brown using the procedure of Example 1, Step 1.ix. Obtained.
MS (ESI, m / z): 343.0 [M + H ^<+ >].

33.iii. 2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-Difluoro-phenyl) -allylamino] -6-[(E) -2- (6-methoxy -[1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetamide:
Starting from intermediate 33.ii (0.110 g, 0.32 mmol) and (E) -3- (2,5-difluoro-phenyl) -propenal (0.059 g, 1.1 eq), the title compound (0.054 g, 34% Yield) was obtained as a white solid according to the procedure of Example 1, Step 1.x. The compound was purified by chromatography on SiO ₂ (DCM-MeOH 19-1 containing 0.5% aqueous NH ₄ OH).
MS (ESI, m / z): 495.0 [M + H ^<+ >].

Example 34: (2R, 3R, 6S)-{3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (3-fluoro-6 -Methoxy-quinolin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetic acid:
34.i. 3-Fluoro-6-methoxy-quinoline-4-carbaldehyde:
N-BuLi (2.5N hexane (10 ml) solution) cooled to −78 ° C. was added to a THF (100 ml) solution of DIPA (3.5 ml). The reaction mixture was warmed to 0 ° C. and stirred at this temperature for 5 minutes. The reaction mixture was stirred for 15 minutes before cooling to -78 ° C. A solution of 3-fluoro-6-methoxy-quinoline (4.38 g, 24.7 mmol) in THF (20 ml + 5 ml rinse) was added and the mixture was stirred at −78 ° C. for 3 hours. DMF (3 ml) was added dropwise. After 15 minutes, the reaction mixture was warmed to room temperature. 10% NaHSO ₄ aqueous solution (10 ml) was added. Volatiles were removed in vacuo and the residue basified with saturated sodium bicarbonate. The aqueous layer was extracted twice with EA (2 × 200 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was chromatographed (Hex-EA 1-1) to give the title aldehyde (3.05 g, 60% yield) as a yellowish solid. The compound was mixed up to 20% of the remaining starting material.
¹ H NMR (CDCl ₃ ) δ: 10.86 (s, 1H); 8.81 (d, J = 1.8 Hz, 1H); 8.50 (d, J = 2.8 Hz, 1H); 8.03 (d, J = 9.2 Hz, 1H ); 7.40 (dd, J = 2.8, 9.2 Hz, 1H); 4.01 (s, 3H).

34.ii. {(2R, 3R, 6S) -2-[(4RS) -2,2-Dimethyl- [1,3] dioxolan-4-ylmethyl] -6-[(E) -2- (3- Fluoro-6-methoxy-quinolin-4-yl) -vinyl] -tetrahydro-pyran-3-yl} -carbamic acid tert-butyl ester:
Starting from Intermediate 34.i (3.05 g, 11.9 mmol) and Intermediate 1.v (6.95 g, 12.9 mmol), the title alkene (5.38 g, 80% yield) was prepared in Example 1, Step 1. Obtained as a pale yellow foam using the procedure of vi. The compound was purified by Hept-EA 1-2 using chromatography as the eluent. The compound was obtained as a 2-1 mixture of epimer and 3-1E-Z mixture.
MS (ESI, m / z): 517.1 [M + H ^<+ >].

34.iii. (2RS) -3-{(2R, 3R, 6S) -3-[(E) -3- (2,5-Difluoro-phenyl) -allylamino] -6-[(E) -2- (3-Fluoro-6-methoxy-quinolin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -propane-1,2-diol:
Starting from intermediate 34.ii (2.63 g, 5.1 mmol), the title compound (1.62 g) was prepared according to Example 2, step 2.iii (deprotection, 67% yield) and Example 1, step 1. Obtained as a yellowish foam using the procedure described for .x (reductive amination, 91% yield). After each step, the crude reaction mixture was dissolved in SiO ₂ using DCM-MeOH 6-1 each containing 1% aqueous NH ₄ OH and DCM-MeOH 9-1 containing 1% aqueous NH ₄ OH as eluents. And purified by chromatography. The compound was obtained as a 2-1 mixture of epimer and 3-1E-Z mixture.
MS (ESI, m / z): 567.7 [M + H ^<+ >].

34.iv. ((2R, 3R, 6S)-{3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (3-fluoro- 6-methoxy-quinolin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetic acid:
Starting from intermediate 34.iii (1.58 g, 3 mmol), the title compound (0.037 g) was obtained in Example 4, step 4.iii (Boc formation, 74% yield), Example 2, step 2. Off using the procedures described in v (aldehyde formation, 82% yield) and 2.vi (acid formation, 98% yield) and Example 4 (step 4.vi, 52% yield). Obtained as a white solid. The compound was purified by chromatography on SiO ₂ using DCM-MeOH 6-1 with 1% aqueous NH ₄ OH after the final step. The compound was obtained as a 2-1E-Z mixture.
MS (ESI, m / z): 513.0 [M + H ^<+ >].

Example 35: {(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (6-methoxy- [ 1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetic acid:
35.i. (2RS) -3-{(2R, 3R, 6S) -3-[(E) -3- (2,5-Difluoro-phenyl) -allylamino] -6-[(E) -2- (6-Methoxy- [1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -propane-1,2-diol:
Starting from Intermediate 32i (1.43 g, 4 mmol), the title compound (1.34 g, 65% yield) is obtained as a colorless foam using the procedure of Example 1, Step 1.x. It was. After purification by chromatography on SiO ₂ (DCM-MeOH 9-1 containing 1% aqueous NH ₄ OH), the compound was obtained as a 2-1 mixture of epimers.
¹ H NMR (d6-DMSO) δ: 8.71 (d, J = 4.6 Hz, 1H); 8.24 (d, J = 9.0 Hz, 1H); 7.84 (d, J = 4.5 Hz, 0.33H); 7.82 (d , J = 4.5 Hz, 0.67H); 7.58-7.45 (m, 2H); 7.27 (d, J = 9.0 Hz, 1H); 7.25 (m, 1H); 7.12 (m, 1H); 7.01-6.92 (m , 1H), 6.63 (d, J = 16.1 Hz, 1H); 6.51 (td, J = 5.1, 16.1 Hz, 1H); 4.68 (br s, 0.67H); 4.51-4.35 (m, 2.33H); 4.21 (m, 0.67H); 4.11 (m, 0.33H); 4.04 (s, 3 x 0.33H); 4.02 (s, 3 x 0.67H); 3.62 (m, 1H); 3.39-3.25 (m, 4H) 2.75 (m, 1H); 2.05-1.37 (m, 7H).
MS (ESI, m / z): 512.0 [M + H ^<+ >].

35.ii. [(E) -3- (2,5-Difluoro-phenyl) -allyl]-{(2R, 3R, 6S) -2-[(2RS) -2,3-dihydroxy-propyl] -6 -[2- (6-Methoxy- [1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-3-yl} -carbamic acid tert-butyl ester:
To a solution of intermediate 35.i (1.34 g, 2.62 mmol) in DCM (13 ml) was added di-tert-butyl dicarbonate (0.9 g) and TEA (0.75 ml). The mixture was stirred at room temperature for 24 hours. Di-tert-butyl dicarbonate (0.5 g) was added and the reaction was allowed to proceed further for 24 hours. The reaction mixture was concentrated to dryness and the residue was chromatographed on SiO ₂ (DCM-MeOH 19-1, then 9-1) to give the title compound (0.77 g, 48% yield) as a colorless foam. .
¹ H NMR (CDCl ₃ ) δ: 8.71 (d, J = 4.7 Hz, 1H); 8.23 (d, J = 9.0 Hz, 0.67H); 8.22 (d, J = 9.0 Hz, 0.33H); 7.68-7.61 (m, 2H); 7.14 (d, J = 9.0 Hz, 1H); 7.13 (m, 1H); 7.01 (m, 1H); 6.94 (m, 1H); 6.77 (dd, J = 5.6, 16.5 Hz, 1H), 6.57 (d, J = 16.1 Hz, 1H); 6.29 (td, J = 5.1, 16.1 Hz, 1H); 4.64 (m, 0.33H); 4.48-4.24 (m, 3.67H); 4.12 (s , 3 x 0.33H); 4.11 (s, 3 x 0.67H); 4.10-3.92 (m, 2H); 3.71 (app td, J = 3.4, 11.0 Hz, 1H); 3.58 (m, 1H); 2.31- 1.71 (m, 8H); 1.50 (s, 9H).

35.iii. {(2R, 3R, 6S) -3- {tert-Butoxycarbonyl-[(E) -3- (2,5-difluoro-phenyl) -allyl] -amino} -6-[(E) -2- (6-Methoxy- [1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetic acid:
Starting from intermediate 35.ii (0.77 g, 1.25 mmol), the title acid (0.48 g) was prepared in Example 2, step 2.v (aldehyde formation, 82% yield) and 2.vi (acid production). , 98% yield) was produced as a colorless foam. The compound was purified by chromatography on SiO ₂ using DCM-MeOH 93-7 after the last step.
¹ H NMR (d6-DMSO) δ: 12.19 (br s, 1H); 8.72 (d, J = 4.8 Hz, 1H); 8.25 (d, J = 9.0 Hz, 1H); 7.85 (d, J = 4.8 Hz , 1H); 7.57-7.47 (m, 2H); 7.27 (d, J = 9.0 Hz, 1H); 7,24 (m, 1H); 7.13 (m, 1H); 6.91 (dd, J = 16.1, 5.3 Hz, 1 H); 6.52 (d, J = 16.1 Hz, 1H); 6.43 (td, J = 5.0, 16.1 Hz, 1H); 4.55-4.45 (m, 2 H); 4.27-4.04 (m, 2H) ; 4.04 (s, 3H); 3.85 (dd, J = 4.8, 16.9 Hz, 1H); 2.88 (dd, J = 9.8, 14.7 Hz, 1H); 2.38 (dd, J = 4.6, 14.7 Hz, 1H); 2.17 (m, 1 H); 2.02-1.85 (m, 2H); 1.61 (m, 1 H); 1.40 (s, 9 H).

35.iv. {(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (6-methoxy- [ 1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetic acid:
A solution of intermediate 35.iii. (0.1 g, 0.17 mmol) in TFA (2 ml) was stirred for 15 minutes at room temperature. The solvent was removed in vacuo and the residue was taken up in water (10 ml) and DCM-MeOH (9-1, 30 ml). The pH of the aqueous layer was adjusted to 7, and the organic layer was separated. The aqueous layer was extracted once more with DCM-MeOH (9-1, 30 ml) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was triturated with ether and the solid was filtered and dried under HV to give the title compound (0.045 g, 54% yield) as an unemployed solid.
MS (ESI, m / z): 496.4 [M + H ^<+ >].

Example 36: [(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- (6-methoxy- [1,5] naphthyridine-4 -Ylcarbamoyl) -tetrahydro-pyran-2-yl] -acetic acid:
36.i. (2S, 5R, 6R) -5-tert-Butoxycarbonylamino-6-[(4RS) 2,2-dimethyl- [1,3] dioxolan-4-ylmethyl] -tetrahydro-pyran-2- carboxylic acid:
Intermediate 1.ii (5 g, 14.48 mmol) in ice-cooled DCM (32 ml), MeCN (32 ml) and water (46 ml) in NaIO ₄ (14.6 g, 68.17 mmol) and RuCl ₃ (0.030 g, 0.15 mmol) Was added. The reaction mixture was stirred at the same temperature for 5 hours. The reaction mixture was diluted with EA (150 ml) and the solid was removed by filtration. MeOH (30 ml) was added and the resulting suspension was filtered. The filtrate was treated with 10% aqueous NaHSO ₃ solution (60 ml). The phases were separated and the aqueous layer was extracted 3 times with EA. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give a brown foam (quantitative). The compound was obtained as a 2-1 mixture of epimers.
MS (ESI, m / z): 360.1 [M + H ^<+ >].
36.ii. {(2S, 5R, 6R) -6-carbamoyl-2-[(4RS) -2,2-dimethyl- [1,3] dioxolan-4-ylmethyl] -tetrahydro-pyran-3-yl} -Carbamic acid tert-butyl ester:
Starting from intermediate 36.i (5.27 g, 14.6 mmol), the title amide (3.16 g, 60% yield) was obtained as a colorless foam using the procedure of Example 10, step 10.ii. Obtained. The compound was purified by EA-cyclohexane 4-1 using chromatography as the eluent. The compound was obtained as a 2-1 mixture of epimers.
MS (ESI, m / z): 359.1 [M + H ^<+ >].

36.iii. {(2S, 5R, 6R) -2-[(4RS) -2,2-Dimethyl- [1,3] dioxolan-4-ylmethyl) -6- (6-methoxy- [1,5] Naphthyridin-4-ylcarbamoyl) -tetrahydro-pyran-3-yl] -carbamic acid tert-butyl ester:
Of intermediate 36.ii (2.3 g, 6.42 mmol), rac-BINAP (0.288 g, 0.46 mmol) (dba) ₃ Pd ₂ .CHCl ₃ (0.120 g, 0.12 mmol) and cesium carbonate (2.56 g, 7.86 mmol) To the mixture was added dioxane (82 ml). The mixture was sonicated for 10 minutes, when trifluoro-methanesulfonic acid 6-methoxy- [1,5] naphthyridin-4-yl ester (prepared as described in WO 03/064431). 2.10 g, 6.81 mmol) was partially added. The resulting mixture was heated at 100 ° C. for 4 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The residue was purified on SiO ₂ (DCM-MeOH 19-1) to give the title amide (reddish foam; 3.27 g, 6.32 mmol) as a 2-1 mixture of epimers.
MS (ESI, m / z): 477.0 [M + H ^<+ >].

36.iv. (2S, 5R, 6S) -5-Amino-6-[(2RS) -2,3-dihydroxy-propyl] -tetrahydro-pyran-2-carboxylic acid (6-methoxy- [1,5] Naphthyridin-4-yl) -amide:
Starting from Intermediate 36.iii (2.72 g, 2.06 mmol), the title amine (1.27 g, 64% yield) is obtained as a reddish solid using the procedure of Example 1, Step 1.viii. It was. The compound was purified by chromatography using DCM-MeOH 6-1 containing 1% aqueous NH ₄ OH as eluent. The compound was obtained as a 2-1 mixture of epimers.
¹ H NMR (d6-DMSO) δ: 10.59 (s, 0.66H); 10.51 (s, 0.34H); 8.70 (d, J = 5.0 Hz, 1H); 8.45 (d, J = 5.0 Hz, 0.34H) 8.39 (d, J = 5.0 Hz, 0.66H); 8.28 (d, J = 9.0 Hz, 1H); 7.33 (d, J = 9.0 Hz, 1H); 4.50 (br s, 1H); 4.47 (dd, J = 4.3, 7.0 Hz, 0.34H); 4.31 (dd, J = 3.5, 9.0 Hz, 0.66H); 4.11 (m, 0.66H); 4.09 (s, 3 x 0.34H); 4.08 (s, 3 x 0.66H); 3.96 (m, 0.34H); 3.63 (m, 1H); 3.37-3.21 (m, 5H), 2.97 (m, 0.66H); 2.91 (m, 0.34H); 2.08 (m, 1H) 1.96 (m, 0.66H); 1.82-1.42 (m, 4.34H).
MS (ESI, m / z): 377.0 [M + H ^<+ >].

36.v. (2S, 5R, 6R) -5-[(E) -3- (2,5-Difluoro-phenyl) -allylamino] -6-[(2RS) -2,3-dihydroxy-propyl]- Tetrahydro-pyran-2-carboxylic acid (6-methoxy- [1,5] naphthyridin-4-yl) -amide:
To a solution of intermediate 36.iv (1.0 g, 2.65 mmol) in 1,2-DCE (30 ml) and MeOH (10 ml) was added 3Å molecular sieve (10 g) and (E) -3- (2,5-difluoro-phenyl). ) -Propenal (0.49 g, 1.1 eq) was added. The mixture was heated at 50 ° C. for 18 hours. After cooling to 0 ° C., NaBH ₄ (1 g) was added and the reaction proceeded for 45 minutes. The reaction mixture was filtered and the solid was washed with DCM-MeOH (9-1, 200 ml). The filtrate was washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was chromatographed (DCM-MeOH 93-7 containing 0.7% aqueous NH ₄ OH) to give the title diol (1.1 g, 78% yield) as a colorless foam. The compound was obtained as a 2-1 mixture of epimers.
¹ H NMR (d6-DMSO) δ: 10.64 (s, 0.66H); 10.56 (s, 0.34H); 8.69 (d. J = 5.0 Hz, 1H); 8.42 (d, J = 5.0 Hz, 0.34H) 8.37 (d, J = 5.0 Hz, 0.66H); 8.28 (d, J = 9.0 Hz, 1H); 7.49 (m, 1H); 7.32 (d, J = 9.0 Hz, 1H); 7.27 (m, 1H 7.12 (m, 1H); 6.63 (d, J = 16.2 Hz, 1H); 6.49 (m, 1H); 4.52-4.42 (m, 3H); 4.26 (m, 1H); 4.06 (s, 3 x 0.34H); 4.04 (s, 3 x 0.66H); 3.65 (m, 1H); 3.44-3.24 (m, 4H); 2.81 (m, 1H); 2.12-1.41 (m, 7H).
MS (ESI, m / z): 529.0 [M + H ^<+ >].

36.vi. [(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- (6-methoxy- [1,5] naphthyridine-4 -Ylcarbamoyl) -tetrahydro-pyran-2-yl] -acetic acid:
Starting from intermediate 36.v (1.1 g, 2.1 mmol), the title compound (0.080 g) was prepared in Example 4, step 4.iii (Boc formation, 68% yield), Example 2, Step 2. Using the procedures described in .v (aldehyde formation) and 2.vi (acid formation, 30% yield, 2 steps) and Example 35, step 35.vi (deprotection, 54% yield) , Obtained as a white solid. The compound was purified by chromatography on SiO ₂ using DCM-MeOH 6-1 with 1% aqueous NH ₄ OH after the final step.
MS (ESI, m / z): 513.4 [M + H ^<+ >].

Pharmacological properties of the compounds of the invention In vitro assay Experimental method:
These assays are shown 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. Was done according to the description. The minimum inhibitory concentration (MIC; mg / l) was determined in the cation-adjusted Mueller-Hinton Broth (BBL) by the microdilution method according to the NCCLS (National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility) guidelines . The pH of the test solution was 7.2-7.3.

result:
All examples were tested against several gram positive and gram negative bacteria. Typical antimicrobial test results are shown in the table below (mg / l MIC).

Claims (9)

A compound selected from the group consisting of: or a salt of one of these compounds:
-(E) -2-{(2R, 3R, 6R)-(3- [3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy- [1,5] Naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -ethanol;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -acryloylamino] -6- [2- (3-methoxy-quinolin-5-yl)- Ethyl] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6R) -6- [2- (3-methoxy-quinolin-5-yl) -ethyl] -3-[(3-oxo-3,4-dihydro-2H-pyrido [3, 2-b] [1,4] thiazine-6-carbonyl) -amino] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6R) -6- [2- (6-Methoxy- [1,5] naphthyridin-4-yl) -ethyl] -3-[(3-oxo-3,4-dihydro-2H -Pyrido [3,2-b] [1,4] thiazin-6-ylmethyl) -amino] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy- [1,5] naphthyridine-4 -Yl) -ethyl] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(1S) -1-hydroxy-2- (6-methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetic acid;
-(1R) -2-{(2S, 5R, 6S) -5- [trans-3- (2,5-difluoro-phenyl) -allylamino] -6-hydroxymethyl-tetrahydro-pyran-2-yl}- 1- (3-fluoro-6-methoxy-quinolin-4-yl) -ethanol;
-(1S) -2-{(2S, 5R, 6S) -5- [trans-3- (2,5-difluoro-phenyl) -allylamino] -6-hydroxymethyl-tetrahydro-pyran-2-yl}- 1- (3-fluoro-6-methoxy-quinolin-4-yl) -ethanol;
-2-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy- [1,5] naphthyridine -4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(1R, 2R) -1,2-dihydroxy-2 -(3-methoxy-quinoxalin-5-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy-quinolin-4-yl) -ethyl ] -Tetrahydro-pyran-2-yl} -acetic acid;
-2-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy-quinolin-4-yl) -Ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(S) -1-hydroxy-2- (6- Methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2R) -2- (3-fluoro-6-methoxy-quinolin-4-yl) -2 -Hydroxy-ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2S) -2- (3-fluoro-6-methoxy-quinolin-4-yl) -2 -Hydroxy-ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2S, 3R, 6S) -6-[(2R) -2- (3-Fluoro-6-methoxy-quinolin-4-yl) -2-hydroxy-ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl} -amide;
-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2S, 3R, 6S) -6-[(2S) -2- (3-Fluoro-6-methoxy-quinolin-4-yl) -2-hydroxy-ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl} -amide;
-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2S, 3R, 6S) -6-[(2R) -2- Hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl} -amide;
-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2S, 3R, 6S) -6-[(2S) -2- Hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl} -amide;
-3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2R) -2-hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl ] -2-Hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2S) -2-hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl ] -2-Hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (3-fluoro-6- Methoxy- [1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetamide;
-(2S, 5R, 6R)-(5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- (2-hydroxy-ethyl))-tetrahydro-pyran-2-carboxylic Acid (6-methoxy- [1,5] naphthyridin-4-yl) -amide;
-(2S, 5R) -5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -tetrahydro-pyran-2-carboxylic acid (6-methoxy- [1,5] naphthyridine-4 -Yl) -amide;
-(1S) -1-{(2S, 5R) -5-[(E) -3- (3-Fluoro-phenyl) -allylamino] -tetrahydro-pyran-2-yl} -2- (6-methoxy- Quinolin-4-yl) -ethanol;
-7-fluoro-6-({(3R, 6S) -6-[(1S) -1-hydroxy-2- (6-methoxy-quinolin-4-yl) -ethyl] -tetrahydro-pyran-3-ylamino } -Methyl) -4H-benzo [1,4] thiazin-3-one;
-3- (2-Fluoro-phenyl) -N-{(3R, 6S) -6-[(1S) -1-hydroxy-2- (6-methoxy-quinolin-4-yl) -ethyl] -tetrahydro- Pyran-3-yl}-(E) -acrylamide;
-3- (3-Fluoro-phenyl) -N-{(3R, 6S) -6-[(1S) -1-hydroxy-2- (6-methoxy-quinolin-4-yl) -ethyl] -tetrahydro- Pyran-3-yl}-(E) -acrylamide;
-8-((1R, 2R) -2-{(2S, 5R) -5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -tetrahydro-pyran-2-yl}- 1,2-dihydroxy-ethyl) -quinoline-2-carbonitrile;
-[(E) -3- (2,5-difluoro-phenyl) -allyl]-{3R, 6S) -6-[(E) -2- (3-fluoro-6-methoxy-quinolin-5-yl ) -Vinyl] -tetrahydro-pyran-3-yl} -amine;
-[(E) -3- (2,5-difluoro-phenyl) -allyl]-{(3R, 6S) -6- [2- (6-fluoro-3-methoxy-quinolin-4-yl) -ethyl ] -Tetrahydro-pyran-3-yl} -amine;
-6-({(3R, 6S) -6- [2- (6-Fluoro-3-methoxy-quinolin-4-yl) -ethyl] -tetrahydro-pyran-3-ylamino} -methyl) -4H-pyrido [3,2-b] [1,4] thiazin-3-one;
-(1R, 2R) -1-{(2R, 5S) -5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -tetrahydro-pyran-2-yl} -2- ( 6-Fluoro-quinolin-4-yl) -ethane-1,2-diol;
-[(E) -3- (2,5-Difluoro-phenyl) -allyl]-{(3S, 6R)-(E) -6- [2- (6-Fluoro-quinolin-4-yl) -vinyl ] -Tetrahydro-pyran-3-yl} -amine;
-[(E) -3- (2,5-Difluoro-phenyl) -allyl]-{(3S, 6R) -6- [2- (6-Fluoro-quinolin-4-yl) -ethyl] -tetrahydro- Pyran-3-yl} -amine; and
-6-({3S, 6R) -6- [2- (6-Fluoro-quinolin-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 {(2R, 3R, 6S) -2- (2-hydroxy-ethyl) -6-[(E) -2- (6-methoxy- [1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-3-yl} -amide;
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (6-methoxy- [1 , 5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetamide;
-(2R, 3R, 6S)-{3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (3-fluoro-6-methoxy- Quinolin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (6-methoxy- [1,5 ] Naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetic acid;
-[(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- (6-methoxy- [1,5] naphthyridin-4-ylcarbamoyl ) -Tetrahydro-pyran-2-yl] -acetic acid. 2. A compound according to claim 1 or a salt of one of these compounds, selected from the group consisting of:
-(E) -2-{(2R, 3R, 6R)-(3- [3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy- [1,5] Naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -ethanol;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -acryloylamino] -6- [2- (3-methoxy-quinolin-5-yl)- Ethyl] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6R) -6- [2- (3-methoxy-quinolin-5-yl) -ethyl] -3-[(3-oxo-3,4-dihydro-2H-pyrido [3, 2-b] [1,4] thiazine-6-carbonyl) -amino] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6R) -6- [2- (6-Methoxy- [1,5] naphthyridin-4-yl) -ethyl] -3-[(3-oxo-3,4-dihydro-2H -Pyrido [3,2-b] [1,4] thiazin-6-ylmethyl) -amino] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy- [1,5] naphthyridine-4 -Yl) -ethyl] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(1S) -1-hydroxy-2- (6-methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetic acid;
-(1R) -2-{(2S, 5R, 6S) -5- [trans-3- (2,5-difluoro-phenyl) -allylamino] -6-hydroxymethyl-tetrahydro-pyran-2-yl}- 1- (3-fluoro-6-methoxy-quinolin-4-yl) -ethanol;
-(1S) -2-{(2S, 5R, 6S) -5- [trans-3- (2,5-difluoro-phenyl) -allylamino] -6-hydroxymethyl-tetrahydro-pyran-2-yl}- 1- (3-fluoro-6-methoxy-quinolin-4-yl) -ethanol;
-2-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy- [1,5] naphthyridine -4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(1R, 2R) -1,2-dihydroxy-2 -(3-methoxy-quinoxalin-5-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy-quinolin-4-yl) -ethyl ] -Tetrahydro-pyran-2-yl} -acetic acid;
-2-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy-quinolin-4-yl) -Ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(S) -1-hydroxy-2- (6- Methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-3- (2,5-Difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2R) 2- (3-Fluoro-6-methoxy-quinolin-4-yl) -2- Hydroxy-ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-3- (2,5-Difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2S) 2- (3-Fluoro-6-methoxy-quinolin-4-yl) -2- Hydroxy-ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2S, 3R, 6S) -6-[(2R) -2- (3-Fluoro-6-methoxy-quinolin-4-yl) -2-hydroxy-ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl} -amide;
-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2S, 3R, 6S) -6-[(2S) -2- (3-Fluoro-6-methoxy-quinolin-4-yl) -2-hydroxy-ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl} -amide;
-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2S, 3R, 6S) -6-[(2R) -2- Hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl} -amide;
-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2S, 3R, 6S) -6-[(2S) -2- Hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl} -amide;
-3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2R) -2-hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl ] -2-Hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2S) -2-hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl ] -2-Hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (3-fluoro-6- Methoxy- [1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetamide;
-(2S, 5R, 6R)-(5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- (2-hydroxy-ethyl))-tetrahydro-pyran-2-carboxylic Acid (6-methoxy- [1,5] naphthyridin-4-yl) -amide;
-(2S, 5R) -5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -tetrahydro-pyran-2-carboxylic acid (6-methoxy- [1,5] naphthyridine-4 -Yl) -amide;
-(1S) -1-{(2S, 5R) -5-[(E) -3- (3-Fluoro-phenyl) -allylamino] -tetrahydro-pyran-2-yl} -2- (6-methoxy- Quinolin-4-yl) -ethanol;
-7-fluoro-6-({(3R, 6S) -6-[(1S) -1-hydroxy-2- (6-methoxy-quinolin-4-yl) -ethyl] -tetrahydro-pyran-3-ylamino } -Methyl) -4H-benzo [1,4] thiazin-3-one;
-3- (2-Fluoro-phenyl) -N-{(3R, 6S) -6-[(1S) -1-hydroxy-2- (6-methoxy-quinolin-4-yl) -ethyl] -tetrahydro- Pyran-3-yl}-(E) -acrylamide;
-3- (3-Fluoro-phenyl) -N-{(3R, 6S) -6-[(1S) -1-hydroxy-2- (6-methoxy-quinolin-4-yl) -ethyl] -tetrahydro- Pyran-3-yl}-(E) -acrylamide;
-8-((1R, 2R) -2-{(2S, 5R) -5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -tetrahydro-pyran-2-yl}- 1,2-dihydroxy-ethyl) -quinoline-2-carbonitrile;
-[(E) -3- (2,5-difluoro-phenyl) -allyl]-{3R, 6S) -6-[(E) -2- (3-fluoro-6-methoxy-quinolin-5-yl ) -Vinyl] -tetrahydro-pyran-3-yl} -amine;
-[(E) -3- (2,5-difluoro-phenyl) -allyl]-{(3R, 6S) -6- [2- (6-fluoro-3-methoxy-quinolin-4-yl) -ethyl ] -Tetrahydro-pyran-3-yl} -amine;
-6-({(3R, 6S) -6- [2- (6-Fluoro-3-methoxy-quinolin-4-yl) -ethyl] -tetrahydro-pyran-3-ylamino} -methyl) -4H-pyrido [3,2-b] [1,4] thiazin-3-one;
-(1R, 2R) -1-{(2R, 5S) -5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -tetrahydro-pyran-2-yl} -2- ( 6-Fluoro-quinolin-4-yl) -ethane-1,2-diol;
-[(E) -3- (2,5-Difluoro-phenyl) -allyl]-{(3S, 6R)-(E) -6- [2- (6-Fluoro-quinolin-4-yl) -vinyl ] -Tetrahydro-pyran-3-yl} -amine;
-[(E) -3- (2,5-Difluoro-phenyl) -allyl]-{(3S, 6R) -6- [2- (6-Fluoro-quinolin-4-yl) -ethyl] -tetrahydro- Pyran-3-yl} -amine; and
-6-({3S, 6R) -6- [2- (6-Fluoro-quinolin-4-yl) -ethyl] -tetrahydro-pyran-3-ylamino} -methyl) -4H-pyrido [3,2- b] [1,4] thiazin-3-one. 2. A compound according to claim 1 or a salt of one of these compounds, selected from the group consisting of:
-(E) -2-{(2R, 3R, 6R)-(3- [3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy- [1,5] Naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -ethanol;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -acryloylamino] -6- [2- (3-methoxy-quinolin-5-yl)- Ethyl] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy- [1,5] naphthyridine-4 -Yl) -ethyl] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(1S) -1-hydroxy-2- (6-methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetic acid;
-(1R) -2-{(2S, 5R, 6S) -5- [trans-3- (2,5-difluoro-phenyl) -allylamino] -6-hydroxymethyl-tetrahydro-pyran-2-yl}- 1- (3-fluoro-6-methoxy-quinolin-4-yl) -ethanol;
-(1S) -2-{(2S, 5R, 6S) -5- [trans-3- (2,5-difluoro-phenyl) -allylamino] -6-hydroxymethyl-tetrahydro-pyran-2-yl}- 1- (3-fluoro-6-methoxy-quinolin-4-yl) -ethanol;
-2-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy- [1,5] naphthyridine -4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(1R, 2R) -1,2-dihydroxy-2 -(3-methoxy-quinoxalin-5-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy-quinolin-4-yl) -ethyl ] -Tetrahydro-pyran-2-yl} -acetic acid;
-2-{(2R, 3R, 6R) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- [2- (6-methoxy-quinolin-4-yl) -Ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(S) -1-hydroxy-2- (6- Methoxy- [1,5] naphthyridin-4-yl) -ethyl] -tetrahydro-pyran-2-yl} -acetamide;
-3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2R) -2- (3-fluoro-6-methoxy-quinolin-4-yl) -2 -Hydroxy-ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2S) -2- (3-fluoro-6-methoxy-quinolin-4-yl) -2 -Hydroxy-ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2R) -2-hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl ] -2-Hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-3- (2,5-difluoro-phenyl) -N-{(2S, 3R, 6S) -6-[(2S) -2-hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl ] -2-Hydroxymethyl-tetrahydro-pyran-3-yl}-(E) -acrylamide;
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (3-fluoro-6- Methoxy- [1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetamide;
-(2S, 5R, 6R)-(5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6- (2-hydroxy-ethyl))-tetrahydro-pyran-2-carboxylic Acid (6-methoxy- [1,5] naphthyridin-4-yl) -amide;
-(2S, 5R) -5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -tetrahydro-pyran-2-carboxylic acid (6-methoxy- [1,5] naphthyridine-4 -Yl) -amide;
-(1S) -1-{(2S, 5R) -5-[(E) -3- (3-Fluoro-phenyl) -allylamino] -tetrahydro-pyran-2-yl} -2- (6-methoxy- Quinolin-4-yl) -ethanol;
-3- (2-Fluoro-phenyl) -N-{(3R, 6S) -6-[(1S) -1-hydroxy-2- (6-methoxy-quinolin-4-yl) -ethyl] -tetrahydro- Pyran-3-yl}-(E) -acrylamide;
-3- (3-Fluoro-phenyl) -N-{(3R, 6S) -6-[(1S) -1-hydroxy-2- (6-methoxy-quinolin-4-yl) -ethyl] -tetrahydro- Pyran-3-yl}-(E) -acrylamide;
-8-((1R, 2R) -2-{(2S, 5R) -5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -tetrahydro-pyran-2-yl}- 1,2-dihydroxy-ethyl) -quinoline-2-carbonitrile;
-[(E) -3- (2,5-difluoro-phenyl) -allyl]-{3R, 6S) -6-[(E) -2- (3-fluoro-6-methoxy-quinolin-5-yl ) -Vinyl] -tetrahydro-pyran-3-yl} -amine;
-[(E) -3- (2,5-difluoro-phenyl) -allyl]-{(3R, 6S) -6- [2- (6-fluoro-3-methoxy-quinolin-4-yl) -ethyl ] -Tetrahydro-pyran-3-yl} -amine;
-(1R, 2R) -1-{(2R, 5S) -5-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -tetrahydro-pyran-2-yl} -2- ( 6-Fluoro-quinolin-4-yl) -ethane-1,2-diol;
-[(E) -3- (2,5-Difluoro-phenyl) -allyl]-{(3S, 6R)-(E) -6- [2- (6-Fluoro-quinolin-4-yl) -vinyl ] -Tetrahydro-pyran-3-yl} -amine;
-[(E) -3- (2,5-Difluoro-phenyl) -allyl]-{(3S, 6R) -6- [2- (6-Fluoro-quinolin-4-yl) -ethyl] -tetrahydro- Pyran-3-yl} -amine;
-6-({3S, 6R) -6- [2- (6-Fluoro-quinolin-4-yl) -ethyl] -tetrahydro-pyran-3-ylamino} -methyl) -4H-pyrido [3,2- b] [1,4] thiazin-3-one;
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (6-methoxy- [1 , 5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetamide;
-(2R, 3R, 6S)-{3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (3-fluoro-6-methoxy- Quinolin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (6-methoxy- [1,5 ] Naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetic acid. 4. A compound according to claim 3 or a salt of one of these compounds, selected from the group consisting of:
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (3-fluoro-6- Methoxy- [1,5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetamide;
-[(E) -3- (2,5-difluoro-phenyl) -allyl]-{3R, 6S) -6-[(E) -2- (3-fluoro-6-methoxy-quinolin-5-yl ) -Vinyl] -tetrahydro-pyran-3-yl} -amine;
-[(E) -3- (2,5-Difluoro-phenyl) -allyl]-{(3S, 6R)-(E) -6- [2- (6-Fluoro-quinolin-4-yl) -vinyl ] -Tetrahydro-pyran-3-yl} -amine;
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (6-methoxy- [1 , 5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetamide;
-(2R, 3R, 6S)-{3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (3-fluoro-6-methoxy- Quinolin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (6-methoxy- [1,5 ] Naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetic acid. 5. A compound according to claim 4 or a salt of one of these compounds, selected from the group consisting of:
-2-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (6-methoxy- [1 , 5] naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetamide;
-(2R, 3R, 6S)-{3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (3-fluoro-6-methoxy- Quinolin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6S) -3-[(E) -3- (2,5-difluoro-phenyl) -allylamino] -6-[(E) -2- (6-methoxy- [1,5 ] Naphthyridin-4-yl) -vinyl] -tetrahydro-pyran-2-yl} -acetic acid. 2. A compound according to claim 1 or a salt of one of these compounds, selected from the group consisting of:
-{(2R, 3R, 6R) -6- [2- (3-methoxy-quinolin-5-yl) -ethyl] -3-[(3-oxo-3,4-dihydro-2H-pyrido [3, 2-b] [1,4] thiazine-6-carbonyl) -amino] -tetrahydro-pyran-2-yl} -acetic acid;
-{(2R, 3R, 6R) -6- [2- (6-Methoxy- [1,5] naphthyridin-4-yl) -ethyl] -3-[(3-oxo-3,4-dihydro-2H -Pyrido [3,2-b] [1,4] thiazin-6-ylmethyl) -amino] -tetrahydro-pyran-2-yl} -acetic acid;
-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2S, 3R, 6S) -6-[(2R) -2- (3-Fluoro-6-methoxy-quinolin-4-yl) -2-hydroxy-ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl} -amide;
-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2S, 3R, 6S) -6-[(2S) -2- (3-Fluoro-6-methoxy-quinolin-4-yl) -2-hydroxy-ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl} -amide;
-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2S, 3R, 6S) -6-[(2R) -2- Hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl} -amide;
-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid {(2S, 3R, 6S) -6-[(2S) -2- Hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl] -2-hydroxymethyl-tetrahydro-pyran-3-yl} -amide;
-7-fluoro-6-({(3R, 6S) -6-[(1S) -1-hydroxy-2- (6-methoxy-quinolin-4-yl) -ethyl] -tetrahydro-pyran-3-ylamino } -Methyl) -4H-benzo [1,4] thiazin-3-one;
-6-({(3R, 6S) -6- [2- (6-Fluoro-3-methoxy-quinolin-4-yl) -ethyl] -tetrahydro-pyran-3-ylamino} -methyl) -4H-pyrido [3,2-b] [1,4] thiazin-3-one;
-6-({3S, 6R) -6- [2- (6-Fluoro-quinolin-4-yl) -ethyl] -tetrahydro-pyran-3-ylamino} -methyl) -4H-pyrido [3,2- b] [1,4] thiazin-3-one.   7. A compound as defined in any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as a medicament.   A pharmaceutical composition comprising as an active ingredient a compound as defined in any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof and at least one therapeutically inert excipient.   Use of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of infection.