Note: Descriptions are shown in the official language in which they were submitted.
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
ANTIBIOTIC COMPOUNDS
The present invention concerns novel antibiotics, pharmaceutical antibacterial
compositions
containing them and the use thereof in the manufacture of a medicament for the
treatment of
infections (e.g. bacterial infections). These compounds are useful
antimicrobial agents
effective against a variety of human and veterinary pathogens including among
others Gram
positive and Gram negative aerobic and anaerobic bacteria and mycobacteria.
The intensive use of antibiotics has exerted a selective evolutionary pressure
on
micro-organisms to produce genetically based resistance mechanisms. Modern
medicine and
socio-economic behaviour exacerbates the problem of resistance development by
creating
slow growth situations for pathogenic microbes, e.g. in artificial joints, and
by supporting
long-term host reservoirs, e.g. in immuno-compromised patients.
In hospital settings, an increasing number of strains of Staphylococcus
aureus, Streptococcus
pneumoniae, Enterococcus spp., and Pseudomonas aeruginosa, major sources of
infections,
are becoming multi-drug resistant and therefore difficult if not impossible to
treat:
- S. aureus is resistant to B-lactam and quinolone antibiotics and now even to
vancomycin;
- S. pneumoniae is becoming resistant to penicillin and quinolone antibiotics
and even to new
macrolides;
- Enteroccocci are quinolone and vancomycin resistant and B-lactam antibiotics
are
inefficacious against these strains;
- Enterobacteriacea are cephalosporin and quinolone resistant;
- P. aeruginosa are 13-lactam and quinolone resistant.
Further new emerging organisms like Acinetobacter spp. or C. difficile, which
have been
selected during therapy with the currently used antibiotics, are becoming a
real problem in
hospital settings.
In addition, microorganisms that are causing persistent infections are
increasingly being
recognized as causative agents or cofactors of severe chronic diseases like
peptic ulcers or
heart diseases.
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-2-
A new type of quinoline or naphthyridine derivatives having antibacterial
activity and
therefore useful for treating infections in mammals, particularly in humans,
has been reported
in the last few years.
WO 99/37635, WO 00/21948, WO 00/21952, WO 00/43383, WO 03/101138,
WO 01/025227, WO 02/040474 and WO 2004/011454 disclose quinoline,
naphthyridine and
quinazoline derivatives containing a 4-methylpiperidinyl spacer.
WO 00/78748, WO 02/50040 and WO 02/050061 disclose quinoline and naphthyridine
derivatives containing a piperazinyl spacer.
WO 01/07432, WO 01/07433, WO 02/08224, WO 02/056882, WO 03/064421,
WO 03/06443 1, WO 2004/02490 and WO 2004/058144 disclose quinoline,
quinoxaline and
naphthyridine derivatives containing a 4-aminopiperidinyl spacer.
WO 04/035569 and WO 2006/014580 disclose quinoline and naphthyridine
derivatives
containing a 3-aminomethylpiperidinyl spacer.
WO 2004/002992, WO 03/087098, WO 2004/014361 and WO 2004/035569 disclose
quinoline, quinoxaline and naphthyridine derivatives containing a 4-
aminocyclohexyl spacer.
In addition, PCT application No. PCT/EP2005/010154 (published as WO
2006/032466)
describes certain bicyclic derivatives as useful antimicrobial agents that are
effective against a
variety of multi-drug resistant bacteria. Said bicyclic derivatives have the
formula (Al)
Ri
V U
W\ M-D
X (Ai)
wherein R' represents alkyl, alkoxy, haloalkoxy, halogen or cyano;
one or two of U, V, W and X represent(s) N, the remaining represent CH, or, in
the case of U,
V and/or W, may also represent CRa and, in the case of X, may also represent
CRb;
Ra represents halogen;
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-3-
Rb represents halogen or alkoxy;
D represents alkyl, aryl or heteroaryl;
M is notably the group M2:
R2
O R5
M2 = --A3 I _
N - A4 ~-
R3 R4
wherein
A3 represents NHCO, CH2CH2, CH=CH, COCH2, CH(OH)CH2, CH2CH(OH),
CH(OH)CH(OH) or OCH2;
A4 represents CH2, CO, CH2CH=CH, COCH=CH or CH2CONH;
R2 represents hydrogen, alkyl, hydroxyalkyl, alkylcarbonyloxyalkyl,
carbamoyloxyalkyl,
carboxyalkyl or carbamoylalkyl;
R3 and R4 each independently represent hydrogen, hydroxy or alkylcarbonyloxy;
or R3 and R4
together represent a bridged dimethylmethylenedioxy chain attached to the
carbons bearing R3
and R4;
R5 represents hydrogen, alkyl or hydroxyalkyl; and
the dotted line represents a single bond or, when R3 and R4 represent
hydrogen, also a double
bond.
This invention relates to selected compounds of formula (Al) as described
above and salts
thereof.
Thus, the compounds of this invention are selected from the following:
- (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;
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-4-
- {(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;
- {(2R,3R,6R)-3-[(E)-3-(2,5-difluoro-phenyl)-allylamino]-6-[(1S)-l-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]naphthyridin-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)-l-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;
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-5-
- 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 ]naphthyridin-4-yl)-amide;
- (1S)-l-{(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)-l-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)-l-hydroxy-2-(6-methoxy-quinolin-4-yl)-
ethyl]-
tetrahydro-pyran-3-yl}-(E)-acrylamide;
- 3-(3-fluoro-phenyl)-N-{(3R,6S)-6-[(1S)-l-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)-l-{(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;
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-6-
- [(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;
and salts thereof.
The invention relates in particular to compounds selected from the following:
- (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]naphthyridin-
4-yl)-ethyl]-tetrahydro-pyran-2-yl}-acetic acid;
- {(2R,3R,6R)-3-[(E)-3-(2,5-difluoro-phenyl)-allylamino]-6-[(1S)-l-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;
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-7-
- (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]naphthyridin-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)-l-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;
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-8-
- 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 ]naphthyridin-4-yl)-amide;
- (1S)-l-{(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)-l-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)-l-hydroxy-2-(6-methoxy-quinolin-4-yl)-
ethyl]-
tetrahydro-pyran-3-yl}-(E)-acrylamide;
- 3-(3-fluoro-phenyl)-N-{(3R,6S)-6-[(1S)-l-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)-l-{(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;
and to salts thereof.
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-9-
The following invention compounds 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 embodiment, the compounds of this invention will be
selected from the
following:
- (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]naphthyridin-
4-yl)-ethyl]-tetrahydro-pyran-2-yl}-acetic acid;
- {(2R,3R,6R)-3-[(E)-3-(2,5-difluoro-phenyl)-allylamino]-6-[(1S)-l-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]naphthyridin-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;
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-10-
- 2-{(2R,3R,6S)-3-[(E)-3-(2,5-difluoro-phenyl)-allylamino]-6-[(S)-l-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 ]naphthyridin-4-yl)-amide;
- (1S)-l-{(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)-l-hydroxy-2-(6-methoxy-quinolin-4-yl)-
ethyl]-
tetrahydro-pyran-3-yl}-(E)-acrylamide;
- 3-(3-fluoro-phenyl)-N-{(3R,6S)-6-[(1S)-l-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)-l-{(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;
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-11-
- [(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 will be salts of these compounds.
According to said first embodiment, the compounds of this invention will in
particular be
selected from the following:
- (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]naphthyridin-
4-yl)-ethyl]-tetrahydro-pyran-2-yl}-acetic acid;
- {(2R,3R,6R)-3-[(E)-3-(2,5-difluoro-phenyl)-allylamino]-6-[(1S)-l-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]naphthyridin-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;
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-12-
- 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)-l-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 ]naphthyridin-4-yl)-amide;
- (1S)-l-{(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)-l-hydroxy-2-(6-methoxy-quinolin-4-yl)-
ethyl]-
tetrahydro-pyran-3-yl}-(E)-acrylamide;
- 3-(3-fluoro-phenyl)-N-{(3R,6S)-6-[(1S)-l-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)-l-{(2R,5S)-5-[(E)-3-(2,5-difluoro-phenyl)-allylamino]-tetrahydro-
pyran-2-yl}-
2-(6-fluoro-quinolin-4-yl)-ethane-1,2-diol;
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-13-
- [(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 will be salts of these compounds.
According to said first embodiment, the compounds of this invention can also
be selected
from the following:
- 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 be salts of these compounds.
According to one variant of this first embodiment, the compounds of this
invention will be
selected from the following:
- (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]naphthyridin-
4-yl)-ethyl]-tetrahydro-pyran-2-yl}-acetic acid;
- {(2R,3R,6R)-3-[(E)-3-(2,5-difluoro-phenyl)-allylamino]-6-[(1S)-l-hydroxy-2-
(6-methoxy-
[1,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-2-yl}-acetic acid;
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-14-
- (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]naphthyridin-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)-l-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 ]naphthyridin-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;
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-15-
- [(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)-l-{(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 will be salts of these compounds.
According to said variant of this first embodiment, the compounds of this
invention will in
particular be selected from the following:
- 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 will be salts of these compounds.
According to another variant of this first embodiment, the compounds of this
invention will
be selected from the following:
- (1S)-l-{(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)-l-hydroxy-2-(6-methoxy-quinolin-4-yl)-
ethyl]-
tetrahydro-pyran-3-yl}-(E)-acrylamide;
- 3-(3-fluoro-phenyl)-N-{(3R,6S)-6-[(1S)-l-hydroxy-2-(6-methoxy-quinolin-4-yl)-
ethyl]-
tetrahydro-pyran-3-yl}-(E)-acrylamide;
or will be salts of these compounds.
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-16-
According to a second embodiment, the compounds of this invention will be
selected from the
following:
- {(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)-l-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 will be salts of these compounds.
The compounds of this invention are suitable for the use as chemotherapeutic
active
compounds in human and veterinary medicine and as substances for preserving
inorganic and
organic materials in particular all types of organic materials for example
polymers, lubricants,
paints, fibres, leather, paper and wood.
These compounds according to the invention are particularly active against
bacteria and
bacteria-like organisms. They are therefore particularly suitable in human and
veterinary
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-17-
medicine for the prophylaxis and chemotherapy of local and systemic infections
caused by
these pathogens as well as disorders related to bacterial infections
comprising pneumonia,
otitis media, sinusitis, bronchitis, tonsillitis, and mastoiditis related to
infection by
Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis,
Staphylococcus
aureus, Enterococcus faecalis, E. faecium, E. casselif avus, S. epidermidis,
S. haemolyticus,
or Peptostreptococcus spp.; pharyngitis, rheumatic fever, and
glomerulonephritis related to
infection by Streptococcus pyogenes, Groups C and G streptococci,
Corynebacterium
diphtheriae, or Actinobacillus haemolyticum; respiratory tract infections
related to infection
by Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae,
Haemophilus influenzae, or Chlamydia pneumoniae; blood and tissue infections,
including
endocarditis and osteomyelitis, caused by S. aureus, S. haemolyticus, E.
faecalis, E. faecium,
E. durans, including strains resistant to known antibacterials such as, but
not limited to, beta-
lactams, vancomycin, aminoglycosides, quinolones, chloramphenicol,
tetracyclines and
macrolides; uncomplicated skin and soft tissue infections and abscesses, and
puerperal fever
related to infection by Staphylococcus aureus, coagulase-negative
staphylococci (i.e., S.
epidermidis, S. haemolyticus, etc.), Streptococcus pyogenes, Streptococcus
agalactiae,
Streptococcal groups C-F (minute colony streptococci), viridans streptococci,
Corynebacterium minutissimum, Clostridium spp., or Bartonella henselae;
uncomplicated
acute urinary tract infections related to infection by Staphylococcus aureus,
coagulase-negative staphylococcal species, or Enterococcus spp.; urethritis
and cervicitis;
sexually transmitted diseases related to infection by Chlamydia trachomatis,
Haemophilus
ducreyi, Treponema pallidum, Ureaplasma urealyticum, or Neiserria gonorrheae;
toxin
diseases related to infection by S. aureus (food poisoning and toxic shock
syndrome), or
Groups A, B, and C streptococci; ulcers related to infection by Helicobacter
pylori; systemic
febrile syndromes related to infection by Borrelia recurrentis; Lyme disease
related to
infection by Borrelia burgdorferi; conjunctivitis, keratitis, and
dacrocystitis related to
infection by Chlamydia trachomatis, Neisseria gonorrhoeae, S. aureus, S.
pneumoniae, S.
pyogenes, H. influenzae, or Listeria spp.; disseminated Mycobacterium avium
complex
(MAC) disease related to infection by Mycobacterium avium, or Mycobacterium
intracellulare; infections caused by Mycobacterium tuberculosis, M. leprae, M.
paratuberculosis, M. kansasii, or M. chelonei; gastroenteritis related to
infection by
Campylobacter jejuni; intestinal protozoa related to infection by
Cryptosporidium spp.;
odontogenic infection related to infection by viridans streptococci;
persistent cough related to
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-18-
infection by Bordetella pertussis; gas gangrene related to infection by
Clostridium
perfringens or Bacteroides spp.; and atherosclerosis or cardiovascular disease
related to
infection by Helicobacter pylori or Chlamydia pneumoniae.
The compounds according to this invention are further useful for the
preparation of a
medicament for the treatment of infections that are mediated by bacteria such
as E. coli,
Klebsiella pneumoniae and other Enterobacteriaceae, Acinetobacter spp.,
Stenothrophomonas
maltophilia, Neisseria meningitidis, Bacillus cereus, Bacillus anthracis,
Corynebacterium
spp., Propionibacterium acnes and bacteroide spp.
The compounds according to this invention are further useful to treat
protozoal infections
caused by Plasmodium malaria, Plasmodium falciparum, Toxoplasma gondii,
Pneumocystis
carinii, Trypanosoma brucei and Leishmania spp.
The present list of pathogens is to be interpreted merely as examples and in
no way as
limiting.
As well as in humans, bacterial infections can also be treated in other
species like pigs,
ruminants, horses, dogs, cats and poultry.
The present invention also relates to pharmacologically acceptable salts, or
solvates and
hydrates, respectively, and to compositions and formulations of the compounds
mentioned
above.
Examples of pharmacologically acceptable salts of sufficiently basic compounds
of this
invention are selected from the group consisting of salts of physiologically
acceptable mineral
acids like hydrochloric, hydrobromic, sulfuric and phosphoric acid; or salts
of organic acids
like methanesulfonic, p-toluenesulfonic, lactic, acetic, trifluoroacetic,
citric, succinic, fumaric,
maleic and salicylic acid. Further, a sufficiently acidic compound of this
invention may form
alkali or earth alkaline metal salts, for example sodium, potassium, lithium,
calcium or
magnesium salts; ammonium salts; or organic base salts, for example
methylamine,
dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine,
choline
hydroxide, meglumin, piperidine, morpholine, tris-(2-hydroxyethyl)amine,
lysine or arginine
salts. The compounds of this invention may be solvated, especially hydrated.
The hydratation
can occur during the process of production or as a consequence of the
hygroscopic nature of
the initially water free compounds of this invention.
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-19-
The pharmaceutical composition according to the present invention contains at
least one
compound of one of the above compound lists (or a pharmaceutically acceptable
salt thereof)
as the active agent and optionally carriers and/or diluents and/or adjuvants,
and may also
contain additional known antibiotics.
As mentioned above, therapeutically useful agents that contain compounds
according to this
invention, their solvates, salts or formulations are also comprised in the
scope of the present
invention. In general, the compounds according to this invention will be
administered by
using the known and acceptable modes known in the art, either alone or in
combination with
any other therapeutic agent. Such therapeutically useful agents can be
administered by one of
the following routes: oral, e.g. as tablets, dragee, coated tablets, pills,
semisolids, soft or hard
capsules, for example soft and hard gelatine capsules, aqueous or oily
solutions, emulsions,
suspensions or syrups, parenteral including intravenous, intramuscular and
subcutaneous
injection, e.g. as an injectable solution or suspension, rectal as
suppositories, by inhalation or
insufflation, e.g. as a powder formulation, as microcrystal or as a spray
(e.g. liquid aerosol),
transdermal, for example via an transdermal delivery system (TDS) such as a
plaster
containing the active ingredient, topical or intranasal. The substance of the
present invention
can also be used to impregnate or coated devices that are foreseen for
implantation like
catheters or artificial joints. The pharmaceutically useful agents may also
contain additives for
conservation, stabilisation, e.g. UV stabilizers, emulsifiers, sweetener,
aromatisers, salts to
change the osmotic pressure, buffers, coating additives and antioxidants.
Another aspect of the invention concerns a method for the treatment of disease
comprising the
administration to the patient of a pharmaceutically active amount of a
compound according to
this invention (or a pharmaceutically acceptable salt thereof).
Moreover, the compounds according to this invention may also be used for
cleaning purposes,
e.g. to remove pathogenic microbes and bacteria from surgical instruments or
to make a room
or an area aseptic. For such purposes, the compounds according to this
invention could be
contained in a solution or in a spray formulation.
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-20-
PREPARATION OF THE COMPOUNDS OF THIS INVENTION
Abbreviations:
The following abbreviations are used:
AcOH acetic acid
AD-mix a 1,4-bis(dihydroquinine)phthalazine, K3Fe(CN)6, K2C03 and
K20s04.2H20
AD-mix 1,4-bis(dihydroquinidine)phthalazine, K3Fe(CN)6, K2C03 and
K20s04.2H20
AIBN 2,2'-azoisobutyronitrile
aq. aqueous
BINAP 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl
Boc2O di-tert-butyl dicarbonate
dba dibenzylideneacetone
DCC dicyclohexyl carbodiimide
1,2-DCE 1,2-dichloroethane
DCM dichloromethane
(DHQ)2PHAL 1,4-bis(dihydroquinine)phthalazine
(DHQD)2PHAL 1,4-bis(dihydroquinidine)phthalazine
DIAD diisopropyl azodicarboxylate
DIBAH diisobutylaluminium hydride
DIPA diisopropylamine
DIPEA N,N-diisopropylethylamine
DMAP 4-dimethylaminopyridine
1,2-DME 1,2-dimethoxyethane
DMF N,N-dimethylformamide
DMSO dimethylsulfoxide
DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidone
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-21-
EA ethyl acetate
ESI electron spray ionisation
ether or Et20 diethyl ether
EtOH ethanol
h hour(s)
HATU O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate
Hept heptane
Hex hexane
HV high vacuum conditions
KHMDS potassium hexamethyldisilazide
MeOH methanol
min minute(s)
MCPBA meta-chloroperbenzoic acid
MeCN acetonitrile
MeOH methanol
MS mass spectroscopy
NB S N-bromosuccinimide
NHS N-hydroxysuccinimide
n-BuLi n-butyl lithium
org. organic
Pd/C palladium on carbon
PPh3 triphenylphosphine
PTSA para-toluene sulfonic acid
quant. quantitative
rac racemic
Rf retention factor
sat. saturated
Si0z silica gel
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-22-
rt room temperature
TBAF tetrabutylammonium fluoride
TEA triethylamine
TFA trifluoroacetic acid
THF tetrahydrofuran
TsC1 para-toluene sulfonyl chloride
wt% weight percent
Preparation methods:
The compounds of this invention can be prepared according to the procedures
described in the
examples hereafter which illustrate the preparation of the pharmacologically
active
compounds of the invention but do not limit the scope thereof.
Whenever the invention compounds are obtained in the form of mixtures of
enantiomers, the
enantiomers can be separated using methods known to one skilled in the art
(e.g. by formation
and separation of diastereomeric salts or by chromatography on a chiral
stationary phase).
Whenever the invention compounds are obtained in the form of mixtures of
diasteromers they
may be separated by an appropriate combination of silica gel chromatography,
high
performance liquid chromatography (HPLC) and crystallization techniques.
EXAMPLES
All temperatures are stated in C. All analytical and preparative HPLC
investigations on non-
chiral phases are performed using RP-C18 based columns. Analytical HPLC
investigations
are performed on two different instruments with cycle-times of -2.5 min and -
3.5 min
respectively.
Preparation A: 3-methoxy-quinoline-5-carbaldehyde:
A.i. 3,5-dibromoquinoline:
To concentrated H2SO4 (130 ml) was added dropwise at 0 C, over 80 min, 3-
bromoquinoline
(50 g) at a rate allowing the internal temperature to be maintained between 0
and 10 C. After
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-23-
the addition was complete, NBS (48 g) was added portionwise and the reaction
mixture was
stirred at rt overnight. The reaction mixture was poured onto ice (2 1) and
the resulting solid
was dissolved in DCM (600 ml). The aq. layer was further extracted with DCM
(600 ml) and
the combined extracts were washed with 1MNaOH (300 mL) and concentrated in
vacuo. The
residue was dispersed in Si02 and the resulting dispersal was loaded on the
top of a column
and eluted with a DCM-Hex (1-1, 3 1) then DCM (3 1) and finally DCM-ether (1-
1, 2 1). The
title compound was recovered from the last fraction after evaporation to yield
40 g of a white
solid.
iH NMR (CDC13) 8: 8.94 (d, J = 2.2 Hz, 1H); 8.73 (d, J = 2.2 Hz, 1H); 8.08 (d,
J = 8.5 Hz,
1 H); 7.88 (d, J = 7.5 Hz, 1 H); 7.62 (dd, J = 7.5, 8.5 Hz, 1 H).
A.H. 5-bromo-3-methoxyquinoline:
To a mixture of sodium methoxide (14.5 g) in DMPU (350 ml) heated at 125 C,
was added in
one portion intermediate A.i (34.5 g). The reaction was then heated at the
same temperature
for 1 h. The reaction mixture was then cooled to rt and poured onto ice (300
g). After the ice
melt, the solid was filtered off and dried under vacuum. The filtrate was
extracted with ether
(4 x 150 ml). The combined extracts were washed with brine and dried over
Na2SO4. After
filtration, the solvent was evaporated and the residue was purified over Si02
(Hex-EA 4-1) to
afford a material that was pooled with the solid. The material was dissolved
in DCM and
dried over Na2SO4. After filtration and evaporation, the solid was further
dried under HV to
afford the title compound (24.5 g) as a beige solid.
iH NMR (CDC13) 8: 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-quinoline-5-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 min, a solution of DMF (10 ml) in ether (20 ml) was quickly
added. The
solution was stirred 15 min and EtOH (5 ml), followed by 1M NaHSO4 (40 ml),
was added.
After warming to rt, the organic layer was diluted with EA (100 ml). The two
layers were
separated and the aq. layer was extracted once with EA (100 ml). The combined
org. layers
were washed with brine and concentrated to dryness. The residue was
chromatographed over
Si0z (EA-Hex 1-2 then 1-1) to afford the title compound (4.75 g) as a
yellowish solid.
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-24-
iH NMR (CDC13) 8: 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+].
Preparation B: 6-methoxy-[1,5]naphthyridine-4-carbaldehyde:
B.i. 2-methoxy-8-styryl-[1,5]naphthyridine:
Trifluoromethanesulfonic acid 6-methoxy-[1,5]naphthyridin-4-yl ester (1.5 g,
4.86 mmol),
trans-phenylvinyl boronic acid (0.8 g, 5.35 mmol) and K2C03 (0.9 g, 6.32 mmol)
were
introduced in a two-neck flask. The atmosphere was flushed with nitrogen.
Dioxane (20 ml)
and water (5 ml) were added. The mixture was stirred at rt for 5 min and
(P(Ph)3)4Pd (0.28 g,
0.24 mmol) was added. The mixture was heated at reflux for 5 h. After cooling,
the reaction
mixture was diluted with EA (10 ml) and water (50 ml). The aqueous layer was
extracted with
EA (2 x 100 ml). The combined extracts were concentrated to dryness. The
residue was
chromatographed over Si0z (Hex-EA 1-1) to afford the title alkene (1.26 g, 4.8
mmol) as an
oil that crystallized on standing.
iH NMR (d6-DMSO) 8: 8.77 (d, J = 4.7 Hz, 1H); 8.28 (d, J = 9.0 Hz, 1H); 8.19
(d,
J = 16.7 Hz, 1 H); 8.01 (d, J = 4.7 Hz, 1 H); 7.91 (d, J = 16.7 Hz, 1 H); 7.74
(m, 2H);
7.40-7.34 (m, 3H); 7.30 (d, J = 9.0 Hz, 1H); 4.12 (s, 3H).
B.H. 1-(6-methoxy-[1,5]naphthyridin-4 yl)-2 phenyl-ethane-1,2-diol:
To a mixture of intermediate B.i (1.26 g, 4.8 mmol) in 2-methyl-2-propanol (24
ml) and water
(24 ml) were added methanesulfonamide (0.52 g) and AD mix (3 (7 g). The
mixture was
stirred at rt for 12 h. Sodium bisulfite (7.5 g) was added carefully and
stirring was continued
20 min. The two layers were decanted and the aqueous layer was extracted with
EA
(2 x 100 ml). The combined organic layers were dried over NazSO4, filtered and
concentrated
to dryness. The residue was triturated in Hex-EA (1-3, 30 ml) and the
resulting solid was
filtered off and dried in vacuo to afford the title diol (1.3 g) as a white
solid.
MS (ESI, m/z): 297.1 [M+H+].
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 Na104 (2.35 g, 10.96 mmol) in water (5 ml). The reaction mixture was
stirred at rt for
30 min. The reaction mixture was diluted with THF (100 ml) and the solids were
filtered off.
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-25-
The filtrate was concentrated to dryness and the residue was resuspended in
water (100 ml),
ether (10 ml) and Hex (100 ml). The slurry was stirred at rt for 15 min and
filtered. The solids
were washed with water and Hex. After drying, the title aldehyde (0.42 g) was
recovered as a
white solid.
iH NMR (d6-DMSO) 8: 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).
Preparation C: (E)-3-(2,5-difluoro-phenyl)-propenal:
C.i. (E)-3-(2,5-difluoro-phenyl)-acrylic acid ethyl ester:
To an iced chilled suspension of NaH (1.13 g, 60% in oil dispersion, 28.2
mmol) in THF
(32 ml) was added triethylphosphonoacetate (5.6 ml, 28.2 mmol). The reaction
mixture was
stirred at rt for 20 min. 2,5-difluoro-benzaldehyde (3.34 g, 23.5 mol) was
added dropwise.
After 30 min, 10% aq. NaHSO4 (100 ml) was added and the mixture was diluted
with EA
(150 ml). The two phases were separated and the aq. layer was extracted twice
(2 x 100 ml).
The combined org. layers were washed with brine (100 ml), dried over Na2SO4,
filtered and
concentrated to dryness. The residue was chromatographed over Si02 (Hex-EA 19-
1) to
afford the title unsaturated ester (5.0 g, 100%) as colourless oil.
iH NMR (CDC13): 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 = 16.1Hz, 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-l-ol:
To a solution of intermediate C.i (5.0 g, 23.5 mmol) in ether (100 ml), cooled
to 0 C, was
added a DIBAH (1M in Hex, 60 ml, 60 mmol). The mixture was stirred at the same
temperature for 40 min. Water (6 ml) was added and the mixture was stirred 30
min. The solid
was filtered off and thoroughly washed with ether. The filtrate was
concentrated to dryness to
afford the title alcohol (4.0 g, 98% yield) as colorless oil.
iH NMR (CDC13): 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, 1 H).
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) was added
at rt, a
solution of Dess-Martin periodinane (15 wt% in DCM, 20 ml). The mixture was
stirred at rt
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-26-
for 3 h. After concentration to dryness, the residue was chromatographed over
Si02 (Hex-EA
9-1) to afford the title aldehyde (1.06 g, 63% yield) as a white solid.
iH 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, 1 H).
Preparation D: 3-methoxy-quinoxaline-5-carbaldehyde:
D.i. 2-cyano-N-(2-methyl-6-nitro-phenyl)-acetamide:
To a solution of 2-methyl-6-nitroaniline (25 g, 164.3 mmol) in benzene (200
ml) were added
cyanoacetic acid (14.5 g, 170.46 mmol) and PC15 (35 g, 168 mmol). The reaction
mixture was
heated at 60 C for 7 h. After cooling to rt, the reaction mixture was filtered
and the solid was
washed with benzene and water. The solid was dried under reduced pressure to
afford the title
acetamide (24 g, 109 mmol) as a yellow solid.
iH NMR (d6-DMSO) 8: 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.H. 3-hydroxy-5-methyl-l-oxy-quinoxaline-2-carbonitrile:
To a solution mixture of intermediate D.i (24 g, 109.5 mmol) in 1M aq. NaOH
(100 ml) was
added pyridine (100 ml). The reaction mixture was stirred at rt for 4 h. The
pH was adjusted
to 6 by addition of 1M aq. HC1. The solid was filtered off and washed with
water. The solid
was triturated with EtOH. After drying under HV, the title nitrile (17.7 g,
87.9 mmol) was
obtained as a yellow solid.
MS (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 h. The reaction mixture was filtered till warm, and the pH of the
filtrate was adjusted to
2 by adding 1M aq. HC1. The pH of the solution was subsequently made basic by
adding solid
NaOH (10 g). EA (150 ml) was added. The aq. layer was extracted twice more
with EA
(2 x 150 ml). The combined organic extracts were dried over NazSO4, filtered
and
concentrated to dryness. The residue was dried under HV to afford the title
intermediate
(11.1 g, 69 mmol) as a yellow solid.
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-27-
iH NMR (d6-DMSO) 8: 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 (1 l.l g, 69.5 mmol) in phosphorus
oxychloride (80 ml) was
heated at 110 C during 2 h. After cooling to rt, the reaction mixture was
poured onto ice
(200 g). The aqueous layer was extracted with EA (2 x 200 ml). The combined
extracts were
washed with brine (100 ml), dried over NazSO4, filtered and concentrated to
dryness. The
residue was chromatographed over silica gel (Hex-EA 1-1) to afford the title
intermediate
(12.5 g, 69.5 mmol) as a red solid.
iH NMR (d6-DMSO) 8: 8.99 (s, 1H); 7.97 (m, 1H); 7.80 (m, 2H); 2.68 (s, 3H).
MS (ESI, m/z): 179.2 [M+H]+.
D.v. 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 h.
After cooling to
rt, 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 NazSO4, filtered and
concentrated to
dryness. The residue was chromatographed over silica gel (Hex-EA 1-4) to
afford the title
intermediate (10.2 g, 58.55 mmol) as a yellow solid.
'H NMR (CDC13) 8: 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 D.v (10.2 g) in CC14 (560 ml) were added AIBN
(0.96 g) and
NBS (25.9 g, 145.5 mmol). The reaction mixture was heated at 80 C for 3 h.
After cooling to
rt, the reaction mixture was washed with water (200 ml) and the organic layer
was dried over
NazSO4, filtered and concentrated in vacuo. The residue was triturated with
MeOH to give,
after drying under HV, the title dibromide (14.4 g, 43.3 mmol) as a slightly
beige solid.
iH NMR (d6-DMSO) 8: 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]+.
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-28-
D.vii. 3-methoxy-quinoxaline-5-carbaldehyde:
To a solution of intermediate D.vi (10.7 g, 32.2 mmol) in EtOH (330 ml) was
added, at rt, a
solution of silver nitrate (15 g) in water (70 ml). The reaction was stirred
at rt for 1 h. The
reaction mixture was diluted with MeCN (200 ml) and the solids were filtered
off and the
filtrate was concentrated in vacuo. The residue was filtered over a silica gel
pad (eluent: EA)
to afford the title aldehyde (6.2 g, 32.2 mmol) as a slightly yellow solid.
iH NMR (d6-DMSO) 8: 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]+.
Preparation E: 3-fluoro-6-methoxy-[1,5] naphthyridine-4-carbaldehyde:
E.i. 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-phenylvinyl boronic acid (4.23 g, 1.05 eq) and K2C03 (4.9 g)
were
introduced in a two-necked flask. The atmosphere was flushed with nitrogen and
dioxane
(40 ml) and water (10 ml) were added. The mixture was stirred at rt for 5 min
and Pd(PPh3)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 x 150
ml). The
combined extracts were washed with brine, dried over NazSO4, filtered and
concentrated to
dryness. The residue was chromatographed (Hept-EA 2-1) to afford the title
compound (7.2 g,
94% yield) as a white solid.
MS (ESI, m/z): 281.0 [M+H]+.
E.H. 1-(3 fluoro-6-methoxy-[1,5]naphthyridin-4 yl)-2 phenyl-ethane-l,2-diol:
The title diol (7.6 g, 94% yield) was obtained as a white foam, starting from
intermediate E.i
(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 an eluent.
iH NMR (CDC13) 8: 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).
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-29-
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 a
solution of Na104 (12.8 g) in water (30 ml). The mixture was stirred at rt for
1 h. The solvent
was removed in vacuo and the residue was diluted with water (500 ml). The
resulting solid
was filtered off, thoroughly washed with water, collected and dried under HV
to afford the
title aldehyde (4.0 g) as a light beige solid.
iH NMR (d6-DMSO) 8: 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]+.
Preparation F: 3-fluoro-6-methoxy-quinoline-5-carbaldehyde:
F.i. 5-bromo-3-fluoro-6-methoxy-quinoline:
To a solution of 3-fluoro-6-methoxy-quinoline (0.89 g) in MeCN (9 ml), cooled
to 0 C, was
added NBS (1 g). The mixture was stirred 2 h at this temperature. The reaction
mixture was
allowed to warm up to rt and proceeded overnight. 10% aq. NaHSO3 (20 ml) was
added. The
mixture was further diluted with water (100 ml) and the resulting solid was
filtered off,
washed with water and dried in vacuo to afford the title compound (1.03 g, 80%
yield) as a
white solid.
iH NMR (d6-DMSO) 8: 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 [M-H+].
F.H. 3-fluoro-6-methoxy-quinoline-5-carbaldehyde:
This aldehyde (0.68 g, 3.31 mmol) was obtained as a white solid, starting from
intermediate
F.i (1.0 g, 3.9 mmol) and using the procedures described in Preparation E,
steps E.i, E.ii and
E.iii.
iH NMR (d6-DMSO) 8: 10.69 (s, 1H); 9.16 (dd, J= 2.9, 11.7 Hz, 1H); 8.88 (d, J=
2.9 Hz,
1 H); 8.3 8 (d, J = 9.0 Hz, 1 H); 7.83 (d, J = 9.0 Hz, 1 H); 4.12 (s, 3H).
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-30-
Preparation G: (3R,6S)-[6-(1-phenyl-lH-tetrazole-5-sulfonylmethyl)-tetrahydro-
pyran-
3-yl]-carbamic acid tert-butyl ester:
G.i. toluene-4-sulfonic acid (2S, 5R)-5-tert-butoxycarbonylamino-tetrahydro
pyran-
2 ylmethyl ester:
To an ice-chilled solution of (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) in DCM
(650 ml) were added TEA (30 ml), DMAP (1.8 g) and TsC1(22.6 g). The reaction
was stirred
at rt for 4 h. Saturated NaHCO3 (100 ml) was added. The volatiles were removed
under
reduced pressure and the residue was taken up in EA (400 ml). The org. layer
was washed
with saturated CuS04 (2 x 150 ml), water (3 x 150 ml) and brine (100 ml). The
org. layer was
dried over NazSO4, filtered and concentrated to dryness to afford after drying
a white solid
(41.8 g) that was carried on without further purification.
G.ii. (3R,6S)-(6-iodomethyl-tetrahydro pyran-3 yl)-carbamic acid tert-butyl
ester:
To a solution of intermediate G.i (18 g, 46.7 mmol) in acetone (200 ml) was
added Nal (20 g).
The reaction mixture was heated at reflux 24 h. After cooling to rt, water
(200 ml) was added
and the volatiles were removed in vacuo. The residue was filtered, thoroughly
washed with
water and Hex and dried under HV to afford the 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-IH-tetrazol-5 ylsulfanylmethyl)-tetrahydro pyran-3
ylJ-carbamic
acid tert-butyl ester:
To a solution of 1-phenyl-lH-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 the
volatiles were removed under reduced pressure. The solid was filtered off,
thoroughly washed
with water and dried under HV to afford the sulphide (13.3 g, quant.) as a
white solid.
MS (ESI, m/z): 392.5 [M+H+].
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-31-
G.iv. (3R,6S)-[6-(1 phenyl-IH-tetrazole-5-sulfonylmethyl)-tetrahydro pyran-3
ylJ-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)
were added ammonium molybdate tetrahydrate (11 g, 8.9 mmol) and then 30% H202
(50 ml).
The mixture was heated at 60 C overnight. The reaction mixture was cooled to
rt, diluted with
water (200 ml) and the volatiles were removed under reduced pressure. The
residue was
partitioned between EA (300 ml) and water (100 ml) and the aq. layer was
extracted with EA
(2 x 300 ml). The combined extracts were concentrated to dryness. The residue
was
resuspended in ether. The solids were filtered off, washed with water and Hex
to afford the
title sulfone (11.8 g, 81 % yield) as a white solid.
iH NMR (CDC13) 8: 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,
1 H).
MS (ESI, m/z): 424.5 [M+H+].
Preparation H: 6-fluoro-quinoline-4-carbaldehyde:
Starting from 4-bromo-6-fluoro-quinoline (see WO 2004/014361 for a
preparation; 6 g,
26.5 mmol), the title aldehyde (4.3 g, 24.5 mmol) was prepared as a beige
solid using the
procedures described in Preparation E, steps E.i, E.ii and E.iii.
iH NMR (d6-DMSO) 8: 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, 9.3 Hz, 1H); 8.11 (d, J = 4.2 Hz, 1H); 7.83 (ddd, J =
2.9, 9.3, 10.8 Hz,
1 H).
Preparation I: (3S,6R)-[6-(1-phenyl-lH-tetrazole-5-sulfonylmethyl)-tetrahydro-
pyran-
3-yl]-carbamic acid tert-butyl ester:
I.i. (S)-(1-hydroxymethyl pent-4-enyl)-carbamic acid tert-butyl ester:
To a suspension of LiBH4 (1.15 g, 53 mmol) in THF (300 ml) at rt was added a
solution of
(S)-2-tert-butoxycarbonylamino-hex-5-enoic acid methyl ester (12.9 g, 53 mmol,
prepared
according to J. Org. Chem. (1995), 60, 2210) in THF (100 ml). The mixture was
stirred at rt
for 4 h, poured into water and extracted with EA. The organic layer was washed
with brine,
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-32-
dried over MgSO4 and concentrated to give the title alcohol (11.4 g, 99%
yield) as a
colourless oil.
iH NMR (CDC13) 8: 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.H. (1 S, 3RS, 4RS)-(1-hydroxymethyl-3-oxiranyl propyl)-carbamic acid tert-
butyl ester:
Intermediate I.i (11.4 g, 53 mmol) was dissolved in 1,2-DCE (300 ml) and water
(250 ml) and
1Mphosphate buffer pH 8(150 ml) was added. MCPBA (14.3 g, 1. 1 eq, 70%) was
added and
the mixture vigorously stirred overnight. The two phases were separated and
the aqueous
phase was extracted once more with DCM. The combined organic layers were
washed with a
sat. NaHCO3 solution, dried over MgSO4, filtered and concentrated to dryness.
The residue
was purified by chromatography over Si02 (Hex:EA 1:1 then EA) to give the
title epoxide
(7.74 g, 63% yield, mixture of diastereomers) as a colourless oil.
iH NMR (CDC13) 8: 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-camphor sulfonic acid (0.1 eq). The reaction was slightly exothermic.
The mixture
was stirred at rt for 3 h, concentrated and purified by chromatography over
Si0z (EA) to give
the title tetrahydropyran derivative (0.874 g, 37% yield) as a colourless
solid.
'H NMR (CDC13) 8: 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).
Liv. (3R,6S)-[6-(1 phenyl-IH-tetrazole-5-sulfonylmethyl)-tetrahydro pyran-3
ylJ-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 procedures described in Preparation G.
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-33-
Example 1: (E)-2-{(2R,3R,6R)-(3-[3-(2,5-ditluoro-phenyl)-allylamino]-6-[2-(6-
methoxy-
[1,5] naphthyridin-4-yl)-ethyl] -tetrahydro-pyran-2-yl}-ethanol:
i.i. [(2R, 3R, 6S)-6-(tert-butyl-dimethyl-silanyloxymethyl)-2-((2RS)-2, 3-
dihydroxy propyl)-
3, 6-dihydro-2H-pyran-3 ylJ-carbamic acid tert-butyl ester:
To a mixture of (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) in 2-methyl-2-propanol (750 ml) and
water (750 ml)
were added potassium ferricyanide (182.4 g, 553.8 mmol), potassium carbonate
(65.8 g,
476.0 mmol), (DHQ)2PHAL (1.12 g, 1.4 mmol) and potassium osmate dihydrate
(0.118 g).
The reaction mixture was mechanically stirred at rt for 24 h. Sodium bisulfite
(316 g) was
added slowly. The two layers were decanted and the aq. layer was extracted
once more with
EA (500 ml). The combined org. extracts were washed with brine, dried over
MgS04, filtered
and concentrated to dryness. The residue was filtered through a pad of Si0z
(Hex-EA 1-4) to
afford 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+].
I.H. [(2R,3R,6S)-2-((4RS)-2,2-dimethyl-[1,3]dioxolan-4 ylmethyl)-6-
hydroxymethyl-
tetrahydro pyran-3 ylJ-carbamic acid tert-butyl ester:
To a mixture of intermediate l.i (61 g, 146.0 mmol) in THF (710 ml) were added
PTSA
(1.38 g, 7.3 mmol) and 2,2-dimethoxypropane (54.0 ml, 439.1 mmol). The
reaction mixture
was stirred at rt for 90 min. TBAF (1M in THF, 230 ml) was added. The reaction
proceeded
for 90 min. The reaction mixture was concentrated to dryness and the residue
was
chromatographed over Si0z (Hex-EA 1-4) to afford 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+].
l.iii. [(2R,3R,6S)-2-((4RS)-2,2-dimethyl-[1,3]dioxolan-4 ylmethyl)-6-
hydroxymethyl-
tetrahydro pyran-3 ylJ-carbamic acid tert-butyl ester:
To a solution of intermediate l.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 h.
The catalyst was
removed by filtration through celite and the filtrate evaporated under reduced
pressure. The
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-34-
residue was purified by column chromatography over Si02 (EA-Hex 4-1 to 1-0) to
afford 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+].
l.iv. [(2R, 3R, 6S)-2-((4R)-2,2-dimethyl-[1,3]dioxolan-4 ylmethyl)-6-(1 phenyl-
JH-tetrazol-
5 ylsulfanylmethyl)-tetrahydro pyran-3 ylJ-carbamic acid tert-butyl ester:
To an ice-chilled solution of intermediate l.iii (19.4 g, 56.1 mmol) in THF
(500 ml) were
added PPh3 (29 g), phenyltetrazole thiol (14 g) and DIAD (16.7 ml) dropwise.
The resulting
solution was stirred at rt overnight. The reaction mixture was concentrated to
dryness and the
residue purified by column chromatography over Si0z (EA-Hex 1-3 to 1-0) to
afford the title
sulfide as a colorless solid (28.85g, 99% yield). The compound was obtained as
a 2-1 mixture
of epimers.
MS (ESI, m/z): 506.0 [M+H+]
l.v. [(2R,3R,6S)-2-((4RS)-2,2-dimethyl-[1,3]dioxolan-4 ylmethyl)-6-(1 phenyl-
JH-tetrazole-
5-sulfonylmethyl)-tetrahydro pyran-3 ylJ-carbamic acid tert-butyl ester:
To a solution of intermediate l.iv (28.4 g) in EtOH (240 ml) and THF (240 ml)
were added
ammonium molybdate heptahydrate (17.73 g) and 50% aq. H202 (82.5 ml). The
mixture was
heated at 60 C overnight. After cooling to rt, the reaction mixture was
diluted with water
(250 ml) and the volatiles were removed under reduced pressure. EA (150 ml)
was added to
the aq. residue and the phases were separated. The aq. layer was extracted
three times with
EA. The combined org. layers were dried over MgS04, filtered and evaporated
under reduced
pressure. The residue was purified by column chromatography over Si0z (DCM-
MeOH 19-1
to 9-1) to afford first the desired sulfone as a colourless thick oil (4.9 g),
then
[(2R,3R,6S)-2-((2RS)-2,3-dihydroxy-propyl)-6-(1-phenyl-lH-tetrazole-5-
sulfonylmethyl)-
tetrahydro-pyran-3-yl]-carbamic acid tert-butyl ester as a white foam (9.4 g).
The latter was
taken up in THF (90 ml), and was treated with PTSA (0.187 g) and 2,2-
dimethoxypropane
(6.95 ml). The reaction mixture was stirred at rt for 2.5 h. Water (8 ml) and
aq. NaHCO3 were
added before concentration to dryness. The residue was partitioned between
water and EA
and the phases were separated. The org. layer was washed with brine, dried
over MgS04,
filtered and evaporated under reduced pressure. The residue was further dried
under HV to
afford more of the title sulfone (9.94 g).
MS (ESI, m/z): 538.0 [M+H+].
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-35-
l.vi. {(2R,3R,6S)-2-((4RS)-2,2-dimethyl-[1,3]dioxolan-4 ylmethyl)-6-trans-[2-
(6-methoxy-
[1,5]naphthyridin-4 yl)-vinylJ-tetrahydro pyran-3 yl}-carbamic acid tert-butyl
ester:
To a solution of 6-methoxy-[1,5]naphthyridine-4-carbaldehyde (see preparation
B; 1.7 g,
9.03 mmol) and intermediate l.v (4 g, 7.45 mmol) in 1,2-DME (40 ml) cooled to -
78 C, was
added dropwise, over 10 min, KHMDS (0.5M in toluene, 24 ml). The mixture was
stirred
30 min at this temperature. The reaction was then allowed to warm up to rt
over 30 min,
whereupon water (50 ml) was added. The two layers were decanted, the aq. layer
was
extracted twice with EA (2 x 150 ml). The combined org. layers were washed
with brine,
dried over Na2SO4, filtered and concentrated to dryness. The residue was
chromatographed
over Si02 (Hex-EA 1-1 then 1-4) to afford the title alkene (2.8 g, 62% yield)
as a colourless
foam.
MS (ESI, m/z): 500.4 [M+H+]
l.vii.a. {(2R,3R,6S)-2-(2-hydroxy-ethyl)-6-trans-[2-(6-methoxy-
[1,5]naphthyridin-4 yl)-
vinylJ-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)-ethylJ-
tetrahydro pyran-3 yl}-carbamic acid tert-butyl ester:
A solution of intermediate l.vi (2.8 g, 5.6 mmol) in a THF-AcOH-water mixture
(1-3-1,
50 ml) was heated at 60 C for 6 h. The reaction mixture was concentrated to
dryness, and the
residue was partitioned between EA and saturated NaHCO3. The pH was adjusted
to 7 by
adding solid NaHCO3. The aq. layer was extracted once with EA and the combined
org.
layers were washed with brine, dried over NazSO4, filtered and concentrated to
dryness. The
residue was taken up in acetone (100 ml) and a warm solution of Na104 (3 g) in
water (10 ml)
was added. The mixture was stirred 1 h. 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 org. layers were dried over NazSO4, filtered and concentrated in
vacuo. The residue
was taken up in MeOH (30 ml) and NaBH4 (0.7 g) was added. The reaction
proceeded for
15 min. 10% aq. NaHSO4 (100 ml) was added. The volatiles were removed in vacuo
and the
aq. residue was extracted three times with EA (3 x 100 ml). The combined org.
layers were
washed with brine, dried over NazSO4, filtered and concentrated to dryness.
The residue was
chromatographed over Si0z (DCM-MeOH 19-1) to afford a colourless foam (1.76 g)
which
was characterized as a mixture of the two title compounds.
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-36-
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)-ethylJ-
tetrahydro pyran-3 yl}-carbamic acid tert-butyl ester:
and
l.viii.b. [(2R,3R,6S)-6-[(IR,2R)-1,2-dihydroxy-2-(6-methoxy-[],5Jnaphthyridin-
4 yl)-ethylJ-
2-(2-hydroxy-ethyl)-tetrahydro pyran-3 ylJ-carbamic acid tert-butyl ester:
To a solution of intermediate l.vii (1.76 g, mixture of compounds), was added
potassium
ferricyanide (4.04 g), K2C03 (1.7 g) methanesulfonamide (0.47 g), (DHDQ)2PHAL
(0.035 g)
and potassium osmate dihydrate (0.005 g). The mixture was stirred 40 h at rt.
Sodium bisulfite
(6 g) was added. The two layers were decanted and the aq. layer was extracted
twice with EA
(2 x 150 ml). The combined org. layers were washed with brine, dried over
NazSO4, filtered
and concentrated to dryness. The residue was chromatographed over Si0z (DCM-
MeOH
19-1) to afford first the title alkane l.viii.a (1.34 g, 3.1 mmol) as a
colourless foam.
MS (ESI, m/z): 432.0 [M+H+].
Elution was pursued with DCM-MeOH 6-1 to give the title diol l.viii.b (0.4 g,
0.86 mmol) as
a colourless foam.
MS (ESI, m/z): 464.3 [M+H+].
l.ix. (2R,3R,6R)-2-{3-amino-6-[2-(6-methoxy-[1,5]naphthyridin-4 yl)-ethylJ-
tetrahydro-
pyran-2 yl}-ethanol:
A solution of intermediate l.viii.a (1.34 g, 3.1 mmol) in TFA (10 ml) was
stirred at rt for
15 min. After evaporation to dryness, the residue was dissolved in water (50
ml), washed once
with EA (50 ml). The pH of the aq. layer was adjusted to 12 adding 3M aq. NaOH
and the aq.
layer was extracted four times with DCM-MeOH 9-1 mixture (4 x 100 ml). The
combined
org. layers were washed with brine, dried over NazSO4, filtered and
concentrated to dryness.
After further drying under HV, the residue was purified by chromatography over
Si0z
(DCM-MeOH 6-1 containing 1% aq. NH4OH) to give the title amine (0.65 g, 63%
yield) as a
colourless foam.
MS (ESI, m/z): 332.3 [M+H+].
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-37-
l.x. (E)-2-{(2R,3R,6R)-3-[3-(2,5-difluoro phenyl)-allylamino]-6-[2-(6-methoxy-
[1,5]naphthyridin-4 yl)-ethylJ-tetrahydro pyran-2 yl}-ethanol:
To a solution of intermediate l.ix (0.1 g, 0.3 mmol) in 1,2-DCE (4.5 ml) and
MeOH (1.5 ml)
were added (E)-3-(2,5-difluoro-phenyl)-propenal (see Preparation C, 0.055 g,
1.1 eq.) and 3A
molecular sieves (1 g). The mixture was heated at 50 C overnight. After
cooling to rt, NaBH4
(0.1 g) was added. The reaction proceeded for 2 h before filtration through a
pad of
hydromatrix (treated with saturated aq. NaHCO3). The filtrate was
concentrated to dryness.
The residue was chromatographed over Si02 (DCM-MeOH 19-1 containing 0.5% aq.
NH4OH) (0.09 g, 61% yield) was obtained as a colourless 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-quinolin-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-S yl)-vinylJ-tetrahydro pyran-3 yl}-carbamic acid tert-butyl ester:
A Julia coupling was performed as described in Example 1, step l.vi, starting
from
intermediate l.v (1.99 g, 3.7 mmol) and 3-methoxy-quinoline-5-carbaldehyde
(see
Preparation A; 0.67 g) to afford the title compound as a white foam (1.07 g,
2.14 mmol). The
compound was purified by column chromatography over Si0z (EA-Hex 1-1). 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-quinolin-
S yl)-ethylJ-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 h. The
catalyst was
removed by filtration. The filtrate was evaporated under reduced pressure and
further dried
under HV to afford 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+].
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-38-
2.iii. 3-(2RS)-{(2R,3R,6R)-3-amino-6-[2-(3-methoxy-quinolin-S yl)-ethyl]-
tetrahydro pyran-
2 yl} propane-l,2-diol:
A solution of intermediate 2.ii (1.03 g) in TFA (21 ml) was stirred for 10
min. Water (7 ml)
was added. The resulting mixture was stirred for 1 h and concentrated to
dryness. The residue
was basified with 1M aq. NaOH. DCM-MeOH 9-1 was added and the phases were
separated.
The aq. layer was extracted six times with DCM-MeOH 9-1 and the combined
extracts were
dried over MgSO4, 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.
'H NMR (CDC13) main signals 8: 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-dif luoro phenyl)-N-{(2R, 3R, 6R)-2-((2RS)-2, 3-dihydroxy
propyl)-
6-[2-(3-methoxy-quinolin-S 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) were added DIPEA (0.514 ml, 3 mmol) and
HATU
(0.456 g, 1.2 mmol). The reaction mixture was stirred at rt for 90 min and
concentrated to
dryness. The residue was dissolved in DCM-MeOH 9-1 (50 ml) and washed with
saturated
NaHCO3 (20 ml). The aq. layer was extracted twice with DCM-MeOH 9-1 (2 x 20
ml) and
the combined org. layers were dried over MgS04, filtered and evaporated under
reduced
pressure. The residue was purified by column chromatography over Si0z (DCM-
MeOH 19-1
containing 1% aq. NH4OH to DCM-MeOH 9-1 containing 1% aq. NH4OH) to afford the
title
amide (0.331 g, 62% yield) as orange solid.
iH NMR (d6-DMSO) main signals 8: 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+].
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-39-
2.v. (E)-3-(2, 5-difluoro phenyl)-1-{(2RS, 5R)-2-hydroxy-5-[2-(3-methoxy-
quinolin-S yl)-
ethylJ-hexahydro pyrano[3,2-b]pyrrol-1 yl} propenone:
To a solution of intermediate 2.iv (0.153 g) in acetone (1.7 ml) was added at
rt a solution of
Na104 (0.156 g) in water (0.5 ml). The reaction mixture was stirred for 30 min
and
concentrated to dryness. The residue was purified over Si02 (EA-Hex 2-1) to
afford a
colourless 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)-acryloylaminoJ-6-[2-(3-
methoxy-quinolin-
S yl)-ethylJ-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) was added dropwise a solution of sodium chlorite
(0.193 g) and
sodium dihydrogen phosphate (0.193 g) in water (2 ml). The resulting solution
was stirred at
rt overnight and the volatiles were removed under HV. The residue was diluted
with water
and Hex. The phases were separated and the org. layer was extracted once with
Hex. The aq.
layer was acidified to pH 3 and extracted three times with EA. The combined
extracts were
washed with cold water and evaporated under reduced pressure. The colourless
gum thus
obtained was triturated in ether, filtered and dried under reduced pressure to
give the title
compound as a white solid (0.069 g, 58% yield).
iH NMR (d6-DMSO) 8: 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, 1 H).
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. 3-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-5yl)-
ethylJ-
tetrahydro pyran-3 yl}-amide:
Starting from 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
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-40-
(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.
iH NMR (d6-DMSO) main signals 8: 11.29 (s, 1H); 8.69 (dd, J= 1.7, 2.7 Hz, 1H);
8.36 (d,
J= 9.3Hz, 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); 4.5 8(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-S yl)-ethyl]-2-(2-oxo-ethyl)-tetrahydro
pyran-3 ylJ-
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 colourless
foam.
MS (ESI, m/z): 521.1 [M+H+].
3.iii. {(2R,3R,6R)-6-[2-(3-methoxy-quinolin-S yl)-ethyl]-3-[(3-oxo-3,4-dihydro-
2H pyrido[3,2-b][1,4] thiazine-6-carbonyl)-aminoJ-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 as an off-white solid using the procedure described in Example 2,
step 2.vi. The
compound was purified by trituration in ether.
'H NMR (d6-DMSO) 8: 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+].
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-41-
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-[],5Jnaphthyridin-4 yl)-
ethylJ-
tetrahydro pyran-2 yl} propane-l,2-diol:
The title compound (1.30 g, 94% yield) was obtained as a white solid starting
from
intermediate 1.vi (1.98 g, 3.98 mmol) using the procedures of Example 2, steps
2.ii and 2.iii.
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]naphthyridin-
4 yl)-ethylJ-tetrahydro pyran-3 ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-
3-one:
Starting from 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
l.x.
iH NMR (d6-DMSO) 8: 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= 1.3, 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); 1.3 7(m, 1H); 1.25 (m, 1 H) .
MS (ESI, m/z): 540.0 [M+H+].
4.iii. {(2R,3R,6R)-2-((2RS)-2,3-dihydroxy propyl)-6-[2-(6-methoxy-
[],5Jnaphthyridin-4 yl)-
ethylJ-tetrahydro pyran-3 yl}-(3-oxo-3,4-dihydro-2M 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 aq. NaOH (1 ml). The solution was cooled to 0 C and Boc2O (0.303
g) was
added. After stirring overnight, 1M aq. NaOH (0.5 ml) and Boc2O (0.3 g) were
added. After
4 h, 1M aq. NaOH (1 ml) and Boc2O (0.3 g) were added again and the reaction
mixture was
stirred for 16 h. EA was added and the phases were separated. The aq. layer
was extracted
twice with EA and the combined org. layers were washed with brine, dried over
MgS04,
filtered and evaporated under reduced pressure. The residue was purified by
column
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-42-
chromatography over Si02 (DCM-MeOH 19-1 containing 1% aq. NH4OH then DCM-MeOH
9-1 containing 1% aq. NH4OH) to afford the title compound as a pale yellow
foam (0.449 g,
76% yield).
iH NMR (CDC13) main signals 8: 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-[I,5]naphthyridin-4 yl)-ethylJ-2-(2-oxo-
ethyl)-tetrahydro-
pyran-3 ylJ-(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 colourless
thick oil. The
compound was purified by column chromatography over Si0z using DCM-MeOH 19-1
as an
eluent.
iH NMR (CDC13) 8: 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); 2.5 9(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]thiazin-
6-ylmethyl)-aminoJ-6-[2-(6-methoxy-[I,5]naphthyridin-4 yl)-ethylJ-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) was
obtained as a yellow solid using the procedure of Example 2, step 2.vi. The
compound was
purified by trituration in ether.
iH NMR (d6-DMSO) 8: 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,
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-43-
J= 3.4 Hz, 2H); 3.22 (m, 1H); 3.07 (m, 1H); 2.79 (m, 1H); 2.3 7(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)-ethylJ-3-[(3-oxo-
3,4-dihydro-
2H pyrido[3,2-b][1,4] thiazin-6 ylmethyl)-aminoJ-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
anhydrous HC1 in dioxane (5N, 0.86 ml). The resulting solution was stirred at
rt for 3 h. 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).
iH NMR (d6-DMSO) 8: 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)-allylaminoJ-6-[2-(6-
methoxy-
[1,5]naphthyridin-4 yl)-ethylJ-tetrahydro pyran-2 yl} propane-l,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 l.x.
iH NMR (d6-DMSO) 8: 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, 1 H); 6.62 (t, J= 16.1 Hz, 1 H); 6.52
(m, 1 H); 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+].
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-44-
5.ii. [(E)-3-(2, 5-difluoro phenyl)-allylJ-{(2R, 3R, 6R)-2-((2RS)-2, 3-
dihydroxy propyl)-
6-[2-(6-methoxy-[1,5]naphthyridin-4 yl)-ethylJ-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 over Si0z (DCM-MeOH 19-1 then 9-1). This
was
obtained as a 2-1 mixture of epimers.
iH NMR (CDC13) main signals 8: 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-dfluoro phenyl)-allylJ-[(2R,3R,6R)-6-[2-(6-methoxy-
[1,5]naphthyridin-
4 yl)-ethylJ-2-(2-oxo-ethyl)-tetrahydro pyran-3 ylJ-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 over Si0z (DCM-MeOH 97-3 to 19-1).
'H NMR (CDC13) 8: 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, 1H); 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)-allylJ-
amino}-
6-[2-(6-methoxy-[1, 5]naphthyridin-4 yl)-ethylJ-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) was
obtained as a colourless foam using the procedure of Example 2, step 2.vi. The
compound
was purified by trituration in ether.
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-45-
iH NMR (CDC13) 8: 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)-allylaminoJ-6-[2-(6-methoxy-
[1,5]naphthyridin-4 yl)-ethylJ-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)
was obtained as a white solid, using the procedure of Example 4, step 4.vi.
'H NMR (D20) 8: 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-[(IR,2R)-1,2-dihydroxy-2-(6-methoxy-[],5Jnaphthyridin-4 yl)-
ethylJ-
2-((4RS)-2,2-dimethyl-[1,3]dioxolan-4 ylmethyl)-tetrahydro pyran-3 ylJ-
carbamic acid
tert-butyl ester:
To a suspension of intermediate 1.vi (1.274 g, 2.55 mmol) and methane
sulfonamide (0.291 g,
3.06 mmol) in 2-methyl-2-propanol (13 ml), water (13 ml) and EA (4 ml) was
added
AD-mix (3 (4.5 g). The reaction mixture was stirred at rt for 24 h. Sodium
metabisulfite (10 g)
and EA (50 ml) were added. The two layers were decanted and the aq. layer was
extracted
twice with EA. The combined org. layers were dried over NazSO4, filtered and
concentrated
in vacuo. The residue was chromatographed over Si0z (DCM-MeOH 9-1) to afford
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+].
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-46-
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 ylJ-tetrahydro pyran-3 yl}-
carbamic acid
tert-butyl ester:
To an ice-chilled solution of intermediate 6.i (1.22 g, 2.30 mmol) in DCM (12
ml) were added
pyridine (1.12 ml, 13.80 mmol) and triphosgene (0.341 g, 1.15 mmol). The
reaction was
stirred 30 min at 0 C and then 1 h at rt. The reaction mixture was diluted
with saturated
NaHCO3 and the two layers were decanted. The org. layer was dried over Na2SO4,
filtered,
and concentrated to dryness. The residue was chromatographed over Si02 (DCM-
MeOH
19-1) to afford the title cyclic carbonate (1.18 g, 92% yield) as a 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-[(IS)-1-
hydroxy-
2-(6-methoxy-[1,5]naphthyridin-4 yl)-ethylJ-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 (moisturized, 0.443 g) and the suspension was stirred under
hydrogen
atmosphere for 2 h. The catalyst was filtered off and the filtrate
concentrated to dryness. The
residue was purified by column chromatography over Si0z (DCM-MeOH 9-1) to
afford 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-[(IS)-1-hydroxy-2-(6-methoxy-
[],5Jnaphthyridin-4 yl)-
ethylJ-tetrahydro pyran-2 yl} propane-l,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.
The compound
was obtained as a 2-1 mixture of epimers.
iH NMR (d6-DMSO) main signals 8: 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+].
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-47-
6.v. (2RS)-3-{(2R, 3R, 6S)-3-[(E)-3-(2, 5-d fluoro phenyl)-allylaminoJ-6-[(1
S)-1-hydroxy-
2-(6-methoxy-[],5Jnaphthyridin-4 yl)-ethylJ-tetrahydro pyran-2 yl} propane-l,2-
diol:
Starting from intermediate 6.iv (0.570g, 1.51mmo1) and (E)-3-(2,5-difluoro-
phenyl)-propenal
(0.279 g, 1. 1 eq), the title compound (0.420g. 52% yield) was obtained as a
white solid
according to the procedure described in Example 1, step l.x.
iH NMR (d6-DMSO) main signals 8: 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 containing 1% aq. NH4OH).
MS (ESI, m/z): 529.8.
6.vi. [(E)-3-(2,5-difluoro phenyl)-allylJ-{(2R,3R,6S)-2-((2RS)-2,3-dihydroxy
propyl)-
6-[(1S)-1-hydroxy-2-(6-methoxy-[1,5]naphthyridin-4 yl)-ethylJ-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 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)-allylJ-
amino}-
6-[(IS)-1-hydroxy-2-(6-methoxy-[],5Jnaphthyridin-4 yl)-ethylJ-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 as a colourless foam using the procedure described in Example 2,
steps 2.v and vi.
MS (ESI, m/z): 614.0 [M+].
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-48-
6.viii. {(2R,3R,6R)-3-[(E)-3-(2,5-difluoro phenyl)-allylaminoJ-6-[(IS)-1-
hydroxy-
2-(6-methoxy-[1,5]naphthyridin-4 yl)-ethylJ-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) was
obtained as a yellowish solid, using the procedure described in Example 4,
step 4.vi. The
compound was triturated in ether.
iH NMR (d6-DMSO) 8: 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); 4.5 8(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-ditluoro-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:
To an ice-chilled solution of (2R,3S,6R)-6-allyl-2-hydroxymethyl-3,6-dihydro-
2H-pyran-3-ol
(obtained as described in Eur. J. Org. Chem. (2003), 2418-2427; 31.55 g, 185.4
mmol) in
DCM (650 ml) was added imidazole (24.96 g, 2 eq.). A solution of
tert-butylchlorodiphenylsilane (50.45 g, 210.7 mmol) in DCM (130 ml) was added
dropwise
over 90 min. After 2 h, aq. sat. NaHCO3 (250 ml) was added. The two layers
were separated
and the org. layer was washed twice with brine, dried over MgS04, filtered and
concentrated
to dryness. The residue was chromatographed over Si0z (Hex-EA 5-1) to afford
the title
compound as a yellow oil (51.52 g, 68% yield).
iH NMR (CDC13) 8: 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 ylJ propane-1,2-diol:
To 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), were added potassium ferricyanide (189.48 g, 3
eq.), K2C03
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-49-
(67.10 g, 3 eq.), (DHQD)2PHAL (1.5121 g, 0.015 eq.) and potassium osmate
dihydrate
(0.1907 g, 0.004 eq.). The reaction mixture was stirred two days and sodium
bisulfite
(150.92 g) was added. The two layers were decanted and the aq. layer was
extracted twice
with EA (2 x 350 ml). The combined org. layers were washed with brine (500
ml), dried over
MgSO4, filtered and concentrated to dryness. The residue was filtered over
Si02 (Hex-EA
1-1, then EA) to afford the title product as a yellow oil (36.33 g, 65%
yield). The compound
was obtained as a 2-1 mixture of epimers.
iH NMR (d6-DMSO) 8: 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, 3H); 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) were
added at rt
PTSA (0.90 g, 4.7 mmol) and 2,2-dimethoxypropane (24 ml, 195.2 mmol). After
2h., water
(100 mL) and saturated NaHCO3 (200 ml) were added and the two phases were
separated.
The aq. layer was extracted with DCM (260 ml). The combined org. layers were
washed with
brine, dried over MgSO4, filtered and concentrated to dryness. The residue was
chromatographed over Si02 (Hex-EA 1-1) to afford the title compound as a
yellow oil
(36.19 g, 74.9 mmol). The compound was obtained as a 2-1 mixture of epimers.
'H NMR (CDC13) 8: 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, 1H); 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.l g, 4.8 mmol). The reaction mixture was stirred under
hydrogen for 2 h. The
catalyst was removed by filtration and the filtrate was concentrated to
dryness to yield 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+].
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-50-
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% in DCM, 50 ml). The mixture was stirred at
rt for 4 h.
The reaction mixture was diluted with DCM (30 ml) and washed with sat. NaHCO3
(30 ml).
The org. layer was dried over Na2SO4, filtered and concentrated to dryness.
The residue was
chromatographed (Hex-EA 3-1) to afford the title compound (10.9 g, 91% yield)
as a
colourless oil. The compound was obtained as a 2-1 mixture of epimers.
iH NMR (CDC13) 8: 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]dioxolan-4 ylmethyl)-tetrahydro pyran-3 ylJ-amine:
To a solution of intermediate 7.v (10.9 g, 22.58 mmol) in 1,2-DCE (60 ml) were
added
benzylamine (2.5 ml, 1 eq.) and sodium triacetoxyborohydride (6.7 g, 1.4 eq.).
The mixture
was stirred overnight at rt. Saturated NaHCO3 (200 ml) was added. The two
layers were
decanted and the org. layer was dried over NazSO4, filtered and concentrated
to dryness. The
residue was chromatographed over Si0z (Hex-EA 3-1) to afford 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
(l.l ml) and 10% Pd/C (4 g). The reaction mixture was then stirred under
hydrogen
atmosphere for 8 h. The reaction mixture was filtered and the catalyst was
washed with EtOH
and water. After concentration, the residue was diluted with sat. NaHCO3 (100
ml) and then
extracted with EA (2 x 250 mL). The combined org. extracts were washed with
brine, dried
over NazSO4, filtered and concentrated to dryness. The residue was
chromatographed over
Si0z (DCM-MeOH 97-3 containing 1% aq. NH4OH) to afford the title amine (5.5 g,
67%
yield) as a colourless oil.
MS (ESI, m/z): 484.1 [M+H+].
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-51-
7.viii. (2S,3R,6S)-[2-(tert-butyl-diphenyl-silanyloxymethyl)-6-((4RS)-2,2-
dimethyl-
[1,3]dioxolan-4 ylmethyl)-tetrahydro pyran-3 ylJ-carbamic acid tert-butyl
ester:
To a solution of intermediate 7.vii (5.5 g, 11.37 mmol) in DCM (65 ml) were
added Boc2O
(3.0 g, 1.2 eq.) and TEA (3.2 mL, 2.0 eq.). The reaction mixture was stirred
overnight at rt.
After concentration to dryness, the residue was chromatographed over Si02 (Hex-
Toluene-
DCM-EA 13-3-1-3) to afford first the (2S,3S,6S)-isomer (1.98 g, 29% yield) as
a 2-1 mixture
of epimers, and then the desired isomer (4.0 g, 60% yield) as a 2-1 mixture of
epimers.
iH NMR (CDC13) 8: 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 ylJ-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 h. The reaction mixture was concentrated to
dryness and the
residue was partitioned between sat. NaHCO3 (40 ml) and EA (100 ml). The org.
layer was
dried over Na2SO4, filtered and concentrated to dryness. The residue was
chromatographed
over Si02 (Hex-EA 1-3) to afford the title diol (3.38 g, 90% yield) as a
colourless 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 ylJ-carbamic acid tert-butyl ester:
To a solution of intermediate 7.ix (1.5 g, 2.75 mmol) in acetone (30 ml) was
added at rt a
solution of Na104 (1.5 g, 2.5 eq.) in water (10 ml). The reaction was stirred
40 min, the solids
were filtered off and the filtrate was concentrated in vacuo. The residue was
partitioned
between water (50 ml) and EA (100 ml). The aq. layer was extracted once with
EA (100 ml)
and the combined extracts were washed with brine, dried over NazSO4, filtered
and
concentrated to dryness. The residue was chromatographed over Si0z (Hex-EA 2-
1) to afford
the title aldehyde (1.3 g) as a colourless foam.
iH NMR (CDC13) 8: 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).
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-52-
7.xi. {(2S, 3R, 6S)-2-(tert-butyl-diphenyl-silanyloxymethyl)-6-[(2RS)-2-(3
fluoro-6-methoxy-
quinolin-4 yl)-2-hydroxy-ethylJ-tetrahydro pyran-3 yl}-carbamic acid tert-
butyl ester:
To a solution of DIPA (0.9 ml, 2.5 eq.) in THF (17 ml) was added at -78 C, n-
BuLi (2.5N in
hexanes, 2.5 ml). The mixture was stirred 5 min at this temperature before
warming to 0 C.
After 15 min, the solution was cooled to -78 C and a solution of 3-fluoro-6-
methoxy-
quinoline (prepared as described in WO 2005/049575; 1.12 g, 2.5 eq.) in THF (5
ml) was
added. The reaction proceeded for 4 h. 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 min before
quick warming
to rt. The reaction was further stirred for 20 min and was quenched with 10%
aq. NaHSO4
(30 ml). The org. layer was diluted with EA (100 ml). The two layers were
decanted and the
aq. layer was extracted twice with EA. The combined org. layers were washed
with brine,
dried over Na2SO4, filtered and concentrated to dryness. The residue was
chromatographed
over Si02 (Hex-EA 2- then 1-1) to afford the title compound (0.98 g, 56%
yield) as a
colourless 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-
ethylJ-
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 in
THF, 2.2 ml). The reaction proceeded at rt for 1 h. After concentration to
dryness, the residue
was chromatographed on Si0z (EA-Hex 3-1) to afford the title compound (0.57 g,
89% yield)
as a colourless foam. The compound was obtained as a 1-1 mixture of isomers.
MS (ESI, m/z): 451.0 [M+H+].
7.xiii. (IRS)-2-((2S,5R,6S)-5-amino-6-hydroxymethyl-tetrahydro pyran-2 yl)-1-
(3 fluoro-
6-methoxy-quinolin-4 yl)-ethanol:
To a solution of intermediate 7.xii (0.57 g, 1.26 mmol) in dioxane (3 ml) was
added HC1 in
dioxane (5N, 3 ml). The mixture was stirred at rt for 3 h. The solvent was
removed in vacuo
and the residue was dissolved in water (5 ml). The pH was adjusted to 7 adding
K2C03. Water
was evaporated and the residue chromatographed on Si0z (DCM-MeOH 6-1 1% aq.
NH4OH)
to afford the title amine (0.4 g, 90% yield) as a colourless foam. The
compound was obtained
as a 1-1 mixture of isomers.
MS (ESI, m/z): 351.0 [M+H+].
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-53-
7.xiv. (IRS)-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, l.l eq), the title compound (0.135 g, 94% yield) was
obtained as a
colourless foam using the procedure of Example 1, step l.x. The compound was
purified by
chromatography over Si0z (DCM-MeOH 93-7 containing 1% aq. NH4OH). The compound
was obtained as a 1-1 mixture of isomers.
MS (ESI, m/z): 503.2 [M+H+].
Example 8: 2-{(2R,3R,6R)-3-[(E)-3-(2,5-ditluoro-phenyl)-allylamino]-6-[2-(6-
methoxy-
[1,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-2-yl}-acetamide
dihydrochloride:
8.i. [(E)-3-(2,5-difluoro phenyl)-allylJ-{(2R,3R,6R)-2-hydroxycarbamoylmethyl-
6-[2-(6-methoxy-[1,5]naphthyridin-4 yl)-ethylJ-tetrahydro pyran-3 yl}-carbamic
acid
tert-butyl ester and {(2R,3R,6R)-2-carbamoylmethyl-6-[2-(6-methoxy-
[1,5]naphthyridin-
4 yl)-ethylJ-tetrahydro pyran-3 yl}-[(E)-3-(2,5-difluoro phenyl)-allylJ-
carbamic acid
tert-butyl ester:
To a solution of intermediate 5.v (0.11 g, 0.19 mmol) in DMF (2.3 ml) were
added DIPEA
(0.16 ml, 0.93 mmol) and HATU (0.11 g, 0.28 mmol). The resulting solution was
stirred at rt
for 30 min. Hydroxylamine hydrochloride (0.019 g, 0.28 mmol) was added. After
stirring at rt
overnight, hydroxylamine hydrochloride (0.019 g, 0.28 mmol) was added and the
reaction
was further stirred at rt for 24 h. The reaction mixture was concentrated to
dryness. The
residue was partitioned between water and DCM-MeOH 9-1 and the phases were
separated.
The aq. layer was extracted five times with DCM-MeOH. The combined org. layers
were
dried over NazSO4, filtered and the filtrate was evaporated under reduced
pressure. The
residue was purified by column chromatography over Si0z (DCM-MeOH 9-1
containing 1%
aq. NH4OH) to afford 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+].
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-54-
8.ii. 2-{(2R, 3R, 6R)-3-[(E)-3-(2, 5-d fluoro phenyl)-allylaminoJ-6-[2-(6-
methoxy-
[1,5]naphthyridin-4 yl)-ethylJ-tetrahydro pyran-2 yl}-acetamide
dihydrochloride:
Starting from {(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 (0.030 g, 0.049 mmol), the title compound (0.017 g, 60% yield) was
obtained as a
yellow solid using the procedure of Example 4, step 4.vi. The compound was
purified by
trituration in ether.
MS (ESI, m/z): 497.0 [M+H+].
Example 9: 2-{(2R,3R,6S)-3-[(E)-3-(2,5-difluoro-phenyl)-allylamino]-
6-[(IR,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-
quinoxalin-S yl)-vinyl]-tetrahydro pyran-3 yl}-carbamic acid tert-butyl ester:
The Julia coupling was performed as in Example 1, step l.vi, starting from
intermediate l.v
(9.67 g, 18 mmol) and 3-methoxy-quinoxaline-5-carbaldehyde (see Preparation D;
3.38 g),
affording the title compound as a yellowish foam (3.72 g, 41% yield). The
compound was
purified by column chromatography over Si0z (EA-Hex 1-1). 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-S yl)-
vinylJ-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 h. The reaction mixture was concentrated to dryness and
the residue
partitioned between EA (200 ml) and saturated NaHCO3 (200 ml). The pH of the
aq. layer
was adjusted to 8 by adding 1M aq. NaOH. The precipitate was then extracted
twice with EA
(2 x 150 ml). The combined extracts were washed with brine, dried over NazSO4,
filtered and
concentrated to dryness. The residue was chromatographed over Si0z (EA-Hept 4-
1) to afford
the title compound (2.45 g) as a colourless foam. The compound was obtained as
a 2-1
mixture of epimers.
MS (ESI, m/z): 460.1.1 [M+H+].
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-55-
9.iii. {(2R,3R,6S)-3-tert-butoxycarbonylamino-6-[(E)-2-(3-methoxy-quinoxalin-S
yl)-vinylJ-
tetrahydro pyran-2 yl}-acetic acid:
Starting from intermediate 9.ii (2.45 g, 5.3 mmol), the title acid (0.65 g,
1.46 mmol) was
obtained as a colourless foam using the procedure of Example 2, steps 2.v and
2.vi. The
compound was purified by chromatography over Si0z using EA-Hex 1-2 as an
eluent.
MS (ESI, m/z): 443.8 [M+H +].
9.iv. {(2R,3R,6S)-2-carbamoylmethyl-6-[(E)-2-(3-methoxy-quinoxalin-S yl)-
vinylJ-
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) were
added at 0 C,
TEA (0.265 ml) and i-butylchloroformate (0.24 g). The reaction was stirred 1 h
at this
temperature then aq. NH4OH (3 ml) was added. The reaction was vigorously
stirred for
30 min. EA (50 ml) was added. The two layers were decanted and the aq. layer
was extracted
once with EA (50 ml). The combined org. layers were washed with brine, dried
over NazSO4,
filtered and concentrated to dryness. The residue was triturated (Hex) to
afford the title amide
(0.47 g) as a light beige solid of 75% purity.
MS (ESI, m/z): 442.8 [M+H +].
9.v. {2R,3R,6S)-2-carbamoylmethyl-6-[(IR2R)-1,2-dihydroxy-2-(3-methoxy-
quinoxalin-
S yl)-ethylJ-tetrahydro pyran-3 yl}-carbamic acid tert-butyl ester:
The asymmetric dihydroxylation of intermediate 9.iv (0.47 g, 1.05 mmol) was
performed
using the procedure of Example 6, step 6.i to give the title diol (0.19 g, 38%
yield) as a
colourless foam. The compound was purified by chromatography over Si0z using
DCM-MeOH 9-1 as an eluent.
iH NMR (d6-DMSO) 8: 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 Hz, 1H); 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+].
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-56-
9.vi. 2-{2R,3R,6S)-3-amino-6-[(IR,2R)-1,2-dihydroxy-2-(3-methoxy-quinoxalin-S
yl)-
ethylJtetrahydro pyran-2 yl}-acetamide:
The title amine (0.071 g, 47% yield) was obtained as a colourless foam
starting from
intermediate 9.v (0.19 g, 0.4 mmol) and using the procedure of Example 1, step
l.ix.
MS (ESI, m/z): 377.2 [M+H+].
9.vii. 2-{(2R,3R,6S)-3-[(E)-3-(2,5-difluoro phenyl)-allylaminoJ-6-[(IR,2R)-1,2-
dihydroxy-
2-(3-methoxy-quinoxalin-S yl)-ethylJ-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), the title compound (0.020 g, 20% yield and 75%
purity) was
obtained as as a colorless foam according to the procedure described in
Example 1, step l.x.
The compound was purified by chromatography over Si0z (DCM-MeOH 9-1 containing
1%
aq. NH4OH).
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)-allylJ-
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-quinoline-4-
carbaldehyde
(1.8 g, 9.6 mmol), the title compound (1.48 g, 2.41 mmol) was obtained as a
colourless foam
using successively the procedures of Example 1, step l.vi (Julia coupling, 46%
yield),
Example 2, steps 2.ii (hydrogenation, 96% yield) and 2.iii (acetonide and Boc
deprotection,
99% yield), Example 1, step l.x (reductive amination, 78% yield), Example 4,
step 4.iii (Boc
formation, 68% yield), and Example 2, steps 2.v (periodic cleavage, 95% yield)
and 2.vi (acid
formation, 99% yield).
MS (ESI, m/z): 581.1 [M+H+].
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-57-
10.ii. {(2R,3R,6R)-3-[(E)-3-(2,5-difluoro phenyl)-allylaminoJ-6-[2-(6-methoxy-
quinolin-
4 yl)-ethylJ-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
obtained as a beige solid using the procedure of Example 4, step 4.vi. The
compound was
purified by trituration in ether.
MS (ESI, m/z): 497.0 [M+H +].
Example 11: 2-{(2R,3R,6R)-3-[(E)-3-(2,5-ditluoro-phenyl)-allylamino]-6-[2-(6-
methoxy-
quinolin-4-yl)-ethyl]-tetrahydro-pyran-2-yl}-acetamide dihydrochloride:
ll.i. {(2R,3R,6R)-2-carbamoylmethyl-6-[2-(6-methoxy-quinolin-4 yl)-ethyl]-
tetrahydro-
pyran-3 yl}-[(E)-3-(2,5-difluoro phenyl)-allylJ-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 obtained as an off-white foam using the procedure of Example 9, step 9.iv.
The
compound was purified by chromatography over Si0z, using DCM-MeOH 19-1
containing
0.5% aq. NH4OH as an eluent.
MS (ESI, m/z): 596.0 [M+H +].
11.ii. 2-{(2R, 3R, 6R)-3-[(E)-3-(2, 5-difluoro phenyl)-allylaminoJ-6-[2-(6-
methoxy-quinolin-
4 yl)-ethylJ-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. The
compound was purified by trituration in ether.
MS (ESI, m/z): 496.0 [M+H +].
Example 12: 2-{(2R,3R,6S)-3-[(E)-3-(2,5-ditluoro-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)-ethylJ-tetrahydro pyran-3 yl}-[(E)-3-(2,5-difluoro phenyl)-allylJ-
carbamic acid tert-
butyl ester:
To a solution of intermediate 6.vii (0.724 g) in THF (8 ml) were added at 0 C,
TEA
(0.427 ml) and i-butylchloroformate (0.367 ml). The reaction was stirred 1 h
at this
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-58-
temperature then aq. ammonia (2.5 ml) was added. The reaction was vigorously
stirred for
45 min. EA (20 ml) was added. The two layers were decanted and the aq. layer
was extracted
once with EA (10 ml). The combined org. layers were washed with brine, dried
over Na2SO4,
filtered and concentrated to dryness. The residue was purified by column
chromatography
over Si02 (DCM-MeOH 19-1 containing 0.5% aq. NH4OH then 9-1 containing 1% aq.
NH4OH) to give the title amide as an off-white foam (0.485 g).
MS (ESI, m/z): 613.0 [M+H+].
12.ii. 2-{(2R,3R,6S)-3-[(E)-3-(2,5-difluoro phenyl)-allylaminoJ-6-[(S)-1-
hydroxy-
2-(6-methoxy-[],5Jnaphthyridin-4 yl)-ethylJ-tetrahydro pyran-2 yl}-acetamide:
5N HC1 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, the residue was finally purified by
column
chromatography over Si0z (DCM-MeOH 19-1 containing 1% aq. NH4OH, then 9-1
containing 1% aq. NH4OH) to afford the title compound as a off-white foam
(0.032 g).
Rf = 0.33 in DCM-MeOH 9-1 containing 1% aq. NH4OH.
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:
Starting from intermediate 7.xiii (0.100 g, 0.29 mmol) and (E)-3-(2,5-difluoro-
phenyl)-acrylic
acid (0.058 g, 0.31 mmol), and using the procedure of Example 2, step 2.iv,
the title amide
(0.123 g, 83% yield) was obtained as a yellow foam. The compound was purified
by
chromatography over Si0z (DCM-MeOH 19-1 containing 1% aq. NH4OH) and obtained
as a
1-1 mixture of epimers.
Rf = 0.41 (DCM-MeOH 9-1 containing 1% aq. NH4OH).
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:
Starting from 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 eq.) and using the
procedure of
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-59-
Example 2, step 2.iv, the title amide (0.072 g, 46% yield) was obtained as a
beige solid. The
compound was purified by chromatography over Si02 (DCM-MeOH 19-1 containing 1%
aq.
NH4OH) and obtained as a 1-1 mixture of epimers.
Rf = 0.41 (DCM-MeOH 9-1 containing 1% aq. NH4OH).
iH NMR (d6-DMSO) 8: 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, 0.5H); 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: 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:
15.i. 2-(tert-butyl-diphenyl-silanyloxymethyl)-6-[(2RS)-2-hydroxy-2-(3-methoxy-
quinolin-
S yl)-ethylJ-tetrahydro pyran-3 yl}-carbamic acid tert-butyl ester:
To a solution of 5-bromo-3-methoxyquinoline (3.12 g) in THF (70 ml), cooled to
-78 C, was
added n-BuLi (2.5N, 5.2 ml). The mixture was stirred at the same temperature
for 15 min and
a solution of intermediate 7.x (1.6 g, 3.12 mmol) in THF (5 ml) was quickly
added. The
reaction proceeded for 5 min before warming to rt. After 15 min, 10% aq.
NaHSO4 (100 ml)
was added. The two layers were decanted and the aq. layer was extracted with
EA (100 ml).
The combined org. layers were washed with brine, dried over NazSO4, filtered
and
concentrated to dryness. The residue was chromatographed on Si0z (Hept-EA 3-1
then 1-1 )
to afford the title compound (0.46 g) as a colourless foam. The compound was
obtained as a
2-1 mixture of isomers.
MS (ESI, m/z): 671.0 [M+H+].
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-60-
15.ii. {(2S, 3R, 6S)-6-[(2RS)-2-hydroxy-2-(3-methoxy-quinolin-S yl)-ethylJ-2-
hydroxymethyl-
tetrahydro pyran-3 yl}-carbamic acid tert-butyl ester:
This alcohol (0.26 g, 86% yield) was obtained as a colourless foam, starting
from
intermediate 15.i (0.46 g, 0.68 mmol) and using the procedure of Example 7,
step 7.xii. The
compound was purified by chromatography over Si02 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-S yl)-ethanol:
This amine (0.15 g, 84% yield) was obtained as a colourless foam, starting
from
intermediate 15.ii (0.23 g, 0.53 mmol) and using the procedure of Example 1,
step l.ix.
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)-ethylJ-2-
hydroxymethyl-
tetrahydro pyran-3 yl}-amide:
Starting from 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 eq.) 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 over Si0z (DCM-MeOH 9-1 containing
1%
aq. NH4OH) and obtained as a 2-1 mixture of epimers.
iH NMR (d6-DMSO) 8: 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+].
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-61-
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 using the procedure of Example 2, step 2.iv, the
title amide (0.095 g,
63% yield) was obtained as a colourless oil. The compound was purified by
chromatography
over Si0z (DCM-MeOH 9-1 containing 1% aq. NH4OH) and obtained as 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)-vinylJ-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 l.v (8.98 g, 16.71 mmol), the title
alkene (4.02 g, 50%
yield) was obtained as a pale yellow foam using the procedure of Example 1,
step l.vi. The
compound was purified by chromatography over Si0z using Hept-EA 1-2 as an
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)-
vinylJ-
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
obtained as an off-white solid, using the procedures of Example 9, steps 9.ii
(deprotection,
80% yield), 9.iii (aldehyde formation then oxidation, respectively 93% and 62%
yield) and
9.iv (amide formation, 51 % yield).
iH NMR (d6-DMSO) 8: 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);
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-62-
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)-
vinylJ-
tetrahydro pyran-2 yl}-acetamide:
This amine (0.132 g, 65% yield) was obtained as a beige solid, starting from
intermediate 17.ii (0.258 g, 0.56 mmol) and using the procedure of Example 1,
step l.ix.
MS (ESI, m/z): 361.0 [M+H+].
17.iv. 2-{(2R,3R,6S)-3-[(E)-3-(2,5-difluoro phenyl)-allylaminoJ-6-[(E)2-(3
fluoro-
6-methoxy-[1,5]naphthyridin-4 yl)-vinylJ-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.), the title compound (0.060 g, 33% yield) was
obtained as a white
solid using the procedure of Example 1, step 1.x.
iH NMR (d6-DMSO) 8: 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 ylmethylJ-tetrahydro pyran-2-carboxylic acid:
To an ice-chilled solution of intermediate l.ii (5 g, 14.48 mmol) in DCM (32
ml), MeCN
(32 ml) and water (46 ml) was added Na104 (14.6 g, 68.17 mmol) and RuC13
(0.030 g,
0.15 mmol). The reaction mixture was stirred at the same temperature for 5 h.
The reaction
mixture was diluted with EA (150 ml) and the solids were removed by
filtration. MeOH
(30 ml) was added and the resulting suspension was filtered. The filtrate was
treated with
aqueous 10% NaHSO3 (60 ml). The phases were separated and the aq. layer was
extracted
three times with EA. The combined org. layers were washed with brine, dried
over Na2SO4,
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-63-
filtered and evaporated under reduced pressure to give a brown foam (quant.).
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-[],3Jdioxolan-4 ylmethylJ-
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 colourless foam using the procedure of Example 12, step 12.i.
The compound
was purified by chromatography over Si0z using EA-cyclohexane 4-1 as an
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 ylJ-carbamic acid tert-
butyl ester:
To a mixture of intermediate 18.ii (2.3 g, 6.42 mmol), rac-BINAP (0.288 g,
0.46 mmol),
(dba)3Pd2.CHC13 (0.120 g, 0.12 mmol) and cesium carbonate (2.56 g, 7.86 mmol)
was added
dioxane (82 ml). The mixture was sonicated for 10 min, whereupon 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 added in one portion. The resulting mixture was heated at 100 C
for 4 h. The
reaction mixture was filtrated through a pad of Celite and the filtrate was
concentrated in
vacuo. The residue was purified over Si0z (DCM-MeOH 19-1) to afford 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 propylJ-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 l.ix. The
compound was
purified by chromatography over Si0z using DCM-MeOH 6-1 containing 1% aq.
NH4OH as
an eluent. The compound was obtained as a 2-1 mixture of epimers.
iH NMR (d6-DMSO) 8: 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);
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-64-
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)-allylaminoJ-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 l.x. The compound was purified by
chromatography over Si0z using DCM-MeOH 9-1 containing 1% aq. NH4OH as an
eluent.
The compound was obtained as a 2-1 mixture of epimers.
iH NMR (d6-DMSO) 8: 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+].
18.vi. [(E)-3-(2, 5-dif luoro phenyl)-allylJ-{(2R, 3R, 6S)-2-[(2RS)-2, 3-
dihydroxy propylJ-
6-(6-methoxy-[1,5]naphthyridin-4 ylcarbamoyl)-tetrahydro pyran-3 yl}-carbamic
acid
tert-butyl ester:
Starting from the intermediate 18.v (0.351 g, 0.66 mmol), this diol (0.307 g,
73% yield) was
obtained as a colourless foam, using the procedure of Example 4, step 4.iii.
The compound
was purified by chromatography over Si0z using DCM containing 7.5% MeOH, and
was
recovered as a 2-1 mixture of epimers.
MS (ESI, m/z): 629.0 [M+H+].
18.vii. [(E)-3-(2,5-difluoro phenyl)-allylJ-[(2R,3R,6S)-2-(2-hydroxy-ethyl)-6-
(6-methoxy-
[1,5]naphthyridin-4 ylcarbamoyl)-tetrahydro pyran-3 ylJ-carbamic acid tert-
butyl ester:
To a solution of intermediate 18.vi (0.294 g, 0.47 mmol) in acetone (4 ml) was
added a
solution of Na104 (0.25 g, 1.17 mmol) in water (0.9 ml). The reaction
proceeded 1 h. The
solids were filtered off and the filtrate concentrated to dryness. The white
residual foam was
taken up in MeOH (3 ml) and NaBH4 (0.042 g, 1.12 mmol) was added portionwise.
The
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-65-
reaction was stirred for 1 h at rt. Water was added and the volatiles were
evaporated under
reduced pressure. DCM-MeOH was added and the phases were separated. The aq.
layer was
extracted twice with DCM-MeOH 9-1 and the combined org. layers were dried over
Na2SO4
and evaporated under reduced pressure. After drying under HV, the title
compound (0.272 g,
97% yield) was obtained as 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)-allylaminoJ-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 obtained as a off-white foam,
starting from
intermediate 18.vii. (0.268 g, 0.45 mmol) and using the procedure of Example
2, step 2.iii.
iH NMR (d6-DMSO) 8: 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:
To a solution of (2S,5R)-5-tert-butoxycarbonylamino-tetrahydro-pyran-2-
carboxylic acid
(obtained as described in Eur. J. Org. Chem. (2003), 2418-2427; 3 g) in EA (50
ml) was
added NHS (1.5 g) and DCC (2.7 g). The reaction was stirred overnight at rt.
The solids were
removed by filtration. The filtrate was concentrated in vacuo and the residue
was taken up in
THF (180 ml). NH3 was bubbled through the solution for 10 min, and the
resulting turbid
mixture was stirred at rt for 1 h. Si0z (20 g) was added in the mixture, and
the volatiles were
removed by rotatory evaporation. The material was chromatographed over Si0z
(DCM-MeOH 19-1) to afford the title compound (1.3 g) as a white solid.
MS (ESI, m/z) : 245.3 [M+H+].
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-66-
19.ii. [(3R,6S)-6-(6-methoxy-[1,5]naphthyridin-4 ylcarbamoyl)-tetrahydro pyran-
3 ylJ-
carbamic acid tert-butyl ester:
To a mixture of intermediate 19.i (0.8 g), cesium carbonate (1.3g), rac-BINAP
(0.145 g) and
(dba)3Pd2.CHC13 (0.057 g) was added dioxane (41 ml). The mixture was sonicated
15 min 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 over Si02 (DCM-MeOH 19-1) to afford the
title amide
(1.3 g) as a foam.
iH NMR (CDC13) 8: 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); 2.3 9(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 l.ix. The compound was purified by
chromatography over Si0z (DCM-MeOH 19-1 containing 1% concentrated aq. NH4OH).
MS (ESI, m/z): 303.2 [M+H+].
19.iv. (2S, 5R)-5-[(E)-3-(2, 5-difluoro phenyl)-allylaminoJ-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 l.x. The compound was purified by
chromatography over Si0z using DCM-MeOH 97-3 containing 0.5% aq. NH4OH as an
eluent.
iH NMR (d6-DMSO) 8: 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, 1 H); 6.50 (td, J = 5.3, 16.2 Hz, 1 H); 4.21 (dd, J = 3.2,
10.7 Hz, 1 H);
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, 1 H).
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-67-
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-S yl)-vinyl]-tetrahydro pyran-3 yl}-
carbamic acid
tert-butyl ester:
Starting from (3R,6S)-[6-(1-phenyl-lH-tetrazole-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
obtained as a colourless solid, using the procedure of Example 1, step 1. vi.
The compound
was purified by trituraton in a Hex-ether mixture.
iH NMR (CDC13) 8: 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-[(IS,2S)-1,2-dihydroxy-2-(6-methoxy-quinolin-4 yl)-ethylJ-
tetrahydro-
pyran-3 yl}-carbamic acid tert-butyl ester:
Starting from intermediate 20.i (9.9 g, 25.7 mmol), the title diol (10.5 g,
97% yield) was
obtained as a colourless foam using the procedure of Example 6, step 6.i. The
compound was
purified by chromatography over Si0z using DCM-MeOH 9-1 as eluent.
iH NMR (d6-DMSO) 8: 8.71 (d, J = 4.5 Hz, 1H); 7.93 (d, J = 9.0 Hz, 1H); 7.54
(d, J = 4.5 Hz,
1H); 7.44-7.3 8(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
ylJ-
tetrahydro pyran-3 yl}-carbamic acid tert-butyl ester:
To an ice-chilled solution of intermediate 20.ii (10.2 g) in DCM (130 ml) were
added pyridine
(12 ml) and triphosgene (3.62 g). The reaction was stirred 30 min at this
temperature and then
90 min at rt. The reaction mixture was diluted with aq. NaHCO3 and the two
layers were
decanted. The org. layer was dried over NazSO4, filtered, and concentrated to
dryness. The
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-68-
residue was chromatographed over Si02 (DCM-MeOH 19-1) to afford the title
cyclic
carbonate (10.5 g) as a a colourless foam.
iH NMR (CDC13) 8: 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, 1 H); 6.27 (d, J = 4.2 Hz, 1 H); 4.61 (m, 1 H); 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-[(1 S)-1-hydroxy-2-(6-methoxy-quinolin-4 yl)-ethylJ-
tetrahydro pyran-
3 yl}-carbamic acid tert-butyl ester:
To a solution of intermediate 20.iii (2.75 g) in EA (250 ml) under argon was
added Pd/C
(1.32 g). The resulting suspension was stirred under hydrogen atmosphere.
After 2.5 h, more
Pd/C (0.66 g) was added and the reaction was stirred overnight under hydrogen
atmosphere.
The catalyst was filtered off and the filtrate concentrated in vacuo. The
residue was purified
by column chromatography over Si0z (DCM-MeOH 19-1 containing 1% aq. NH4OH) to
afford the title compound as a white foam (1.23 g).
iH NMR (d6-DMSO) 8: 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. (1 S)-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
min. The solution
was concentrated to dryness, basified with a 2M aq. NaOH solution, diluted
with
DCM-MeOH 9-1 and the phases separated. The aq. layer was extracted 6 times
with
DCM-MeOH 9-1. The combined org. layers were dried over NazSO4, filtered and
concentrated to dryness to afford a white solid (0.768 g).
iH NMR (DMSO) 8: 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);
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-69-
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, 1 H); 1.92 (m, 1 H); 1.56 (m, 2H); 1.39 (br s, 2H)1.13 (m, 1 H).
MS (ESI, m/z): 303.2 [M+H+].
20.vi. (IS)-1-{(2S,5R)-5-[(E)-3-(3 fluoro phenyl)-allylaminoJ-tetrahydro pyran-
2 yl}-
2-(6-methoxy-quinolin-4 yl)-ethanol:
Starting from intermediate 20.v (0.1 g, 0.33 mmol) and and (E)-3-(3-fluoro-
phenyl)-propenal
(0.050 g, 1.0 eq.), the title compound (0.063 g, 43% yield) was obtained as a
white solid using
the procedure of Example 1, step l.x. The compound was purified by
chromatography over
Si02 using DCM-MeOH 97-3 containing 0.5% aq. NH4OH as an 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:
Starting from intermediate 20.v (0.051 g, 0.17 mmol) and 7-fluoro-3-oxo-3,4-
dihydro-
2H-benzo[1,4]thiazine-6-carbaldehyde (obtained as described in WO 02/056882,
0.036 g,
1.0 eq.), the title compound (0.020 g, 23% yield) was obtained as a white
solid using the
procedure of Example 1, step l.x. The compound was purified by chromatography
over Si02
using DCM-MeOH 19-1 containing 0.5% aq. NH4OH as an eluent.
iH NMR (d6-DMSO) 8: 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 as a
white solid using
the procedure of Example 2, step 2.iv. The compound was purified by
chromatography over
Si0z using DCM-MeOH 97-3 containing 0.5% aq. NH4OH as an eluent.
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-70-
iH NMR (d6-DMSO) 8: 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 over
Si0z using DCM-MeOH 97-3 containing 0.5% aq. NH4OH as an eluent.
iH NMR (d6-DMSO) 8: 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-ditluoro-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, was
added
dropwise a solution of DMSO (3.5 ml) in DCM (25 ml). After 15 min stirring, a
solution of
(3R,6S)-(6-hydroxymethyl-tetrahydro-pyran-3-yl)-carbamic acid tert-butyl ester
(prepared as
described in Eur. J. Org. Chem. (2003), 2418-2427) in DCM (25 ml) was added
dropwise.
The reaction mixture was stirred 1 h and a solution of TEA (15 ml) in DCM (15
ml) was
added dropwise. The reaction proceeded for 1 h, with warming to 0 C. Saturated
NaHCO3
(50 ml) was added. The org. layer was separated, dried over NazSO4, filtered
and concentrated
in vacuo. The residue was chromatographed over Si0z (Hex-EA 1-2) to afford the
title
aldehyde (2.5 g) as a colourless 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) were added
K2C03
(5.38 g) and dimethyl-2-oxophosphonate (2.13 ml). The mixture was stirred 2 h
at rt and a
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-71-
solution of intermediate 24.i (2.5 g) in MeOH (30 ml) was added. The mixture
was stirred
overnight at rt. After concentration to dryness, the residue was partitioned
between water
(50 ml) and EA (100 ml). The aq. layer was extracted with EA (2 x 100 ml). The
combined
org. layers were washed with brine, dried over Na2SO4, filtered and
concentrated to dryness.
The residue was filtered through Si02 (EA-Hex 1-3) to afford the title alkyne
(1.9 g) as a
white solid.
iH NMR (CDC13) 8: 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); 2.5 0(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)-tetrahydropyran-3
ylJ-carbamic acid
tert-butyl ester:
To a solution of intermediate 24.ii (1.95 g, 8.65 mmol) in THF (26 ml) was
added
bis(triphenylphosphine) palladium dichloride (0.12 g, 0.17 mmol) and then
tributyltin hydride
(2.75 ml, 10.38 mmol). The mixture was stirred at rt for 20 min. The reaction
mixture was
concentrated to dryness and the residue was chromatographed over Si0z (Hex
then Hex-EA
9-1) to afford the title stannane (3.4 g) as an equimolar mixture of cis and
trans isomers.
24.iv. trans-{(3R, 6S)-6-[2-(6-methoxy-[], 5Jnaphthyridin-4 yl)-vinylJ-
tetrahydro pyran-3 yl}-
carbamic acid tert-butyl ester:
To a solution of intermediate 24.iii (5 g) in dioxane (freshly distilled, 50
ml) were added
trifluoromethanesulfonic acid 2-cyano-quinolin-8-yl ester (2.0 g, 6.6 mmol),
LiC1 (0.936 g),
2,6-di-tert-butyl-4-methylphenol (few seeds), (PPh3)4Pd (0.153 g). The mixture
was heated at
100 C overnight. After cooling, the solids were filtered off and the filtrate
was concentrated
to dryness. The residue was chromatographed over Si0z (Hex-EA 1-1) to afford
the title
alkene (1.80 g, 71% yield) as a white solid.
iH NMR (d6-DMSO) 8: 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+].
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-72-
24.v. (3R,6S)-{6-[(IR,2R)-2-(cyano-quinolin-8 yl)-1,2-dihydroxy-ethylJ-
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.
MS (ESI, m/z): 419.2 [M+H+].
24.vi. 8-[(IR,2R)-2-((2S,5R)-5-amino-tetrahydro pyran-2 yl)-1,2-dihydroxy-
ethylJ-quinoline-
2-carbonitrile:
The title amine (0.62 g, 74% yield) was obtained as a colourless solid
starting from
intermediate 24.v (l.l g, 2.61 mmol) and using the procedure of Example 1,
step l.ix.
MS (ESI, m/z): 314.2 [M+H+].
24.vii. 8-((IR,2R)-2-{(2S,5R)-5-[(E)-3-(2,5-difluoro phenyl)-allylaminoJ-
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 eq.), the title compound (0.04 g, 17% yield) was
obtained as a white
solid according to the procedure of Example 1, step l.x. The compound was
purified by
chromatography over Si0z using DCM-MeOH 19-1 containing 0.5% aq. NH4OH as an
eluent.
iH NMR (d6-DMSO) 8: 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, 1H); 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); 4.3
5(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,
1 H).
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-
quinolin-5-yl)-vinyl] -tetrahydro-pyran-3-yl}-amine:
25.i. {(3R, 6S)-6-[(E)-2-(3 fluoro-6-methoxy-quinolin-S yl)-vinylJ-tetrahydro
pyran-3 yl}-
carbamic acid tert-butyl ester:
Starting from (3R,6S)-[6-(1-phenyl-lH-tetrazole-5-sulfonylmethyl)-tetrahydro-
pyran-3-yl]-
carbamic acid tert-butyl ester (described in Preparation G; 1.43 g, 3.4 mmol)
and 3-fluoro-
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-73-
6-methoxy-quinoline-5-carbaldehyde (0.462 g, 2.25 mmol), the title alkene
(0.85 g, 62%
yield) was obtained as a white solid, using the procedure of Example 1, step
1. vi. The
compound was purified by chromatography over Si02 using EA-Hex 1-las eluent.
iH NMR (d6-DMSO) 8: 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-S yl)-vinylJ-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 l.ix. The
compound was purified by chromatography over Si02 using DCM-MeOH 9-1
containing 1%
aq. NH4OH as eluent.
MS (ESI, m/z): 465.6 [M+H+].
25.iii. [(E)-3-(2, 5-difluoro phenyl)-allylJ-{3R, 6S)-6-[(E)-2-(3 fluoro-6-
methoxy-quinolin-
S yl)-vinylJ-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
colourless oil
using the procedure of Example 1, step l.x. The compound was purified by
chromatography
over Si0z using DCM-MeOH 19-1 containing 0.5% aq. NH4OH as an 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)-ethylJ-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 under hydrogen atmosphere
for 2 h. The
catalyst was removed by filtration and the filtrate was concentrated to
dryness to afford the
title compound (0.55 g) as a white solid.
MS (ESI, m/z): 405.0 [M+H+].
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-74-
26.ii. (3R,6S)-6-[2-(6 fluoro-3-methoxy-quinolin-4 yl)-ethylJ-tetrahydro pyran-
3 ylamine:
The title amine (0.3 g, 72% yield) was obtained as a colourless oil, starting
from intermediate
26.i (0.55 g, 1.36 mmol) and using the procedure of Example 1, step l.ix. The
compound was
purified by chromatography over Si02 using DCM-MeOH 9-1 containing 1% aq.
NH4OH as
eluent.
MS (ESI, m/z): 305.1 [M+H+].
26.iii. [(E)-3-(2,5-dfluoro phenyl)-allylJ-{(3R,6S)-6-[2-(6 fluoro-3-methoxy-
quinolin-4 yl)-
ethylJ-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
colourless oil
using the procedure of Example 1, step l.x. The compound was purified by
chromatography
over Si0z using DCM-MeOH 19-1 containing 0.5% aq. NH4OH as an eluent.
iH NMR (d6-DMSO) 8: 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, 1 H), 7.63 (d, J = 9.2 Hz, 1H); 7.48 (m, 1H); 7.24 (m, 1H); 7.11
(m, 1 H) 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, 1H); 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:
Starting from 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 over Si0z using DCM-MeOH 9-1
containing 1%
aq. NH4OH as an eluent.
MS (ESI, m/z): 482.8 [M+H+].
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-75-
Example 28: (1R,2R)-1-{(2R,5S)-5-[(E)-3-(2,5-ditluoro-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)-vinylJ-tetrahydro pyran-3
yl}-carbamic acid
tert-butyl ester:
Starting from (3S,6R)-[6-(1-phenyl-lH-tetrazole-5-sulfonylmethyl)-tetrahydro-
pyran-3-yl]-
carbamic acid tert-butyl ester (see preparation I, 1.69 g, 4 mmol) and 3-
methoxy-quinoline-
5-carbaldehyde (see preparation D, 0.7 g, 4 mmol), the title alkene (1.03 g,
69% yield) was
obtained as a white solid, using the procedure of Example 1, step 1. vi. The
compound was
purified by chromatography over Si0z using Hept-EA 1-1 then 1-4 as eluent.
MS (ESI, m/z): 373.1 [M+H+].
28.ii. {(3S,6R)-6-[(IR,2R)-2-(6 fluoro-quinolin-4 yl)-1,2-dihydroxy-ethylJ-
tetrahydro pyran-
3 yl}-carbamic acid tert-butyl ester:
Starting from intermediate 28.i (0.497 g, 1.33 mmol), the title diol (0.54 g,
99% yield) was
obtained as a white solid using the procedure of Example 6, step 6.i.The
compound was
purified by chromatography over Si0z using DCM-MeOH 9-1 as eluent.
MS (ESI, m/z): 407.0 [M+H+].
28.iii. (IR,2R)-1-[(2R,5S)-5-amino-tetrahydro pyran-2 ylJ-2-(6 fluoro-quinolin-
4 yl)-ethane-
1,2-diol:
The title amine (0.21 g, 51% yield) was obtained as a colourless foam,
starting from
intermediate 28.ii (0.54 g, 1.32mmol) and using the procedure of Example 1,
step l.ix.
MS (ESI, m/z): 307.1 [M+H+].
28.iv. (IR,2R)-1-{(2R,5S)-5-[(E)-3-(2,5-difluoro phenyl)-allylaminoJ-
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 l.x. The compound was purified by
chromatography over Si0z using DCM-MeOH 9-1 containing 1% aq. NH4OH as an
eluent.
MS (ESI, m/z): 458.9 [M+H+].
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-76-
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)-vinylJ-tetrahydro pyran-3
ylamine:
The title amine (0.135 g, 82% yield) was obtained as a colourless foam,
starting from
intermediate 28.i (0.226 g, 0.6 mmol) and using the procedure of Example 1,
step l.ix. The
compound was purified by chromatography over Si02 using DCM-MeOH 9-1
containing 1%
aq. NH4OH as an eluent.
MS (ESI, m/z): 273.2 [M+H+].
29.ii. [(E)-3-(2,5-difluoro phenyl)-allylJ-{(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) and (E)-3-(2,5-difluoro-
phenyl)-
propenal (0.089 g, 1. 1 eq.), the title compound (0.112 g, 54% yield) was
obtained as a
colourless oil according to the procedure of Example 1, step l.x. The compound
was purified
by chromatography over Si0z using DCM-MeOH 97-3 containing 0.3% aq. NH4OH as
an
eluent.
iH NMR (d6-DMSO) 8: 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 colourless foam starting
from
intermediate 28.i (0.277 g, 0.74 mmol) and using the procedure of Example 2,
step 2.ii. The
compound was purified by chromatography over Si0z using DCM-MeOH 9-1
containing 1%
aq. NH4OH as an eluent.
MS (ESI, m/z): 375.1 [M+H+].
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-77-
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 obtained as a yellowish oil, starting
from
intermediate 30.i (0.261 g, 0.7 mmol) and using the procedure of Example 1,
step l.ix. The
compound was purified by chromatography over Si02 using DCM-MeOH 9-1
containing 1%
aq. NH4OH as an eluent.
MS (ESI, m/z): 275.1 [M+H+].
30.iii. [(E)-3-(2,5-d fluoro phenyl)-allylJ-{(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
colourless oil
according to the procedure of Example 1, step l.x. The compound was purified
by
chromatography over Si0z using DCM-MeOH 19-1 containing 0.5% aq. NH4OH as an
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:
Starting from 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
l.x. The
compound was purified by chromatography over Si0z using DCM-MeOH 9-1
containing 1%
aq. NH4OH as an eluent.
iH NMR (d6-DMSO) 8: 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+].
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-78-
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)-vinylJ-tetrahydro
pyran-2 yl}-
propane-l,2-diol:
Starting from intermediate l.vi (2.19 g, 4.39 mmol), the title compound (1.35
g, 85% yield)
was obtained as an off-white solid using the procedure of Example 2, step
2.iii. 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)-
vinylJ-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)-vinylJ-tetrahydro pyran-3 yl}-amide:
Starting from intermediate 32.i (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 l.x., the title compounds were obtained as white
solids. The
isomers were partially separated by chromatography over Si0z (DCM-MeOH 93-7
containing
0.7% aq.NH4OH) to afford a first eluting isomer (0.019 g, 6% yield), a
fraction containing
both isomers (0.12 g, 39% yield) and the second eluting isomer (0.055 g, 18%
yield).
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)-vinylJ-2-(2-oxo-ethyl)-tetrahydro pyran-3 ylJ-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.
iH NMR (d6-DMSO) 8: 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, 1 H); 7.11 (dd, J 4.0, 16.8 Hz, 1 H); 4.76 (m, 1 H); 4.65 (m, 1 H);
4.05 (m, 1 H);
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+].
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-79-
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-[I,5]naphthyridin-4 yl)-
vinylJ-
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) was
added, at 0 C, NaBH4 (0.02 g). The reaction was stirred 1 h at this
temperature. Water (2 ml)
was added. The volatiles were removed in vacuo and the residue was
chromatographed
(DCM-MeOH 19-1 containing 0.5% aq. NH4OH) to afford a solid that was further
triturated
in ether, 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-[I,5]naphthyridin-4
yl)-vinylJ-
tetrahydro pyran-3 yl}-carbamic acid tert-butyl ester:
Starting from intermediate l.vi (5.5 g, 11 mmol), the title amide (0.602 g,
1.36 mmol) was
obtained as a yellowish solid, using the procedures described respectively in
Example 9,
step 9.ii. (deprotection, 89% yield), Example 2, steps 2.v (aldehyde
formation, 99% yield) and
2.vi (acid formation, 76% yield) and Example 9, step 9.iv (30% yield).
MS (ESI, m/z): 521.8 [M+H+].
33.ii. 2-{3-amino-6-[(E)-2-(6-methoxy-[I,5]naphthyridin-4 yl)-vinylJ-
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 brown solid using the procedure of Example 1, step 1.ix.
MS (ESI, m/z): 343.0 [M+H+].
33.iii. 2-{(2R,3R,6S)-3-[(E)-3-(2,5-difluoro phenyl)-allylaminoJ-6-[(E)-2-(6-
methoxy-
[1,5]naphthyridin-4 yl)-vinylJ-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 as a white
solid according to the procedure of Example 1, step l.x. The compound was
purified by
chromatography over Si0z (DCM-MeOH 19-1 containing 0.5% aq. NH4OH).
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-80-
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:
To a solution of DIPA (3.5 ml) in THF (100 ml), cooled to -78 C, was added n-
BuLi (2.5N in
hexanes, 10 ml). The reaction mixture was stirred 5 min at this temperature
before warming to
0 C. The reaction mixture was stirred 15 min before cooling to -78 C. 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 3 h at -78 C. DMF (3 ml) was added dropwise. After 15 min, the
reaction mixture was
warmed up to rt. 10% aq. NaHSO4 (10 ml) was added. The volatiles were removed
in vacuo
and the residue was made basic with sat. sodium bicarbonate. The aq. layer was
extracted
twice with EA (2 x 200 ml). The combined org. layers were washed with brine,
dried over
NazSO4, filtered and concentrated to dryness. The residue was chromatographed
(Hex-EA
1-1) to afford the title aldehyde (3.05 g, 60% yield) as a yellowish solid.
The compound was
contaminated by 20% of the remaining starting material.
iH NMR (CDC13) 8: 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 ylmethylJ-6-[(E)-2-(3
fluoro-
6-methoxy-quinolin-4 yl)-vinylJ-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 obtained as a pale yellow foam using
the procedure of
Example 1, step l.vi. The compound was purified by chromatography using Hept-
EA 1-2 as
an eluent. The compound was obtained as a 2-1 mixture of epimers and a 3-1 E-Z
mixture.
MS (ESI, m/z): 517.1 [M+H+].
34.iii. (2RS)-3-{(2R,3R,6S)-3-[(E)-3-(2,5-difluoro phenyl)-allylaminoJ-6-[(E)-
2-(3 fluoro-
6-methoxy-quinolin-4 yl)-vinylJ-tetrahydro pyran-2 yl} propane-l,2-diol:
Starting from intermediate 34.ii (2.63 g, 5.1 mmol), the title compound (1.62
g) was obtained
as a yellowish foam, using the procedures described in Example 2, step 2.iii
(deprotection,
67% yield) and in Example 1, step l.x (reductive amination, 91% yield). After
each step, the
crude reaction mixture was purified by chromatography over Si0z using
respectively
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-81-
DCM-MeOH 6-1 containing 1% aq. NH4OH and DCM-MeOH 9-1 containing 1% aq.
NH4OH as eluents. The compound was obtained as a 2-1 mixture of epimers and a
3-1 E-Z
mixture.
MS (ESI, m/z): 567.7 [M+H+].
34.iv. (2R,3R,6S)-{3-[(E)-3-(2,5-difluoro phenyl)-allylaminoJ-6-[(E)-2-(3
fluoro-6-methoxy-
quinolin-4 yl)-vinylJ-tetrahydro pyran-2 yl}-acetic acid:
Starting from intermediate 34.iii (1.58 g, 3 mmol), the title compound (0.037
g) was obtained
as an off-white solid using the procedures described in Example 4, step 4.iii
(Boc formation,
74% yield), Example 2, steps 2.v (aldehyde formation, 82% yield) and 2.vi
(acid formation,
98% yield), and Example 4, step 4.vi (52% yield). The compound was purified by
chromatography over Si0z using DCM-MeOH 6-1 containing 1% aq. NH4OH) after the
last
step. The compound was obtained as a 2-1 E-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-dfluoro phenyl)-allylaminoJ-6-[(E)-2-
(6-methoxy-
[1,5]naphthyridin-4 yl)-vinylJ-tetrahydro pyran-2 yl} propane-l,2-diol:
Starting from intermediate 32.i (1.43 g, 4 mmol) and (E)-3-(2,5-difluoro-
phenyl)-propenal
(0.672 g, 1.0 eq), the title compound (1.34 g, 65% yield) was obtained as as a
colourless foam
using the procedure of Example 1, step l.x. After purification by
chromatography over Si0z
(DCM-MeOH 9-1 containing 1% aq. NH4OH), the compound was obtained as a 2-1
mixture
of epimers.
iH NMR (d6-DMSO) 8: 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, 1 H), 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+].
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-82-
35.ii. [(E)-3-(2, 5-difluoro phenyl)-allylJ-{(2R, 3R, 6S)-2-[(2RS)-2, 3-
dihydroxy propylJ-
6-[2-(6-methoxy-[1,5]naphthyridin-4 yl)-vinylJ-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 rt for 24 h.
Di-tert-butyl dicarbonate (0.5 g) was added and the reaction proceeded further
24 h. The
reaction mixture was concentrated to dryness and the residue was
chromatographed over Si02
(DCM-MeOH 19-1 then 9-1) to afford the title compound (0.77 g, 48% yield) as a
colourless
foam.
'H NMR (CDC13) 8: 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, 1 H), 6.5 7(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)-allylJ-
amino}-
6-[(E)-2-(6-methoxy-[],5Jnaphthyridin-4 yl)-vinylJ-tetrahydro pyran-2 yl}-
acetic acid:
Starting from intermediate 35.ii (0.77 g, 1.25mmo1), the title acid (0.48 g)
was prepared as a
colourless foam using the procedures described in Example 2, steps 2.v
(aldehyde formation,
82% yield) and 2.vi (acid formation, 98% yield). The compound was purified by
chromatography over Si0z using DCM-MeOH 93-7) after the last step.
iH NMR (d6-DMSO) 8: 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)-allylaminoJ-6-[(E)-2-(6-
methoxy-
[1,5]naphthyridin-4 yl)-vinylJ-tetrahydro pyran-2 yl}-acetic acid:
A solution of intermediate 35.iii. (0.1 g, 0.17 mmol) in TFA (2 ml) was
stirred at rt for
15 min. 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 aq. layer was adjusted to 7 and the org.
layer was
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
- 83 -
separated. The aq. layer was extracted once more with DCM-MeOH (9-1, 30 ml)
and the
combined org. layers were washed with brine, dried over Na2SO4, filtered and
concentrated to
dryness. The residue was triturated in ether and the solid was filtered off,
dried under HV to
afford the title compound (0.045 g, 54% yield) as a colourless 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]naphthyridin-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 ylmethylJ-tetrahydro pyran-2-carboxylic acid:
To an ice-chilled solution of intermediate l.ii (5 g, 14.48 mmol) in DCM (32
ml), MeCN
(32 ml) and water (46 ml) was added Na104 (14.6 g, 68.17 mmol) and RuC13
(0.030 g,
0.15 mmol). The reaction mixture was stirred at the same temperature for 5 h.
The reaction
mixture was diluted with EA (150 ml) and the solids were removed by
filtration. MeOH
(30 ml) was added and the resulting suspension was filtered. The filtrate was
treated with aq.
10% NaHSO3 (60 ml). The phases were separated and the aq. layer was extracted
three times
with EA. The combined org. layers were washed with brine, dried over NazSO4,
filtered and
evaporated under reduced pressure to give a brown foam (quant.). 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-[],3Jdioxolan-4 ylmethylJ-
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 colourless foam using the procedure of Example 10, step 10.ii.
The compound
was purified by chromatography using EA-cyclohexane 4-1 as an 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 ylJ-carbamic acid tert-
butyl ester:
To a mixture of intermediate 36.ii (2.3 g, 6.42 mmol), rac-BINAP (0.288 g,
0.46 mmol),
(dba)3Pd2.CHC13 (0.120 g, 0.12 mmol) and cesium carbonate (2.56 g, 7.86 mmol)
was added
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-84-
dioxane (82 ml). The mixture was sonicated for 10 min, whereupon 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 added in one portion. The resulting mixture was heated at 100 C
for 4 h. The
reaction mixture was filtrated through a pad of celite and the filtrate was
concentrated in
vacuo. The residue was purified over Si02 (DCM-MeOH 19-1) to afford 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 propylJ-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) was
obtained as a reddish solid using the procedure of Example 1, step l.viii. The
compound was
purified by chromatography using DCM-MeOH 6-1 containing 1% aq. NH4OH as an
eluent.
The compound was obtained as a 2-1 mixture of epimers.
iH NMR (d6-DMSO) 8: 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)-allylaminoJ-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)
were added 3A molecular sieves (10 g) and (E)-3-(2,5-difluoro-phenyl)-propenal
(0.49 g,
1.1 eq). The mixture was heated at 50 C for 18 h. After cooling to 0 C, NaBH4
(1 g) was
added, and the reaction proceeded for 45 min. The reaction mixture was
filtered and the solids
were washed with DCM-MeOH (9-1, 200 ml). The filtrate was washed with brine
(50 ml),
dried over NazSO4, filtered and concentrated to dryness. The residue was
chromatographed
(DCM-MeOH 93-7 containing 0.7% aq. NH4OH) to afford the title diol (1.1 g, 78%
yield) as
a colourless foam. The compound was obtained as a 2-1 mixture of epimers.
iH NMR (d6-DMSO) 8: 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);
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-85-
7.32 (d, J = 9.0 Hz, 1 H); 7.27 (m, 1 H); 7.12 (m, 1 H); 6.63 (d, J = 16.2 Hz,
1 H); 6.49 (m, 1 H);
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-dfluoro phenyl)-allylaminoJ-6-(6-methoxy-
[1,5]naphthyridin-4 ylcarbamoyl)-tetrahydro pyran-2 ylJ-acetic acid:
Starting from intermediate 36.v (l.l g, 2.1 mmol), the title compound (0.080
g) was obtained
as a white solid using the procedures described in Example 4, step 4.iii (Boc
formation, 68%
yield), Example 2, steps 2.v (aldehyde formation) and 2.vi (acid formation,
30% yield, two
steps), and Example 35, step 35.vi (deprotection, 54% yield). The compound was
purified by
chromatography over Si0z using DCM-MeOH 6-1 containing 1% aq. NH4OH after the
last
step.
MS (ESI, m/z): 513.4 [M+H+].
Pharmacological properties of the invention compounds
In vitro assay
Exp erimental_ metho d:
These assays have been performed following the description given in "Methods
for dilution
Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, 4th
ed.; Approved
standard: NCCLS Document M7-A4; National Committee for Clinical Laboratory
Standards:
Villanova, PA, USA, 1997". Minimal inhibitory concentrations (MICs; mg/1) were
determined in cation-adjusted Mueller-Hinton Broth (BBL) by a microdilution
method
following NCCLS guidelines (National Committee for Clinical Laboratory
Standards.
Methods for Dilution Antimicrobial Susceptibility). The pH of the test medium
was 7.2-7.3.
CA 02643962 2008-08-27
WO 2007/105154 PCT/IB2007/050784
-86-
Results:
All Examples were tested against several Gram positive and Gram negative
bacteria.
Typical antibacterial test results are given in the table hereafter (MIC in
mg/1).
Example S. aureus A798 S. Pneumoniae 49619 M. catarrhalis A894
No.
1 <=.031 <=.031 <=.031
9 <=.031 <=.031 <=.031
16 0.063 1 0.25
21 0.125 0.5 <=.031
