HETEROAROMATIC COMPOUNDS HAVING SPHINGOSINE-1-PHOSPHATE (S1P) RECEPTOR AGONIST AND/OR ANTAGONIST BIOLOGICAL ACTIVITY

COMPOSES HETEROAROMATIQUES PRESENTANT UNE ACTIVITE BIOLOGIQUE AGONISTE ET/OU ANTAGONISTE SUR LE RECEPTEUR SPHINGOSINE-1-PHOSPHATE (S1P)

English Abstract

A novel compound having antagonist activity at the S1P3 receptor represented by the formula (I); [C(R3)2]a(W)b[C(R3)2]c[P(O)(OR3)2]d[C(V)x(OR4)y(R4)z]e wherein X is selected from the group consisting of CR3 and N; Y is selected from the group consisting of CR3 and N; Z is selected from the group consisting of CR3 and N; and at least one of X, Y and Z is N; W is NR3 or O; V is oxo or represents two H atoms; provided that when V is two H atoms, z is 0; R1 is an aryl group; R2 is an aryl group; R3 is selected from the group consisting of H and alkyl and lower alkyl; R4 is selected from the group consisting of H and alkyl; and 2 of said R3 or R4 may together form a cyclic alkyl ring having from 3 to 6 carbon atoms; a is 0 or an integer of from 1 to 6; b is 0 or 1; c is O or an integer of from 1 to 6; d is 0 or 1; e is 0 or 1; x is 1; y is 0 or an integer of from 1 to 3; z is 0 or an integer of from 1 to 3; provided however that when d is 0, e is 1, and when e is 0, d is 1, and when y is 0, z is 1 and when z is 0, y is 1.

French Abstract

L'invention concerne un nouveau composé présentant une activité antagoniste sur le récepteur S1P3, qui est représenté par la formule (I) : [C(R3)2]a(W)b[C(R3)2]c[P(O)(OR3)2]d[C(V)x(OR4)y(R4)z]e, dans laquelle X est sélectionné dans le groupe comprenant CR3 et N; Y est sélectionné dans le groupe comprenant CR3 et N; Z est sélectionné dans le groupe comprenant CR3 et N; et au moins un des éléments parmi X, Y et Z représente N; W représente NR3 ou O; V représente oxo ou deux atomes H; sous réserve que lorsque V représente deux atomes H, z vaut 0; R1 représente un groupe aryle; R2 représente un groupe aryle; R3 est sélectionné dans le groupe comprenant H et alkyle et alkyle inférieur; R4 est sélectionné dans le groupe comprenant H et alkyle; et 2 desdits éléments R3 ou R4 peuvent former ensemble un anneau alkyle cyclique comprenant entre 3 et 6 atomes de carbone; a vaut 0 ou un nombre entier compris entre 1 et 6; b vaut 0 ou 1; c vaut 0 ou un nombre entier compris entre 1 et 6; d vaut 0 ou 1; e vaut 0 ou 1; x vaut 1; y vaut 0 ou un nombre entier compris entre 1 et 3; z vaut 0 ou un nombre entier compris entre 1 et 3; sous réserve cependant que lorsque d vaut 0, e vaut 1; que lorsque e vaut 0, d vaut 1; que lorsque y vaut 0, z vaut 1 et que lorsque z vaut 0, y vaut 1.

Claims

73
What is claimed is:
Claim 1. A novel compound having antagonist activity at the S1P3 receptor
which is represented by the formula I
<IMG>
wherein
X is selected from the group consisting of CR3 and N;
Y is selected from the group consisting of CR3 and N;
Z is selected from the group consisting of CR3 and N;
and at least one of X, Y and Z is N;
W is NR3 or O;
R1 is an aryl group;
R2 is an aryl group;
R3 is selected from the group consisting of H and alkyl; and 2 of
said R3 groups together with N may form a heterocylic ring having from 2
to 6 carbon atoms;
R4 is selected from the group consisting of H, alkyl, OR3, and
N(R3)2;
a is 0 or an integer of from 1 to 6;
b is 0 or 1;
c is 0 or an integer of from 1 to 6;
d is 0 or 1;
e is 0 or 1;
u is 0 or 1;
v is 0 or an integer of from 1 to 2;

74
x is 0 or 1;
y is 0 or an integer of from 1 to 3;
z is 0 or an integer of from 1 to 3;
provided however that when d is 0, e is 1, and when e is 0, d is 1.
Claim 2. The compound of claim 1 wherein R1 is selected, from the group
consisting of phenyl and substituted derivatives thereof;
R2 is selected, preferably from the group consisting of phenyl, furanyl,
thienyl,
pyridyl, pyranyl and substituted derivatives thereof;
R3 is selected from the group consisting of H and lower alkyl;
R4 is selected from the group consisting of H and lower alkyl;
a is 0 or an integer of from 1 to 3;
c is 0 or an integer of from 1 to 5;
Claim 3. The compound of claim 2, wherein e is 0.
Claim 4. The compound of claim 3, wherein R1 is represented by the general
formula
<IMG>

75
wherein R5 is selected from the group consisting of H, alkyl, trifluoromethyl,
trifluoromethyloxy, halo and lower alkylthio.
Claim 5. The compound of claim 4, wherein R2 is selected from the group
consisting of furanyl, thienyl, pyridyl and pyranyl or R2 is
<IMG>
represented by the general formula
wherein R5 is selected from the group consisting of H, alkyl, trifluoromethyl,
trifluoromethyloxy, halo, and lower alkylthio .
Claim 6. The compound of claim 5 wherein R3 is H.
Claim 7. The compound of claim 6, wherein c is 1, 2 or 3.
Claim 8. The compound of claim 7, wherein a is 1.
Claim 9. The compound of claim 8, wherein Z is N and X and Y are CR3.
Claim 10. The compound of claim 9, wherein W is NR3, R2 is phenyl and R5
is selected from the group consisting of H and methyl.
Claim 11. The compound of claim 9, wherein R2 is pyridyl and R5 is ethyl,
and W is NR3.
Claim 12. The compound of claim 2, wherein d is 0.

76
Claim 13. The compound of claim 12, wherein R1 is represented by the
general formula
<IMG>
wherein R5 is selected from the group consisting of H, alkyl, trifluoromethyl,
trifluoromethyloxy, halo, and loweralkylthio
Claim 14. The compound of claim 13, wherein R2 is represented by the
general formula
<IMG>
wherein R5 is selected from the group consisting of H, lower alkyl,
trifluoromethyl,
trifluoromethyloxy, halo, and lower alkylthio or R2 is selected from the group
consisting of furanyl, thienyl, pyridyl and pyranyl.
Claim 15. The compound of claim 14 wherein R3 is H.
Claim 16. The compound of claim 15 wherein a is 1.
Claim 17. The compound of claim 15 wherein x is 1 and z is 0.
Claim 18. The compound of claim 17 wherein R4 is selected from the group
consisting of H, methyl and ethyl,

77
Claim 19. The compound of claim 18 wherein Z is N, X and Y are CR3, R2 is
pyridyl, and R5 is selected from the group consisting of H, methyl, ethyl,
propyl
and trifluoromethyl.
Claim 20. The compound of claim 18 wherein X, Y and Z are N, R5 is
selected from the group consisting of H, methyl, ethyl, propyl and
trifluoromethyl.
Claim 21. The compound of claim 18 wherein X and Z are N and Y is CR3.
Claim 22. The compound of claim 15 wherein y is 0.
Claim 23. The compound of claim 1 selected from the group consisting of
<IMG>

78
<IMG>

79
<IMG>

80
<IMG>
Claim 14. A compound having antagonist activity at the S1P3 receptor
comprising a 6-membered heteroaromatic ring including one, two or three
enchained nitrogen atoms and the remaining ring atoms being carbon, an aryl
radical directly bonded to said 6-membered heteroaromatic ring at both of the
5 and
6 positions and a side chain at the 2 position of said 6-membered
heteroaromatic
ring, wherein said side chain terminates with an end group selected from the
group
consisting of a phosphonic acid, a lower alkyl ester thereof, a carboxylic
acid, a

81
lower alkyl ester thereof, a lower alkyl ether and a lower alkylcarboxy, and
any
pharmaceutically acceptable salt thereof.
Claim 25. The compound of claim 25 wherein said one, two or three enchained
nitrogen atoms are at the 1, or 1 and 3, or 1 and 4, or 1, 3 and 4 positions,
respectively.

Description

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1
18063-B(AP)
HETEROAROMATIC COMPOUNDS HAVING SPHINGOSINE-1-
PHOSPHATE (S1P) RECEPTOR AGONIST AND/OR ANTAGONIST
BIOLOGICAL ACTIVITY
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to derivatives and/or analogues of sphingosine
and
pharmaceutical compositions, including such derivatives and/or analogues,
which
are useful as drugs for the treatment of fungal infections, allergic diseases,
immune
disorders, etc.
2. Summary of the Art
Sphingosine is a compound having the chemical structure shown in the general
formula described below, in which Y' is hydrogen. It is known that various
sphingolipids, having sphingosine as a constituent, are widely distributed in
the
living body including on the surface of cell membranes of cells in the nervous
system.
H OH NH2
I 1 1
H3C -(CHz)1z - C= CH - CH - CH - CHzO-Y~
I
H
A sphingolipid is one of the lipids having important roles in the living body.
A
disease called lipidosis is caused by accumulation of a specified sphingolipid
in the
body. Sphingolipids present on cell membranes function to regulate cell
growth;
participate in the development and differentiation of cells; function in
nerves; are
involved in the infection and malignancy of cells; etc. Many of the
physiological

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2
roles of sphingolipids remain to be solved. Recently the possibility that
ceramide, a
derivative of sphingosine, has an important role in the mechanism of cell
signal
transduction has been indicated, and studies about its effect on apoptosis and
cell
cycle have been reported.
Sphingosine-l-phosphate is an important cellular metabolite, derived from
ceramide that is synthesized de novo or as part of the sphingomeyeline cycle
(in
animals cells). It has also been found in insects, yeasts and plants.
The enzyme, ceramidase, acts upon ceramides to release sphingosine, which is
phosphorylated by spingosine kinase, a ubiquitous enzyme in the cytosol and
endoplasmic reticulum, to form sphingosine-l-phosphate. The reverse reaction
can
occur also by the action of sphingosine phosphatases, and the enzymes act in
concert to control the cellular concentrations of the metabolite, which
concentrations are always low. In plasma, such concentration can reach 0.2 to
0.9
M, and the metabolite is found in association with the lipoproteins,
especially the
HDL. It should also be noted that sphingosine-l-phosphate formation is an
essential step in the catabolism of sphingoid bases.
Like its precursors, sphingosine-l-phosphate is a potent messenger molecule
that
perhaps uniquely operates both intra- and inter-cellularly, but with very
different
functions from ceramides and sphingosine. The balance between these various
sphingolipid metabolites may be important for health. For example, within the
cell,
sphingosine-l-phosphate promotes cellular division (mitosis) as opposed to
cell
death (apoptosis), which it inhibits. Intracellularly, it also functions to
regulate
calcium mobilization and cell growth in response to a variety of extracellular
stimuli. Current opinion appears to suggest that the balance between
sphingosine-
1-phosphate and ceramide and/or spingosine levels in cells is critical for
their
viability. In common with the lysophospholipids, especially lysophosphatidic
acid,

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with which it has some structural similarities, sphingosine-l-phosphate exerts
many
of its extra-cellular effects through interaction with five specific G protein-
coupled
receptors on cell surfaces. These are important for the growth of new blood
vessels, vascular maturation, cardiac development and immunity, and for
directed
cell movement.
Sphingosine-1 phosphate is stored in relatively high concentrations in human
platelets, which lack the enzymes responsible for its catabolism, and it is
released
into the blood stream upon activation of physiological stimuli, such as growth
factors, cytokines, and receptor agonists and antigens. It may also have a
critical
role in platelet aggregation and thrombosis and could aggravate cardiovascular
disease. On the other hand the relatively high concentration of the metabolite
in
high-density lipoproteins (HDL) may have beneficial implications for
atherogenesis. For example, there are recent suggestions that sphingosine-1-
phosphate, together with other lysolipids such as sphingosylphosphorylcholine
and
lysosulfatide, are responsible for the beneficial clinical effects of HDL by
stimulating the production of the potent antiatherogenic signaling molecule
nitric
oxide by the vascular endothelium. In addition, like lysophosphatidic acid, it
is a
marker for certain types of cancer, and there is evidence that its role in
cell division
or proliferation may have an influence on the development of cancers. These
are
currently topics that are attracting great interest amongst medical
researchers, and
the potential for therapeutic intervention in sphingosine-l-phosphate
metabolism is
under active investigation.
Fungi and plants have sphingolipids and the major sphingosine contained in
these
organisms has the formula described below. It is known that these lipids have
important roles in the cell growth of fungi and plants, but details of the
roles remain
to be solved.

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4
OH OH NH2
I I I
H3C -(CHz)1z - CH2 - CH - CH - CH - CHzOH
Recently it has been known that derivatives of sphingolipids and their related
compounds exhibit a variety of biological activities through inhibition or
stimulation of the metabolism pathways. These compounds include inhibitors of
protein kinase C, inducers of apoptosis, immuno-suppressive compounds,
antifungal compounds, and the like. Substances having these biological
activities
are expected to be useful compounds for various diseases.
Derivatives of sphingosine have been prepared in various patents. For example,
see U.S. Patents 4,952,683, 5,110,987, 6,235,912 Bl, 6,239,297 Bl.
SUMMARY OF THE INVENTION
The present invention provides a derivative or analogue of sphingosine that is
able
to regulate the functions of sphingolipid, and pharmaceutical compositions
comprising said derivative or analogue.
These compounds are represented by the formula I, each of which compounds may
have sphingosine-l-phosphate receptor agonist and or antagonist biological
activity:
R1 X' Y
~
R2 Z~[C(R3)2la(W)b[C(R3)2]cLP(O)(OR3)2]dLC(v)x(OR4)Y(R4)zle
1

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wherein
5 X is selected from the group consisting of CR3 and N;
Y is selected from the group consisting of CR3 and N;
Z is selected from the group consisting of CR3 and N;
and at least one of X, Y and Z is N;
W is NR3 or 0;
V is oxo or represents two H atoms;
provided that when V is two H atoms, z is 0;
R' is an aryl group and is selected, preferably, from the group consisting of
phenyl and substituted derivatives thereof;
R2 is an aryl group and is selected, preferably from the group consisting of
phenyl, furanyl, thienyl, pyridyl, pyranyl and substituted derivatives
thereof;
R3 is a hydrocarbyl or substituted hydrocarbyl radical which is selected,
preferably, from the group consisting of H and alkyl and more preferably, R3
is
selected from the group consisting of H and lower alkyl, e. g. Ci to C6 alkyl
;
R4 is a hydrocarbyl or substituted hydrocarbyl radical which is selected,
preferably, from the group consisting of H and alkyl and, more preferably, R4
is
selected from the group consisting of H and lower alkyl, e. g. Ci to C6 alkyl;
and 2 of said R3 or R4 may together form a cyclic alkyl ring having from 3
to 6 carbon atoms;
a is 0 or an integer of from 1 to 6, e. g. 0 or an integer of from 1 to 3;

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6
bis0orl;
c is 0 or an integer of from 1 to 6, e. g. 0 or an integer of from 1 to 5;
dis0orl;
eis0orl;
xisl;
y is 0 or an integer of from 1 to 2;
z is 0 or an integer of from 1 to 2;
provided however that when d is 0, e is 1, and when e is 0, d is 1, and when
y is 0, z is 1 and when z is 0, y is 1.
Specific Examples of the compounds of formula I include
O
O
N~O\ N O\ ~\ N N~~P\ NH
O
These compounds may be synthesized as illustrated by the synthesis scheme
below:
It is noted that, in the general synthetic schemes used throughout this patent
application, the various substituents designated as R, Ri, R2 etc. may
represent
substituents which differ from the substituents that R, Ri, R2 etc. represent
in the
above formula I. However, it will be apparent to the skilled artisan that it
is
intended for the definition of the invention, as claimed, that the definition
of the
substituents in formula I control in defining the scope of the invention,
while the
substituents of the general synthetic scheme are for the purpose of showing
the
making of the claimed compounds

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7
R\ R
O + H2N`N O\ 0- EtOH N`N NN
~
O
O H2N ~\ I N~O\ + ~\ I N~O\
O R / O
R = H, alkyl (1:1)
Seperated by MPLC
R' R~
N, ~ \ I \
~ N + R3 CHCI3, heat
N~O\ N N O\
R2 O C) R2 O
1) Dibal-H R1
2) NaCNBH3, HOAc R3
Bu4NOH H O
H2N-----P OH N N,/\/P-OH
0 OH
R2
R1, R2, R3 = H, alkyl
In general, a diphenylethyl-1,2-dione (e.g. benzil) is treated with methyl
oxalamidrazonate in ethanol to produce a methy15,6-diphenyl-1,3,4-triazine-2-
carboxylate (as a mixture of geometric isomers if the dione is asymmetrical).
These
triazines can undergo Diels-Aler reactions with a pyrrolidine enamine compound
to
give a methy15,6-diphenylpyridine-2-carboxylate derivative. These compounds
can be reduced with diisobutylaluminum hydride to the corresponding aldehyde
derivatives, which then can be converted into a number of homologs and
derivatives. For instance, the aldehyde can be converted into a secondary
amine by
reacting it with a primary amine in the presence of a reducing agent, such as
sodium cyanoborohydride. Alternatively, the aldehyde may be reduced to an
alcohol and treated with an alkyl halide in the presence of a mild base to
produce
alkyl ethers. Those skilled in the art will recognize that these compounds may
be
used to prepare many other homologs, many of which are described in the
Specific
Examples section below.

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8
DETAILED DESCRIPTION OF THE INVENTION
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s . = .. _ \ ; ~.,.,
,_.~~ . = _ .\ . . ,~. . . . . =~. . . . . .
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2_ = ~ ~ = `. ~ . \" - =~- , " . .
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~___ `ti~ ,:;;
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v_..,. , <. ~~ t.. =a" = <= ?ii;.,
e*:- ~= D\ ~F. = c~`:., = ' 28
=` ` ~ ~ ~ \ '
---- ---`----- --------- --------- ----~ ~-- --------- ------------------------
~ --------- `-------- --------- ---------

CA 02662852 2009-03-06
WO 2008/030843 PCT/US2007/077588
9
~~~ -~. =\`=\ ~'= . =-~ .- .\__*_-___ ~: ~.=~ ~ ~ \ ~~~ . ~ ~ . Cl~ . =-. .= =-
\ ~ . ~~ . ~ ..
~ic`;"
ad, + \"~+ ~ ::~, '~'~ 'l= . ~"*
\ I\ p~ \ I\ H p
Pt O OPh
N O~ N OPh
O \ I O
H 1-4 H
NP~- NH O-
\ ~ N~P~-- O O- N
N
I O NH
O O
O O
\ ~ \ H 0 H 0.N
N NPt NH O- N NP~
I 5
. . ;_.
: : .` . : . ~ ` ` - > -------- =_ . .` _...:. , . .:i`
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=_c_"_" -___;c____ _________.
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~ , . ,~. ; . . .
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1\ ..> > `+. .. ~ ~ ...~..,=,
..c,. ~.
C:`'=.~\= ~.,_\~ . fi \.\ ~ _\. .. _ .\ =- ________~~ =~\ \ _ ~ ..\
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. = _ =~~ ~..
2~T' ~ -~ ., ;~. \ . , ~ . ; . . ~ . ~ ,,.~ ~ \` . .,. . \. . ~.\.,, .=-. =~.
.a;,_____ _________. c_~~_~, - = _____ ~__ ____ ` c_ \ _________ = . __~~_c*~
_________ ________z _____ ____________ ~ _c________ ______~__'____C ~ L'_
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vi. .'1=r ~.. - A=:' A._~ +1=~_ - ~ At - _=. :_^~i~l.C:: _ = .=~-

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õh% :.~.C:.
In the novel compounds of this invention R3 and R4 may be independently
selected
5 from the group consisting of hydrogen, straight or branched chain alkyl
having 1 to
12 carbons, cycloalkyl having 3 to 6 carbons, alkenyl having 2 to 6 carbons
and 1
or 2 double bonds, alkynyl having 2 to 6 carbons and 1 or 2 triple bonds,
aryl,
preferably a carbocyclic aryl group having from 6 to 14 carbon atoms or a
heterocyclic aryl group having from 2 to 14 carbon atoms and from 1 to 3
10 heteroatoms selected from the group consisting of nitrogen, oxygen and
sulfur,
halo, e.g. fluoro or chloro, Ci to C12 haloalkyl, e.g. trifluoromethyl,
hydroxyl, Ci to
C 12 alkoxy, Ci to C 12 alkylcarbonyl, formyl, oxycarbonyl, carboxy, Ci to C
12 alkyl
carboxylate, Ci to C12 alkyl amide, aminocarbonyl, amino, cyano, diazo, nitro,
thio,
sulfoxyl, or sulfonyl groups.
Ri and R2 are aryl groups which may be any carbocyclic aryl or heterocyclic
aryl
group including but not limited to benzene, pyridine, pyrazine, pyridazine,
pyrimidine, triazine, thiophene, furan, thiazole, thiadiazole, isothiazole,
oxazole,oxadiazole, isooxazole, naphthalene, quinoline, tetralin, chroman,
thiochroman, tetrahydroquinoline, dihydronaphthalene, tetrahydronaphthalen,
chromene, thiochromene, dihydroquinoline, indan, dihydrobenzofuran,
dihydrobenzothiophene, indene, benzofuran, benzothiophene, coumarin and
coumarinone. Such aryl groups can be bonded to the above moiety at any
position.
Such aryl group may itself be substituted with any common organic functional
group including but not limited to alkyl, alkenyl, alkynyl, aryl, halo,
haloalkyl,
hydroxyl, alkoxyl, alkylcarbonyl, formyl, oxycarbonyl, carboxyl, alkyl
carboxylate,
alkyl amide, aminocarbonyl, amino, cyano, diazo, nitro, thio, sulfoxyl, or
sulfonyl
groups.

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Preferably, the carbocyclic aryl group will comprise from 6 to 14 carbon
atoms,
e.g. from 6 to 10 carbon atoms. Preferably the heterocyclic aryl group will
comprise from 2 to 14 carbon atoms and one or more, e.g. from 1 to 3
heteroatoms
selected from the group consisting of nitrogen, oxygen and sulfur.
In one aspect of the invention wherein e is 0, the compounds have a side chain
which terminates in a phosphonic acid or a phosphonic acid ester group.
Preferably R' is selected from the group consisting of phenyl and substituted
derivatives thereof.
Preferably R2 is selected from the group consisting of phenyl, furanyl,
thienyl,
pyridyl, pyranyl and substituted derivatives thereof.
Preferably R3 and R4 are H or lower alkyl.
Preferably a is 0 or an integer of from 1 to 3 and c is 0 or an integer of
from 1 to 5.
In these compounds, R' is represented, preferably, by the general formula
wherein R 5 is selected from the group consisting of H, alkyl,
trifluoromethyl,
trifluoromethyloxy, halo, e. g.chloro, and loweralkylthio.
In said phosphonic acid terminated compounds, preferably R2 is selected from
the
group consisting of furanyl, thienyl, pyridyl and pyranyl or R2 is

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R5
represented by the general formula
wherein R 5 is selected from the group consisting of H, alkyl,
trifluoromethyl,
trifluoromethyloxy, halo, e. g. chloro, and loweralkylthio .
In these phosphonic acid terminated compounds, preferably R3 is H, and
Furthermore, in said compounds, preferably c is 1, 2 or 3 and a is 1.
Finally, in said phosphonic acid-terminated compounds most preferably Z is N,
X
and Y are CR3, W is NR3, R2 is phenyl and R 5 is selected from the group
consisting of H and methyl or R2 is pyridyl and R5 is ethyl
In another aspect of the present invention d is 0 and therefore the compounds
have
a side chain which terminates in a carbon-oxygen radical such as a carboxylic
acid,
an ester thereof, an ether, an alcohol, or an alkyl carboxy group.
In these carbon-oxygen terminated compounds, R' may be represented by the
general formula
-)5
wherein R 5 is selected from the group consisting of H, alkyl,
trifluoromethyl,
trifluoromethyloxy, halo, e. g. chloro, and loweralkylthio
Furthermore R2 may also be represented by the general formula

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~
wherein R 5 is selected from the group consisting of H, lower alkyl,
trifluoromethyl,
trifluoromethyloxy, halo, e. g. chloro, and loweralkylthio or R2 is selected
from the
group consisting of furanyl, thienyl, pyridyl and pyranyl.
In such compounds, preferably R3 is H and more preferably, a is 1.
More preferably, in said compounds x is 1, z is 0 and R4 is selected from the
group
consisting of H, methyl and ethyl.
Finally, in the carbon-oxygen compounds of this invention preferably is Z is
N, X
and Y are CR3, R2 is pyridyl, R4 is selected from the group consisting of
methyl
and ethyl and R 5 is selected from the group consisting of H, methyl, ethyl,
propyl
and trifluoromethyl, or
X, Y and Z are N, R4 is selected from the group consisting of methyl and ethyl
and
R 5 is selected from the group consisting of H, methyl, ethyl, propyl and
trifluoromethyl, or
X and Z are N and Y is CR3.
Unless otherwise indicated, the following terms as used throughout this
specification have the following meanings:
"Me" refers to methyl.

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"Et" refers to ethyl.
"tBu" refers to t-butyl.
"iPr" refers to i-propyl.
"Ph" refers to phenyl.
"Pharmaceutically acceptable salt" refers to those salts which retain the
biological
effectiveness and properties of the free bases and which are obtained by
reaction
with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric
acid,
nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-
toluenesulfonic acid, salicylic acid and the like.
"Alkyl" refers to a straight-chain, branched or cyclic saturated aliphatic
hydrocarbon. Preferably, the alkyl group has 1 to 12 carbons. More preferably,
it is
a lower alkyl of from 1 to 7 carbons, most preferably 1 to 4 carbons. Typical
alkyl
groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary
butyl,
pentyl, hexyl and the like. The alkyl group may be optionally substituted with
one
or more substituents are selected from the group consisting of hydroxyl,
cyano,
alkoxy, .= 0, .= S, NOz, halogen, dimethyl amino, and SH.
"Alkenyl" refers to a straight-chain, branched or cyclic unsaturated
hydrocarbon
group containing at least one carbon--carbon double bond. Preferably, the
alkenyl
group has 2 to 12 carbons. More preferably it is a lower alkenyl of from 2 to
7
carbons, most preferably 2 to 4 carbons. The alkenyl group may be optionally
substituted with one or more substituents selected from the group consisting
of
hydroxyl, cyano, alkoxy, 0, S, NOz, halogen, dimethyl amino, and SH.

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"Alkynyl" refers to a straight-chain, branched or cyclic unsaturated
hydrocarbon
containing at least one carbon--carbon triple bond. Preferably, the alkynyl
group
has 2 to 12 carbons. More preferably it is a lower alkynyl of from 2 to 7
carbons,
most preferably 1 to 4 carbons. The alkynyl group may be optionally
substituted
5 with one or more substituents selected from the group consisting of
hydroxyl,
cyano, alkoxy, 0, S, NOz, halogen, dimethyl amino, and SH.
"Alkoxyl" refers to an "O-alkyl" group.
10 "Aryl" refers to an aromatic group which has at least one ring having a
conjugated
pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl
groups. The aryl group may be optionally substituted with one or more
substituents
selected from the group consisting of halogen, trihalomethyl, hydroxyl, SH,
OH,
NOz, amine, thioether, cyano, alkoxy, alkyl, and amino.
"Alkaryl" refers to an alkyl that is covalently joined to an aryl group.
Preferably,
the alkyl is a lower alkyl.
"Carbocyclic aryl" refers to an aryl group wherein the ring atoms are carbon.
"Heterocyclic aryl" refers to an aryl group having from 1 to 3 heteroatoms as
ring
atoms, the remainder of the ring atoms being carbon. Heteroatoms include
oxygen,
sulfur, and nitrogen.
"Hydrocarbyl" refers to a hydrocarbon radical having only carbon and hydrogen
atoms. Preferably, the hydrocarbyl radical has from 1 to 20 carbon atoms, more
preferably from 1 to 12 carbon atoms and most preferably from 1 to 7 carbon
atoms.

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"Substituted hydrocarbyl" refers to a hydrocarbyl radical wherein one or more,
but
not all, of the hydrogen and/or the carbon atoms are replaced by a halogen,
nitrogen, oxygen, sulfur or phosphorus atom or a radical including a halogen,
nitrogen, oxygen, sulfur or phosphorus atom, e.g. fluoro, chloro, cyano,
nitro,
hydroxyl, phosphate, thiol, etc.
"Amide" refers to --C(O)--NH--R', wherein R' is alkyl, aryl, alkylaryl or
hydrogen.
"Thioamide" refers to --C(S)--NH--R', wherein R' is alkyl, aryl, alkylaryl or
hydrogen.
"Amine" refers to a--N(R")R"' group, wherein R" and R"' are independently
selected from the group consisting of alkyl, aryl, and alkylaryl.
"Thioether" refers to --S--R", wherein R" is alkyl, aryl, or alkylaryl.
"Sulfonyl" refers to --S(O)z --R"", where R"" is aryl, C(CN)=C-aryl, CHz CN,
alkyaryl, sulfonamide, NH-alkyl, NH-alkylaryl, or NH-aryl.
SPECIFIC EXAMPLES
Specific compounds of the invention and their activity at the sphingosine-1-
phosphate receptors are reported in Table I, below.
Compounds were also assessed for their ability to activate or block activation
of the
human SIP3 receptor in T24 cells stably expressing the human SIP3 receptor.
Ten
thousand cells/well were plated into 384-well poly-D-lysine coated plates one
day
prior to use. The growth media for the SIP3 receptor expressing cell line was
McCoy's 5A medium supplemented with 10% charcoal-treated fetal bovine serum
(FBS), 1% antibiotic-antimycotic and 400 g/ml geneticin. On the day of the

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17
experiment, the cells were washed twice with Hank's Balanced Salt Solution
supplemented with 20 mM HEPES (HBSS/Hepes buffer). The cells were then dye
loaded with 2 uM Fluo-4 diluted in the HBSS/Hepes buffer with 1.25 mM
Probenecid and incubated at 37 C for 40 minutes. Extracellular dye was removed
by washing the cell plates four times prior to placing the plates in the FLIPR
(Fluorometric Imaging Plate Reader, Molecular Devices). Ligands were diluted
in
HBSS/Hepes buffer and prepared in 384-well microplates. The positive control,
Sphingosine-l-Phosphate (SIP), was diluted in HBSS/Hepes buffer with 4 mg/ml
fatty acid free bovine serum albumin. The FLIPR transferred 12.5 1 from the
ligand microplate to the cell plate and took fluorescent measurements for 75
seconds, taking readings every second, and then for 2.5 minutes, taking
readings
every 10 seconds. Drugs were tested over the concentration range of 0.61 nM to
10,000 nM. Data for Ca+2 responses were obtained in arbitrary fluorescence
units
and not translated into Ca+2 concentrations. IC50 values were determined
through a
linear regression analysis using the Levenburg Marquardt algorithm. In Table
1,
NA is defined as "Not Active," ND is defined as "Not Determined," % efficacy
is
defined as "percent of receptor activity induced by a test compound at the
highest
dose test (10 M) relative to the receptor activity induced by 5 nM
sphingosine-l-
phosphate.," and % inhibition is defined as "percent of receptor activity
induced by
5 nM sphingosine-l-phosphate that is inhibited by a test compound at the
highest
dose tested (10 M)."

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Table 1
Example Structure S1P1 EC5o S1P3ICso
Number (% efficacy) (% inhibiton)
1.6 M
63 H
P ND
I o OH (83)
O 121 nM 231 nM
64 " "~~ oRH (36) (98)
65 0 170 nM 319 nM
N NP~ OH OH (57) (98)
1.8 M
66 I\ ,N I NP OH NA (99)
11
/ O
F
F
ND
N
67 I\ ~ I N~~P~ OH ND (95)
OH
68 O NA 1.1 M
~N N`_,-,,iPOHH (95)
N
69 N N~ O NA 1(68 gM
P\OH
N OH
70 N H NA ND
(30)
N 'OH OH
O
/ l
114 nM 319 nM
H
71 I\ N N,,-iP\OH (69) (98)

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Table 1
Example Structure S1P1 EC5o S1P3ICso
Number (% efficacy) (% inhibiton)
72 O NA 4.0 M
P OH (27)
- 0,
N ~ OH
0 1.9 M
73 N o-~'=OH NA (11)
HO
74 ~ NA ND
O~~iP-OH
HO
75 H R NA N D
OH
HO
76 NJ "~r H NA N D
0
77 NA NA
N ~-OEt
EtO
78 NA NA
N ~OH
HO
79 \ ~H NA ND
N~-/P'OH
HO
80 \ I)"H NA ND
N N~~OH
HO

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As a result of the above activity of the compounds utilized in the method of
the
present invention, it is clear that such compounds may be used in treating the
following diseases and conditions for the following reasons.
Pain
5 S I P increases capsaicin responsiveness of DRG neurons
S I P pathway, SIP3, SIPl deregulated in multiple pain models
(EHT/AGN)
Glaucoma
SIPl/3 subtypes expressed in primary HTM cells
10 S I P decreases outflow facility >30% in perfused porcine eyes (See
IOVS 45, 2263; 2004)
Altered paracellular permeability
Dry Eye/Immunology
Induces lymphocyte sequestration without affecting T cell proliferation
15 Angiogenesis disorders
siRNA knockdown of S I P 1 and S I P3 inhibits angiogenesis
SIPl/3 subtypes expressed in VEC
promote VEC migration
promote barrier assembly and integrity
20 Cardiovascular (S1P3)
SIP3 "knock out" mice lack S I P induced COPD
SIP3 agonism is dose limiting effect of FTY720
Wound Healing
S I P is released from activated platelets
The invention is further illustrated by the following examples which are
illustrative of a specific mode of practicing the invention and are not
intended as
limiting the scope of the claims.
To assess the potential lymphopenic effect of a compound, male C57/Blk6
mice (Charles River, Wilmington, MA at 8 weeks of age and weighing -30 grams)

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received a single (IP) injection of vehicle or Compound 65 (3 mg/kg). Four
hours
post-injection animals were anesthetized with iso/Oz mix, blood was collected
by
retro-orbital bleeding into a BD Biosciences Microtainer tube containing the
anti-
coagulant dipotassium-EDTA (-300-500 ul of blood collected). After blood
collection, animals were humanely euthanized using Iso/0z mix overdose or
cervical
dislocation.Hematologic assessments of blood samples from treated animals was
conducted using an automated Advia 120 hematology analyzer [Bayer Diagnostics,
Tarrytown, NY]. The Advia 120 analyzes K-EDTA anticoagulated whole blood
using cytochemical reactions and flow-cytometry measurements to enumerate and
differentiate leukocytes (white blood cells), enumerate and characterize
erythrocytes
(red blood cells), thrombocytes (platelets), and reticulocytes (immature red
blood
cells). Leukocytes are enumerated and differentiated using a combination of
two
methods, a Peroxidase method and a Basophil Lobularity method, which generate
relative and absolute counts for neutrophils, lymphocytes, monocytes,
eosinophils,
and basophils. In the Peroxidase method a cell suspension passes through the
flowcell where the absorption (correlating to cytoplasmic peroxidase staining)
and
forward light-scattering (correlating to cell size) are measured. In the
Basophil
Lobularity method a suspension cell nuclei are passed though a flowcell where
the
low-angle light scatter and high-angle light scatter are measured correlating
to
nuclear size and complexity. When necessary leukocyte differentials may be
performed manually from Romanowski stained blood smears. In addition, an
adaptation of the classic cyan-methemoglobin spectrophotometric methodology
was
used to measure total hemoglobin concentration. Using the data obtained from
direct
measurements erythrocytic and thrombocytic indices were derived by the Advia
120
software. The results are summarized in Table 2.

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Table 2
DRUG DOSE/ROUTE LYMPHOCYTE#
x103/uL
VEHICLE 1 ml/kg IP 6.10 0.6
65 3 mg/kg IP 3.25 0.7**
**p<0.01 vs. Vehicle
An art-accepted model or assay for measuring an analgesic effect of a
compound in chronic pain (in particular peripheral neuropathy) is the model
known
as Kim and Chung 1992, Pain 150, pp 355-363 (Chung model). This model
involves the surgical ligation of the L5 (and optionally the L6) spinal nerves
on one
side in experimental animals. Rats recovering from the surgery gain weight and
display a level of general activity similar to that of normal rats. However,
these
rats develop abnormalities of the foot, wherein the hindpaw is moderately
everted
and the toes are held together. More importantly, the hindpaw on the side
affected
by the surgery appears to become sensitive to low-threshold mechanical stimuli
and
will perceive pain instead of the faint sensation of touch. This sensitivity
to
normally non-painful touch, called "tactile allodynia", develops within the
first
week after surgery and lasts for at least two months. The allodynia response
includes lifting the affected hindpaw to escape from the stimulus, licking the
paw
and holding it in the air for many seconds. None of these responses is
normally
seen in the control group.
To produce the tactile allodynia, rats are anesthetized before surgery. The
surgical site is shaved and prepared either with betadine or Novacaine.
Incision is
made from the thoracic vertebra Xlll down toward the sacrum. Muscle tissue is
separated from the spinal vertebra (left side) at the L4 - S2 levels. The L6
vertebra
is located and the transverse process is carefully removed with a small
rongeur to
expose the L4 - L6 spinal nerves. The L5 and L6 spinal nerves are isolated and

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tightly ligated with 6-0 silk thread. The same procedure is done on the right
side as
a control, except no ligation of the spinal nerves is performed.
After a complete hemostasis is confirmed, the wounds are sutured. A small
amount of antibiotic ointment is applied to the incised area, and the rat is
transferred to the recovery plastic cage under a regulated heat-temperature
lamp.
On the day of the experiment, at least seven days after the surgery, typically
six rats per test group are administered the test drugs by intraperitoneal
(i.p.)
injection or oral gavage (p.o.). For i.p. administration, the compounds are
formulated in H20 and given in a volume of 1 ml/kg body weight by injecting
into
the intraperitoneal cavity. For p.o. administration, the compounds are
formulated
in H20 and given in a volume of 1 ml/kg body weight using an 18-gauge, 3 inch
gavage needle that is slowly inserted through the esophagus into the stomach.
Tactile allodynia is assessed via von Frey hairs, which are a series of fine
hairs with incremental differences in stiffness. Rats are placed in a plastic
cage with
a wire mesh bottom and allowed to acclimate for approximately 30 minutes. To
establish the pre-drug baseline, the von Frey hairs are applied
perpendicularly
through the mesh to the mid-plantar region of the rats' hindpaw with
sufficient
force to cause slight buckling and held for 6-8 seconds. The applied force has
been
calculated to range from 0.41 to 15.1 grams. If the paw is sharply withdrawn,
it is
considered a positive response. A normal animal will not respond to stimuli in
this
range, but a surgically ligated paw will be withdrawn in response to a 1-2
gram
hair. The 50% paw withdrawal threshold is determined using the method of
Dixon,
W.J., Ann. Rev. Pharmacol. Toxicol. 20:441-462 (1980) hereby incorporated by
reference. Tactile allodynia is measured prior to and 15, 30, and 60 minutes
after
drug administration. The post-drug threshold is compared to the pre-drug
threshold
and the percent reversal of tactile sensitivity is calculated based on a
normal
threshold of 15.1 grams.
Table 3 below indicates the degree of pain reversal obtained in the Chung
model with exemplary compounds of the invention. The intraperitonial (i.p.)

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and/or intravenous (iv) administration of the compounds was dosed (as
indicated)
and the peak percentage of reversal of allodynia was measured at 15, 30 or 60
minutes after administration, as is indicated in the table. Data are expressed
as the
highest % allodynia reversal (out of 3 time points: 15 min, 30 min, or 60 min.
post-
drug) with a minimum of a 20% allodynia reversal in the rat Chung model.
Comparisons between groups (drug treated vs. saline treated) were made using a
two-tailed, 2-sample, unpaired t-test.
Table 3
DOSE/ % Allodynia Reversal
DRUG ROUTE 15 min. 30 min. 60 min.
post post post
64 3.0 mg/kg IP 35.1 20.6 54.1=L 17.9* 91.7=L5.3**
65 0.3 mg/kg IP 8.6=L 1.8 95.9=L 4.1** 80.8=L14.5**
*p<0.05, **p<0.01 vs. Vehicle
The foregoing description details specific methods and compositions that can
be employed to practice the present invention, and represents the best mode
contemplated. Thus, however detailed the foregoing may appear in text, it
should not
be construed as limiting the overall scope hereof; rather, the ambit of the
present
invention is to be governed only by the lawful construction of the appended
claims.
Unless otherwise indicated, the following Chemical Abbreviations are used in
the
examples:
NH4C1: ammonium chloride
CHC13 : chloroform
Et20: diethyl ether
DIBAL-H: diisobutylaluminum hydride

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DME : 1,2-dimethoxyethane
DMF: N,N-dimethylformamide
DMSO: dimethylsulfoxide
EtOH: ethanol
5 1 EtOAc: ethyl acetate
HC1: hydrogen chloride or hydrochloric acid
NH2OH-HC1: hydroxylamine hydrochloride
Mel: iodomethane
i-PrOH: isopropanol
10 MgSO4: magnesium sulfate
MeOH: methanol
NH2OMe-HC1: methoxylamine hydrochloride
CH2C12: methylene chloride
KOH: potassium hydroxide
15 K2C03: potassium carbonate
PTLC: preparative thin layer chromatography
MPLC: medium pressure liquid chromatography
RuC12(PPh3)4: Na: sodium
NaOEt: sodium ethoxide
20 NaOH: sodium hydroxide
Na2SO4: sodium sulfate
NaHCO3: sodium bicarbonate
NaBH4: sodium borohydride
NaBH3CN: sodium cyanoborohydride
25 NaH: sodium hydride
H2SO4: sulfuric acid
Bu4NOH: tetrabutylammonium hydroxide
THF: tetrahydrofuran
Pd(PPh3)4: palladium tetrakis(tripenylphosphine)

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TMSI: iodotrimethylsilane
All other chemicals were purchased from Aldrich Chemical Company, and they
were used as provided.

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Scheme 1
R a Br + Li - O b
R =Me 1 R = Me
R =Et 2 R = Et
R= n-Pr 3 R= n-Pr
R=CF3 4R=CF3
R= n-CgHig 5 R= n-CgHig
R R1
O N,N N,N
c I ~i0'~ + \ N~p~~
O N II
O R O
6R=Me 11 Ri=H 17R2 =Me
7 R= Et 12 Ri =Me 18 Rz = Et
8 R= n-Pr 13 Ri = Et 19 Rz = CF3
9 R= CF3 14 R' = n-Pr 20 Rz = n-CgHig
R= n-CgHig 15 R' = CF3
16 R' = n-CgHig
d d
R1 R1
\ I \ R3 \ I \ R3 \ I \
I e ~
N Oll N
Rz O N O Rz O
30 Ri=H,Rz=R3=H 21Ri=R3=H 27R2=Me
31 Ri=Me,Rz=R3=H 22Ri=Me,R3=H 28R2 =Et
32 Ri = Et, Rz = R3 = H 23 Ri = Et, R3 = H 29 Rz = CF3
33 Ri = n-Pr, Rz = R3 = H 24 Ri = n-Pr, R3 = H
34 Ri = CF3, Rz = R3 = H 25 Ri = CF3, R3 = H
35 Ri =R3 = H, Rz= CF3 26 Ri = Et, R3 =Me
36 Ri = Et, Rz =H, R3 = Me
(a) B(OiPr) 3, Pd(PPh3)4, DME, THF, 90 C, 2 hours; (b) RuC1z(PPH3) 3, PhIO,
CH2C12; (c) ethyl oxalaniidrazonate, ethanol; (d) i)
pyrrolidine, CH3CHO, K2C03, toluene, ii) CHC13, 72 C; (e) c. H2SO4, MeOH, 70
C.
5
Example 1
1-(2-p-Tolylethynyl)benzene (Compound 1). General Procedure A. To a
solution of lithium phenylacetylide (15.2 ml, 15.2 mmol) in DME (20 ml) under
Argon at -78 C was added triisopropoxylborane (3.5 ml, 15.2 mmol). The
mixture
10 was stirred at -78 C for 1.5 hours. A solution of 1-bromo-4-methylbenzene
(2 g,
11.7 mmol) in DME/THF (10 mUl Oml) was degassed with dry argon, Pd(PPh3)4

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(405 mg, 0.35 mmol) was added and the solution was degassed for another 5 min.
The degassed solution was cannulated into the first solution, and the mixture
was
heated under argon at 85 C for 2 hours. The mixture was cooled to room
temperature, and it was diluted with ethyl acetate, and washed with water. The
separated organic layer was washed with water and brine, and dried over MgSO4.
The filtered solvent was concentrated in vacuo, and the residue was purified
by
column chromatography (silica, 5% ethyl acetate in hexane) to give the title
compound as a yellow solid.
iH NMR (300 MHz, CDC13): b 2.37 (s, 3 H), 7.16 (d, J= 8.50 Hz, 2 H), 7.29 -
7.38
(m, 3 H), 7.43 (d, J= 7.92 Hz, 2 H), 7.48 - 7.56 (m, 2 H).
Example 2
1-(2-(4-Ethylphenyl)ethynyl)benzene (Compound 2) Following General
Procedure A, lithium phenylacetylide (14.0 ml, 14.1 mmol),
triisopropoxylborane
(3.2 ml, 14.1 mmol), 1-bromo-4-ethylbenzene (2 g, 10.8 mmol) and Pd(PPh3)4
(375
mg, 0.32 mmol) in DME (30m1) and THF (10 ml) were reacted to obtain the title
compound as a yellow oil.
iH NMR (300 MHz, CDC13): b 1.24 (t, J= 7.62 Hz, 3 H), 2.66 (q, J= 7.62 Hz, 2
H), 7.18 (d, J= 8.21 Hz, 2 H), 7.28 - 7.39 (m, 3 H), 7.45 (d, J= 8.21 Hz, 2
H), 7.49
-7.56(m,2H).
Example 3
1-(2-(4-n-Proylphenyl)ethynyl)benzene (Compound 3) Following General
Procedure A, lithium phenylacetylide (13.0 ml, 13.1 mmol),
triisopropoxylborane
(3.0 ml, 13.1 mmol), 1-bromo-4-n-propylbenzene (2 g, 10.1 mmol) and Pd(PPh3)4
(348 mg, 0.30 mmol) in DME (30 ml) and THF (10 ml) were reacted to obtain the
title compound as a yellow oil.

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iH NMR (300 MHz, CDC13) b 0.94 (t, J= 7.33 Hz, 17 H), 1.57 - 1.73 (m, 2 H),
2.5 7 - 2.62 (m, 2 H), 7.16 (d, J = 8.5 0 Hz, 2 H), 7.29 - 7.40 (m, J = 2.05
Hz, 3 H),
7.44 (d, J = 8.5 0 Hz, 2 H), 7.49 - 7.5 5 (m, 2 H).
Example 4
1-(2-(4-Trifluoromethylphenyl)ethynyl)benzene (Compound 4) Following
General Procedure A, lithium phenylacetylide (17.3 ml, 17.3 mmol),
triisopropoxylborane (4.0 ml, 17.3 mmol), 1-bromo-4-trifluoromethyl-benzene (3
g, 13.3 mmol) and Pd(PPh3)4 (462 mg, 0.40 mmol) in DME (40 ml) and THF (15
ml) were reacted to obtain the title compound as a yellow solid.
iHNMR(300MHz,CDC13)b7.31-7.42(m,3H),7.50-7.58(m,2H),7.57-
7.68(m,4H).
Example 5
1-(2-(4-n-Nonanylphenyl)ethynyl)benzene (Compound 5) Following General
Procedure A, lithium phenylacetylide (12.4 ml, 12.4 mmol),
triisopropoxylborane
(2.8 ml, 12.4 mmol), 1-bromo-4-n-nonanylbenzene (2.7 g, 9.5 mmol) and
Pd(PPh3)4 (331 mg, 0.40 mmol) in DME (30 ml) and THF (10 ml) were reacted to
obtain the title compound as a yellow solid.
iH NMR (300 MHz, CDC13) b 0.88 (t, J= 7.04 Hz, 3 H), 1.17 - 1.38 (m, 12 H),
1.54 - 1.68 (m, 2 H), 2.55 - 2.65 (m, 2 H), 7.15 (d, J= 8.21 Hz, 2 H), 7.28 -
7.39
(m, 3 H), 7.44 (d, J = 8.21 Hz, 2 H), 7.4 8 - 7.5 6 (m, 2 H).
Example 6
1-Phenyl-2-p-tolylethane-1,2-dione (Compound 6). General Procedure B. To a
suspension of iodosobenzene (2.5 g, 11.3 mmol) in CH2C12 (30 ml) was added
RuC12(PPh3)4 (45 mg, 0.04 mmol). A solution of 1-(2-p-tolylethynyl)benzene

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(Compound 1, 835 mg, 4.3 mmol) in CH2C12 (10 ml) was cannulated into the
suspension. The resulting mixture was stirred at room temperature overnight
resulting in a homogeneous solution. The solvent was removed in vacuo, and the
residue was purified by silica gel chromatography (10% ethyl acetate in
hexane) to
5 produce the title compound as a yellow oil.
iH NMR (300 MHz, CDC13) b 2.44 (s, 3 H), 7.31 (d, J = 7.92 Hz, 2 H), 7.51 (t,
J
7.62Hz,2H),7.59-7.71(m,1H),7.87(d,J=8.21Hz,2H),7.92-8.00(m,2H).
Example 7
10 1-(4-Ethyl-phenyl)-2-phenyl-ethane-1,2-dione (Compound 7). Following
General Procedure B, iodosobenzene (1.5g, 6.7 mmol), RuC12(PPh3)4 (21 mg, 0.02
mmol) and 1-(2-(4-ethylphenyl)ethynyl)benzene (Compound 2, 360 mg, 1.8
mmol) in CH2C12 (30 ml) were reacted to produce the title compound as a yellow
oil.
15 iH NMR (300 MHz, CDC13) b 1.26 (t, J= 7.62 Hz, 3 H), 2.73 (q, J= 7.62 Hz, 2
H),7.34(d,J=8.50Hz,2H),7.45-7.56(m,2H),7.59-7.70(m,1H),7.90(d,J
=8.21Hz,2H),7.93-8.01(m,2H).
Example 8
20 1-(4-n-Propyl-phenyl)-2-phenyl-ethane-1,2-dione (Compound 8). Following
General Procedure B, iodosobenzene (2.2 g, 10.0 mmol), RuC12(PPh3)4 (38 mg,
0.04 mmol) and 1-(2-(4-n-propylphenyl)ethynyl)benzene (Compound 3, 860 mg,
3.9 mmol) in CH2C12 (50 ml) were reacted to produce the title compound as a
yellow oil.
25 iH NMR (300 MHz, CDC13) b 0.95 (t, J= 7.62 Hz, 3 H), 1.58 - 1.76 (m, 2 H),
2.60
-2.69(m,2H),7.31(d,J=8.21Hz,2H),7.46-7.56(m,2H),7.61-7.70(m,1
H), 7.89 (d, J= 8.21 Hz, 2 H), 7.94 - 8.01 (m, 2 H).

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Example 9
1-(4-Trifluoromethyl -phenyl)-2-phenyl-ethane-1,2-dione (Compound 9).
Following General Procedure B, iodosobenzene (5.5g, 24.3 mmol), RuC12(PPh3)4
(96 mg, 0.10 mmol) and 1-(2-(4-trifluoromethyl phenyl)ethynyl)benzene
(Compound 4, 1.9 g, 8.1 mmol) in CH2C12 (100 ml) were reacted to produce the
title compound as a yellow solid.
iH NMR (300 MHz, CDC13) b 7.49 - 7.59 (m, 2 H), 7.65 - 7.74 (m, 1 H), 7.79 (d,
J
=8.21Hz,2H),7.94-8.02(m,2H),8.11(d,J=8.21Hz,2H).
Example 10
1-(4-n-Nonanylphenyl)-2-phenylethane-1,2-dione (Compound 10). Following
General Procedure B, iodosobenzene (744 mg, 3.39 mmol), RuC12(PPh3)4 (11 mg,
0.01 mmol) and 1-(2-(4-n-nonanylphenyl)ethynyl)benzene (Compound 5, 343 mg,
1.12 mmol) in CH2C12 (30 ml) were reacted to produce the title compound as a
yellow oil.
iH NMR (300 MHz, CDC13) b 0.87 (t, J= 6.74 Hz, 3 H), 1.14 - 1.40 (m, 12 H),
1.55-1.71(m,2H),7.48-7.53(m,2H),7.60-7.72(m,1H),7.88(d,J=8.21
Hz, 2 H), 7.94 - 8.02 (m, 2 H).
Example 11
Ethy15,6-Diphenyl-1,2,4-triazine-3-carboxylate (Compound 11). General
Procedure C. A solution of ethyl oxalamidrazonate (Compound 37, 236 mg, 1.8
mmol) in ethanol (20 ml) was cannulated slowly into a stirring solution of
benzil
(500 mg, 2.4 mmol) in ethanol (20 ml) under argon at room temperature. After
the
addition was completed, the reaction was stirred at room temperature overnight
(- 16 hours). The mixture was then refluxed for 1 hour. The solvent was
removed in
vacuo, and the crude products was purified by column chromatography (silica
gel,
20% ethyl acetate in hexane) to obtain the title compound as an oil.

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iH NMR (300 MHz, acetone-d6) b 1.45 (t, J= 7.04 Hz, 3 H), 4.54 (q, J= 7.13 Hz,
2 H), 7.38 - 7.58 (m, 6 H), 7.61 - 7.72 (m, 4 H).
Example 12 and Example 17
Ethy15-Phenyl-6 p-tolyl-[1,2,4]triazine-3-carboxylate (Compound 12), and
Ethy16-Phenyl-5-p-tolyl-[1,2,4]triazine-3-carboxylate (Compound 17).
Following General Procedure C, ethyl oxalamidrazonate (Compound 37, 121 mg,
0.9 mmol), 1-phenyl-2 p-tolylethane-1,2-dione (Compound 6, 268 mg, 1.2 mmol)
in ethanol (10 ml) were reacted, and the products were separated by
recrystalization
from 5% ethyl acetate in hexane to produce Compound 12 and Compound 17 as
yellow solids.
Compound 12: 'H NMR (300 MHz, CDC13): b 1.50 (t, J= 7.33 Hz, 3 H), 2.39 (s,
3 H), 4.61 (q, J= 7.04 Hz, 2 H), 7.19 (d, J= 7.92 Hz, 2 H), 7.32 - 7.49 (m, 3
H),
7.52 (d, J = 8.21 Hz, 2 H), 7.63 - 7.69 (m, 2 H).
Compound 17: 'H NMR (300 MHz, CDC13): b 1.51 (t, J= 7.04 Hz, 3 H), 2.37 (s,
3 H), 4.61 (q, J= 7.04 Hz, 2 H), 7.15 (d, J= 7.92 Hz, 2 H), 7.3 5 - 7.51 (m, 3
H),
7.5 6 (d, J = 8.5 0 Hz, 2 H), 7.60 - 7.66 (m, 2 H).
I
Example 13 and Example 18
2o Ethy16-(4-Ethylphenyl)-5-phenyl -[1,2,4]triazine-3-carboxylate (Compound
13), and Ethy15-(4-Ethylphenyl)-6-phenyl- [ 1,2,4] triazine-3-carboxylate
(Compound 18). Following General Procedure C, ethyl oxalamidrazonate
(Compound 37, 117 mg, 0.9 mmol) and 1-(4-Ethyl-phenyl)-2-phenyl-ethane-1,2-
dione (Compound 7, 276 mg, 1.2 mmol) in ethanol (10 ml) were reacted, and the
products were separated by recrystalization from 5% ethyl acetate in hexane to
produce Compound 13 and Compound 18 as yellow solids.
Compound 13: 'H NMR (300 MHz, CDC13): b 1.26 (t, J= 7.81 Hz, 3 H), 1.51 (t, J
= 7.32 Hz, 3 H), 2.69 (q, J= 7.81 Hz, 2 H), 4.61 (q, J= 7.32 Hz, 2 H), 7.23
(d, J=

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7.32Hz,2H),7.35-7.38(m,2H),7.45-7.47(m,1H),7.56(d,J=8.30Hz,2
H), 7.67 (d, J= 7.81 Hz, 2 H).
Compound 18: 'H NMR (300 MHz, CDC13): b 1.23 (t, J= 7.81 Hz, 3 H), 1.51 (t,
J= 7.32 Hz, 3 H), 2.67 (q, J= 7.81 Hz, 2 H), 4.62 (q, J= 7.32 Hz, 2 H), 7.19
(d, J
=8.79Hz,2H),7.39-7.42(m,2H),7.45-7.48(m,1H),7.59(d,J=8.30Hz,2
H), 7.65 (d, J= 8.30 Hz, 2 H).
I
Example 14
Ethy15-Phenyl-6-(4-propylphenyl)-[1,2,4]triazine-3-carboxylate (Compound
14). Following General Procedure C, ethyl oxalamidrazonate (Compound 37, 460
mg, 1.5 mmol) and 1-(4-n-propylphenyl)-2-phenyl-ethane-1,2-dione (Compound
8, 588 mg, 2.3 mmol) in ethanol (40 ml) were reacted and the product was
recrystalized from 5% ethyl acetate in hexane to produce the title compound as
yellow solid.
iH NMR (300 MHz, CDC13) b 0.95 (t, J= 7.33 Hz, 3 H), 1.51 (t, J= 7.04 Hz, 3
H),
1.62-1.74(m,2H),2.55-2.63(m,2H),4.61(q,J=7.13Hz,2H),7.20(d,J=
8.50 Hz, 2 H), 7.32 - 7.49 (m, 3 H), 7.50 - 7.57 (m, 2 H), 7.62 - 7.70 (m, 2
H).
Example 15 and Example 19
2o Ethy16-(4-Trifluoromethyl-phenyl)-5-phenyl -[1,2,4]-triazine-3-carboxylate
(Compound 15), and Ethy15-(4-Trifluoromethylphenyl)-6-phenyl-[1,2,4]-
triazine-3-carboxylatate (Compound 19). Following General Procedure C, ethyl
oxalamidrazonate (Compound 37, 1.2 g, 8.8 mmol) and 1-(4-tirfluoromethyl-
phenyl)-2-phenyl-ethane-1,2-dione (Compound 9, 1.6 g, 5.9 mmol) in ethanol (40
ml) were reacted, and the products were separated by recrystalization from 5%
ethyl acetate in hexane to produce Compound 15 and Compound 19 as yellow
solids.

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Compound 15: 'H NMR (300 MHz, CDC13) b 1.52 (t, J= 7.18 Hz, 3 H), 4.63 (q, J
=7.04Hz,2H),7.38-7.54(m,3H),7.56-7.68(m,4H),7.78(d,J=8.21Hz,2
H).
Compound 19: 'H NMR (300 MHz, CDC13) b 1.52 (t, J= 7.18 Hz, 3 H), 4.63 (q,
J= 7.13 Hz, 2 H), 7.35 - 7.54 (m, 3 H), 7.59 - 7.70 (m, 4 H), 7.73 - 7.81 (m,
2 H).
Example 16 and Example 20
Ethy16-(4-nonylphenyl)-5-phenyl-1,2,4-triazine-3-carboxylate (Compound 16),
and ethyl 5-(4-nonylphenyl)-6-phenyl-1,2,4-triazine-3-carboxylate (Compound
20). Following General Procedure C, ethyl oxalamidrazonate (Compound 37, 108
mg, 0.83 mmol) and 1-(4-nonylphenyl)-2-phenylethane-1,2-dione (Compound 10,
252 mg, 0.75 mmol) in ethanol (10 ml) were reacted and the mixture purified by
MPLC to isolate Compound 16 and Compound 20 as yellow oils.
Compound 16: 'H NMR (300 MHz, CDC13): b 0.88 (t, J= 7.04 Hz, 3 H), 1.18 -
1.39(m,12H),1.51(t,J=7.l8Hz,3H),1.56-1.72(m,2H),2.58-2.70(m,2
H), 4.61 (q, J= 7.23 Hz, 2 H), 7.20 (d, J= 8.21 Hz, 2 H), 7.31 - 7.41 (m, 2
H), 7.33
- 7.40 (m, 1 H), 7.53 (d, J= 8.21 Hz, 2 H), 7.61 - 7.70 (m, 2 H).
Compound 20: 'H NMR (300 MHz, CDC13): 1H NMR (300 MHz, Solvent) b 0.88
(t, J= 7.04 Hz, 3 H), 1.17 - 1.37 (m, 12 H), 1.52 (t, J= 7.04 Hz, 3 H), 1.55 -
1.66
(m, 2 H), 2.54 - 2.69 (m, 2 H), 4.62 (q, J = 7.04 Hz, 2 H), 7.16 (d, J = 8.21
Hz, 2
H), 7.33 - 7.53 (m, 3 H), 7.58 (d, J= 8.21 Hz, 2 H), 7.60 - 7.70 (m, 2 H).
I
Example 21
Ethy15,6-diphenylpyridine-2-carboxylate (Compound 21). General Procedure
D. Ethy15,6-diphenyl-[1,2,4]-triazine-3-carboxylate (Compound 11, 200 mg, 0.66
mmol) and crude 1-vinylpyrrolidine (Compound 38, 2 g) in CHC13 (20 ml) was
heated at 75 C overnight under nitrogen. The solvent was removed in vacuo,
and

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the residue was purified by silica gel column chromatography (20 % ethyl
acetate
in hexane) to yield the title compound as a light yellow solid.
iH NMR (300 MHz, CDC13) b 1.46 (t, J= 7.18 Hz, 3 H), 4.50 (q, J= 7.13 Hz, 2
H), 7.13 - 7.33 (m, 8 H), 7.35 - 7.44 (m, 2 H), 7.84 (d, J= 7.92 Hz, 1 H),
8.12 (d, J
5 = 7.92 Hz, 1 H).
Example 22
6-Phenyl-5-p-tolyl-pyridine-2-carboxylic acid ethyl ester (Compound 22).
Following General Procedure D, ethyl 5-phenyl-6p-tolyl-[1,2,4]-triazine-3-
10 carboxylate (Compound 12, 177 mg, 0.56 mmol) and crude 1-vinylpyrrolidine
(Compound 38, 730 mg) in CHC13 (10 ml) were reacted to produce the title
compound as a yellow solid.
iH NMR (300 MHz, CDC13) b 1.45 (t, J = 7.18 Hz, 3 H), 2.34 (s, 3 H), 4.49 (q,
J
7.04 Hz, 2 H), 7.05 - 7.11 (m, 4 H), 7.17 - 7.28 (m, 3 H), 7.36 - 7.44 (m, 2
H), 7.82
15 (d, J= 7.92 Hz, 1 H), 8.10 (d, J= 7.92 Hz, 1 H).
Example 23
Ethy15-(4-Ethyl-phenyl)-6-phenyl-pyridine-2-carboxylate (Compound 23).
Following General Procedure D, ethyl 6-(4-ethyl-phenyl)-5-phenyl-
[1,2,4]triazine-
20 3-carboxylate (Compound 13, 105 mg, 0.30 mmol) and crude 1-vinylpyrrolidine
(Compound 38, 2 g) in CHC13 (10 ml) were reacted to produce the title compound
as a yellow solid.
iH NMR (300 MHz, CDC13) b 1.19 (t, J= 7.62 Hz, 3 H), 1.45 (t, J= 7.04 Hz, 3
H),
2.5 8(q, J= 7.62 Hz, 2 H), 4.47 (q, J= 7.04 Hz, 2 H), 7.09 - 7.16 (m, 4 H),
7.22 -
25 7.30 (m, 3 H), 7.36 - 7.42 (m, 2 H), 7.83 (d, J= 7.92 Hz, 1 H), 8.10 (d, J=
7.91
Hz, 1 H).
Example 24

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Ethy16-Phenyl-5-(4-propylphenyl)-pyridine-2-carboxylate (Compound 24).
Following General Procedure D, ethyl 5-phenyl-6-(4-propyl-phenyl)-[1,2,4]-
triazine-3-carboxylate (Compound 14), (153 mg, 0.46 mmol) and crude 1-
vinylpyrrolidine (Compound 38, 2 g) in CHC13 (10 ml) were reacted to produce
the title compound as a yellow oil.
iH NMR (300 MHz, CDC13) b 0.94 (t, J= 7.33 Hz, 3 H), 1.45 (t, J= 7.04 Hz, 3
H),
1.56-1.72(m,2H),2.55-2.62(m,2H),4.49(q,J=7.23Hz,2H),7.09(s,4H),
7.20-7.30(m,3H),7.36-7.45(m,2H),7.84(d,J=7.92Hz,1H),8.11(d,J=
7.92 Hz, 1 H).
Example 25
Ethy16-Phenyl-5-(4-trifluoromethylphenyl)-pyridine-2-carboxylate
(Compound 25). Following General Procedure D, ethyl 6-(4-
tirfluoromethylphenyl)-5-phenyl -[1,2,4]triazine-3-carboxylate (Compound 15),
(378 mg, 1.01 mmol) and crude 1-vinylpyrrolidine (Compound 38, 780 mg) in
CHC13 (10 ml) were reacted to produce the title compound as a yellow oil.
iH NMR (300 MHz, CDC13) b 1.47 (t, J= 7.18 Hz, 3 H), 4.52 (q, J= 7.04 Hz, 2
H),7.15-7.22(m,2H),7.30-7.36(m,3H),7.47-7.58(m,4H),8.18(d,J=
7.92 Hz, 1 H).
Example 26
Ethy15-(4-Ethylphenyl)-3-methyl-6-phenyl-pyridine-2-carboxylate
(Compound 26). Following General Procedure D, ethyl 6-(4-ethylphenyl)-5-
phenyl-[1,2,4]-triazine-3-carboxylate (Compound 13, 200 mg, 0.60 mmol) and
crude 1-propenyl-pyrrolidine (Compound 39, 2 g) in CHC13 (10 ml) were reacted
to produce the title compound as a yellow oil.

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iH NMR (500 MHz, CDC13) b 1.23 (t, J= 7.81 Hz, 3 H), 1.45 (t, J= 7.08 Hz, 3
H),
2.56 - 2.69 (m, 5 H), 4.47 (q, J= 7.08 Hz, 2 H), 7.01 - 7.15 (m, 4 H), 7.16 -
7.30
(m, 3 H), 7.35 - 7.42 (m, 2 H), 7.60 (s, 1 H).
Example 27
Ethy15-Phenyl-6 p-tolyl-pyridine-2-carboxylate (Compound 27). Following
General Procedure D, ethyl 6-phenyl-5p-tolyl-[1,2,4]triazine-3-carboxylate
(Compound 17, 361 mg, 1.13 mmol) and crude 1-vinylpyrrolidine (Compound
38, 806 mg) in CHC13 (10 ml) were reacted to produce the title compound as a
yellow oil.
iH NMR (300 MHz, CDC13) b 1.45 (t, J = 7.18 Hz, 3 H), 2.30 (s, 3 H), 4.49 (q,
J
7.04 Hz, 2 H), 7.05 (d J = 7.92 Hz, 2 H), 7.14 - 7.24 (m, 2 H), 7.27 - 7.3 3
(m, 5 H),
7.82 (d, J= 7.92 Hz, 1 H), 8.09 (d, J= 7.91 Hz, 1 H).
Example 28
Ethy15-(4-Ethylphenyl)-6-phenyl-pyridine-2-carboxylic acid ethyl ester
(Compound 28). Following General Procedure D, ethyl 5-(4-ethylphenyl)-6-
phenyl-[1,2,4]triazine-3-carboxylate (Compound 18, 245 mg, 0.74 mmol) and
crude 1-vinylpyrrolidine (Compound 38, 572 mg) in CHC13 (10 ml) were reacted
to produce the title compound as a yellow oil.
iH NMR (300 MHz, CDC13) b 1.19 (t, J= 7.62 Hz, 3 H), 1.45 (t, J= 7.18 Hz, 3
H),
2.60 (q, J= 7.62 Hz, 2 H), 4.49 (q, J= 7.04 Hz, 2 H), 7.06 (d, J= 7.92 Hz, 2
H),
7.27 - 7.36 (m, 5 H), 7.82 (d, J= 7.92 Hz, 1 H), 8.09 (d, J= 7.91 Hz, 1 H).
Example 29
Ethy15-Phenyl-6-(4-trifluoromethyl-phenyl)-pyridine-2-carboxylate
(Compound 29). Following General Procedure D, ethyl 5-(4-

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trifluoromethylphenyl)-6-phenyl-[1,2,4]-triazine-3-carboxylate (Compound 19, 1
g, 2.68 mmol) and crude 1-vinylpyrrolidine (Compound 38, 1.4 g) in CHC13 (20
ml) were reacted to produce the title compound as a yellow oil.
iH NMR (300 MHz, CDC13) b 1.46 (t, J= 7.18 Hz, 12 H), 4.51 (q, J= 7.23 Hz, 2
H), 7.21 - 7.42 (m, 5 H), 7.85 (d, J= 7.92 Hz, 1 H), 8.15 (d, J= 8.21 Hz, 1
H).
Example 30
Methy15,6-diphenylpyridine-2-carboxylate (Compound 30). General
Procedure E. A solution of ethy15,6-diphenylpyridine-2-carboxylate (Compound
21, 30 mg, 0.1 mmol) and conc. H2SO4 (3 drops) in MeOH (5 ml) was heated at 50
C overnight. The mixture was diluted with water, and the products were
extracted
with ethyl acetate. The organic layer was washed with water and brine, and
dried
over Na2SO4. The filtered solvent was concentrated in vacuo and the residue
was
purified by column chromatography (20 % ethyl acetate in hexane) to obtain the
title compound as a yellow solid.
iH NMR (500 MHz, CDC13) b 4.02 (s, 3 H), 7.15 - 7.31 (m, 8 H), 7.38 (d, J=
7.81
Hz, 2 H), 7.86 (d, J= 8.30 Hz, 1 H), 8.15 (d, J= 7.81 Hz, 1 H).
Example 31
Methyl 6-Phenyl-5p-tolyl-pyridine-2-carboxylate (Compound 31).
Following General Procedure E, ethyl 6-phenyl-5p-tolyl-pyridine-2-carboxylate
(Compound 22, 70 mg, 0.22 mmol) and conc. H2SO4 (3 drops) in MeOH (3 ml)
were reacted to produce the title compound as a yellow solid.
iH NMR (300 MHz, CDC13) b 2.34 (s, 3 H), 4.01 (s, 3 H), 7.05 - 7.11 (m, 4 H),
7.19-7.30(m,3H),7.35-7.44(m,2H),7.84(d,J=7.92Hz,1H),8.13(d,J
7.92 Hz, 1 H).

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Example 32
Methyl 5-(4-Ethylphenyl)-6-phenyl-pyridine-2-carboxylate (Compound 32).
Following General Procedure E, ethyl 5-(4-ethylphenyl)- 6-phenylpyridine-2-
carboxylate (Compound 23, 45 mg, 0.15 mmol) and conc. H2SO4 (3 drops) in
MeOH (3 ml) were reacted to produce title compound as a yellow solid.
iH NMR (300 MHz, CDC13) b 1.23 (t, J= 7.62 Hz, 3 H), 2.64 (q, J= 7.62 Hz, 2
H), 4.02 (s, 3 H), 7.05 - 7.16 (m, 4 H), 7.19 - 7.29 (m, 3 H), 7.34 - 7.44 (m,
2 H),
7.84 (d, J= 7.92 Hz, 1 H), 8.13 (d, J= 7.92 Hz, 1 H).
Example 33
Methyl 6-Phenyl-5-(4-propylphenyl)-pyridine-2-carboxylate (Compound 33).
Following General Procedure E, ethyl 6-phenyl-5-(4-propylphenyl)-pyridine-2-
carboxylate (Compound 24, 67 mg, 0.19 mmol) and conc. H2SO4 (3 drops) in
MeOH (3 ml) were reacted to produce the title compound as a white solid.
iH NMR (300 MHz, CDC13) b 0.93 (t, J= 7.33 Hz, 3 H), 1.56 - 1.71 (m, 2 H),
2.51
-2.63(m,2H),4.02(s,3H),7.01-7.13(m,4H),7.16-7.31(m,3H),7.34-7.43
(m, 2 H), 7.85 (d, J= 7.92 Hz, 1 H), 8.14 (d, J= 7.92 Hz, 1 H).
Example 34
Methyl6-Phenyl-5-(4-trifluoromethylphenyl)-pyridine-2-carboxylate
(Compound 34).
Following General Procedure E, ethyl6-phenyl-5-(4-trifluoromethylphenyl)-
pyridine-2-carboxylate (Compound 25, 110 mg, 0.29 mmol) and conc. H2SO4 (5
drops) in MeOH (5 ml) were reacted to produce the title compound as a white
solid.
iH NMR (300 MHz, CDC13) b 4.03 (s, 3 H), 7.08 - 7.22 (m, 3 H), 7.29 - 7.37 (m,
2
H), 7.51 (s, 4 H), 7.90 (d, J= 7.92 Hz, 1 H), 8.20 (d, J= 7.92 Hz, 1 H).

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Example 35
Methyl5-Phenyl-6-(4-trifluoromethylphenyl)-pyridine-2-carboxylate
(Compound 35). Following General Procedure E, ethyl 5-phenyl-6-(4-
5 trifluoromethylphenyl)-pyridine-2-carboxylate (Compound 29, 103 mg, 0.28
mmol) and conc. H2SO4 (5 drops) in MeOH (5 ml) were reacted to produce the
title
compound as a white solid.
iH NMR (300 MHz, CDC13) b 4.03 (s, 3 H), 7.21 - 7.40 (m, 7 H), 7.55 (d, J=
8.50
Hz, 2 H), 7.86 (d, J= 7.92 Hz, 1 H), 8.18 (d, J= 7.92 Hz, 1 H).
Example 36
Methyl 5-(4-Ethylphenyl)-3-methyl-6-phenylpyridine-2-carboxylate
(Compound 36). Following General Procedure E, ethyl 5-(4-ethylphenyl)-3-
methyl-6-phenylpyridine-2-carboxylate (Compound 26, 29 mg, 0.08 mmol) and
conc. H2SO4 (3 drops) in MeOH (5 ml) were reacted to produce the title
compound
as an oil.
iH NMR (500 MHz,CDC13) b 1.23 (t, J= 7.57 Hz, 3 H), 2.58 - 2.68 (m, 5 H), 3.99
(s,3H),7.05-7.13(m,4H),7.18-7.25(m,3H),7.34-7.40(m,2H),7.61(s,1
H).
Scheme 2

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41
O O
H2N-T-1- Oi~ + H2NNH2 EtOH _A. H2N"NY-1- O~-'
g NH2
37
R
N O K2CO3
~/ ) + R~H toluene~ N
~ 0
R= Me, Et 38, R= H
39, R = Me
Example 37
Ethyl oxalamidrazonate (Compound 37). A solution of anhydrous hydrazine (0.5
ml, 15.0 mmol) in ethanol (5 ml) was added dropwise to a stirred solution of
ethyl
thiooxamate (2 g, 15.0 mmol) in ethanol (45 ml) under argon at room
temperature.
The mixture was stirred at room temperature for 1 hour, and the solvent was
removed in vacuo and dried under high vacuum to get a white solid which was
maintained in argon atmosphere after drying. The white solid was used in the
next
step without further purification.
Example 38
1-vinylpyrrolidine (Compound 38). General Procedure F. To a suspension of
K2C03 (3.8 g, 28.1 mmol) and pyrrolidine (1 g, 14.0 mmol) in toluene (10 ml)
was
added acetylaldehyde under argon at 0 C. The mixture was stirred at room
temperature overnight. After filtration, the filtrate was concentrated in
vacuo to
yield a crude oil which was used in the next reaction without further
purification.
Example 39

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42
1-Propenylpyrrolidine (Compound 39). Following General Procedure F, K2C03
(3.8 g, 28.1 mmol), pyrrolidine (1 g, 14.0 mmol) and propionaldehyde (1.6 g,
28.1
mmol) in toluene (10 ml) were reacted to produce the title compound as a brown
oil.
Example 40
(E)-3-(4-ethylphenyl)prop-2-en-l-ol (Compound 40). General Procedure G. A
solution of ethyl chloroformate (1.l ml, 11.4 mmol) in THF (5 ml) was added to
a
solution of 4-ethylcinnamic acid (2 g, 11.4 mmol) and triethylamine (1.6 ml,
11.4
mmol) in THF (50 ml) at -5 C to -10 C, and the solution was stirred for 30
min.
The resulting white precipitate was filtered off, rinsed with THF (10 ml), and
the
combined filtrates were added to a solution of NaBH4 (945 mg, 24.9 mmol) in
H20
(20 ml) slowly in order to maintain an internal temperature of 10 C to 15 C.
After
the addition was completed, the reaction was stirred at room temperature for 4
hours, and then it was made acidic with HC1(20 %). The layers were separated,
and the aqueous layer was extracted with ethyl acetate. The combined organic
layers were washed with NaHCO3 (aq), and water, and brine, and dried over
Na2SO4. The filtered solution was concentrated in vacuo, and the residue was
purified by column chromatography (20 % ethyl acetate in hexane) to yield a
white
solid.
iH NMR (500 MHz, CDC13): b ppm 1.23 (t, J= 7.32 Hz, 3 H), 2.64 (q, J= 7.32
Hz, 2 H), 4.31 (s, 2 H), 6.30 - 6.39 (m, 1 H), 6.61 (d, J=16.11 Hz, 1 H), 7.16
(d, J
=8.30Hz,2H),7.32(d,J=8.30Hz,2H).
Scheme 3

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~
OH ~ I \ OH b O
R R / R
R= Et 40 R= Et 42 R= Et
R=Me 41R=Me 43R=Me
V A COOEt COOEt
R I/ N3 d` R I44R=Et 46R=Et
45 R= Me 47 R= Me
e _ C ' f I \
R NnN' \ COOEt R COOMe
48 R = 4-(trifluoromethyl)phenyl 51 R = 4-(trifluoromethyl)phenyl
49 R = 4-pyridyl 52 R = 4-pyridyl
50 R = 2-pyridyl 53 R = 2-pyridyl
(a) i) Ethyl chloroformate, TEA, THF, ii) NaBH4, H20, THF; (b) (COCl)z, DMSO,
TEA, -60 C;
(c) ethyl azidoacetate, NaOEt, EtOH; (d) PPh3, ether; (e) R'CHO, CH3CN, 60 C;
(f) MeOH, c.H2SO4, 60 C.
Example 41
(E)-3-(4-methylphenyl)prop-2-en-l-ol (Compound 41). Following General
Procedure G, ethyl chloroformate (1.2 ml, 12.3 mmol), 4-methylcinnamic acid (2
g,
12.3 mmol) and triethylamine (1.7 ml, 12.3 mmol) in THF (50 ml) were reacted
to
produce a mixed anhydride, which was then were reacted with NaBH4 ( 1.02 g,
27.2 mmol) in H20 (20 ml) to produce title compound as a white solid.
iH NMR (500 MHz, CDC13): b ppm 2.34 (s, 3 H), 4.31 (t, J= 4.88 Hz, 2 H), 6.30
- 6.39 (m, 1 H), 6.61 (d, J=16.11 Hz, 1 H), 7.14 (d, J= 8.30 Hz, 2 H), 7.29
(d, J
8.30 Hz, 2 H).

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Example 42
(E)-3-(4-ethylphenyl)acrylaldehyde (Compound 42). General Procedure H. To
a solution of oxalyl chloride (5.9 ml, 11.8 mmol, 2 M in CH2C12) in CH2C12 (20
ml)
was added a solution of DMSO (1.l ml, 15.7 mmol) in CH2C12 (3 ml) dropwise at -
60 C. A solution of (E)-3-(4-ethylphenyl)prop-2-en-l-ol (Compound 40, 1.3 g,
7.8 mmol) in CH2C12 (5 ml) was cannulated slowly into the above mixture at -60
C. After the reaction was stirred at the same temperature for 1 hour, a
solution of
triethylamine (4.4 ml, 31.4 mmol) in CH2C12 (5 ml) was added into the
reaction,
which was stirred an additional 1 hour at -60 C. The reaction was quenched
with
water, and the products were extracted with CH2C12. The organic layer was
washed
with 5% aqueous NaHCO3, and brine, and dried over MgSO4. The filtered solution
was concentrated in vacuo, and the residue was purified by column
chromatography (silica gel, 15% ethyl acetate in hexane) to obtain the title
compound as a clear oil.
iH NMR (500 MHz, CDC13): b ppm 1.26 (t, J= 7.32 Hz, 3 H), 2.70 (q, J= 7.32
Hz, 2 H), 6.72 (dd, J=7.81, 16.11 Hz, 1 H), 7.28 (d, J= 8.30 Hz, 2 H), 7.48
(d, J
15.62 Hz, 1 H),7.50 (d, J= 8.30 Hz, 2 H), 9.70 (s, 1 H).
Example 43
(E)-3-(4-methylphenyl)acrylaldehyde (Compound 43). Following General
Procedure H, oxalyl chloride (7.1 ml, 14.2 mmol, 2 M in CH2C12), DMSO (1.3 ml,
18.9 mmol), (E)-3-(4-methylphenyl)prop-2-en-l-ol (Compound 41, 1.4 g, 9.5
mmol) and triethylamine (4.4 ml, 31.4 mmol)in CH2C12 (5 ml) were reacted to
obtain the title compound as an oil.
iH NMR (500 MHz, CDC13): b 2.40 (s, 3 H), 6.72 (dd, J=7.81, 16.11 Hz, 1 H),
7.25 (d, J= 7.81 Hz, 2 H), 7.44 (d, J= 16.11 Hz, 1 H),7.48 (d, J= 8.30 Hz, 2
H),
9.70 (s, 1 H).

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Example 44
Ethyl (2Z,4E)-2-azido-5-(4-ethylphenyl)penta-2,4-dienoate (Compound 44).
General Procedure I. A solution of NaOEt in ethanol was prepared in situ by
dissolving Na (948 mg, 41.3 mmol) in 30 ml of ethanol. To this solution was
added
5 a solution of (E)-3-(4-ethylphenyl)acrylaldehyde (Compound 42, l.lg , 6.9
mmol)
and ethyl azidoacetate (13 ml, 41.3 mmol) in EtOH (20 ml) dropwise at -10 C.
After the addition was complete, the solution was stirred for an additional 1
hour at
-10 C. The reaction was quenched by adding water, and the product was
extracted
with ethyl acetate. The organic phase was washed with water, and brine, and
dried
10 over MgzSO4. The solvent was removed in vacuo, and the residue was purified
by
column chromatography (silica gel, 20% ethyl acetate in hexane) to obtain the
title
compound as a pale solid.
iH NMR (500 MHz, CDC13): b 1.24 (t, J= 7.81 Hz, 3 H), 1.37 (t, J= 7.32 Hz, 3
H), 2.66 (q, J= 7.81 Hz, 2 H), 4.34 (q, J= 7.32 Hz, 2 H), 6.76 (d, J=11.23 Hz,
1
15 H), 6.81 (d, J= 16.11 Hz, 1 H), 7.15 (dd, J= 11.23, 15.62 Hz, 1 H), 7.19
(d, J=
8.30 Hz, 2 H),7.39 (d, J= 8.30 Hz, 2 H).
Example 45
Ethyl (2Z,4E)-2-azido-5-(4-methylphenyl)penta-2,4-dienoate (Compound 45).
20 Following General Procedure I, a 1.38 M solution of NaOEt in ethanol (30
ml),
(E)-3-(4-methylphenyl)acrylaldehyde (Compound 43, l.lg , 7.5 mmol) and ethyl
azidoacetate (12 ml, 37.5 mmol) in EtOH (20 ml) were reacted to produce the
title
compound as a solid.
iH NMR (500 MHz, CDC13): b 1.37 (t, J= 7.32 Hz, 3 H), 2.36 (s, 3 H), 4.34 (q,
J
25 7.32 Hz, 2 H), 6.76 (d, J=10.25 Hz, 1 H), 6.81 (d, J=15.62 Hz, 1 H), 7.11
(dd, J
11.23, 15.62 Hz, 1 H), 7.17 (d, J= 8.30 Hz, 2 H),7.39 (d, J= 7.81 Hz, 2 H).
Example 46

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46
3-Ethoxycarbonyl-1,1,1-triphenyl-6-(4-ethylphenyl)-2-aza-1 25-phosphahexa-1,
3,5-triene (Compound 46). General Procedure J. A solution of
triphenylphosphine (1.2 g, 4.54 mmol) in diethyl ether (10 ml) was added
dropwise
to a solution of ethyl (2Z,4E)-2-azido-5-(4-ethylphenyl)penta-2,4-dienoate
(Compound 44, 1.2 g, 4.54 mmol) in diethyl ether (20 ml) at 0 C. The solution
was stirred for 12 hours at room temperature. Evaporation of solvent afforded
a
crude yellow solid, which was purified by column chromatography (silica gel,
20
% ethyl acetate in hexane) to give the title compound.
iH NMR (500 MHz, CDC13): b 1.04 (t, J= 7.81 Hz, 3 H), 1.23 (t, J= 7.32 Hz, 3
lo H), 2.62 (q, J= 7.81 Hz, 2 H), 3.89 (q, J= 7.32 Hz, 2 H), 6.60 (d, J=15.62
Hz, 1
H), 6.70 (dd, J= 3.91, 10.74 Hz, 1 H), 7.12 (d, J= 8.30 Hz, 2 H), 7.30 (d, J=
8.30
Hz, 2 H), 7.41 - 7.50 (m, 9 H), 7.66 (dd, J= 11.23, 15.62 Hz, 1 H),7.73 - 7.77
(m,
6 H).
Example 47
3-Ethoxycarbonyl-1,1,1-triphenyl-6-(4-methylphenyl)-2-aza-1A5-phosphahexa-
1, 3,5-triene (Compound 47). Following General Procedure J, triphenylphosphine
(1.5 g, 5.8 mmol) ethyl (2Z,4E)-2-azido-5-(4-methylphenyl)penta-2,4-dienoate
(Compound 45, 1.5 g, 5.8 mmol) in diethyl ether (50 ml) were reacted to
produce
the title compound as a yellow solid.
iH NMR (500 MHz, CDC13): b 1.04 (t, J= 7.32 Hz, 3 H), 2.33 (s, 3 H), 3.89 (q,
J=
7.32 Hz, 2 H), 6.60 (d, J=16.11 Hz, 1 H), 6.70 (dd, J= 3.91, 11.23 Hz, 1 H),
7.09
(d, J= 8.30 Hz, 2 H), 7.27 (d, J= 8.30 Hz, 2 H), 7.41 - 7.50 (m, 9 H), 7.66
(dd, J=
11.23, 16.11 Hz, 1 H), 7.73 - 7.77 (m, 6 H).
Example 48
Ethy15-(4-ethylphenyl)-6-(4-(trifluoromethyl)phenyl)pyridine-2-carboxylate
(Compound 48). General Procedure K. 4-(trifluoromethyl)benzaldehyde (153

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47
mg, 1.88 mmol) was added to a stirred solution of 3-ethoxycarbonyl-1,1,1 -
triphenyl-6-(4-ethylphenyl)-2-aza-lA5 -phosphahexa-1, 3,5-triene (Compound 46,
444 mg, 0.88 mmol) in dry acetonitrile (10 ml) and the solution was heated to
60
C for 18 hours. The solution was concentrated in vacuo, and the crude product
was
passed through a silica gel column with 15% ethyl acetate in hexane as eluant
to
give the title compound as a yellow oil.
iH NMR (500 MHz, CDC13): b 1.24 (t, J 7.81 Hz, 3 H), 1.46 (t, J= 7.32 Hz, 3
H), 2.67 (q, J= 7.81 Hz, 2 H), 4.51 (q, J= 7.32 Hz, 2 H), 7.09 (d, J= 8.30 Hz,
2
H), 7.16 (d, J= 8.30 Hz, 1 H), 7.49 - 7.55 (m, 4 H), 7.88 (d, J= 7.81 Hz, 1
H),
lo 8.16 (d, J= 7.81 Hz, 1 H).
Example 49
Ethy13-(4-Ethylphenyl)-[2,4']-bipyridinyl-6-carboxylate (Compound 49).
Following General Procedure K, 4-pyridinecarboxaldehyde (92 mg, 0.86 mmol)
and 3-ethoxycarbonyl-1,1,1-triphenyl-6-(4-ethylphenyl)-2-aza-lA s-phosphahexa-
l,
3,5-triene (Compound 46, 434 mg, 0.86 mmol) in dry acetonitrile (10 ml) were
reacted to produce the title compound as a yellow solid.
iH NMR (500 MHz, CDC13): b 1.24 (t, J= 7.81 Hz, 3 H), 1.46 (t, J= 7.32 Hz, 3
H), 2.67 (q, J= 7.81 Hz, 2 H), 4.51 (q, J= 7.32 Hz, 2 H), 7.09 (d, J= 8.30 Hz,
2
2o H), 7.16 (d, J= 8.30 Hz, 1 H), 7.33 (dd, J= 1.46, 4.39 Hz, 2 H), 7.90 (d,
J= 7.81
Hz, 1 H), 8.21 (d, J= 7.81 Hz, 1 H), 8.52 (dd, J= 1.46, 4.39 Hz, 2 H).
Example 50
Ethy13-(4-Ethylphenyl)-[2,2']-bipyridinyl-6-carboxylate (Compound 50).
Following General Procedure K, 2-pyridinecarboxaldehyde (41 mg, 0.38 mmol)
and 3-ethoxycarbonyl-1,1,1-triphenyl-6-(4-ethylphenyl)-2-aza-lA s-phosphahexa-
l,
3,5-triene (Compound 46, 193 mg, 0.38 mmol) in dry acetonitrile (5 ml) were
reacted to produce the title compound as a yellow solid.

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iH NMR (500 MHz, CDC13): b 1.22 (t, J= 7.81 Hz, 3 H), 1.45 (t, J= 7.32 Hz, 3
H), 2.62 (q, J= 7.81 Hz, 2 H), 4.52 (q, J= 7.32 Hz, 2 H), 7.05 - 7.11 (m, 4
H),
7.17 - 7.20 (m, 1 H), 7.49 (dd, J=0.98, 7.81 Hz, 1 H), 7.58 -7.62 (m, 1 H),
7.92 (d,
J= 7.81 Hz, 1 H), 8.20 (d, J= 7.81 Hz, 1 H), 8.50 - 8.55 (m, 1 H).
Example 51
Methyl5-(4-ethylphenyl)-6-(4-(trifluoromethyl)phenyl)pyridine-2-carboxylate
(Compound 51). Following General Procedure E, ethyl5-(4-ethylphenyl)-6-(4-
(trifluoromethyl)phenyl)pyridine-2-carboxylate (Compound 48, 60 mg, 0.15
mmol) and conc. H2SO4 (10 drops) in methanol were reacted to produce the title
compound as a light yellow solid.
iH NMR (500 MHz, CDC13): b ppm 1.24 (t, J= 7.81 Hz, 3 H), 2.67 (q, J= 7.81
Hz, 2 H), 4.03 (s, 3 H), 7.09 (d, J= 8.30 Hz, 2 H), 7.16 (d, J= 8.30 Hz, 1 H),
7.49
- 7.55 (m, 4 H), 7.89 (d, J= 7.81 Hz, 1 H), 8.18 (d, J= 7.81 Hz, 1 H).
Example 52
Methyl5-(4-ethylphenyl)-6-(pyridin-4-yl)pyridine-2-carboxylate (Compound
52). Following General Procedure E, ethyl 5-(4-ethylphenyl)-6-(pyridine-4-
yl)phenyl)pyridine-2-carboxylate (Compound 49, 48 mg, 0.14 mmol) and conc.
H2SO4 (10 drops) in methanol were reacted to produce the title compound as a
light
yellow solid.
iH NMR (500 MHz, CDC13): b ppm 1.24 (t, J= 7.81 Hz, 3 H), 2.65 (q, J= 7.81
Hz, 2 H), 4.03 (s, 3 H), 7.09 (d, J= 7.81 Hz, 2 H), 7.16 (d, J= 7.81 Hz, 1 H),
7.32
(dd, J= 1.46, 4.39 Hz, 2 H), 7.90 (d, J= 8.30 Hz, 1 H), 8.21 (d, J= 8.30 Hz, 1
H),
8.52 (dd, J= 1.46, 4.39 Hz, 2 H).
Example 53

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Methyl 5-(4-ethylphenyl)-6-(pyridin-2-yl)pyridine-2-carboxylate (Compound
53). Following General Procedure E, ethyl 5-(4-ethylphenyl)-6-(pyridine-2-
yl)phenyl)pyridine-2-carboxylate (Compound 50, 16 mg, 0.05 mmol) and conc.
H2SO4 (10 drops) in methanol were reacted to produce the title compound as a
light
yellow solid.
iH NMR (500 MHz, CDC13): b ppm 1.22 (t, J= 7.81 Hz, 3 H), 2.63 (q, J= 7.81
Hz, 2 H), 4.02 (s, 3 H), 7.05 - 7.11 (m, 4 H), 7.18 - 7.22 (m, 1 H), 7.42 (dd,
J
=0.98, 7.81 Hz 1 H), 7.56 - 7.63 (m, 1 H), 7.93 (d, J= 8.30 Hz, 1 H), 8.23 (d,
J=
8.30 Hz, 1 H), 8.55 -8.57 (m, 1 H).
Example 54
5, 6-diphenylpyridine-2-carbaldehyde (Compound 54). General Procedure L.
To a solution of ethy15,6-diphenylpyridine-2-carboxylate (Compound 21, 145 mg,
0.48 mmol) in CH2C12 (5 ml) at -78 C was added DIBAL-H (0.72 ml, 0.72 mmol,
1.0 M in Toluene) and the mixture was stirred between -78 C and -60 C for 1
hour under argon. The reaction was quenched with aq, NH4C1, diethyl ether and
400 mg Celite were added, and the mixture was stirred at room temperature 30
min.
The solid was filtered off and rinsed with ether, and the combined filtrate
was
concentrated in vacuo, and the residue was purified by column chromatography
(silica gel, 15% ethyl acetate in hexane) to produce the title compound.
iH NMR (500 MHz, CDC13) b 7.17 - 7.22 (m, 2 H), 7.27 - 7.32 (m, 6 H), 7.40 -
7.43 (m, 2 H), 7.92 (d, J= 7.91 Hz, 1 H), 8.01 (d, J= 7.91 Hz, 1 H), 10.19 (s,
1 H).
Scheme 4

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R1 R1 R1
\ \ a \ \ \ \
+
Rz N R2 I N O \ N OH
O H /
21 Ri = H, R2 = phenyl 54 Ri = H, R2 = phenyl 60 Ri = Me
22 Ri = Me, R2 = phenyl 55 Ri = Me, R2 = phenyl 61R1 = Et
23 Ri = Et, R2 = phenyl 56 Ri = Et, R2 = phenyl 62 Ri = n-Pr
25 Ri -CF3, R2 = phenyl 57 Ri -CF3, R2 = phenyl
49 Rl = Et, R2 = 4-pyridyl 58 R1= Et, R2 = 4-pyridyl
24 Rl = n-Pr, R2 = phenyl 59 R1= n-Pr, R2 = phenyl
b c
R1
R1
\ I \ \
\ \ I ~ ON/\/P03H2
R2 N NPO3H2 N
63 Ri = H, Rz = phenyl, n= 3 72 Ri = Et
64 Ri = Me, Rz = phenyl, n= 3 73 Ri = Me
65 Ri = Et, Rz = phenyl, n= 3 74 Ri = n-Pr
66 Ri = Et, Rz = phenyl, n= 2
67 Ri -CF3, R2 = phenyl, n= 3
68 Ri = Et, R2 = 4-pyridyl, n= 3
69 Ri = Et, R2 = 4-pyridyl, n= 2
70 Ri =Et, R2 = phenyl, n= 4
71 Ri = n-Pr, R2 = phenyl, n= 3
(a) DiBAL-H, CHzCIz, -78 C to -60 C; (b) n-Bu4NOH, NH2(CH2) õP03H2, MeOH,
Na(BH3)CN, 50 C; (c)i) NaH,
Br(CHz)3PO(OEt)z, DMF, 110 C; ii) TMSI, CHC13.
Example 55 and Example 60
6-Phenyl-5-p-tolylpyridine-2-carbaldehyde (Compound 55) and (6-phenyl-5 p-
5 tolylpyridin-2-yl)methanol (Compound 60). Following General Procedure L,
ethyl 6-phenyl-5-p-tolylpyridine-2-carboxylate (Compound 22, 1.1 g, 3.47 mmol)
and DIBAL-H (5.2 ml, 5.21 mmol, l.OM in cyclohexane) in CH2C12 (30 ml) were
reacted to produce Compound 55 and Compound 60 after separation by column
chromatography (silica gel, 15% ethyl acetate in hexane).
10 Compound 55: 'H NMR (500 MHz, CDC13): b 2.38 (s, 3 H), 7.08 - 7.18 (m, 4
H),
7.29 - 7.38 (m, 3 H, 7.42 - 7.52 (m, 2 H), 7.94 (d, J= 7.32 Hz, 1 H), 8.03 (d,
J=
7.81 Hz, 1 H), 10.27 (s, 1 H).

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Compound 60: 'H NMR (300 MHz, CDC13): b 2.34 (s, 3 H), 4.84 (s, 2 H), 7.02 -
7.13 (m, 4 H), 7.21 - 7.31 (m, 4 H), 7.35 - 7.42 (m, 2 H), 7.71 (d, J= 7.62
Hz, 1 H).
Example 56 and Example 61
5-(4-Ethylphenyl)-6-phenylpyridine-2-carbaldehyde (Compound 56) and [5-(4-
Ethylphenyl)-6-phenylpyridin-2-yl] -methanol (Compound 61). Following
General Procedure L, ethyl 5-(4-ethylphenyl)-6-phenylpyridine-2-carboxylate
(Compound 23, 200 mg, 0.60 mmol) and DIBAL-H (1.2 ml, 1.20 mmol, 1.0 M in
CH2C12) in CH2C12 (5 ml) were reacted to produce Compound 56 and Compound
61 after separation by column chromatography (silica gel, 15% ethyl acetate in
hexane).
Compound 56: 'H NMR (500 MHz, CDC13): b 1.27 (t, J= 7.81 Hz, 3 H), 2.67 (q,
J= 7.81 Hz, 2 H), 7.13 - 7.17 (m, 4H), 7.30 - 7.34 (m, 3 H), 7.44 - 7.47 (m, 2
H),
7.93 (d, J= 7.81 Hz, 1 H), 8.02 (d, J= 7.81 Hz, 1 H), 10.23 (s, 1 H).
Compound 61: 'H NMR (300 MHz, CDC13): b ppm 1.24 (t, J= 7.81 Hz, 3 H),
2.66 (q, J= 7.81 Hz, 2 H), 4.85 (d, J= 3.42 Hz, 2 H), 7.08 - 7.13 (m, 4H),
7.25 -
7.28 (m, 5 H), 7.39 (d, J= 7.81 Hz, 1 H), 7.74 (d, J= 7.81 Hz, 1 H).
I
Example 57
5-(4-Trifluoromethylphenyl)-6-phenylpyridine-2-carbaldehyde (Compound
57). Following General Procedure L, ethyl 5-(4-trifluoromethylphenyl)-6-
phenylpyridine-2-carboxylate (Compound 25, 74 mg, 0.20 mmol) and DIBAL-H
(0.3 ml, 0.30 mmol, 1.0 M in hexane) in CH2C12 (3 ml) were reacted to produce
the
title compound after purification by column chromatography (silica gel, 15%
ethyl
acetate in hexane).
iH NMR (300 MHz, CDC13) b 7.29 - 7.39 (m, 2 H), 7.45 - 7.62 (m, 4 H), 7.95 (d,
J
= 7.92 Hz, 1 H), 8.05 (d, J= 7.92 Hz, 1 H), 10.19 (s, 1 H).

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Example 58
3-(4-Ethylphenyl)-[2,4']-bipyridinyl-6-carbaldehyde (Compound 58)
Following General Procedure L, ethyl 3-(4-ethylphenyl)-[2,4']-bipyridinyl-6-
carboxylate (Compound 49, 164 mg, 0.49 mmol) and DIBAL-H (0.75 ml, 0.75
mmol, 1.0 M in CH2C12) in CH2C12 (5 ml) were reacted to produce the title
compound after purification by column chromatography (silica gel, 15% ethyl
acetate in hexane).
iH NMR (300 MHz, CDC13): b 1.25 (t, J= 7.81 Hz, 3 H), 2.68 (q, J= 7.81 Hz, 2
H), 7.11 ((d, J= 8.30 Hz, 2 H), 7.18 (d, J= 7.81 Hz, 1 H), 7.34 (dd, J= 1.95,
4.39
l o Hz, 2 H), 7.94 (d, J= 7.32 Hz, 1 H), 8.06 (d, J= 7.81 Hz, 1 H), 8.56 (dd,
J= 1.95,
4.39 Hz, 2 H), 10.17 (s, 1 H).
Example 59 and Example 62
6-Phenyl-5-(4-propylphenyl)pyridine-2-carbaldehyde (Compound 59) and (6-
Phenyl-5-(4-propylphenyl)pyridin-2-yl)methanol (Compound 62). Following
General Procedure L, ethyl 6-phenyl-5-(4-propyl-phenyl)-pyridine-2-carboxylate
(Compound 24, 370 mg, 0.49 mmol) and DIBAL-H (2.1 ml, 2.1 mmol, 1.0 M in
cyclohexane) in CH2C12 (5 ml) were reacted to produce Compound 59 and
Compound 62 after separation by column chromatography (silica gel, 15% ethyl
acetate in hexane).
Compound 59: 'H NMR (500 MHz, CDC13): b 0.94 (t, J= 7.32 Hz, 3 H) ,1.59 -
1.71 (m, 2 H), 2.54 - 2.62 (m, 2 H), 7.11 (s, 4 H), 7.26 - 7.35 (m, 3 H), 7.40
- 7.45
(m, 2 H), 7.91 (d, J= 7.81 Hz, 1 H), 7.99 (d, J= 7.81 Hz, 1 H), 10.19 (s, 1
H).
Compound 62: 'H NMR (500 MHz, CDC13): b 0.94 (t, J= 7.32 Hz, 3 H), 1.60 -
1.70 (m, 2 H), 2.54 - 2.62 (m, 2 H), 4.87 (s, 2 H), 7.04 - 7.13 (m, 4 H), 7.22
- 7.32
(m, 4 H), 7.40 (d, J= 7.32 Hz, 2 H), 7.77 (d, J= 7.81 Hz, 1 H).
Example 63

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{3-[(5,6-Diphenylpyridin-2-ylmethyl)-amino]-propyl}-phosphonic Acid
(Compound 63). General Procedure M. To a solution of 5,6-diphenylpyridine-2-
carbaldehyde (Compound 54, 95 mg, 0.37 mmol) and (3-amino-propyl)-
phosphonic acid (51 mg, 0.37 mmol) in MeOH (3 ml) was added Bu4NOH (0.4 ml,
0.37 mmol, 1M in MeOH) under argon. The mixture was stirred at 50 C for 30
min. before adding NaCNBH3 (23 mg, 0.37 mmol) to the mixture. The solution was
stirred at 50 C for 3 hours, and then it was concentrated in vacuo. The
resulting
crude solid was purified MPLC column chromatography (silica gel, 0 - 100%
MeOH in ethyl acetate) to obtain the title compound as a white solid.
iH NMR (300 MHz, CDC13): b 1.69 - 1.76 (m, 2 H), 2.00 - 2.08 (m, 2 H), 3.09
(t,
J= 6.95 Hz, 2 H), 4.19 (s, 2 H), 7.02 - 7.09 (m, 2 H), 7.19 - 7.26 (m, 5 H),
7.30 -
7.36 (m, 3 H), 7.60 - 7.72 (m, 2 H).
Example 64
{3-[(6-Phenyl-5-p-tolylpyridin-2-ylmethyl)-amino]-propyl}-phosphonic Acid
(Compound 64). Following General Procedure M, 6-phenyl-5-p-tolylpyridine-2-
carbaldehyde (Compound 55, 67 mg, 0.25 mmol), (3-aminopropyl)-phosphonic
acid (34 mg, 0.25 mmol), Bu4NOH (0.2 ml, 0.25 mmol, 1 M in MeOH) and
NaCNBH3 (15 mg, 0.25 mmol) in MeOH (3 ml) were reacted to produce the title
compound as a white solid.
iH NMR (500 MHz, CD3OD): b 1.69 - 1.76 (m, 2 H), 2.00 - 2.08 (m, 2 H), 2.34
(s, 3 H), 3.19 (t, J= 6.80 Hz, 2 H), 4.39 (s, 2 H), 7.08 - 7.16 (m, 4 H), 7.25
- 7.31
(m, 3 H), 7.39 - 7.42 (m, 2 H), 7.54 (d, J= 7.80 Hz, 1 H), 7.89 (d, J= 7.81
Hz, 1
H).
Example 65
3- { [5-(4-Ethylphenyl)-6-phenylpyridin-2-ylmethyl] -amino}-propyl)-
phosphonic Acid (Compound 65). Following General Procedure M, 5-(4-

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ethylphenyl)-6-phenylpyridine-2-carbaldehyde (Compound 56, 43 mg, 0.15
mmol), (3-aminopropyl)-phosphonic acid (21 mg, 0.15 mmol), Bu4NOH (0.15 ml,
0.15 mmol, 1 M in MeOH) and NaCNBH3 (9 mg, 0.15 mmol) in MeOH (3 ml)
were reacted to produce the title compound as a white solid.
iH NMR (500 MHz, CD3OD): b 1.24 (t, J= 7.81 Hz, 3 H), 1.69 - 1.75 (m, 2 H),
2.00 - 2.08 (m, 2 H), 2.66 (q, J= 7.81 Hz, 2 H), 3.19 (t, J= 6.35 Hz, 2 H),
4.36 (s,
2 H), 7.10 - 7.16 (m, 4 H), 7.25 - 7.31 (m, 3 H), 7.39 - 7.42 (m, 2 H), 7.54
(d, J=
8.30 Hz, 1 H), 7.88 (d, J= 7.81 Hz, 1 H).
Example 66
(2-{[5-(4-Ethyl-phenyl)-6-phenyl-pyridin-2-ylmethyl]-amino}-ethyl)-
phosphonic Acid (Compound 66). Following General Procedure M, 5-(4-ethyl-
phenyl)-6-phenyl-pyridine-2-carbaldehyde (Compound 56, 31 mg, 0.11 mmol), (3-
amino-ethyl)-phosphonic acid (14 mg, 0.11 mmol), Bu4NOH (0.11 ml, 0.11 mmol,
1 M in MeOH) and NaCNBH3 (7 mg, 0.11 mmol) in MeOH (2 ml) were reacted to
produce the title compound as a white solid.
iH NMR (500 MHz, CD3OD): b 1.23 (t, J= 7.81 Hz, 3 H), 1.90 -1.96 (m, 2 H),
2.66 (q, J= 7.81 Hz, 2 H), 3.19 (t, J= 6.35 Hz, 2 H), 4.34 (s, 2 H), 7.09 -
7.16 (m,
4 H), 7.25 - 7.29 (m, 3 H), 7.39 - 7.42 (m, 2 H), 7.53 (d, J= 7.81 Hz, 1 H),
7.87 (d,
J= 8.30 Hz, 1 H).
Example 67
(3-{ [6-Phenyl-5-(4-trifluoromethylphenyl)-pyridin-2-ylmethyl] -amino}-
propyl)-phosphonic Acid (Compound 67). Following General Procedure M, 5-(4-
trifluoromethylphenyl)-6-phenyl-pyridine-2-carbaldehyde (Compound 57, 58 mg,
0.18 mmol), (3-amino-propyl)-phosphonic acid (25 mg, 0.18 mmol), Bu4NOH
(0.18 ml, 0.18 mmol, 1 M in MeOH) and NaCNBH3 (11 mg, 0.18 mmol) in MeOH
(3 ml) were reacted to produce the title compound as a white solid.

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iH NMR (500 MHz, CD3OD): b 1.02 (t, J= 7.33 Hz, 3 H), 1.65 - 1.75 (m, 2 H),
1.95 - 2.08 (m, 2 H), 3.16 (t, J= 6.35 Hz, 2 H), 4.36 (s, 2 H), 7.16 - 7.21
(m, 2 H),
7.29 - 7.31 (m, 3 H), 7.52 - 7.59 (m, 5 H), 7.91 (d, J= 7.92 Hz, 1 H).
5 Example 68
(3-{ [3-(4-Ethylphenyl)- [2,4'] -bipyridin-6-ylmethyl] -amino}-propyl)-
phosphonic Acid (Compound 68). Following General Procedure M, 3-(4-ethyl-
phenyl)-[2,4']-bipyridinyl-6-carbaldehyde (Compound 58, 50 mg, 0.17 mmol), (3-
amino-propyl)-phosphonic acid (24 mg, 0.17 mmol), Bu4NOH (0.17 ml, 0.17
10 mmol, 1 M in MeOH) and NaCNBH3 (11 mg, 0.17 mmol) in MeOH (3 ml) were
reacted to produce the title compound as a white solid.
iH NMR (500 MHz, CD3OD): 61.25 (t, J= 7.81 Hz, 3 H), 1.69 -1.79 (m, 2 H), 2.00
- 2.09 (m, 2 H), 2.66 (q, J= 7.81 Hz, 2 H), 3.17 (t, J= 6.83 Hz, 2 H), 4.37
(s, 2 H),
7.16 (d, J= 8.30 Hz, 2 H), 7.22 (d, J= 8.30 Hz, 2 H), 7.49 (dd, J= 1.95, 4.88
Hz, 2
15 H), 7.64 (d, J= 7.81 Hz, 1 H), 7.94 (d, J= 7.81 Hz, 1 H), 8.45 (dd, J=
1.46, 4.3 9
Hz, 2 H).
Example 69
(2-{[3-(4-Ethyl-phenyl)-[2,4']-bipyridinyl-6-ylmethyl]-amino}-ethyl)-
20 phosphonic Acid (Compound 69). Following General Procedure M, 3-(4-ethyl-
phenyl)-[2,4']-bipyridinyl-6-carbaldehyde (Compound 58, 39 mg, 0.14 mmol), (3-
amino-ethyl)-phosphonic acid (17 mg, 0.14 mmol), Bu4NOH (0.14 ml, 0.14 mmol,
1 M in MeOH) and NaCNBH3 (9 mg, 0.14 mmol) in MeOH (3 ml) were reacted to
produce the title compound as a white solid.
25 iH NMR (500 MHz, CD3OD): b 1.25 (t, J= 7.81 Hz, 3 H), 1.90 -1.99 (m, 2 H),
2.69 (q, J= 7.81 Hz, 2 H), 3.30 (t, J= 6.83 Hz, 2 H), 4.39 (s, 2 H), 7.14 (d,
J= 8.30
Hz, 2 H), 7.20 (d, J= 8.30 Hz, 2 H), 7.48 (dd, J= 1.46, 4.39 Hz, 2 H), 7.62
(d, J
7.81 Hz, 1 H), 7.93 (d, J= 7.81 Hz, 1 H), 8.45 (dd, J= 1.95, 4.88 Hz, 2 H).

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Example 70
4-((5-(4-Ethylphenyl)-6-phenylpyridin-2-yl)methylamino)butylphosphonic
Acid (Compound 70). Following General Procedure M, 5-(4-ethyl-phenyl)-6-
phenyl-pyridine-2-carbaldehyde (Compound 56, 58 mg, 0.18 mmol), 4-
aminobutylphosphonic acid (21 mg, 0.18 mmol), Bu4NOH (0.18 ml, 0.18 mmol, 1
M in MeOH) and NaCNBH3 (9 mg, 0.18 mmol) in MeOH (2 ml) were reacted to
produce the title compound as a white solid.
iH NMR (500 MHz, CD3OD): b 1.23 (t, J= 7.81 Hz, 3 H), 1.56 - 1.70 (m, 6 H),
2.61 - 2.71 (m. 4 H), 3.85 (s, 2 H), 7.07 - 7.12 (m, 4 H), 7.25 - 7.33 (m, 5
H), 7.66
(d, J= 8.30 Hz, 1 H), 7.83 (d, J= 8.30 Hz, 1 H).
Example 71
3-((6-Phenyl-5-(4-propylphenyl)pyridin-2-yl)methylamino)propylphosphonic
Acid (Compound 71). Following General Procedure M, 6-phenyl-5-(4-
propylphenyl)pyridine-2-carbaldehyde (Compound 59, 74 mg, 0.25 mmol), (3-
amino-propyl) phosphonic acid (34 mg, 0.25 mmol), Bu4NOH (0.25 ml, 0.25
mmol, 1M in MeOH) and NaCNBH3 (15 mg, 0.25 mmol) in MeOH (5 ml) were
reacted to produce the title compound as a white solid.
iH NMR (500 MHz, CD3OD) b 0.94 (t, J= 7.32 Hz, 3 H), 1.58 - 1.78 (m, 4 H),
1.92 - 2.09 (m, 2 H), 2.51 - 2.66 (m, 2 H), 3.05 (t, J= 6.59 Hz, 2 H), 4.23
(s, 2 H),
7.03 - 7.16 (m, 4 H), 7.19 - 7.32 (m, 3 H), 7.36 - 7.38 (m, 2 H), 7.55 (d, J=
7.81
Hz, 1 H), 7.85 (d, J= 8.30 Hz, 1 H).
Example 72
{3- [5-(4-Ethyl-phenyl)-6-phenyl-pyridin-2-ylmethoxy] -propyl}-phosphonic
Acid (Compound 72). General Procedure N. To a suspension of NaH (11 mg,
0.48 mmol) in DMF (1 ml) was added a solution of [5-(4-ethyl-phenyl)-6-phenyl-

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pyridin-2-yl] -methanol (Compound 61, 69 mg, 0.24 mmol) at 0 C under argon.
After the mixture was stirred for 30 min., a solution of (3-bromo-propyl)-
phosphonic acid diethyl ester (123 mg, 0.48 mmol) was added into the mixture
and
the reaction was heated to 110 C overnight. The reaction was quenched with
water, and the products were extracted with ethyl acetate. The combined
organic
layers were washed with water, and brine, and dried over Na2SO4. The filtered
solvents were concentrated in vacuo, and the residue was purified by MPLC on
silica gel (0 - 100 % ethyl acetate in hexane) to produce a crude mixture
containing
{3-[5-(4-Ethyl-phenyl)-6-phenyl-pyridin-2-ylmethoxy]-propyl}-phosphonic acid
diethyl ester.
To a solution of crude {3-[5-(4-ethyl-phenyl)-6-phenyl-pyridin-2-ylmethoxy]-
propyl}-phosphonic acid diethyl ester (18 mg, 0.039 mmol) in CHC13 (2 ml) at
room temperature was added TMSI (77 mg, 0.39 mmol) dropwise. After the
mixture was stirred for 1 hour, the solvent was removed in vacuo to recover a
yellow oily residue. The residue was taken-up in THF/H20 (4:1) and stirred at
room temperature overnight. The mixture was extracted with ethyl acetate. The
combined organic layers were washed with NaHSO3, and water, and brine, and
dried over Na2SO4. The filtered solvents were concentrated in vacuo and the
residue was purified by MPLC on silica gel (0 - 100% MeOH in ethyl acetate) to
give the title compound as a white solid..
iH NMR (500 MHz, CD3OD): 61.20 (t, J= 7.81 Hz, 3 H), 1.67 - 1.73 (m, 2 H),
1.90 - 2.01 (m, 2 H), 2.61 (q, J= 7.81 Hz, 2 H), 3.67 (t, J= 6.35 Hz, 2 H),
4.69 (s,
2 H), 7.04 - 7.10 (m, 4 H), 7.23 - 7.29 (m, 5 H), 7.59 (d, J= 7.81 Hz, 1 H),
7.84 (d,
J=7.81Hz,1H).
Example 73
3-((6-Phenyl-5-p-tolylpyridin-2-yl)methoxy)propylphosphonic Acid
(Compound 73). Following General Procedure N, NaH (17 mg, 0.67 mmol), [5-
(4-methyl-phenyl)-6-phenyl-pyridin-2-yl] -methanol (Compound 60, 91 mg, 0.33

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58
mmol) in DMF (3 ml) was refluxed to produce crude {3-[5-(4-methyl-phenyl)-6-
phenyl-pyridin-2-ylmethoxy]-propyl}-phosphonic acid diethyl ester, which was
then reacted with TMSI (0.13 ml, 0.09 mmol) in CHC13 (3 ml) to obtain the
title
compound as an oil.
iH NMR (500 MHz, CD3OD) b 1.73 - 1.88 (m, 2 H), 1.90 - 2.05 (m, 2 H), 2.30 (s,
3 H), 3.69 (t, J= 6.35 Hz, 2 H), 4.69 (s, 2 H), 6.97 - 7.12 (m, 4 H), 7.20 -
7.34 (m,
5 H), 7.58 (d, J= 8.30 Hz, 1 H), 7.86 (d, J= 8.30 Hz, 1 H).
Example 74
3-((6-Phenyl-5-(4-propylphenyl)pyridin-2-yl)methoxy)propylphosphonic Acid
(Compound 74). Following General Procedure N, NaH (17 mg, 0.67 mmol), [5-
(4-methyl-phenyl)-6-phenyl-pyridin-2-yl] -methanol (Compound 62, 105mg, 0.35
mmol) in DMF (3 ml) was refluxed to produce crude {3-[5-(4-n-propyl-phenyl)-6-
phenyl-pyridin-2-ylmethoxy]-propyl}-phosphonic acid diethyl ester, which was
then reacted with TMSI (0.13 ml, 0.09 mmol) in CHC13 (3 ml) to obtain the
title
compound as an oil.
Scheme 5

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59
O I
OH a b
81 82
I ~ \ N~Z COOMe COOMe
c N d N=PPh3
83 84
e I
-~ I N~ N COOMe
(a) i) Ethyl chloroformate, TEA, THF, ii) NaBH41 H20, THF; (b) (COC02, DMSO,
TEA, -60 C; (c) ethyl azidoacetate, NaOMe,
MeOH; (d) PPh3, ether; (e) PhCHO, CH3CN, 60 C.
Example 81
(E)-3-(4-Isopropylphenyl)prop-2-en-l-ol (Compound 81). Following General
5 Procedure G, 4-iso-propylcinnamic acid (3 g, 15.8 mmol), ethyl chloroformate
(1.6
ml, 15.8 mmol) and triethylamine (2.2 ml, 15.8 mmol) in THF (100m1) were
reacted to produce a mixed anhydride, which was then were reacted with NaBH4
(1.3 g, 34.7 mmol) in H20 (30 ml) to produce title compound as a white solid.
1H NMR (300 MHz, CDC13) b ppm 1.26 (d, J=7.04 Hz, 6 H), 2.86 - 2.97 (m, 1 H),
10 4.32 (dd, J=5.86, 1.17 Hz, 2 H), 6.29 - 6.38 (m, 1H), 6.61 (d, J=16.12 Hz,
1 H),
7.16 - 7.24 (d, J=8.21 Hz, 2 H), 7.33 (d, J=8.21 Hz, 2 H)
Example 82
(E)-3-(4-Isopropylphenyl)acrylaldehyde (Compound 82). Following General
15 Procedure H, oxalyl chloride (9.5 ml, 19.0 mmol, 2M in CH2C12), DMSO (1.8
ml,
25.3 mmol), (E)-3-(4-isopropylphenyl)prop-2-en-l-ol (Compound 81, 2.2g, 12.6

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mmol) and triethylamine (7.1 ml, 50.7 mmol) in CH2C12 (100 ml) were reacted to
obtain the title compound as an oil.
iH NMR (300 MHz, CDC13) b ppm 1.28 (d, J=7.04 Hz, 6 H), 2.77 - 3.11 (m, 1 H),
6.70 (dd, J=15.83, 7.62 Hz, 1 H), 7.31 (d, J=8.21 Hz, 1 H), 7.45 - 7.59 (m, 3
H),
5 9.70 (d, J=7.62 Hz, 1 H)
Example 83
Methyl (2Z,4E)- 2-Azido-5-(4-isopropylphenyl)penta-2,4-dienoate (Compound
111). Following General Procedure I, a 1.34 M solution of NaOMe in methanol
(30
lo ml), (E)-3-(4-isopropylphenyl)acrylaldehyde (Compound 82,1.4 g, 8.0 mmol)
and
ethyl azidoacetate (12 ml, 40.2 mmol) in MeOH (20 ml) were reacted to produce
the title compound as a solid.
iH NMR (300 MHz, CDC13) b ppm 1.26 (d, J=6.74 Hz, 6 H), 2.80 - 3.02 (m, 1 H),
3.88 (s, 3 H), 6.70 - 6.87 (m, 2 H), 7.13 (dd, J=15.54, 11.43 Hz, 1 H), 7.22
(d,
15 J=8.21 Hz, 2 H), 7.43 (d, 2 H)
Example 84
3-Methoxycarbonyl-1,1,1-triphenyl-6-(4-isopropylphenyl)-2-aza-1k5-
phosphahexa-1,3,5-triene (Compound 84). Following General Procedure J,
20 triphenylphosphine (1.4g, 5.2 mmol), methyl (2Z,4E)- 2-azido-5-(4-
isopropylphenyl)penta-2,4-dienoate (Compound 83, 1.4 g, 5.2 mmol) in diethyl
ether (50 ml) were reacted to produce the title compound as a yellow solid.
iH NMR (300 MHz, CDC13) b ppm 1.26 (d, J=6.74 Hz, 6 H), 2.81 - 2.98 (m, 1 H),
3.44 (s, 3 H), 6.58 - 6.76 (m, 2 H), 7.15 (d, J=8.21 Hz, 2 H), 7.32 (d, J=8.50
Hz, 2
25 H), 7.37 - 7.57 (m, 9 H), 7.76 (ddd, J=12.09, 7.99, 1.32 Hz, 7 H)
Example 85

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Methyl 5-(4-Isopropyl-phenyl)-6-phenyl-pyridine-2-carboxylate (Compound
85). Following General Procedure K, Benzaldehyde (0.48 g, 4.6 mmol) and 3-
Methoxycarbonyl-1,1,1-triphenyl-6-(4-isopropylphenyl)-2-aza-1 k 5 -phosphahexa-
1,3,5-triene (Compound 84, 2.3 g, 4.6 mmol) in dry acetonitrile (100 ml) were
reacted to produce the title compound as a yellow solid.
iH NMR (300 MHz, CDC13) b ppm 1.25 (d, J=7.04 Hz, 6 H), 2.78 - 3.00 (m, 1 H),
4.03 (s, 3 H), 7.06 - 7.19 (m, 4 H), 7.21 - 7.32 (m, 3 H), 7.35 - 7.46 (m, 2
H), 7.86
(d, J=7.92 Hz, 1 H), 8.14 (d, J=7.92, 1 H)
Scheme 6
R R R
I I
\ I \ a \ I \ \ I \
+
N O~ N O I ~ OH
I N
O
85 R= i-Pr 56 R= Et 87 R= i-Pr
86 R = i-Pr
\~ \ \
\ N N1,1~/PO3H2 N N~~~COOH
75 76
(a) DiBAL-H, CH2C12-78 C to -60 C; (b) n-Bu4NOH, NH2(CH2) 3P03H2, MeOH,
Na(BH3)CN, 50 C; (c) NH2(CH2) 4CO2H, MeOH, Na(BH3)CN, AcOH.
Example 86 and Example 87

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5-(4-Isopropyl-phenyl)-6-phenyl-pyridine-2-carbaldehyde (Compound 86) and
(5-(4-Isopropylphenyl)-6-phenylpyridin-2-yl)methanol (Compound 87).
Following General Procedure L, methyl 5-(4-isopropyl-phenyl)-6-phenyl-pyridine-
2-carboxylate (Compound 85, 283 mg, 0.86 mmol) and DIBAL-H (0.9 ml, 1.72
mmol, 1.0 M in cyclohexane) in CH2C12 (10 ml) were reacted to produce
Compound 86 and compound 87 after separation by column chromatography
(silica gel, 15% ethyl acetate in hexane).
Compound 86: 'H NMR (300 MHz, CDC13) b ppm 1.26 (d, J=6.74 Hz, 6 H), 2.81
-3.00(m,1H),7.08-7.21(m,4H),7.28-7.35(m,3H),7.38-7.48(m,2H),
1 o 7.90 (d, J=7.92 Hz, 1 H), 7.99 (d, J=7.92 Hz, 1 H), 10.19 (s, 1 H)
Compound 87: 'H NMR (300 MHz, CDC13) b ppm 1.25 (d, J=6.74 Hz, 6 H), 2.77
-3.01(m,1H),4.85(d,J=3.52Hz,2H),7.03-7.19(m,4H),7.19-7.33(m,4H),
7.32 - 7.46 (m, 2 H), 7.74 (d, J=7.92 Hz, 1 H)
Example 75
3-{[5-(4-Isopropylphenyl)-6-phenylpyridin-2-ylmethyl] amino}-propyl-
phosphonic Acid (Compound 75). Following General Procedure M, 5-(4-
isopropyl-phenyl)-6-phenyl-pyridine-2-carbaldehyde (Compound 86, 150 mg, 0.5
mmol), (3-aminopropyl)-phosphonic acid (69 mg, 0.5 mmol), Bu4NOH (0.5 ml, 0.5
mmol, 1 M in MeOH) and NaCNBH3 (31 mg, 0.5 mmol) in MeOH (5 ml) were
reacted to obtain the title compound as a white solid.
iH NMR (300 MHz, CD3OD) b ppm 1.23 (d, J=6.74 Hz, 6 H), 1.60 - 1.81 (m, 2 H),
1.90-2.13(m,2H),2.79-2.99(m,1H),3.19(t,J=6.74Hz,2H),4.36(s,2H),
7.04 - 7.21 (m, 4 H), 7.21 - 7.33 (m, 3 H), 7.33 - 7.44 (m, 2 H), 7.51 (d,
J=7.92 Hz,
1 H), 7.86 (d, J=7.92 Hz, 1 H)
Example 76

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63
4-{[5-(4-Ethyl-phenyl)-6-phenyl-pyridin-2-ylmethyl]-amino}-butyric Acid
(Compound 76). 5-(4-Ethyl-phenyl)-6-phenyl-pyridine-2-carbaldehyde
(Compound 56, 20 mg, 0.07 mmol), 5-amino-pentanoic acid (17 mg, 0.14 mmol),
NaCNBH3 (4 mg, 0.07 mmol) and HOAc (1 drop) in MeOH (2 ml) were reacted
overnight. The solvent was removed and the resulting crude solid was purified
by
MPLC column chromatography (silica gel, 0 - 100 % ethyl acetate in hexane) to
obtain the title compound as a white solid.
iH NMR (300 MHz, CD3OD) b ppm 1.21 (t, J=7.62 Hz, 3 H), 1.60 - 1.82 (m, 4 H),
2.20 (t, J=6.30 Hz, 2 H), 2.62 (q, J=7.62 Hz, 2 H), 3.02 (t, J=7.15 Hz, 2 H),
4.30 (s,
1o 2 H), 7.03 - 7.16 (m, 4 H), 7.20 - 7.30 (m, 3 H), 7.33 - 7.37 (m, 2 H),
7.49 (d,
J=7.92 Hz, 1 H), 7.86 (d, J=7.33 Hz, 1 H)
Scheme 7

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64
S~ - a ~Ph3PI~~O' /
Si-
~
88
~ \ \
\ I i H ~ \ I N O,Si-
N
00
56 89
\ I \ d
_~ I \
N O~Si - N OH
90 91
f
e A \ _~ ~ \ 0~OEt
I N OEt
I N
92 77
9 O/OH
N OH
78
(a) PPh3, THF, 70 C, 2 days; (b) n-BuLi, THF, 10, 0 C to rt; (c) Hz balloon,
MeOH, EtOAc; (d) TBAF, THF;
(e) PPh3, Iz, CHzC1z; (f) P(OEt)3, 130 C; (g) TMSBr, CHC13.
Example 88

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[4-(Tert-butyl-dimethyl-silanyloxy)-butyl]-triphenyl-k5-phosphane Iodide Salt
(Compound 88). Tert-butyl(4-iodobutoxy)dimethylsilane (2 g, 6.4 mmol) was
treated with triphenylphosphine (2.2 g, 8.3 mmol) in THF (30 ml). After
heating at
C for 2 hours, the solution was cooled to room temperature and then diluted
5 with pentane (50 ml), whereupon the product precipitated as a white solid,
which
was filtered and washed with an additiona150 ml of pentane to afford a white
solid.
iH NMR (300 MHz, CDC13) b ppm -0.03 (s, 6 H), 0.78 (s, 9 H), 1.71 - 1.85 (m, 2
H), 1.86 - 2.01 (m, 2 H), 3.68 (t, J=5.42 Hz, 2 H), 3.72 - 3.88 (m, 2 H), 7.41
- 7.90
(m, 15 H)
Example 89
6-(5-(Tert-butyldimethylsilyloxy)pent-l-enyl)-3-(4-ethylphenyl)-2-
phenylpyridine (Compound 89). To a solution of [4-(tert-butyl-dimethyl-
silanyloxy)-butyl]-triphenyl-ks-phosphane iodide salt (Compound 88, 451 mg,
0.8
mmol) in THF (2 ml) was added n-BuLi (0.3 ml, 0.8 mmol, 2.5 M in hexane) at 0
C. The solution was warmed to room temperature and allowed to stir for an
additiona145 min. A solution of 5-(4-ethyl-phenyl)-6-phenyl-pyridine-2-
carbaldehyde (Compound 56, 174 mg, 0.6 mmol) in THF (3 ml) was cannulated
into the first solution, and the reaction was stirred at room temperature
overnight.
The reaction was quenched with water, and the products were extracted with
ethyl
acetate. The organic layer was washed with brine, and dried over MgSO4, and
concentrated in vacuo. The residue was purified by column chromatography
(silica
gel, 15 % ethyl acetate in hexane) to give the title compound as a oil. 'H NMR
shows it is a mixture of cis/tran isomers. MS (ES+) M+l : 458
Example 90
6-(5-(Tert-butyldimethylsilyloxy)pentyl)-3-(4-ethylphenyl)-2-phenylpyridine
(Compound 90). A solution of 6-(5-(tert-butyldimethylsilyloxy)pent-l-enyl)-3-
(4-

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66
ethylphenyl)-2-phenylpyridine (Compound 89, 45 mg, 0.1 mmol) and Pd-C (2 mg,
10% wt) in MeOH (5 ml) was hydrogenated under Hz balloon atmosphere
overnight. The catalyst was filtered away and the filtrate was concentrated in
vacuo
and purified by MPLC column chromatography (silica gel, 15 % ethyl acetate in
hexane) to obtain the title compound as a oil.
iH NMR (300 MHz, CDC13) b ppm 0.06 (s, 6 H), 0.90 (s, 9 H), 1.23 (t, J=7.62
Hz,
3 H), 1.61 - 1.93 (m, 4 H), 2.63 (q, J=7.82 Hz, 2 H), 2.89 (d, J=7.62 Hz, 2
H), 3.53
- 3.71 (m, 2 H), 4.23 (dd, J=5.86, 3.52 Hz, 2 H), 7.02 - 7.14 (m, 4 H), 7.17
(d,
J=7.92 Hz, 1 H), 7.23 (dd, J=3.37, 1.61 Hz, 2 H), 7.32 - 7.40 (m, 1 H), 7.53
(t,
lo J=2.78 Hz, 1 H), 7.62 (d, J=7.92 Hz, 1 H), 7.72 (dd, J=5.57, 3.22 Hz, 1 H)
Example 91
5-(5-(4-Ethylphenyl)-6-phenylpyridin-2-yl)pentan-l-ol (Compound 91). To a
solution of 6-(5-(tert-butyldimethylsilyloxy)pentyl)-3-(4-ethylphenyl)-2-
phenylpyridine (Compound 90, 44 mg, 0.1 mmol) in THF (2 ml) was added TBAF
(0.2 ml, 1.0 M in THF) at room temperature. The reaction was completed after
stirring overnight at room temperature. The reaction was quenched with water
and
extracted with ethyl acetate. The organic layer was washed with brine, and
dried
over MgSO4, and concentrated in vacuo. The residue was purified by column
chromatography (silica gel, 20 % ethyl acetate in hexane) to give the title
compound as a oil.
iH NMR (300 MHz, CDC13) b ppm 1.23 (t, J=7.62 Hz, 3 H), 1.43 - 1.58 (m, 2 H),
1.59 - 1.74 (m, 2 H), 1.74 - 1.94 (m, 2 H), 2.64 (q, J=7.62 Hz, 2 H), 2.90 (d,
J=7.92
Hz, 2 H), 3.67 (t, J=6.45 Hz, 2 H), 7.01 - 7.14 (m, 4 H), 7.17 (d, J=7.92 Hz,
1 H),
7.25 (t, J=6.30 Hz, 3 H), 7.30 - 7.44 (m, 2 H), 7.63 (d, 1 H)
Example 92

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3-(4-Ethylphenyl)-6-(5-iodopentyl)-2-phenylpyridine (Compound 92). Iodine
(31 mg, 0.12 mmol) was added into a solution of triphenylphosphine (32 mg,
0.12
mmol) in CH2C12 at 0 C and allowed the mixture to stir for 5 mins. To the
resulting yellow slurry was added dropwise a solution of 5-(5-(4-ethylphenyl)-
6-
phenylpyridin-2-yl)pentan-l-ol (Compound 91, 28 mg, 0.08 mmol) and imidazol
in CH2C12. The mixture was stirred overnight and then diluted with CH2C12,
washed with NaHSO3, and water, and brine, and dried over Na2SO4. The filtrate
was concentrated in vacuo, and the residue was purified by MPLC (silica gel,
20 %
ethyl acetate in hexane) to produce the title compound as a white solid.
iH NMR (300 MHz, CDC13) b ppm 1.15 (t, J=7.48 Hz, 3 H), 1.38 - 1.59 (m, 3 H),
1.69 - 1.92 (m, 3 H), 2.56 (q, J=7.62 Hz, 2 H), 2.81 (d, J=7.62 Hz, 2 H), 3.15
(t,
J=7.04 Hz, 2 H), 6.95 - 7.05 (m, 4 H), 7.09 (d, J=7.62 Hz, 1 H), 7.12 - 7.21
(m, 3
H), 7.29 (dd, J=3.81, 2.64 Hz, 2 H), 7.55 (d, 1 H)
Example 93
Diethyl5-(5-(4-ethylphenyl)-6-phenylpyridin-2-yl)pentylphosphonate
(Compound 77). A solution of 3-(4-ethylphenyl)-6-(5-iodopentyl)-2-
phenylpyridine (Compound 92, 28 mg, 0.06 mmol) and triethyl phosphate (1.5 ml)
was heated at 130 C overnight. Triethyl phosphate was removed under vacuum to
give the crude oil. The crude material was purified by MPLC (silica gel, 20%
ethyl
acetate in hexane) to obtain the title compound as a white solid.
iH NMR (300 MHz, CD3OD) b ppm 1.20 (t, J=7.62 Hz, 3 H), 1.31 (t, J=7.04 Hz, 6
H), 1.45 - 1.90 (m, 8 H), 2.60 (q, J=7.43 Hz, 2 H), 2.86 (t, J=7.92 Hz, 2 H),
4.07
(qd, J=7.23, 7.04 Hz, 4 H), 7.06 (q, J=8.31 Hz, 4 H), 7.27 (d, J=2.05 Hz, 5
H), 7.33
(d, J=7.92 Hz, 1 H), 7.74 (d, 1 H)
Example 78

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5-(5-(4-Ethylphenyl)-6-phenylpyridin-2-yl)pentylphosphonic Acid (Compound
78). To a solution of diethyl5-(5-(4-ethylphenyl)-6-phenylpyridin-2-
yl)pentylphosphonate (Compound 77, 20 mg, 0.04 mmol) in CHC13 under argon
was added bromotrimethylsilane (0.03 ml, 0.22 mmol) at room temperature. After
the reaction was stirred for 4 hours at room temperature, excess TMSBr was
removed under high vacuum. The residue was then treated with MeOH for 10 min
at room temperature, and the solvent was removed in vacuo. Trituation of the
residue several times with diethyl ether followed by removal of the final
traces of
diethyl ether under high vacuum yielded the title compound as a white solid.
iH NMR (300 MHz, CD3OD) b ppm 1.20 (t, J=7.48 Hz, 3 H), 1.53 - 1.99 (m, 8 H),
2.63 (q, J=7.72 Hz, 2 H), 3.15 (d, J=8.21 Hz, 2 H), 7.08 - 7.24 (m, 4 H), 7.37
- 7.63
(m, 5 H), 8.01 (d, J=8.21 Hz, 1 H), 8.54 (d, 1 H)
Scheme 8
R,
R
~ \ \ ~
O + HzN ~COOH = HC1 a I i O
N ~
O H~ I/ O
R2
93Ri=H,R2=H
R= H, Me 94Ri=Me,R2=H
R / R 95Ri=H,R2=Me
\ N
b I ~ c N
i
\ I ~ N',,""/P03H2
\ N H
N
O
96R=Me 79R=Me
97R=H 80R=H
(a) i)NaOH, MeOH, 69 C, 3days, ii) c. H2SO4, MeOH, 69 C, 3 hrs.,rii)
recrystalization froml -5%
ethyl acetate/ hexane; (b) i) DiBAL-H, CH2C12, -78 C ; ii) NMO, TPAP, CH3CN,
CH2C12; (c)
NHz(CHz)3P03Hz, n-Bu4NOH, MeOH, Na(BH3)CN, 50 C.

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69
Example 93
Methy15,6-Diphenyl-pyrazine-2-carboxylate (93). General Procedure O. To a
solution of benzyl (500 mg, 2.38 mmol) and 2,3 -diaminopropionic acid
monohydro chloride (334 mg, 2.38 mmol) in MeOH (10 ml) was added NaOH (380
mg, 9.51 mmol) at room temperature. After the mixture was refluxed for 6
hours, it
was cooled down in an ice-bath, and conc. H2SO4 (1 ml) was added dropwise, and
the reaction mixture was stirred under reflux for 3 hours. MeOH was removed
under vacuum, and the residue was dissolved in water, and extracted with ethyl
acetate. The separated organic layer was washed with NaHCO3 (sat.), and water,
and brine, and dried over Na2SO4, and concentrated in vacuo. The residue was
purified by column chromatography (15% ethyl acetate in hexane) to give the
title
compound as a yellow solid.
iH NMR (300 MHz, CDC13) b ppm 4.06 (s, 3 H), 7.27 - 7.40 (m, 6 H), 7.45 - 7.54
(m, 4 H), 9.28 (s, 1 H).
Example 94 and Example 95
Methyl6-Phenyl-5-p-tolylpyrazine-2-carboxylate (Compound 94) and Methyl
5-Phenyl-6 p-tolylpyrazine-2-carboxylate (Compound 95). Followin General
Procedure 0, 1-phenyl-2 p-tolylethane-1,2-dione (287 mg, 1.3 mmol) and 2,3-
diaminopropionic acid monohydro chloride (180 mg, 1.3 mmol) NaOH (205 mg,
5.2 mmol) in MeOH (10 ml) was refluxed for 48 hours. Then it was cooled down
in
an ice-bath, and conc. H2SO4 (lml) was added dropwise and the reaction mixture
mixture was stirred under refluxed for 3 hours. Recrystalization from 3 to 5%
ethyl
acetate in hexane was used to isolate isomer the two isomers, Compound 94 and
Compound 95. The structure of Compound 95 was confirmed by x-ray
crystalography.

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Compound 94: 'H NMR (300 MHz, CDC13) b ppm 2.36 (s, 3 H), 4.06 (s, 3 H),
7.13 (d, J=7.92 Hz, 2 H), 7.30 - 7.45 (m, 5 H), 7.52 (dd, J=7.48, 2.20 Hz, 2
H),
9.27 (s, 1 H)
Compound 95: 'H NMR (300 MHz, CDC13) b ppm 2.36 (s, 3 H), 4.06 (s, 3 H),
5 7.12 (d, J=7.92 Hz, 2 H), 7.37 (dd, J=16.86, 7.77 Hz, 5 H), 7.52 (dd,
J=7.92, 1.76
Hz, 2 H), 9.26 (s, 1 H)
Example 96
6-Phenyl-5-p-tolylpyrazine-2-carbaldehyde (Compound 96). Following
10 General Procedure L, methyl 6-phenyl-5p-tolylpyrazine-2-carboxylate
(Compound 94, 60 mg, 0.2mmol) and DiBAL-H (0.4 ml, 0.4 mmol, 1 M in
cyclohexane) in CH2C12 (2 ml) were reacted to produce the title compound as a
oil.
iH NMR (300 MHz, CDC13) b ppm 2.37 (s, 3 H), 7.14 (d, J=7.92 Hz, 2 H), 7.33 -
7.47 (m, 5 H), 7.54 (dd, J=7.77, 1.91 Hz, 2 H), 9.15 (s, 1 H), 10.26 (s, 1 H)
Example 79
3-((6-Phenyl-5-p-tolylpyrazin-2-yl)methylamino)propylphosphonic Acid
(Compound 79). Following General Procedure M, 6-phenyl-5-p-tolylpyrazine-2-
carbaldehyde (Compound 96, 37 mg, 0.14 mmol), (3-aminopropyl)-phosphonic
acid (19 mg, 0.14 mmol), Bu4NOH (0.14 ml, 0.14 mmol, 1 M in MeOH) and
NaCNBH3 (8 mg, 0.14 mmol) in MeOH (2 ml) were reacted to obtain the title
compound as a white solid.
iH NMR (300 MHz, CD3OD) b ppm 1.74 (dd, J=17.15, 7.18 Hz, 2 H), 2.05 (dd,
J=11.73,6.45Hz,2H),2.34(s,3H),3.21-3.35(m,2H),4.49(s,2H),7.14(d,
J=7.92 Hz, 4 H), 7.25 - 7.40 (m, 3 H), 7.50 (dd, J=7.92, 1.76 Hz, 2 H), 8.70
(s, 1 H)
Example 97

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5,6-Diphenylpyrazine-2-carbaldehyde (Compound 97). Following General
Procedure L, methy15,6-diphenyl-pyrazine-2-carboxylate (Compound 93, 408 mg,
1.5 mmol) and DiBAL-H (3.3 ml, 3.3 mmol, 1 M in cyclohexane) in CH2C12 (5 ml)
were reacted to produce title compound as a oil.
iH NMR (300 MHz, CDC13) b ppm 7.29 - 7.46 (m, 6 H), 7.53 (d, J=6.74 Hz, 4 H),
9.17 (s, 1 H), 10.27 (s, 1 H)
Example 80
3-((5,6-Diphenylpyrazin-2-yl)methylamino)propylphosphonic Acid
(Compound 80). Following General Procedure M, 5,6-diphenylpyrazine-2-
carbaldehyde (Compound 97, 44 mg, 0.14 mmol), (3-aminopropyl)-phosphonic
acid (28 mg, 0.14 mmol), Bu4NOH (0.14 ml, 0.14 mmol, 1 M in MeOH) and
NaCNBH3 (12 mg, 0.14 mmol) in MeOH (5 ml) were reacted to obtain the title
compound as a white solid.
iH NMR (300 MHz, CD3OD) b ppm 1.60 - 1.83 (m, 2 H), 1.98 - 2.17 (m, 2 H),
3.23 - 3.40 (m, 2 H), 4.51 (s, 2 H), 7.20 - 7.62 (m, 10 H), 8.73 (s, 1 H)
While this invention has been described with respect to various specific
examples
and embodiments, it is to be understood that the invention is not limited
thereto and
that it can be variously practiced within the scope of the following claims.
In
particular, the present invention contemplates and includes a compound
comprising
a 6-membered heteroaromatic ring including one, two or three enchained
nitrogen
atoms at the 1, or 1 and 3 or 1, 3 and 4 positions, respectively, and the
remaining
ring atoms being carbon, an aryl radical directly bonded to said 6-membered
heteroaromatic ring at both of the 5 and 6 positions and a side chain at the 2
position of said 6-membered heteroaromatic ring, wherein said side chain
terminates with an end group selected from the group consisting of a
phosphonic
acid, a lower alkyl ester thereof, a carboxylic acid, a lower alkyl ester
thereof, a

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lower alkyl ether and a lower alkylcarboxy and a compound comprising a 6-
membered heteroaromatic ring including one, two or three enchained nitrogen
atoms and the remaining ring atoms being carbon, an aryl radical directly
bonded to
said 6-membered heteroaromatic ring at both of the 5 and 6 positions and a
side
chain at the 2 position of said 6-membered heteroaromatic ring, wherein said
side
chain terminates with an end group selected from the group consisting of a
phosphonic acid, a lower alkyl ester thereof, a carboxylic acid, a lower alkyl
ester
thereof, a lower alkyl ether and a lower alkylcarboxy.

Representative Drawing