PYRIMIDINE DERIVATIVES INTERMEDIATES FOR PRODUCING AMINOPYRIMIDINES AS SORBITOL DEHYDROGENASE INHIBITORS

PRODUITS INTERMEDIAIRES DE DERIVES DE PYRIMIDINE SERVANT A SYNTHETISER DES AMINOPYRIMIDINES COMME INHIBITEURS DE LA SORBITOL-DEHYDROGENASE

English Abstract

Disclosed are pyrimidine compounds of formula Z:
(see formula I)
formula ZZ:
(see formula II)
formula III:
(see formula III)
wherein R100 is (C1-C8) alkyl, benzyl or phenyl, said benzyl or
phenyl being unsubstituted or substituted, as well as a
process for preparing the compound of formula Z. Those
compounds are useful as intermediates for producing
aminepyridine compounds of the formula:



(see formula IV)
in which R1 is formyl, acetyl, etc.; R2 is H, alkyl or
alkoxy; and R3 is a substituted amino group such as
(see formula V)
in which R9 is pyrimidyl or triazinyl, useful as sorbitol
dehydrogenase inhibitors.

Claims

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CLAIMS:

1. A compound of the formula Z:
Image

2. A compound of the formula ZZ:
Image
wherein R100 is (C1-C8) alkyl, benzyl or phenyl, wherein the
benzyl and phenyl are unsubstituted or substituted with up
to three substituents each independently selected from the
group consisting of halo and (C1-C4) alkyl .

3. A compound of the formula III:



-261-

Image
wherein:
R100 is (C1-C8) alkyl, benzyl or phenyl, wherein the
benzyl and phenyl are unsubstituted or substituted with up
to three substituents each independently selected from the
group consisting of halo and (C1-C4) alkyl; and
R101 is hydrogen, benzyl CO2R90, where R90 is
selected from (C1-C4) alkyl, (C1-C4) allyl, trichloroethyl and
benzyl substituted with up to two (C1-C4)alkoxy.

4 . The compound of claim 3 wherein R100 is (C1-C4) alkyl
and R101 is benzyl or tert-butyloxycarbonyl.

S. The compound of claim 3 or 4 wherein R100 is
n-butyl or ethyl and R101 is benzyl.

6. The compound of claim 3 or 4 wherein R100 is
n-butyl or ethyl and R101 is tert-butyloxycarbonyl.

7. A process for preparing a compound of the
formula Z:


-262-

Image
comprising:
a) reacting R-(+)-2-hydroxy-propionamide with
triethyloxonium tetrafluoroborate in a reaction inert
solvent for 10 minutes to 24 hours at 0°C to ambient
temperature to form a corresponding imidate;
b) reacting the corresponding imidate with
anhydrous ammonia in a reaction inert solvent for 2 hours to
24 hours at 0°C to ambient temperature to form
R-(+)-2-hydroxy-propionamidine hydrochloride; and
c) reacting the R-(+)-2-hydroxy-propionamidine
hydrochloride with ethyl 3-hydroxy-acrylate sodium salt and
a suitable base in a reaction inert solvent to form the
compound of formula Z.

Description

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PYRIMIDINE DERIVATIVES INTERMEDIATES FOR PRODUCING
AMINOPYRIMIDINES AS SORBITOL DEHYDROGENASE INHIBITORS ,
This is a divisional application of Canadian
Patent Application No. 2,366,858 filed September 27, 2001.
The parent application describes novel
aminopyrimidine derivatives and to the use of such
derivatives and related compounds to inhibit sorbitol
dehydrogenase (SDH), lower fructose levels, or treat or
prevent diabetic complications such as diabetic neuropathy,
diabetic retinopathy, diabetic nephropathy, diabetic
cardiomyopathy, diabetic microangiopathy and diabetic
macroangiopathy in mammals. The parent also describes
pharmaceutical compositions containing such pyrimidine
derivatives and related compounds. The parent also
describes pharmaceutical compositions comprising a
combination of a sorbitol dehydrogenase inhibitor of
formula I and an aldose reductase inhibitor and to the use
of such compositions to treat or prevent diabetic
complications in mammals. The parent also describes
pharmaceutical compositions comprising a combination of a
sorbitol dehydrogenase inhibitor of formula I and an NHE=1
inhibitor and to the use of such compositions to reduce
tissue damage resulting from ischemia, and particularly to
prevent perioperative myocardial ischemic injury. The
present divisional application is directed to specific novel
pyrimidine derivatives of the formulae Z, ZZ and III
described hereinunder and their production processes.
Throughout the specification, it should be
understood that the expression "present invention" or the
like encompasses the subject matters of both the parent and
divisional applications.


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~ -la-
S. Ao et al., Metabolism, 40, 77-87 (1991) have
shown that significant functional improvement in the nerves
of diabetic rats (based on nerve conduction velocity) occurs
when nerve fructose levels are pharmacologically lowered,
and that such improvement correlates fore closely with the
lowering of nerve fructose than the lowering of nerve
sorbitol. Similar results were reported by N. E. Cameron
and M. A. Cotter, Diabetic Medicine, 8, Suppl. 1, 35A-36A
(1991). In both of these cases, lowering of nerve fructose
was achieved using relatively high dose of aldose reductase
inhibitors, which inhibit the formation of sorbitol, a
precursor of fructose, from glucose via the enzyme aldose
reductase.
U.S. Patent Nos. 5,138,058 and 5,215,990 each
disclose compounds of the formula:
2 3
R ~N/R
R5
N
Ri/ \N/ 4
R


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2-
where R'. R~, R', R' and RS are as disclosed therein. Said o~mpounds are
disclosed
as having utility as tools in screening for aldose reductase inhibitors due to
tt~e sorbitol
aoarmulating activity of said compounds:
Commonly assigned U.S. Patent Nos. 5,728,704 and 5,866,578
each disclose compounds of the formula A,
A
wherein R' through RS are defined as disclosed therein. Further, U.S.
5,728,704
discloses that sorbitol dehydrogenase compounds have utility in the treatment
of
diabetic complications.
Pyrimidine derivatives of the formula I, as defined below, and their
pham~aoeutically axeptable salts, lower fiuctose levels in the tissues of
mammals
affected by diabetes (e.g., nerve, kidney and retina tissue) and are useful in
the
treatment and prevention of the diabetic complications referred to above.
These
compounds, or their metabolites in vivo, are inhibitors of the enzyme sorbibot
dehydrogenase, which catalyzes the oxidation of sorbitol to fructose.
SUMMARY OF THE INVENTION
The present invention is directed to a oort~potrnd of the fornxrla I
R'
R~
~N
N R'
a prodrug thereof or a pham~aceutically acceptable salt of said compound or
said
prodrug, wherein:
R' is fomryl, acetyl, propionyl, carbamoyl or -C(OH)R'R°;
R' and Rs are each independently hydrogen, methyl, ethyl or hydroxy-(C,-
C~alkyl;
.
R' is hydrogen, (C,-C,~Ikyl or (C,-C,)alk~Oxy;

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R' is a radical of the formula
~ ~R9 , ~ n , R23
zN ~N N
( i1 ~ G' ( _). ~G' 2e
G R
N ,
R3a I . R3d ( , R3c ( .
R~°
.


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-4-
R" Raa
A-N
\ 8 N /N
Ra2 ~ Raz
Rao ~ ~ Ran
R'z~ R'=
R~ Rs~
HO R4z
N~R4o Ra, ~R"a ' R" Rsu
E
N N
Rae Ras Rak I R» I
N
Rai (
Y, ~as R4~ Yt
R~\NiYwRsa ss\
R ~N~Rs, N
R,\ iY (CH2)m (CHz)"
R3m I ~ Ran
Rss/N\ R~
Y'
Ni \ R's
a~ ,
R \N~Y~Rsa
(CHz)k
or
R3p I ~ N
' N J
R I _


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-5-
wherein said radical of formula R'~ is additionally substituted on the ring by
Re, R' and
R°;
said radical of formula R~° is additionally substituted on the ring by
R'°, R'° and R~°;
G, G' and G= are taken separately and are each hydrogen and R° is
hydrogen, (C,-
C,~Ikyl. (C,-C,)alkoxycarbonyl, (C,-C,)alkoxy-(C,-C,~Ikyl, hydroxy-(C,-C,~Ikyl
or
phenyl optionally independently substituted with up to three hydroxy, halo,
hydroxy-
(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl; (C,-C,)alkyl or (C,-C,)alkoxy,
wherein said
(C,-C,)alkyl in the definition of R° and said (C,-C,~Ikoxy in the
defirirtion of Rare
optionally and independently substituted with up to five tiuoro; R' and
R° are each
independently hydrogen or (C,-C,~lkyl; or
G and G' are taken together and are (C,-C,~Ikylene and Re, R', R° and
Gz are
hydrogen; or
G' and GZ are taken together and are (C,-C,)alkylene and R°, R',
R° and G are
hydrogen;
q~0orl;
X is a covalent bond, -(C=NR'°)-, oxycarbonyl, vinylenylcart~onyl,
oxy(C,-
C,~Ikylenylcarbonyl, (C, C,)alkylenylcarbonyl, (C,-C,~Ikenylcarbonyl, thio(C,_
C,~Ikylenyicarbonyl, vinylenylsulfonyl; sutfinyl-(C,-C,~Ikylenytcarbonyl,
sulfonyl-(C,-
C,)alkylenylcarbonyl or carbonyl(C°-C,)alkylenylcarbonyl; wherein said
oxy(C,-
C,)alkylenylcarbonyl, (C,-C,~Ikylenylcarbonyl, (C,-C,~Ikenylrarbonyl and
thio(C,-
C,)alkylenytcarbonyl in the definition of X are each optionally and
independently
substituted with up to two (C,-C,)alkyl, benryl o~ Ar, said vinylenylsutfortyl
and said
vinylenylcarbonyl in the definition of X are optionally substituted
independently on one
or two vinylenyl carbons with (C,-C,~Ikyl, benzyl or Ar; and said carbonyl(Co-
C,)alkyienylcarbonyl in the definition of X is optionally substituted
independently with up
to three (C,-C,~Ikyl, benzyl or Ar;
R'° is hydrogen or (C,-C,)alkyl;
R9 is (C,-C,kydoatkyl, Ar'-(C°-C,~Ikylenyl or (C,-C°~fkyl
optionally substituted with
up to five fluoro; provided that when q = 0 and X is a covalent bond,
oxycartrorryl or
(C,-C,)alkylenylcartionyl; then R° is not (C,-Ca~lkyl:
Ar and Ar' ere independently a fully saturated, partially saturated or fully
unsaturated
five- to eight-membered ring optionally having up to four heteroatoms selected


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..6_
independently from oxygen, sulfur and nitrogen, or a bicydic ring consisting
of two
fused independently partially saturated, fully saturated or fully unsaturated
five- to
seven-membered rings, taken independently, optionally having up to four
heteroatoms
selected independently from nitrogen, sulfur and oxygen, or a tricyGic ring
consisting
of three fused independently partially saturated, fully saturated or fully
unsaturated five
to seven membered rings, taken independently, optionally having up to four
heteroatoms selected independently from nitrogen, sulfur and oxygen, said
partially
saturated. fully saturated ring or fully unsaturated monocydic ring, bicyGic
ring or
tricydic ring optionally having one or two oxo groups substituted on carbon or
one or
two oxo groups substituted on sulfur,
Ar and Ar' are optionally independently substituted on carbon or nitrogen, .on
one ring
if the moiety is monocydic, on one or both rtngs if the moiety is bicydic, or
on one, two
or three rings if the moiety is tricydic, with up to a total of four
substituents
independently selected from R", R'2, R'~ and R"; wherein R", R'Z, R" and R"
are
each taken separately and are each independently halo, formyl, (C,-
Cs~lkoxycarbonyl, (C,-C6)alkylenyloxycarbonyl, (C,-C,)alkoxy tC,-C,)alkyl,
C(OH)R'SR'B, naphthyl, phenyl, imidazolyl, pyridyl, triazolyl, morpholinyl,
(Co-
C,)alkylsutfamoyl, N-(Co-C,)alkylrzrbamoyl, N,Nrdi-(C,-C,)alkylcarbamoyl, N-
phenylcarbamoyl, N-(C,-C,~Ikyl-N-phenylcarbamoyl, N.,N-Biphenyl carbamoyl, (C,-

C,~Ikylcarbonylamido, (C3-C,)cydoalkylcarbonytamido, phenylcartionytamido,
piperidinyl, pyrrolidinyl, piperazinyl, cyano, benzimidazolyl, amino, anilino,
pyrimidyl,
oxazolyl, isoxazoiyl, tetrazolyl, thienyl, thiazolyl, ben~othiazolyl,
pyrrolyl, pyrazoiyt;
tetrahydroquinolyl, tetrahydroisoquinolyt, benzoxazolyl, pyridazinyl,
pyridyloxy,
pyridylsulfanyi, furanyl, 8-(C,-C,~Ikyl-3,8-diaza[3.2.1]bicydoodyl, 3.5-dioxo-
1,2,4-
triazinyl, phenoxy, thiophenoxy, (C,-C,)alkylsulfanyl, (C,-C,~fkylsulfonyl,
(C3-
C~kydoalkyl, (C,-C,)alkyl optionally substituted with up to five fluoro or tC,-
C,~Ikoxy
optionally substituted with up to five fluoro; said naphthyl, phenyl, pyridyl,
piperidinyl,
benzimidazolyl, pyrimidyl, thienyl, benzothiazolyl, pyrroiyl,
tetrahydroquinolyl,
tetrahydroisoquinolyl, bentoxazolyl, pyridazinyl, pyridyioxy, pyridylsulfanyl,
furanyl,
thiophenoxy,-anilino and phenoxy in the definition of R", R'~, R" and R" are
optionally substituted with up to three substituer~ts independently sele~ed
from
hydroxy, halo, hydroxy-(C,-C,~Ikyl.'(C,-C,~Ikoxy-(C,-C,)alkyt. (C,-C,~Iky
optimally
substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted
with up to flue


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tluoro; said imidazolyl, oxazolyl, isoxazolyl, thiazolyl and pyrazotyl in the
definition of
R", R'Z, R" and R" are optionally substituted with up to two substituents
independently selected from hydroxy, halo, hydroxy-(Ca-C,)alkyl, (C,-C,)alkoxy-
(C,-
C,)alkyl, (C,-C,)alkyl optionally substituted'with up to five fluoro and (C,-
C,)alkoxy
optionally substituted with up to five fluoro; said morphofinyl in the
definition of R",
R'~, R" and R" is optionally substituted with up to two substituents
independently
selected from (C,-C,~Ikyl; said pyrrolidinyl in the definition of R", R'Z, R"
and R" is
optionally substituted with up to two substituents independently selected from
hydroxy,
hydroxy-(C,-C,)alkyl, (C,-C,~lkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally
substituted
with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to
flue fluoro; said
piperazinyl in the definition of R", R'Z, R" and R" is optionally substituted
with up to
three substituents independently selected from (C,-C,)alkoxy-(C,-C,~Ik~l,
hydroxy-
(C,-C,)alkyl, phenyl, pyridyl, (Co-C,)alkylsulfamoyl, (C,-C;)alkyl optionally
substituted
with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to
five fluoro; said
triazolyl in the definition of R", R'~, R" and R" is optionally substituted
with hydroxy,
halo, hydroxy-(C,-C,~Ikyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,~alkyl optionally
substituted with up to flue fluoro and (C,-C,)alkoxy optionally substituted
with up to five
fluoro; said tetrazolyl in the definition of R", R'z, R" and R" is opti~afly
substituted
with hydroxy-(C=-Chalky! or (C,-C,~Ikyl optionally substituted with up to five
fluoro;
and said phenyl and pyridyl which are optionally substituted on piperazine in
the
definition of R", R'2, R" and R" are optionally substituted with up to three
hydroxy,
halo, hydroxy-(C,-C,~Ikyl, (C,-C,~lkoxy-(C,-C,)alkyl, (C,-C.~Ikyl optionally
substituted with up to 5ve fluoro and (C,-C,)alkoxy optionally substituted
with up to five
fluoro; or
R" and R'= are taken together on adjacent carbon atoms and are
-CH20C(CH,)ZOCHZ- or -0-(CHZ)o-0-, and R" and R" are taken separately and are
each independently hydrogen or (C,-C,~Ikyl;
pisl,2or3;
R's and R'6 are taken separately and are each independently hydrogen, (C,-
C,)alkyl
optionally substituted with up to five fluoro; or R'S and R'6 are taken
separately and R's
is hydrogen and R'° is (C,-Cskycloalkyl, hydroxy-(C,-~C,~lkyl, Phenyl.
PY~.
pyrirnidyl, thienyl, furanyl, thiazolyl, oxazolyl. imidazolyl, benzothiazotyi
or
benzoxazolyl; or R'S and R'6 are taken together and are (C,-Ca~lkylene;


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G', G' and Gs are taken separately and are each hydrogen; r is 0; R'°
is hydrogen,
(C,-C,)atkyl. (C,-C,)alkoxycarbonyl, (C,-C,)alkoxy-(C;-C,)alkyl, hydroxy-(C,-
C,)alkyl or
phenyl optionally independently substituted with up to three hydroxy, halo,
hydroxy-
(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)atkyl or (C,-C,)atkoxy,
wherein said
6 (C,-C,)alkyl in the definition of R6 and said (C,-C,)atkoxy in the
definition of Raar~e
optionally and independently substituted with up to five tluoro; and
R'° and R~° are
each independently (C,-C,)alkyl; or
G', G' and GS are taken separately and are each hydrogen; r is 1; R'°
is hydrogen,
(C,-C,)alkyl, (C;-C,)alkoxycarbonyl, (C,-C,)alkoxy-(C,-C,)alkyl, hydroxy-(C,-
C,)alkyl or
phenyl optionally independently substituted with up to three hydroxy, halo,
hydroxy-
(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl or (C,-C.)alkoxy,
whec~;in said
(C,-C,)alkyl in the definition of R6 and said (C,-C,)alkoxy in the definition
of Rsare.
optionally and independently substituted with up to five fluoro; and
R'° and R~° are
each independently hydrogen or.(C,-C,)alkyl; or
G' and G' are taken together and are (C,-C~)afkylene; r is 0 or 1; and
R'°, R'°, Rm and
Gs are hydrogen; or
G' and GS are taken together and are (C,-C°)alkylene; r is fl or 1; and
R'°, R'°, Rm and
G' are hydrogen;
R" is SOzNR2'R~, CONR2'R~, (C,-Cs)alkoxycarbonyl, (C,-C6)alkylcarbonyl, Ar~-
carbonyl, (C,-C°)alkylsulfonyt, (C,-C6)alkylsulfinyl, Ar? sutfonyl, Are-
sufinyl and (C,-
C6)allcyl;
R2' and R~ are taken separately and are each independenti)r selected from
hydrogen,
(C,-C°)alkyl, (C,-C,)cydoalkyl and Are-(Co-C,)atkylenyl; or
R=' and R~ are taken together with the nitrogen atom to which they are
attad~ed to
form azetidinyl, pyrrolidinyl, piperidcnyl, pcperazinyl, motpholinyl,
a~epinyl,
azabicydo[3.22]nonanyl, azabicydo[22.1]heptyl, 6,7-dihydro-SH-
dibenzo[c,e]azepinyl,1,2,3,4-tetrahydro-isoquinolyl or
5,6,7,&tetrahydropyrido[4,3-
d]pyrimidyt; said azetidinyl in the definition of R~' and t~ is optionally
substituted
independently uvith one substctuent seceded from hydroxy, amino, hydroxy-(C,-
C,)alkyl, (C,-C,)alkoxy-(C,-C,)altcyl, (C,-C,)alky! optionally substituted
with up to flue
fluoro and (C,-C,)alkoxy optionally substit<rted with up to five fluoro; said
pymdidinyl,
piperidinyl; azepinyi in the definition of RZ' and R~ are optionally
substituted
independently with up to two substituents independently selected from hydroxy,


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amino, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,~Ikyl. (C,-C,)alkyl
optionally
substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted
with up to five
fluoro; said morpholinyl in the definition of RZ' and R~ is optionally
substituted with up
to two subsiituents independently selected from hydroxy-(C,-C,~Ikyl, (C,-
C,~lkoxy-
(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to flue 8uo~o and
(C,-C,)alkoxy
optionally substituted with up to five fluoro; said piperazinyl in the
definitioh of R2' and
R~ is optionally substituted independently with up to three substituents
independently
selected from phenyl, pyridyl, pyrimidyl; (C,-C,~Ikoxy~carbonyl and (C,-
C,)alkyl
optionally substituted with up to five fluoro; said 1,2,3,4-tetrahydro-
isoquinolyl and said
5,6,7,8-tetrahydropyrtdo[4,3-dJpyrimidyl in the definition of R~' and !~ are
optionally
substituted independently with up to three substituents independently selected
from
hydroxy, amino, halo, hydroxy-(C,-C,)alkyl, (C,-C,)atkoxy-(C,-C,)alkyl, (C,-
C,)alkyl.
optionally substituted with up to five fluoro and (C,~C,)alkoxy optionally
substituted
with up to five fluoro; and said 6,7-dihydro-5H-diben2ojc,e]azepinyl in
the'definition of
7 5 R~' and R~ is optionally substituted with up to four substituents
independently
selected from hydroxy, amino, halo, hydroxy-(C,-C,)alkyf, (C,-C,~lkoxy-(C,-
C,~alkyl,
(C,-C,)alkyl optionally substituted with up to five fluoro and (C,-C,~Ikoxy
optionally
substituted with up to five fluoro; said pyrimidyt, pyridyl and phenyl which
are
optionally substituted on said piperazine in the definition of Rs' and R~ is
optionally
substituted with vp to three substituents selected from hydroxy, amino,
hydroxy-(C,-
C,~Ikyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,~Ikyf optionally substituted with
up to five
fluoro and (C,-C,~Ikoxy optionally substituted with up to five fluoro;
Arz is independently defined as set forth for Ar and Ar' above;
said Ar= is optionally independently substituted as set forth for Ar and Ar'
above;
R~' is CONR~'R~ or S02R~R~, wherein R~ is hydrogen (C,-C,~tkyl or Ar,'-(Co-
C,)alkylenyl and R~ is Ar'-(Co-C,)alkylenyl; provided that when Ar' is phenyl,
naphthyl
or biphenyl, then R~' cannot be CONR~R~ where Rte' is hydrogen of Ar' and
R~° is
Ar':
R~' is hydrogen, (C,-C,~Ikyl. (C,-C,)alkoxycarbonyl. (C,-C,~Ikoxy-(C,-C,~lkyl.
hydroxy-(C,-C,~(kyl or phenyl optionally independently substituted with up to
three
hydroxy, halo, hydroxy-(C,-C,~Ikyl. (C,-C,~Ikoxy-(C,-Cajalkyl, (C,-Cs~tkyl or
~C,-
C,j~alkoxy, wherein said (C,-C,~Ikyl in fhe definition of fZ° and said
(C,-C,~Ikoxy in
the definition of R° are optionally and independenfly substituted with
up to five tluoro;


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Ar' is independently defined as set forth for Ar and Ar' above;
said Ar' is optionally independently substituted as set forth for Ar and Ar'
above;
R~' is hydrogen or (C,-C,~Ikyl;
R~ and R'° are each independently hydrogen, hydroxy, halo, hydroxy-(C,-
C,~Ikyl,
(C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up bo
fnre fluoro, (C,-
C,)alkoxy optionally substituted with up to five fluoro, phenyl, pyridyl,
pyrifiidyi, thienyl,
furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, SOZNR'°R",
CONR'°R" or NR'°R";
said thienyl, pyrimidyl, furanyl, thiazolyl and oxazolyl in the definition of
R'° and R~ are
optionally substituted by up to two hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-
C,)alkoxy-
(C,-C,)alkyl, (C,-C,)alky! optionally substrtuted with up to five fluoro or
(C,-C,)alkoxy
optionally substituted with up to five fluoro; said phenyl, pyridyl, phenoxy
and
thiophenoxy in the definition of R~ and R~ are optionally substituted by dp to
three
hydroxy, halo, hydroxy-(C,-C,~Ikyi, (C,-C,)alkoxy-(C,-C,~Ikyl, (C,-C,~Ikyl
optionally
substituted with up to five fluoro or (C,-C,~lkoxy optionally substituted with
up to five
fluoro;
R'° and R" are each independently hydrogen, (C,-C,)alkyl, (C,-
C~)cydoalkyl or
phenyl, said phenyl is optionally substituted with up to three hydroxy, halo,
hydroxy-
(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted
with up to
five fluoro or (C,-C,)atkoxy optionally substituted with up to five fluoro; or
R'° and R" are taken together with the nitrogen to which they are
attad~ed to form
indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; said
pymolidinyl and
pipe~dinyl in the definition of R'° and R" are optionally substituted
with up to two
hydroxy, amino, hydroxy-(C,-C,)alkyl, {C,-C,)alkoxy-(C,-C,~(kyl, (C,-C,)alkyl
optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally
substituted with
up to five fluoro; said indolinyl and piperazinyl in the definition of
R'° and R" are
optionally substituted with up to three hydroxy, amino, hydroxy-(C,-C,~Ikyl,
(C,-
C,~Ikoxy-(C,-C,~lkyi, (C,-C,~Ikoxycarbonyl. (C,~C.)alkyl oPtionaliY
substituted with
up to five fluoro or (C,-C,)alkoxy optionally substituted_with up to five
tluoro; said
morpholinyl in the definition of R'° and R" is optionally substituted
with up to two
substituents independently selected from hydroxy-(C,-C,~Ikyl, (C,-C,)alkoxy-
(C,-
C,~Ikyl, (C,-C,)alkyl optionally substituted with up to five fluoro and (C,-
C,~Ikoxy
optionally Substituted with up to five fiuoro;
A is N optionally substituted with hydrogen or (C,-C,)alkyl and B is carb~yl;
or


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A is cart~onyl and B is N optionally substituted with hydrogen or (C,-C,~Ikyl;
R'~ is hydrogen or (C,-C,)alkyl;
R" is phenyl, pyridyl, pyrimidyl, thiazolyl, oxazolys, benzyl, quinolyl,
isoquinolyl,
phthalizinyl, quinoxanlyl, benzothiazoyl, beivzoxazoiyl, ben~ofuranyl or
benzothienyl;
said phenyl, pyridyl, pyrimidyl, thiazotyl, oxazolyl, benzyl, quinolyl,
isoquinolyl,
phthalizinyi, quinoxanlyl, benzothiazoyl, benzoxazolyl, benzofuranyl and
benzothienyl
in the definition of R" are optionally substituted with up to three phenyl,
phenoxy,
NR"R'~, halo, hydroxy, hydroxy-(C,-C,~lkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-
C,)alkyl
optionally substituted with up to flue fluoro or (C,-C,)alkoxy optionatf)r
substituted with
up to five fluoro;
R~' and R'~ are each independently hydrogen, (C,-C, alkyl), phenyl or
phenylsulfonyl;
said phenyl and phenylsulfonyl in the definition of R" and R'~ are optionally
substituted with up to three halo, hydroxy, (C,-C,~Ikyl optionally substituted
with up to
five fluoro or (C,-C,~lkoxy optionally substituted with up to flue fluoro;
D is CO, CHOH or CH2;
EisO.NHorS;
R'~ and R" are taken separately and are each independently hydrogen, halo,
cyano,
hydroxy, amino. (C,-CB)alkylamino, di-(C,-C6)alkylamino. pyrroGdir~,
piperidino,
morpholino, (C,-C,~Ikoxy-(C,-C,)alkyl, hydroxy-(C,-C,)atkyl, Ar', (C,-C,)atkyl
optionally substituted with up to five.fluoro or (C,-C,)alkoxy optionally
subsfltuted with
up to flue fluoro;
R'°, R'~ and R'° are each independently hydrogen or (C,-C,)-
alkyl;
A~' is phenyl. furanyl, thienyl. PY~YI. PYh~dyl, PY~nyr or pyridazinyl; said
Ar' being
optionally substituted with up to three hydroxy, (C,-C,)alkoxy-(C,-C,)alkyl,
halo,
hydroxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five
fluoro or (C,-
C,~Ikoxy optionally substituted with up to five fluoro; or
R'~ and R" are taken together on adjacent carbon atoms and are -O-(CH~h-O-;
tisl,2or3;
Y is (C=-Ca)atkylene;
R", R'~ and R'~ ~ar~e each independently hydrogen or (C,-C,)alkyl;
m and n are each independently 1, 2 or 3, provided that the sum of m and n is
2, 3 or
k is 0,1. 2, 3 or 4;


CA 02484282 2000-03-16
WO OOI59510 PCT/IB00/00296
-12-
Y' is a covalent bond, carbonyl, sulfonyl or oxycarbonyl;
R" is (C3-C,)cydoalkyl, Ars-(Co-C,)alkylenyl, NR"R'° or (C,-Cs~lkyl
optionally
substituted with one to five fluoro; provided that when Y' is a covalent bond
or
oxycarbonyl, then R" is not NR"R'°;
R" and R'° are taken separately and are each independently selected
from hydrogen,
Ars, (C,-Ca)alkyl and Ar5-(Co-C,)alkylenyl; or
R" and R'° are taken together with the nitrogen atom to which they are
attached to
form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,
azepinyl,
azabicydo[32.2]nonanyl, azabicydo[2.2.1]heptyl, 1,2,3,4-tetrahydroisoquinolyl,
6,7-
dihydro-SH-dibenzo[c,e]a2epinyl or 5,6,7,8-tetrahydropyrido[4,3~jpyrimidyl;
said
azetidinyl in the definition of R" and R'° are optionally substituted
with one hydroxy,
amino, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyi
optionally
substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted
with up to five
fluoro; said pyrrolidinyl, piperidinyl and azepinyl in the definition of R"
and R'° are
7 5 optionally substituted with up to two hydroxy, amino, hydroxy-{C,-C,~Ikyl,
(C,-
C,)alkoxy-(C,-C,)alkyl, (C,-C,~Ikyl optionally substituted with up to five
fluoro or (C,-
C,)alkoxy optionally substituted with up to five fluoro; said rnorphofinyl in
the definition
of R" and R'° is optionally substituted with up to tviro substituents
independently
selected from hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl; (C,-C,)alkyl
optionally
substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted
with up to five
fluoro; said piperazinyl, 1,2,3,4-tetrahydroisoquinolyl and
5,6,7,&tetrahydro[4,3-
d]pyrimidyl in the definition of R" and R'° are optionally substituted
with up to thn:e
hydroxy, amino, halo, hydroxy-(C,-C,)alkyf, (C,-C,)alkoxy-(C,-C,~Ikyl, (C,-
C,~Ikyl
optionally substituted'with up to frve fluoro or (C,-C,)alkoxy optionally
substituted with
up to five fluoro; and said 6,7-dihydro-5H-dibenzo[c,e~azepinyl in the
definition of R"
and R'° are optionally substituted with up to four hydroxy, amino,
halo, hydro~cy-(C,-
C,)alkyL (C,-C,~Ikoxy-(C,-C,~Ikyl, (C,-C,~Ikyl optiona8y substituted with up
to five
fluoro or (C,-C,~Ikoxy optionally substituted with up to five fluoro;
Ars is independently defined as set forth for Ar and Ar' above;
Ar5 is optionally-independently substituted as set forth for Ar and Ar' above;
R'2 and R'b are independently hydrogen, (C,-Crkydoalkyl, Ara-(Co-C~~tkylenyl,
Ar6-
(C=-C,)alkenyl, Ar°-carbonyl or (C,-Cb~alkyl optionally substituted
with up to flue fluoro;
Ar' is independently defined as set forth for Ar and Ar' above;


CA 02484282 2000-03-16
WO 00159510 PCTIIBOOI00296
-13-
Ar° is optionally independently substituted as set forth for Ar and Ar'
above; and
R" and R"' are each independently hydrogen or (C,-C4)alkyl.
A preferred group of compounds of formula I, designated Group A, are those
compounds of formula 1, prodnrgs thereof a'nd pham~aceutically
acceptable salts of said compounds or said prodrugs, wherein:
R' is
R"
N
)r~as G~.
~,3
. N
substituted by R'°, R'9 or R~°;
G', G' and GS are taken.separately and are each hydrogen, r is 0 and
R'° is hydrogen,
(C,-C,)alkyl, (C,-C,~Ikoxycarbonyl or phenyl optionally substituted by up to
thn:e
hydroxy, halo, hydroxy-(C,-C,~lkyl, {C,-C,)alkoxy-(C,-C.)alkyl, (C,-C,~tkyl
optionally
. substituted with up to five fluoro or (G,-C,~Ikoxy optionally substituted
with up to five
fluoro; R'9 and R~° are each independently (C,-C,)alkyl;
G', G' and G5 are taken separately and are each hydrogen; r is 1; and
R'° is
hydrogen, (C,rC,)alkyl, (C,-C,)alkoxycarbonyl or phenyl optionally substituted
by up to
three hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,~Ikyl, (C,-
C,)atkyl
optionally substituted with up to five fluoro or {C,-C,)atkoxy optionally
substituted with
up to five fluoro; R'° and R~° are each independently hydrogen
or (C,-C,)alkyt; or
G' and G' are taken together and are (C,-C,)alkylene; r is 0 or 1; and
R'°, R'°, R~° and
G° are hydrogen; or
G' and GS are taken together and are (C,-C,)alkylene; r is 0 or 1; and
R'°, R'9, R~° and
G' are hydrogen;
R" is SOzNR~'R~, CONRz'R~, (C,-Cs)alko~cycarbonyl, (C,-Cs~lkylcarbonyl, Ar?
carbonyl, (C,-C6~Ikytsulfonyl, (C,-Ce)alkylsulfinyl, Arz-sulfonyl, Are-sufinyl
and (C,-
C,~~Ikyi;
RZ' and R~ are taken separately and are each independently selected from
hydrogen,
(C,-Ce~lkyl. (C~-C~kydoalkyl and Arz-(Cro~,~alkylenyl; or


CA 02484282 2000-03-16
wo oo~s9sio rcrnsooioo~96
-14-
RZ' and R~ are taken together with the nitrogen atom to which they are
attached to
form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morphoiinyi,
azepinyl,
azabicyclo[3.2.2]nonanyl, azabicyclo[2.2.1]heptyl, 6,7-dihydro-5H-
dibenzo[c,e]azepinyl, 1,2,3,4-tetrahydro-i5oquinolyl or 6,6,7.8-
tetrahydropyrido[4,3-
d]pyrimidyl; said azetidinyl in the definition of R2' and R~ is optionally
substituted
independently with one substituent selected from hydroxy, amino, hydronyr-(C;-
C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with
up to five
fluoro and (C,=C,)alkoxy optronally substituted with up to five fluoro; said
pyrrolidinyl,
piperidinyl, morpholinyl, azepinyl in the definition of RZ' and R~ are
optionally
substituted independently with up to two substituents independently selected
from
hydroxy, amino, hydroxy-(C; C,)alkyl, (C,-C,~ikoxy-(C,-C,)alkyl, (C,-C,~tkyl
optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally
sWbstituted
with up to five fluoro; said morpholinyl in the definition of Rz' and R~ is
optionally
substituted with up to two substituents independently selected from hydroxy-
(C,-
C,~Ikyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,~lkyl optionally substituted with
up to five
fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said
piperazinyl in
the definition of RZ' and R~ is optionally substituted independently with up
to three
substituents independently selected from phenyl, pyridyl, pyrtimidyl, (C,-
C,)alkoxycarbonyl and (C,-C,)alkyl optionally substituted with up to five
fluoro; said
1,2.3,4-tetrahydro-isoquinolyl and said 5,6,7,&tetrahydropyrido[4,3-
d]pyrimidyl in the
definition of RZ' and R~ are optionally substituted independently with up to.
there
substituents independently selected from hydroxy, amino, halo, hydroxy-(C,-
C,)alkyl,
(C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to
fire fluoro and
(C,-C,~Ikoxy optionally substituted with up to five fluoro: said pyimidyl.
PY~yr ~
phenyl which are optionally substituted on said piperazine in the definition
of R~' and
R'~ is optionally substituted with up to three substituents selected from
hydroxy,
amino, hydroxy-(C,-C.)alkyl. (C,-C,~Ikoxy-(C,-C.~Ikyl. (C,-C,~tkyl optionally
substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted
with up to flue
fluoro; and said 6,7-dihydro-SH-dibenzo[c,e]azepinyl in the definition of Rr
and R~ is
optionally substituted with up to four substituents independenthr selected
from
hydroxy, amino, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-
C,j~alkyl
optionally substituted with up to five fluoro and (~,-C,)alkoxy opflonaiiy
subst~uted
with up to five fluoro.


CA 02484282 2000-03-16
pCT/IB00/00396
WO 00/59510
-15-
Another preferred group of compounds of formula t, designated Group B, are
those compounds of formula I, prodrugs thereof and ph2rmaceutically
acceptable salts of said compounds or said prodrugs, wherein:
R' is
Rz'
I ,
N '
Rza
N
~ ;
R~' is CONR~R~, SOZRnR~, wherein R~ is hydrogen (C,-C,)alkyl or Ar'-(Co-
C,)alkylenyl and R~ is Ar'-(Co-C,)alkylenyl; provided that when Ar' is phenyl,
naphthyl~
or biphenyl, then Rte' cannot be CONRz''R~ where Rn is hydrogen or Ar' and R~
is
RZ' is hydrogen, (C,-C,)alkyl; (C,-C,)alkoxycarbonyl or phenyl optionally
substituted by
up to three (C,-C,)alkyl optionally substituted with up to five fluoro, (C,-
C,)alkoxy
optionally substituted with up to five fluoro, hydroxy, halo or hydroxy-(C,-
C3)alkyl.
Another preferred group of compounds of formula !, designated Group C, are
those compounds of formula I, prodnrgs thereof arid pharmaceutically
acceptable salts of said compounds or said prodrugs, wherein:
R' is
~~ Rze
or
R~' is hydrogen or (C,-C,)alkyt;
R~ and R~° are each independently hydrogen, hydroxy, halo, hydroxy-(C,-
C4~tkyl,
(C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to
five fluoro, (C,-
C,~Ikoxy optionally substituted with up to five fluoro, phenyl, pyridyl,
pyrimidyl, thienyl,
furanyl, thiazolyl, oxazofyl, phenoxy, thiophenoxy, S02NR'°R",
CONR'°R" or NR'°R";


CA 02484282 2000-03-16
WO 00/59510 PGTIIB00/00296
-16-
said thienyl, pyrimidyl, furanyl, thiazolyl and oxazolyl in the definition of
R'° and R'° are
optionally substituted by up to two hydroxy, halo, hydrotcy-(C,-C,)alkyl, (C,-
C,)alkoxy-
(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro or
(C,-C,)alkoxy
optionally substituted with up to flue fluoro:,said phenyl, pyridyl, phenoxy
and
thiophenoxy in the definition of R'° and R~ are optionally substituted
by up to three
hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl
optionally
substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted
with up to five
fluoro;
R'° and R" are each independently hydrogen, (C,-C,)alkyl, (C,-
C,kycloalky4 or
phenyl, said phenyl is optionally substituted with up to three hydroxy, halo,
hydroxy-
(C,-C,)alkyl, (C,-C.~tkoxy-(C,-C,jalkyl, (C,-C.~IkYI optionally substituted
with up to
five fluoro or (C,-C,)alkoxy optionally substituted with up to flue fluoro; or
R'° and R" are taken together with the nitrogen to which they are
attached to form
indolinyl, pyrrolidinyt, piperidinyt, piperaLnyl or motpholinyl; said
pyrrolidinyl and
piperidinyl in the definition'of R'° and R" are optionally substituted
with up to two
hjrdroxy, amino, hydroxy-(C,-C,)alkyl, (C,-C,)atkoxy-(C,-C,)alkyl, (C,-C,~Ikyl
optionally substituted with up to flue fluoro or (C,-C,~Ikoxy optionally
substituted with
up to five fluoro; said indolinyl and piperazinyl in the definition of
R'° and R" are
optionally substituted with up to three hydroxy, amino, or hydroxy-(C,-
C,)alkyl, (C,-
C,)alkoxy-(C,-C,~lkyl, (C,-C,~Ikoxycar6onyt, (C,-C,~Ikyl optionally
substituted with
up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five
fluoro; said
morpholinyl in the definition of R'° and R" is optionally substituted
with up to two
substituents independently selected from hydroxy-(C,-C,)alkyt, (C,-C,)alkoxy-
(C,-
C,~Ikyl, (C,-C,)alkyi optionally substituted with up to five fluoro and (C,-
C,)alkoxy
optionally substituted with up to flue fluoro.
Yet another preferred group of compounds of fomwla I, designated Group D,
are those compounds of formula 1, prodrugs then:of and pham~aoeuticapy
acceptable salts of said compounds or said prodrugs, wherein:
R' is


CA 02484282 2000-03-16
WO 00159510
-17-
Ru ,R~ ,
A_. ~ ~N
B N ~N
R3z ~ or , . Rs~.
N N
pGT/iB00/00296
A is N optionally substituted with hydrogen or (C,-C,)alkyt and B is carbonyl;
or
A is carbonyl and 8 is N optionally substituted with hydrogen or (C,-C,)aikyl;
R'~ is hydrogen or (C,-C,)alkyl;
R" is phenyl, pyridyl, pyrimidyl, thiazolyl, oxazQlyl, benzyl, quinolyl,
isoquinolyl,
phthalizinyl, quinoxaniyl, benzothiazoyl, benzoxazolyl, benzofuranyl or
benzothisnyl;
said phenyl, pyiidyl, pyrimidyl, thiazolyl, oxazotyl, benzyt, quinolyl,
isoquinolyl,
phthaiizinyl, quinoxanlyl, benzothiazoyl, benzoxazolyl, benzofuranyl and
benzothienyl
in the definition of R" are optionally substituted with up to three phenyl,
phenoxy,
NR~"R", halo, hydroxy, hydroxy-(C,-C,~Ikyl, (C,-C,)alkoxy-(C,-C,~lkyl, (C,-
C,)alkyl
optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally
substituted with
up to five fluoro;
R" and R" are each independently hydrogen, (C,-C, alkyl), phenyl or
phenylsulfonyt;
said phenyl and phenylsulfonyl in the definition of R" and R" are optionally
substituted with up to three halo, hydroxy, (C,-C,)alkyt optionally
substituted with up to
five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro.
Still another preferred group of compounds of formula l, designated Group ~,
are those compounds of formula I, prodrugs thet'eof and pharmaceutically
acceptable salts of said compounds or said prodrugs, wherein:
R' is

CA 02484282 2000-03-16
WO 00159510
pC'r/iB00~0296
-1 &
or
D is CO, CHOH or CHz; ' ,
E is O, NH or S;
R'~ and R" are taken separately and are each independently hydrogen, halo,
cyano,
hydroxy, amino, (C,-C6)alkylamino, di-(C,-Ca)alkytamino, pyrrolidino;
pipe~idino,
morpholino, (C,-C,)alkoxy-(C,-C,~Ikyt, hydroxy-(C,-C,~Ikyl, At', (C,-C,~Ikyl
optionally substituted with up to fnre fluoro or (C,-C,)alkoxy optionally
substituted with
up to five fluoro;
R'°, R'~ and R'° are each independently hydrogen or (C,-
C,ratkyt;
Ar' is phenyl, furanyl, thienyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl;
said Ar being
optionally substituted with up to three hydroxy, (C,-C4)alkoxy-(C,-G4)alkyl,
halo,
hydroxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to fnre
fluoro or (C,-
C,)alkoxy optiona8y substituted with up to five fluoro; or
R'~ and R" are taken together on adjacent carbon atoms and are -O-(CH2~-O-;
tis1,2or3.
Stil! another preferred group of compounds of formuta t, designated Group F,
are those compounds of formula 1, prodrugs thereof and phamiaceuticatly
acceptable salts of said compounds or said prodrugs, wherein:
R' is
..as ,


CA 02484282 2000-03-16
WO 00159510
-i 9-
PCTIIB00/00296
Y2 ~ts , R'~ Y,
R'\N~YwRas R's N a N
R
R~ \ iY {CH CHZ)
I ' ~
R's/N\
N~Y~R's
R \N~Y,~R's
{CH=)k ',
or
J
I
Y is (C2-Ca~lkylene;
R", R'~ and R'~ are each independently hydrogen or (C,-C,)alkyl;
m and n are each independently 1, 2 or 3, provided that the sum of m and n is
2. 3 or
4;
kisOto4;
Y' is a covalent bond, carbonyl, sulfonyl or oxycarbonyl;
R" is (C3-C,)cydoalkyl, Ar5-(Co-C,)alkylenyl. NR"R'° or (C,-Ca)alkyl
optionally
substituted with one to five fiuoro; provided that when Y' is a covalent bond
or
oxycarbonyl, then R" is not NR"R'°;
R" and R'° are taken separately and are each independently selected
from hydrogen,
Ars. (C,-C,)alkyl and Ar5-(Co-C,)alkylenyl; or
R" and R'° are taken together with the nitrogen atom to which they are
attadied to
form azetidinyl, pyfrolidinyl, pipetidinyl, piperazinyl, morpholinyl,
a~epinyl,
azabicydo[3.2.2]nonanyl, azabicydo[22.1]heptyl,1,2,3,4-tetrahydroisoquindyl,
6,7-
dihydro-5H-dibenzo[c,e]azepinyl or 5,fi;7,8-tetrahydropyrido[4,3-d]pyrimidyt;
said
azetidinyl in the definition of R" and R'° are optionally substituted
with one hydroxy,


CA 02484282 2000-03-16
WO 00/59510 PCT/IB00/00296
-20-
amino, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C; C,)alkyl, (C,-C,)alkyl
optionally
substituted with up to five fluoro or (C,-C,)a(koxy optionally sut;stituted
with up to five
fluoro; said pyrrolidinyl, piperidinyl and azepinyl in the definition of R"
and R'° are
optionally substituted with up to two hydroxy, amino, hydroxy-(C,-C,)alkyl,
(C,-
C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five
fluoro o~ (C,-
C,)alkoxy optionally substituted with up to five fluoro; said morpholinyl in
the definition
of R" and R'° is optionally substituted with up to two substituents
independently
selected from hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C')alkyl
optionally
substituted with up to five fluoro and (C,-C,~Ikoxy optionally substituted
with,up to flue
fluoro; said piperaziny(,1,2,3,4-tetrahydroisoquinolyl and 5,6,7,8-
tetrahydro[4,3-
d]pyrimidyi in the definition of R" and R'° are optionally substituted
with up to three
hydroxy, amino, halo, hydroxy-(C,-C,~Ikyt, (C,-C,)alkoxy-(C,-C,)atkyl,
(C,~,)alkyl
optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally
substituted with
up to five fluoro; and said 6,7-dihydro-5H-dibenzo[c,e]azepinyl in the
definition of R"
and R'° are optionally substituted with up to four hydroxy, amino,
halo, hydroxy-(C,-
C,~Ikyl, (C,-C,)alkoxy-(C;-C,~Ikyl, (C,-Ca)alkyi optionally substituted with
up to five
fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro.
A preferred group of compounds within Group F, designated Group FA, are
those compounds, prodnrgs thereof and pharmaceutically acceptable salts of
said
compounds or said prodnrgs wherein:
R' is (R~1-hydroxy-ethyl;
RZ is hydrogen;
R' is
N~YsRas
(CH2)k
N~
k is 0;
Y' is a covalent bond; and


CA 02484282 2000-03-16
WO 00159510
-21-
R" is 4-pyrimidinyl substituted at the 2-position with 1-hydroxymethyl.
PCT/IB00/00296
A preferred group of compounds within Group .FA, designated Group FB, are
those compounds, prodrugs thereof and pharmaceutically acceptable salts of
said
compounds or said prodrugs, which is 1 R-(4-{1'-[2-(, R-hydroxy-
ethylrpyrimidin-4-ylj-
[4.4~bipiperidinyl-,-yl}-pyrimidin-2-yl)-ethanol.
Another preferred group of compounds of formula I, designated Group G, are
those compounds of formula I, prodrugs thereof and phamiaceuticatty
acceptable salts of said compounds or said prodrugs, wherein:
R' is
HO R,T
R" Ra,. ~ Ra, R4"
N . or I
,o
R"and R"' are independently hydrogen, (C,-C,kydoallcyl, Ar'-(CQ-C,)alkylenyl,
Ars-
(C2-C,)alkenyl, Are-carbonyl or (C,-C6)alkyl optionally substituted with up to
five fluoro;
and
R" and R"' are independently hydrogen or (C,-C,)alkyt.
Still another preferred group of compounds of formula I, designated Group H,
are those compounds of formula I, prodnrgs thereof and pharmaceutically
acceptable
salts of said compounds or said prodrugs, wherein:
R' is C(OH)R'R5, where R' and Rs are each independently hydrogen or methyl;
RZ is hydrogen;
R' is
N
T
( ~)~ G,
V
N
wherein said R' is substituted by R°, R' or R°;


CA 02484282 2000-03-16
WO 00/59510 PGTIIB00/00~96
G, G' and GZ are taken separately and are each hydrogen and R° is
hydrogen or (C,- ,
C,)alkyl; R' and R° are each independently hydrogen or (C,-
C,)atkyl; or
G and G' are taken together and are (C,-C,)alkylene and R°, R',
R° and G2 are
hydrogen; or
G' and GZ are taken together and are (C,-C,)alkylene and R°, R',
R° and G are
hydrogen;
qis0orl;
X is a covalent bond, oxycarbonyl,vinytenylcarbonyt, oxy(C,-
C,)alkylenylcarbonyl,
thio(C,-C,~Ikylenylcarbonyl or vinylenylsulfonyt; said vinylenylcarbonyl and
said
vinylenylsulfonyl in the definition of X are optionally substituted on one or
two vinylenyf
carbons with (C,-C,)alkyl, benzyl or Ar, said oxy(C,-C,)alkylenyicarbonyl and
said
thio(C,-C,)alkyfenylcarbonyl in the definition of X are optionally substituted
with up to
two (C,-C,)alkyl, benzyl or Ar;
R' is (C3-C~)cyctoalkyl, Ar'-(Co-C,)alkylenyl or (C,-C°)alkyl
optionally substituted with
up to five fiuoro;
Ar' is phenyl, naphthyl; pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,
triazinyl, quinofyl,
isoquinolyl, quinazolyl, quinoxalyl, phthatazinyl, annotinyl, naphthyridinyl,
pteridinyl,
pyrazinopyrazinyl, pyrazinopyridazinyl, pyrimidopyridazinyt,
pyrimidopyrimidyl,
pyridopyrimidyl, pyridopyrazinyt, pyridopyridazinyl, pyn-olyl, furanyl,
thienyl, imidazolyl,
oxazolyl, thiazolyl, PY~oIYf, isoxazolyl, isothiazolyt, triazolyl,
oxadiazolyl, thiadiazolyl,
tetrazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl,
benzothiazolyl, indazolyl, benzisoxazolyl, benzisothiazofyi, pyrrolopyridyl,
furopyridyl,
thienopyridyl, imidazolopyridyl, oxazotopyridy(, thiazofopyridyl,
pyrazolopyridyl,
isoxazotopyridyl, isothiazolopyridyl, pyrrolopyrimidyl, furopyrimidyl,
thienopyrimidyl,
imidazolopyrimidyl, oxazotopyrimidyl, thiazolopyrimidyl, pyrazolopyrimidyl,
isoxazolopyrimidyl, isothiazolopyrimidyl, pyrrolopyrazinyl, furopyrazinyl,
thienopyrazinyl, imidazolopyrazinyl, oxazolopyrazinyl, thiazolopyrazinyl,
pyrazolopyrazinyl, isoxazolopyrazinyl, isothiazolopyrazinyl, pyn-
otopyridazinyl,
furopyridazinyl, thienopyridazinyl, imidazolopyridazinyl, oxazoiopyridazinyl,
3b thiazolopyridazinyl, pyrazolopyridazinyl, isoxazolopyridazinyl or
isothiazolopyridazinyl;
and
said Ar' is optionally substituted as set forth above.


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A preferred group of compounds within Group H, designated Group HA, are ~ ,
those compounds, prodrugs thereof and pharmaceutically
acceptable salts of said compounds or said prodrugs, wherein:
X is a covalent bond, oxycarbonyl or vinylehylcarbonyl optionally substituted
on one or
two vinyienyl carbons with (C,-C,~Ikyl, benzyl or Ar,
R° is Ar'-(Co-C,)alkylenyl; .
Ar' is phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, triazinyl, quinolyl,
isoquinoiyl,
quinazolyl, quinoxalyl, furanyl, thienyl, indolyl, benzofuranyl; benzothienyl;
benzoxazolyl, benzothiazolyl, furopyridyl, oxazotopyridyl, thiazoiopyridyl,
thienopyridyl,
1 fl furopyrimidyl, thienopyrimidyl, oxazolopyrimidyl or thiazolopyrimidyl;
and
said Ar' is optionally substituted as set forth in daim 1.
A preferred group of compounds within,Group HA, designated Group H8, are
those compounds, prodrugs thereof and phamnaceuticaliy
acceptable salts of said compounds or said prodnrgs, wherein:
R2 is hydrogen;
R~ is hydrogen or methyl;
RS is methyl;
G, G' and GZ are hydrogen;
R° and R' are each independently hydrogen or methyl;
R° is hydrogen.
A preferred group of compounds within Group H8, designated Group HC, are
those compounds, prodrugs thereof and pharmaceutically acceptable salts of
said
compounds or said prodrugs wherein:
R' is (R)-1-hydroxy-ethyl; and
R' is
O R°
N
Me ~ Me


CA 02484282 2000-03-16
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A preferred compound within Group HC is the compound wherein R° is
2-
faro[3.2-c]pyridyl, a prodrug thereof or a pham~aceut~ally acceptable salt of
said
compound or said prodrug.
Another preferred compound within Group HC as the compound wherein R9 is
2-(4-chloro-faro[3,2-cjpyridyl), a prodrug thereof or a pham~aceutically
acceptable salt
of said compound or said prodrug.
Another preferred compound within Group HC is the compound wherein Rs is
2-(4-pyrrolidin-1-yl-faro[3,2-cjpyridyl), a prodrug thereof or a
pharmaceutically
acceptable salt.of said compound or said prodnrg.
Another preferred compound within Group HC is the compound wherein
R° is
2-(4-morpholin-4-yl-furo[3,2-cJpyridyt), a prodrug thereof or a
pham~aceutically
acceptable salt of said compound or said prodrug.
Another preferred compound within Group HC is the compound wherein R' is
2-imidazo[1,2-a]pyridyl, a prodrug thereof or a pham~aceutiraliy acceptable
salt of
said compound or said prodrug.
Preferred compounds within Group HC are faro[3,2-c]pyridin-2-yl-{4-i2-(1R-
hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-methanone; (4-
chloro-
faro[3.2-clPYridin-2-yl]"{4-[2-(1 R-hydroxy-ethyl~pyrimidin-4-ylj-3R,5S-
dimethyh
piperazin-1-yI}-methanone; {4-[2-(1R-hydroxy-ethyl~pyrimidin-4-yf]-3R,5S-
dimethyl-
piperazin-1-yt}-(4-pyrrolidin-1-yf-faro[3,2-cJpyridin-2-y1j~methanone; ~4-[2-
(1R-hydroxy-
ethyl)-pyrimidin~-ytj-3R,5S-dimethyl-piperazin-1-yl}-(4-morpholin-4-yl-
furo(3,2-
cJpyridin-2-yl)-methanone; and {4-i2-(1R-hydroxy-ethylj~pyrimidin-4-y()-3R,5S-
dimethyl-piperazin-1-YI}-imidazo[1.2-a]PYcidin-2-yl-methanone.
Another preferred group of compounds within Group HB, designated Group
HD, are those compounds, prodnrgs thereof and pham~ac~eutically acceptable
salts of
said compounds or said prodrugs wherein:
R' is (Rr1-hydroxy-ethyl; and
Ra ~


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rc~rnsoo~ooZ96
O Re '
Me N Me
~N
A preferred compound within Group HO is the compound wherein R9 is 2-
furo[3,2-c]pyridyl, a prodrug thereof or a pharmaceutically acceptable salt of
said
compound or said prodrug.
An espeaally prefen-ed compound within Group HD is furo[3,2-cjpyridin-2-yl-
{4-[2-(1R-hydroxy-ethyl~pyrimidin-4 y~-2R,6S-dimethyl-piperazin-1-yl}-
methanone.
Another preferred group of compounds within Group H8, designated Group
HE, are those compounds, prodrugs thereof and pharmaceutically acceptable
salts of
said compounds or said prodrugs wherein:
R' is (R}-1-hydroxy-ethyl; and
R~ is
A preferred compound within Group HE is the compound wherein R9 is 3-
pyridyl, a prodrug thereof or a phan'naceutically acceptable salt of said
compound or
said prodnrg.
Another preferred compound within Group HE is the compound wherein Rs is
3-(2-methytpyridyl~; a prodnrg thereof or a pham~aceuticatly acceptable salt
of said
compound or said prodcug.
Another preferred t;ompound within Group HE is the compound wherein
R° is
3-(5-chloropyridyl), a prodrug thereof or a phamnaceutically acceptable salt
of said
compound or said~prodrug.


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Another preferred compound within Group HE is the compound wherein R9 is
3-(6-methylpyridyl), a prodrug thereof or a pharmaceutically acceptable salt
of said
compound or said prodrug.
Prefer-ed compounds within Group HE are 4-[2-(1R-hydrooy-ethyl)-pyrimidin-
4-yl]-2R,6S-dimethyl-piperazine-1-carboxylic acid pyridin-3-yl ester, 4-[2-(1R-
hydroxy-
ethyl~pyrimidin-4-y1j-2R,6S-dimethyl-piperazine-1-carboxylic acid 2-methyl-
pyridin-3-
yl ester; 4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yfJ-2R,6S-dimethyl-piperazine-1-
carboxylic acid 5-chloro-pyridin-3-yl ester, and 4-[2-(1 R-
hydroxy~thyl~pyrimidin-4-yij-
2R,6S~imethyl-piperazine-1-carboxylic aad 6-methyl-pyridin-3-yl ester.
Another preferred group of compounds within Group HB, designated Group
HF, are those compounds, prodrugs thereof and pharmaceutically acceptable
salts of
said compounds or said prodrugs wherein:
R' is (R)-1-hydroxy-ethyl; and
R' is
O~\~R°
M N~ vMe
N ,
A preferred compound within the Group HF is the compound wherein R9 is 2-
thienyi, a prodrug thereof or a pharmaceutically acceptable salt of said
compound or
said prodrug.
An espeaally preferred compound within Group HF is (E)-1-{4-[2-(1 R-
hydroxy-ethyl)-pyrimidin-4-ylJ-2R,6S-dimethyl-piperazin-1-yl)-3-thiophen-2-yl-
propenone.
Another prefer-ed group of compounds within Group HB, designated Group
HG, are those compounds, prodnrgs thereof and pharmaceutically acceptable
salts of
said compounds or said prodrugs wherein:
R' is (R~1-hydroxy-ethyl;
R' is


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Rg .
M N Me
and
R' is pyrimidyl or triazinyl; said pyrimidyl or triazinyl is optionally
substituted with up to
two hydroxy, (C,-C,)alkyl, (C3-C,)cycloalkyl, (C,-C,)alkoxy, hydroxy-(C,-
C,)alkyl, (C,-
C,)alkoxy-(C,-C,)alkylenyl, phenyl, piperazinyl optionally substituted with
(C,-C,)alkyl,
or imidazolyl optionally substituted with up to two (C,-C,)alkyf.
A preferred group of compounds within Group HG, designated Group HH, are
those compounds, prodrugs thereof and phamiaceutrcally acceptable salts of
said
compounds or said prodrugs wherein: R' is pyrimid-2-yl optionally ubstituted
with up
to two (C,-C,)alkyl, hydroxy-(C,-C,)alkyl or (C,-C,)alkoxy-(C,-C,)alkyl.
A preferred compound within the Group HH is the compound wherein R9 is
4,6-dimethytpyrimid-2-yl, a prodrug thereof or a pham~aceutically acceptable
soft of
said compound or said prodnrg.
Another prefer-ed compound within the Group HH is the compound wherein
R° is 4-methoxymethyl-6-methylpyrimid-2-yl, a prodrug thereof or a
phanraceutically
acceptable salt of said compound or said prodnrg.
Another preferred compound within the Group HH is the compound wherein
R' is 4-hydroxymethyl-6-methylpyrimid-2-yl, a prodrug thereof or a
pham~aceutically
acceptable salt of said compound or said prodrug.
A preferred group of compounds within the Group HH are 1 R-(4-[4-(4,6-
dimethyl-pyrimidin-2-yl~3R,5S-dimethyl-piperazin-1 ylj-pyrimidin-2-yl}-
ethanol;1R-{4-
[4-(4-methoxymethyl-6-methyl-pyrimidin-2-yI~3R,5S-dimethyl-piperazin-1 y(J-
pyrimidin-2-yl}-Ethanol; and 1 R-{4-[4-(4-hydroxyrr~ethyl-6-methyl-pyrimidin-2-
yl~
3R.5S-dirc~ethyl-piperazin-1-ylj-pyrimidin-2-yt}-ethanol.
Another preferred group of compounds within the Group HG, designated HI,
are those compounds, prodrugs thereof and pharmaceutically acceptable salts of
said compounds or said prodrugs wherein: R° is pyrimid-4-yl optionaNy
substfirted
with up to two (C,-C,)afkylpiperazin-1-yl or imidazotyl; and said imidazotyl
is optionally
substituted iNith up to two (C,-C,}alkyl.


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A preferred compound within the Group HI is the compound wherein R9 is 2-
{4-methylpiperazin-1-ylrpyrimid-4-yl, a prodrug thereof or a pham~aceuticaliy
acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HI is the compound wherein R9
is 2-{4-ethyipiperazin-1-ylr pyrimid~l-yl, a prodrug thereof or a
pharmaceutically
acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HI is the compound wherein R9
is 2-(4-methy(imidazol-1-yl~ pyrimid-4-yl, a prodnrg thereof or a
pharmaceutically
acceptable salt of said compound or said prodrug wherein.
Another preferred compound within the Group HI is the compound wherein R9
is 2-(2-methylimidazol-1-y1r pyrimid-4-yl, a prodrug thereof or a
pharmaceutically
acceptable salt of said compound or said prodrug wherein.
Another prefer-ed compound within the Group HI is the compound wherein R9
is 2-(2,4-dimethylimidazol-1-yl)- pyrimid-4-yl, a prodrug thereof or a
pham~aoeutically
acceptable salt of said compound or said prodrug.
Another preferred compound within the Group Hl is the compound wherein R'
is 2-(4-isopropylpiperazin-1-yl~ pyrimid-4-yl, a prodrug then~f or a
pharmaceutically
acceptable salt of said compound or said prodrug. ,~
Preferred compounds within Group HI are 1 R-(4-{3R,5S-dimethyf-4-[2-(4-
methyl-piperazin-1-yl}-pyrimidin~-yt)-piperazin-1-yl}-pyrimidin-2-yl~ethanol;
1R-(4-{4-
[2-(4-ethyl-piperazin-1-yl}-pyrimidin-4-ytj-3R,5S-dimethyl-piperazin-1-y(}-
pyrimidin-2-
yf~ethanol; 1 R-(4-{3R,5S-dimethyf~-[2-(4-methyl-in~idazol-1-yt)-pyrimidin-4-
ylj-
piperazin-1-yf}-pyrimidin-2-yl)-ethanol; 1R-(4-{3R,5S-dimethyl~-[2-(2-methyl-
imidazof-
1-yl~pyrimidin~-ylJ-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;1 R-(4-{4-[2-{2,4-
dimethyl-
imidazol-1-ylrpyrimidin-4-y(j-3R,5S-dimethyl-piperazin-1 yt}-pyrimidin-2-
yl~thanol;
and 1 R-(4-{4-[2-(4-isopropyl-piperazin-1-yl~pyrimidin-4-y(j-3R;5S-dimethyl-
piperazin-
1-yl)-pyrimidin-2-yl)-ethanol.
Another preferred group of compounds within Group HG, designated Group
HJ, are those compounds, prodrugs thereof and pharmaceutically acceptable
salts
of said compounds or said prodrugs wherein: R° is [1,3.5J-triazin-2-yl
optionally
substituted with up to two hydroxy, (C,-C,~Ikyl, (C3-C,)cydoalkyl, (C,-
C,)atkoxy,
hydroxy-(G,-C,)atkyl, (C,-C,~Ikylpiperazin-1-yl or phenyl.


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A preferred compound within the Group HJ is the compound wherein R9 is 4-
methyl-6-(4-methylpiperazin-1-ylr[1,3,5)-triazin-2-yl, ,a prodrug thereof or a
pharmaceutically acceptable salt of said compound or said prodnrg.
Another prefer-ed compound within the Group HJ is the compound wherein
R°
is 4-methoxy-6-methyl-[1,3,5J-triazin-2-yl.~ ~ a P~ro9 ~reof or a
pharmaceutically
acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HJ is the compound wherein
R°
is 4,6-dimethyoxy-[1,3,5]-triazin-2-yl, a prodnrg thereof or a
pharmaceutically
acceptable salt of said compound or.said prodrug.
p Another prefer-ed compound within the Group HJ is the compound wherein
R°
is 4-ethoxy-6-methyl-[1,3,5j-triazin-2-yl, a prodrug thereof or a
pharmaceutically
acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HJ is the compound wherein
R°
is 4-isopropoxy-6-methyl-[1.3.5)-triazin-2-yl, a prodrug thereof or a
pharmaceutically
acceptable salt of said compound or said prodnrg.
Another preferred compound within the Group HJ is thewcompound wherein
R°
is 4-phenyl-[1,3,5j-triazin-2-yl, a prodnrg thereof or a pharmaceutically
acceptable salt
of said compound or said prodnrg.
Another preferred compound within the Group HJ is the compound wherein
R°
is 4-hydroxymethy!-6-methoxy-[1,3.5j-triazin-2-yl, a prodrug thereof or a
pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HJ is the compound wherein
R°
is 4-isopropoxy-6-methoxy-[1.3,5]-triazin-2-yl, a prodrug thereof or a
pharmaceutically
acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HJ is the compound wherein
R°
is 4-isopropyl-[1.3,5]-triazin-2-yl, a prodnrg thereof or a phamiaoeutically
acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HJ is the compound wherein
R°
is 4-ethyl-6-methoxy-[1,3,5j-triazin-2-yl, a prodrug (hereof or a
phanraoeutically
acceptable salt of said compound or said prodcug.
Another preferred compound within the Group HJ is the compound wherein
R°
is 4-cydoprppyl-[1,3.5j-triazin-2-yl, a prodrug thereof or a phamvaoeutically
acceptable
salt of said compound. or said prodcug:


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Another preferred compound within the Group HJ is the compound 'wherein R9
is 4,6-dimethyl-[1,3,5j-triazin-2-yl, a prodrug thereof or a pharmaceutically
acceptable
salt of said compound or said prodrug.
Another preferred compound within the Group HJ is the compound wherein R9
is 4-methyl-6-phenyl-[1,3,5j-triazin-2-yl, a prodrug thereof or a
pham~aceutically
acceptable salt of said compound or said prodrug.
Preferred compounds within the Group HJ are 1 R-(4-{3R,5S-dimethyl~-(4-
methyl-6-{4-methyl-piperazin-1-yIH1,3,5jtriavn-2-yl]-piperazin-1-yl}-Pyrimidin-
2-ylr
ethanol; 1R-{4-[4-(4-methoxy-6-methyl[1,3,5jtriazin-2-yl~3R,5S-dimethyl-
piperazirrl-
yQ-pyrimidin-2-yf}-ethanol; 1R-{4-[4-(4,6~imetho~cy-[1,3,5]triazin-2-yl}-
3R,5S~imethyl-
piperazin-1-yI]-pyrimidin-2-Y(}-ethanol; 1R-{4-[4-(4-ethoxy-6-methyl-
[1.3,Sjtriazin-2-y(~
3R,5S-dimethyl-piperazin-1-ylj-pyrimidin-2-yl}~thanol; 1R-{4-[4-(4-isopropoxy-
6-
methyl-[1,3,5jtriazin-2-yl)-3R,5S-dimethyl-piperazin-1-y(j-pyrimidin-2-yl}-
ethanol; 1R-
{4-[3R,5S-dimethyl-4-(4-phenyl-[1,3,5)triazin-2-yl}-piperazin-1-yf J-pyrimidin-
2-yl}-
ethanol; 1R-{4-[4-{4-hydroxymethyl-G-methoxy-[1,3,5]triazin-2-yl~3R,5S-
dimethyl-
piperazin-1-ylj-pyrimidin-2-yf}-ethanol; 1 R-{4-[4-(4-isoPropoXy-6=methoxy-
[1,3,Sjtriazin-2-yl}-3R,5S-dimethyl-piperazin-1-ylj-pyrimidin-2-yl}~thanol; 1R-
{4-[4-(4-
isopropyl-[1,3,5jtriazin-2-yl~3R,5S-dimethyl-piperazin-1-y1]-pyrimidin-2-yl}-
ethanol;
1 R-{4-[4-(4.6-dimethyl-[1,3,5jtriazin-2-yl}-3R,5S-dimethyl-piperazin-1 y(j-
pyrimidin-2-
yl}-ethanol; 1 R-{4-[3R,5S~imethyi-4-(4-methyl-fi-phenyl-[1,3,SJtriazin-2-yl}-
piperazin-
1-y(]pyrimidin-2-y1}-ethanol; 1 R-{4-[4-(4-cydopropyl-[1,3,5jtriazin-2-
yl~3R,5S-
dimethyl-ptperazin-1-y(j-pyrimidin-2-yI}-ethanol; and 1R-{4-[4-(4-ethyl-6-
methoxy-
[1.3,5]triazin-2-yl~3R,5S-dimethyl-piperazin-1-Y(j-Pyrimidin-2-YI}-ethanol.
Another group of preferred compounds within the Group HB, designated
Group HK, are those compounds, prodrugs thereof and pharmaceutically
acceptable
salts of said compounds or said prodrugs wherein:
R' is (R~1-hydroxy-ethyl;
R' is
R~
N
Me ~ Me
and


CA 02484282 2000-03-16
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R° is pyrimidyl or triazinyl, said pyrimidyl and triazinyl optionally
substituted with up to
two hydroxy, (C,-C,)alkyl, (Cs-C,kydoalkyt. (C,-C,)atkoxy, hydroxy-(C,-
C,~Ikyl, (C,-
C,)atkoxy-(C,-C,)alkyl, triazolyl, acetyl, morpholinyl, (C,-
C,)alkylpiperazinyl, phenyl or
imidazoiyl optionally substituted with up to two (C~~C,)alkyl.
A preferred group of compounds within the Group HK, designated HL, are
those compounds, prodrugs thereof and pharmaceutically acceptable salts of
said
compounds or said prodrugs wherein: R9 is pyrimid-2-yl optionally substituted
with up
to two (C,-C,)alkyl, hydroxy-(C,-C,)alkyl or triazolYl.
A preferred compound within the Group HL is the compound wherein R9 is
4.6-dimethyl-pyrimid-2-yl, a prodrug thereof or a pham~aceuticalfy acceptable
salt
of said compound or said prodrug.
Another preferred compound within the Group HL is the compound wherein R'
is 4-hydroxymethyl-6-methylpyrimid-2-yl, a prodrug thereof or a
pharmaceutically
acceptable salt of said compound or said pcodrug.
Another preferred compound within the Group HL is the compound wherein
R°
is 4-[1,2,4]-triazol-1-yl-pyrimid-2-yl, a prodrug thereof or a
pharmaceutically
acceptable salt of said compound or said prodrug.
Preferred compounds within the Group HL are 1 R-{4-[4(4,6-dimethyl-
pyrimidin-2-yl}-2R,6S-dimethyl-piperazin-1-yl}- PYrimidin-2-yl}-ethanot;1R-{4-
[4-(4-
hydroxymethyl-6-methyl-pyrimidin-2-yl)-2R,6S-dimethyl-piperazin-1-ylj-
pyrimidin-2-yl}-
ethanol; and 1R-{4-{2R,6S-dimethyl-4-(4-[1,2,4]triazol-1-yl-pyrimidin-2-yl)-
piperazin-1-
yfj-pyrimidirr2-yl)-ethanol.
Another preferred group of compounds within the Group HK, designated
Group HM, are those compounds, prodrugs thereof and phamnaceutically
acceptable salts of said compounds or said prodrugs wherein: R9 is pyrimid~-yl
optionally substituted with up to two (C,-C,)alkyl, hydroxy-(C,-C,~Ikyl,
acetyl,
morpholinyt, (C,-C,)alkylpiperazinyl, triazolyl or imidazolyl optionally-
substituted with
up to two (C,-C,)alkyl.
A preferred compound within the Group HM is the compound wherein
R° is
2,6-dimethyl-pyrimid-4-yt, a prodrug thereof or a pham~aceutically axeptable
salt
of said compound or said prodrug.


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Another preferred compound w'tthin the Group HM is the compound wherein
R° is 2-hydroxymethyl-6-methyl-pyrimid-4-yl, a prodrug thereof or a
pham~aceutically
acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HM is the compound wherein
R9 is 2-acetyl-pyrimid~-yl, a prodrug thereof or a pharmaceutically acceptable
salt
of said compound or said prodrug.
Another preferred compound within the Group HM is the compound wherein
R9 is 2-morpholin-4-yl-pyrimid~-yl, a prodrug thereof or a pham~aceutically
acceptable salt of said compound or said~prodrug.
0 Another~preferred compound within the Group HM is the compound wherein
R9 is 2-(4-methylpiperazin-1-yl~pyrimid~-yl, a prodnrg thereof or a
pham~aceuticaliy
acceptable salt of said compound or said prodnrg.
Another preferred compound within the Group HM is the compound wherein
R9 is 2-[1.2,4]-triazol-1-yl-pyrimid-4-yl,a prodrug thereof or a
pharmaceutically
acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HM is the compound wherein
R9 is 2-(1 S-hydroxyethyl}-pyrimid~-yl, a prodrug thereof or a
pham~aceutically
acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HM is the compound wherein
R' is 2-(1 R-hydroxyethyl)-pyrimid-4 yl, a prodrug thereof or a
pharmaceutically
acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HM is the compound wherein
R9 is 2-(4-ethyfpiperazin-1-yl}-pyrimid-4-yl, a prodrug thereof or a
pham~aceutically
acceptable salt of said compound or said prodrug.
Another prefer-ed compound within the Group HM is the compound wherein
R° is 2-(4-methylimidazol-1-yl)-Pyrimid-4-yl, a prodnrg thereof or a
phamiaceuticaliy
acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HM is the compound wherein
R9 is 2-(2,4-dimethylimidazol-1-yl~pyrimid~-yl, a prodrug thereof or a
pham~aceutically acceptable salt of said compound or said prodnrg.
Preferred compounds within the HB Group are 1R-{4-[4-(2,6-dimethyl-
pyrimidin-4-yl~2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-y1}-ethanol; 1f~-(4-
{4-[2-(1R-
hydroxy-ethyl~Pyrimidin~-YI]-2R,6S-dimethyl-piperazin-1-YI}-Pyrimidin-2-
yl~thanol;


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1 R-{4-(4-(2-hydroxymethyl-6-methyl-pyrimidin-4-yl~2R,6S-dimethyl-piperazin-1-
yfj-
pyrimidin-2-yl}-ethanol; 1 R-(4-{4-[2-(7 S-hydroxy-ethyl)-pyrimidin-4-y(]-
2R,fiS-dimethyl-
piperazin-1-yl}-pyrimidin-2-ylrethanol; (4-{4-[2-(1R-hydroxy-ethyl~pyrimidin-4-
yl]-
3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanone; 1R-{4-(2R,6S-dimethyf-
4-(2-
morpholin-4-yl-pyrimidin-4-yl)-piperazin-1~-ylj-pyrimidin-2-yl}-ethanol; 1 R-
(4-{2R,6S-
dimethyl~-[2-(4-methyl-piperazin-1-yl}-pyrimidin-4-yQ-piperazin-1-yl}-
pyrimidin-2-yl~
ethanol; 1R-{4-[2R,6S-dimethyl-4-(2-[1,2,4]triazol-1-yl-pyrimidin-4-
yl~piperazin-1-yl]-
pyrimidin-2-yI}-ethanol; 1 R-(4-{4-[2-(1 R-hydroxy-ethyl)-pyrimidin-4-ylj-
2R,6R-dimethyl-
piperazin-1-yf}-pyrimidin-2-yl~ethanol; ~ 1 R-(4-{4-[2-(4-ethyl-piperazin-1-
yl)-~pydmidin-4-
ylJ-2R,6S-dirnethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1 R-(4-{2R,6S-
dimethyl-4-[2-
{4-methyl-imidazol-1-yl)-pyrimidin-4-yfj-piperazin~l-yl}-pyrimidin-2-yl)-
ethanol; and 1R-
{4-{4-[2-(2,4-dimethyl-imidazol-1-yl~pyrimidin-4-yQ-2R,6S-dimethyl-piperazin-1-
yl}-
pyrimidin-2-yl~thanol.
Another prefen-ed compound within the Group HB is the compound wherein
R' is (Rr1-hydroxyethyl; R' is
R°
N
Me'~~~ N Me
and
R9 is 2-(1R-hydroxyethyl-pyrimid-4-yl, a prodrug thereof or a pharmaceutically
acceptable salt of said compound or said prodrug.
A preferred group of compounds within the Group HK, designated Group HN,
are those compounds, prodrugs thereof and pharmaceutically acceptable salts of
said
compounds and said prodnrgs, wherein R9 is (1,3,5]-triazin-2-yl optionally
substituted
with up to two hydroxy, (C,-C,)alkyl, (C,-C,)cydoalkyl, hydroxy-(C,-C,)alkyl,
(C,-
C,~Ikoxy-(C,-C,)alkyl, (C,-C,)alkoxy, morpholinyl or phenyl.
A preferred compound within the Group HN is the compound wherein R° is
4-
morpholin-4-yl-[1,3,57-triazin-2-yl, a prodrug thereof or a pham~aceutically
acceptable salt of said compound or said prodnrg.
Another preferred compound within the Group HN is the compound wherein
R° is 4-methoxy-6-methyl-[1,3,5]-triazin-2-yl, a prodrug thereof or a
pharmaceutically
acceptable salt of said compound or said prodnrg.


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Another preferred compound within the Group HN is the,compound wherein
R° is 4,6-dimethoxy-[1.3,5]-triazin-2-yl, a prodrug thenaof or a
pharmaceutically
acceptable salt of said compound or said prodnrg:
Another preferred compound within the Group HN is the compound wherein
R9 is 4-phenyl-j1,3,5]-triazin-2-yl, a prodrug thereof or a pharmaceutically
acceptable salt of said compound or said prodrug.
Another prefer-ed compound within the Group HN is the compound wherein
R9 is 4-cydopropyl-[7 ,3,5]-triazin-2-yl, a prodrug thereof or a
pham~aceutically
acceptable salt of said compound or said prodrug.
Another~preferred compound within the Group HN is the compound wherein
R9 is 4,6-dimethyl-[1,3,5]-triazin-2-yl, a prodrug thereof or a
pham~aceuticatly
acceptable salt of said compound or said prodnrg.
Another preferred compound within the Group HN is the compound wherein
R9 is 4-hydroxymethyl-6-phenyl-[1,3,5]-triazin-2-yl, a prodrug then:of or a
pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HN is the compound wherein
R° is 4-methoxy-6-methoxymethyl-[1,3.5]-triazin-2-yl, a prodrug
thenof or a
pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HN is the compound wherein
R° is 4-methyl-[1,3,5j-triazin-2-yl, a prodrug thereof or a
phannaaeutically acceptable
salt of said compound or said prodrug.
Another preferred compound within the Group HN is the compound wherein
R9 is 4-methoxymethyl-6-phenyl-[1,3,5~triazin-2-yl, a prodnrg thereof or a
phamiaoeutically acxeptable salt of said compound or said prodrug.
Preferred compounds within the Group HN are 1R-{4-~2R,6S-dimethyl-4-
(4-morpholin-4-yl-[1.3,5]triazin-2-yl~Piperazin-1-y(j-Pyrimidin-2-yl}-ethanol;
1R-{4-[4-
(.4-methoxy-6-methyl-[1,3,5jtriazin-2-yl}-2R,6S-dimethyl-piperazin-1 y(J-
pyrimid'm-2-yl}-
ethanol;1 R-{4-[4-(4,6-dimethoxy-[1,3,5]triazin-2-yl~2R,6S-dimethy!-piperazin-
1 yIJ-
pyrimidin-2-y1}-ethanol; 1R-{4-[4-(4-cydopropy!-[1,3,5)triazin-2-yl]-2R,6S-
dimethyl-
piperazin-1 yQ-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4,6-dimethyl-[t,3,5jtriazin-
2-yl~
2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[4-(4-
hydroxymethyl.~.
phenyl-[1,3,5]triazin-2-yl~2R.6S-dimett~yl-piperazin-1-yl]-pyrimidin-2-
yl~ethanot; 1R-
{4-[4-(4-methoxy-6-methoxymethyl-[1,3,5]triazin-2-yl}-2R,6S-dimethyl-piperazin-
1-y(j-


CA 02484282 2000-03-16
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pyrimidin-2-yl}-ethanol; 1 R-(4-[2R,6S-dimethyl-4-(4-methyl-[1,3,5]triazin-2-
yl)-
piperazin-1-ylj-pyrimidin-2-yl-ethanol; 1R-{4-[4-(4-methoxymethyl-6-phenyl-
j1.3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
and 1 R-{4-
[2R,6S-dimethyl-4-(4-phenyl-[1,3,5]triazin-2-yl~piperazin-1 ylJ-pyrimidin-2-
yl)-ethanol.
Another preferred group of compounds within the Group H8, designated
Group HO, are those compounds, prodnrgs thereof and pharmaceutically
acceptable salts of said compounds or said prodrugs wherein:
R' is (R)-1-hydroxy-ethyl;
R' is .
R°
N ~.
N
~ ; and
R9 is pyrimidyl, quinoxaiyl or oxazoiopyridyl optionally substituted with up
to two (C,-
C,)alkyl, (C,-C,)alkoxy or hydroxy-(C,-C,)alkyl.
A preferred compound within the Group HO is the compound wherein
R°
is 4-hydroxymethyl-6-methyl-pyrimid-2-yl, a prodrug thereof or a
pharmaceutically
acceptable salt of said compound or said prodnrg.
Another preferred compound within the Group HO is the compound wherein
R' is 2-hydroxymethyl-pyrimid-4-yl, a prodrug then~f or a pharmaceutically
acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HO is the compound wherein
Rg is 2-hydroxymelhyl-6-methyl-pyrimid-4-yI, a prodrug thereof or a
pham~aceutically
acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HO is the compound wherein
Rs is 2-(oxazolo[5,.4-b]pyridyl), a prodrug thereof or a pharmaceutically
acceptable salt
of said compound or said prodnrg.
Another preferred compound within the Group HO is the compound wherein
R9 is 2-(oxazolo[4,5-b]pyridyl, a prodrug thereof or a pharmaceutically
acceptable salt
of said compound or said prodrug.


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pCTIIB00100296
Another preferred compound within the Group HO is the ,compound wherein
R9 is 2-quinoxalyl, a prodrug thereof or a pharmaceutically acceptable salt of
said
compound or said prodrug.
Preferred compounds within the Group HO are 1 R-{4-[4-(4-
hydroxymethyl-6-methyl-pyrimidin-2-yl}-35-methyl-piperazin-1-ylJ-pyrimidin-2-
yf}-
ethanol; 1 R-(4-[4-(2-hydroxymethyl-pyrimidin-4-yl~3S-methyl-piperazin-1-y(j-
,
pyrimidin-2-yfj~-ethanol; 1 R-[4-[4-(2-hydroxymethyl-6-methyl-pyrtmidin-4-
yl~3S-
methyl-piperazin-1-yl]-py-rimidin-2-yl}-ethanol; 1 R-[4-(3S-methyl-4-
oxazofo[5,4-
bjpyridin-2-yl-piperazin-1-yl)~pyrimidin-2-y(j-ethanol; 1R-[4-(3S-methyl-4-
oxazolo[4,5-
bjpyridin-2-yl-piperazin-1-yl)-pyrimidin-2-y(j-ethanol; and 1 R-[4-(3S-methyl-
4-
quinoxalin-2-yl-piperazin-1-yl)-pyrimidin-2-y(J-ethanol.
Another preferred group of compounds within the Group HB, designated
Group NP, are those compounds, prodrugs thereof and pharmaceutically
acceptable salts of said compounds or said prodrugs wherein:
R' is (R)-1-hydroxy-ethyl;
R' is
R°
N
N Me
and
R9 is pyrimidyl optionally substituted with up to two (C,-C,)alkyl, (C,-
C,)alkoxy,
hydroxy-(C,-C,)alkyl:
A preferred compound within the Group HP is the compound wherein
R° is 2-
(1 R-hydroxyethyl)-pyrimid-4-yl, a prodnrg thereof or a phamaaceutically
acceptable
salt of said compound or said prodrug.
A preferred compound within the Group HP is 1 R-(4-{4-[2-(1 R-hydroxy-ethylr
pyrimidin-4-ylJ-2R-methyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol.
Another preferred group of compounds within the Group HB, designated HQ,
are those compounds, prodnrgs thereof and pham~aceuticalty acceptable salts of
said compounds or said prodrugs wherein:
R' is (R~-1 ~ydroxy-ethyl;
R' is


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pG"f/IB00/00296
R~ ,
Me,,, N ~ '
N Me -
and
R9 is pyrimidyl optionally substituted with up to two (C,-C,)alkyl, (C,-
C,)alkoxy,
hydroxy-(C,-C,)alkyl.
A preferred compound within the Group HQ is the compound wherein R9 is 2-
(1 R-hydroxyethyl)-pyrimid~-yl, a prodrug thereof or a pharmaceutically
acceptable
salt of said compound or said prodrug.
An especially prefer-ed compound within the Group HQ is (4-(4-~2-(1 R-
hydroxy-ethyl}-pyrimidin-4-y~-2R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2~y1}-
ethanol.
Another preferred group of compounds within the Group HB, designated
Group HR, are those compounds, prodrugs thereof and pharmaceutically
acceptable
salts of said compounds or said prodrugs wherein:
R' is (S~1-hydroxy~thyl;
R' is
Ro
N
Me ~ Me
; and
R' is pynmidyl optionally substituted with up to two (C,-C,)alkyl, (C,-
C,)alkoxy or
hydroxy-(C,-C,)alkyl.
A preferred compound within the Group HR is the compound wherein R9 is 2-
(1R-hydroxy~thyl~pyrimid-~-yl, a prodrug thereof or a pharmaceutically
acceptable
salt of said compound or said prodrug.
An espeaally preferred compound within the Group HR is 1S-(4-{4-(2-(1R-
hydroxy-ethyl~pyrimidin-~-yt]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl}-
ethanol.
Yet another preferred group of compounds within the Group HB, designated
Group HS; are those compounds, prodrugs thereof and pharmaoeuticaAy acceptable
salts of said compounds or said prodrugs wherein:


CA 02484282 2000-03-16
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-38-
R' is acetyl:
R' is
R°
N
Me ~ ~Me
and
pC'fIB00/00296
R9 is pyrimidyl optionally substituted with up to two (C,-C,~Ikyl, (C,-
C,~Ikoxy, acetyl
or hydroxy-(C,-C,)alkyl.
A prefer-ed compound within the Group HS is the compound wherein R9 is 2-
acetyl-pyrimid~-yl, a prodrug thereof or a phamiaceut~cally acceptable salt of
said
compound or said prodrug.
A preferred compound within the Group HS is the compound wherein R9 is 2-
7 0 (1 R-hydroxyethyl~pyrimid-4-yl, a prodrug thereof or a pharmaceutically
acceptable
salt of said compound or said prodrug.
Espeaally preferred compounds within the Group HS are 1-{4r(4-(2-acetyl-
pyrimidin-4-ylj-2R'.6S'-dimethyl-piperazin-1-yfJ-pyrimidin-2 yl}-ethanone or 1-
j~-{4-
j2-('1 R-hydroxy-ethyl)-pyrimidin-4-yQ-2R,6S-dimethyl-piperazin-1-y(}-
pyrimidin-2-yl)-
ethanone
A pharmaceutical composition, designated Composition A, comprising a
compound of formula I, a prodrug thereof ar a pharmaceutically acceptable salt
of said
compound or said prodrug and a pham~aceutically acceptable carrier or diluent.
A method of inhibiting sorbitol dehydrogenase in a mamma! in need of such
inhibition comprising administering to said mammal a sorbitol dehydrogenase
inhibiting amount of a compound of formula I, a prodrug thereof or a
pharmaceutically
acceptable salt of said compound or said prodnrg.
A method of treating diabetes in a mammal suffering from diabetes c;ornprising
administering to said mammal an effective amount of a compound of formula I, a
prodrug thereof or a pharmaceutically acceptable salt of said compound or said
prodnrg.
A method, designated Method A, of treating or preventing diabetic
complications in a mammal comprising administering to said mammal an effective


CA 02484282 2000-03-16
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amount of a compound of formula l, a prodrug thereof or a pharmaceutically
acceptable salt of said compound or said prodnrg:
A method of Method A wherein said mammal is suffering from diabetes.
A method of Method A wherein said diabetic complication is diabetic
neuropathy.
A method of Method A wherein said diabetic compf~cation is diabetic
nephropathy.
A method of Method A wherein said diabetic complication is diabetic
retinopathy.
A method of Method A wherein said diabetic complication is foot ~rl~rs.
A method of Method A wherein said diabetic complication is a cardiovascular
condition.
A pham~aoeutical composition, designated Composition B, comprising a
compound of formula I, a prodrug thereof or a pham~aceutically axeptabfe salt
of said
~ 5 compound or said prodrug and an aldose reductase inhibitor, a prodrug
thereof or a
pharmaceutically acceptable salt of said aldose reduetase inhibitor or said
prodrug.
A composition of Composition B additionally composing a pham~aceuticatly
acceptable carrier or diluent.
A method of treating diabetes in a mammal suffering from diabetes comprising
20 administering to said mammal an effective amount of a compound of fomnula
I, a
prodrug thereof or a pharmaceutically acceptable salt of said compound or said
prodrug and an aldose reductase inhibitor, a prodrug of said aldose reductase
inhibitor or a pharmaceutically acceptable salt of said aldose reductase
inhibitor or
said prodrug.
25 "'" A method, designated Method B, of treating or preventing diabetic
complications in a mammal comprising administering to said mammal an effective
amount of a compound of formula 1, a prodrug thereof or a pham~aoeuticaUy
acceptable of said compound or said prodrug and an atdose reductase inhibitor,
a
prodrug of said aldose reductase inhibitor or a phamvaceuticalfy acceptable
salt of
30 said aldose reductase inhibitor or said prodrug thereof.
A method of Method B wherein said mammal is suffering from diabetes.
A method of Method B wherein said diabetic complication is diabetic
neuropathy:


CA 02484282 2000-03-16
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-40- , ,
A method of Method B wherein said diabetic complication is diabetic
nephropathy.
A method of Method 8 wherein said. diabetic complication is diabet<c
retinopathy.
A method of Method B wherein said diabetic complication is foot~Ulcers.
A method of Method B wherein said diabetic oompf~cation is a cardiovasarlar
condition.
A phamiaoeutical composition, designated Composition C, c~rnprising a
compound of formula l, a prodrug thereof or a pharmaceutically acceptable salt
of said
compound or said prodrug and a sodium hydrogen ion exchange (NH~-7 )
inhibitor, a
prodrug of said NHE-1 inhibitor or a pham~aceutically acceptable salt of~~aid
NHE-1
inhibitor or said prodrug thereof.
A method, designated Method C, of treating ischemia in a mammal suffering
from ischemia comprising administering to said mammal an effective amount of a
compound of formula I, a prodrug thereof or a pham~aceuticatiy acoeptabfe salt
of said
compound or said prodrug and a sodium hydrogen ion exchange (NHE-1) inhibitor,
a
prodrug of said NHE-1 inhibitor or a pham~aceutically acceptable satt of said
NHE-1
inhibitor or said prodrug.
A method of Method C wherein said ischemia is perioperatnie myocardial
ischemia.
A method of treating or preventing diabetic complications in a mammal,
designated Method D, comprising administering to said mammal an effective
amount
of a compound of fofnwla I, a prodrug thereof or a pharmaceutically acceptable
salt of
said compound or said prodrug and a sodium hydrogen ion exchange (NHE-1 )
inhibitor, a prodrug of said NHE-1 inhibitor or a pham~aceutically acceptable
salt of
said NHE-l inhibitor or said prodtug.
A method of Method D wherein said mammal is suffering from diabetes.
A method of Method D wherein said diabetic complication is d'~abetic
neuropathy.
A method of Method D wherein said diabetic complication is diabetic
nephropathy.
A method of Method D wherein said diabetic ~lication is diabetic
retinopathy.


CA 02484282 2000-03-16
~ WO 00/59510
pCT/IB00100296
. -41 _
A method of Method D wherein said diabetic complication is foot ulcers.
A method of Method D wherein said diabetic complication is a cardiovascular
condition.
A method of treating diabetes in a mammal suffering from diabetes comprising
administering to said mammal an effective aniount of a compound of formula I,
a
prodrug thereof or a pharmaceutically acceptable salt of said compound pr said
prodrug, and a sodium hydrogen ion exchange (NHE-1 ) inhibitor, a prodrug of
said
NHE-1 inhibitor or a pham~aceuticafly acceptable salt of said NHE-1 inhibitor
or said
prodrug.
A kit comprising:
a. a compound of formula l, a prodrug thereof or a
pharmaceutically acceptable salt of said compound or said prodrug in a fjrst
unit
dosage form;
b. an aldose reductase inhibitor, a prodrug thereof or a
pharmaceutically acceptable salt of said prodrug or said aldose reductase
inhibitor in
a second unit dosage form; and
c. a container.
A kit comprising:
a. a compound of formula 1, a prodrug thereof or a
phamfaceuticafly acceptable salt of said compound or said prodrug in a first
unit
dosage form;
b. a sodium hydrogen ion exchange (NHE-1 ) inhibitor, a prodrug
thereof or a pharmaceutically acceptable salt of said prodrug or said NHE-1
inhibitor
in a second unit dosage form; and
c. a container.
A method, designated Method E, of inhibiting sorbitol dehydrogenase in a
mammal in need thereof comprising administering to said mammal Composition A.
A method of Method E wherein said ischemia is perioperative myocardial
ischemia.
A method of treating ischemia in a mammal suffering from ischemia
comprising administering to said mammal Composition C.
A method, designated Method F, of treating or preventing diabetic
complications in a mammal comprising administering to said mammal Composition
A.


CA 02484282 2000-03-16
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~2-
A method of Method F wherein said mammal is suffering from diabetes.
A method, designated Method G, of treating or, preventing diabetic
complications in a mammal comprising administering to said mammal Composition
B.
A method of Method G wherein said mammal is suffering from diabetes.
A method, designated Method H, of treating or preventing diabetic
complications in a mammal comprising administering to said mammal Composition
C.
A method of Method H wherein said mammal is suffering from diabetes.
A compound of formula I, a prodrug thereof or a pham~aceutically
acceptable salt of said compound or said prodnrg, wherein:
R' is C(OH)R'R~S, where R' and R5 are each independently hydrogen or methyl;
RZ is hydrogen;
R' is
X~Ro
(CH2)k
N
s
( s) ~ G,
G or
N
wherein said piperazinyl R' is substituted by R6, R' or R°;
G, G' and G2 are taken separately and are each hydrogen and Re is hydrogen or
(C,-
C,)alkyl; R' and R° are each independently hydrogen or (C,-
C,)allcyl; or
G and G' are taken together and are (C,-C,jalkylene and R6, R', R° and
G2 are
hydrogen; or
G' and G= are taken together and are (C,-C3~Ikylene and R6, R', R°
and G are
hydrogen;
qis0orl;
X is a covalent bond, oxycarbonyl,vinylenylcart~onyl, oxy(C,-
C,)alkylenyicarbonyl,
thio(C,-C,)alkylenyfcarbonyl or vinylenylsutfonyl; said vinylenylcarbonyl and
said
vinylenylsulfonyl in the definition of X are optionally substituted on one or
iwo vinylenyl
carbons with (C,-C,)alkyl, benryl or Ar; said oxy(C,-C,)alkylenytcarbonyl and
said


CA 02484282 2000-03-16
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pCTIIB00/00296
thio(C,-C,)alkylenylcarbonyl in the definition of X are optionally substituted
with up to
two (C,-C,)alkyl, benzyl or Ar;
R9 is (C3-C,)cydoalkyl, Ar'-(Co-C,)alkylenyl or (C,-C6)atkyl optionally
substituted with
up to five fiuoro;
Ar' is phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyi,
triazinyl, quinolyl,
isoquinolyl, quinazolyl, quinoxalyl, phthalazinyl, dnnolinyi, naphthyridinyl;
pteridinyl,
pyrazinopyrazinyl, pyrazinopyridazinyl, pyrimidopyridazinyl,
pyrimidopyrimidyl,
pyridopyrimidyl; py~dopyrazinyl, pyridopyridazinyl, pyrrolyl, furanyl,
thienyl, imidazolyl,
oxazolyl, thiazolyl, pyrazolyl, isoxazolyi, isothiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl,
tetrazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl,
benzothiazolyl, indazolyl, benzisoxazoiyl, benzisothiazolyl, pyrrolopyridyl,
furopyridyl,
thienopyridyi, imidazoiopyridyl, oxazolopyridyl, thiazoiopyridyl,
pyrazolopyridyl,
isoxazolopyridyl, isothiazoiopyridyl, pyrrolopyrimidyl, furopyrimidyl,
thienopyrimidyl,
imidazoiopyrimidyl, oxazolopyrimidyl, thiazolopyrimidyl, pyrazolopyrimidyl,
isoxazolopyrimidyl, isothiazolopyrimidyl, pyrrolopyrazinyl, furopyrazinyl,
thienopyrazinyl, imidazolopyrazinyl, oxazolopyrazinyl, thiazolopyrazinyl,
pyrazolopyrazinyl, isoxazolopyrazinyl, isothiazolopyrazinyl,
pyrrolopyridazinyl,
furopyridazinyl, thienopyridazinyl, imidazoiopyridazinyl, oxazolopyridazinyl,
thiazoiopyridazinyl, pyrazolopyridazinyl, isoxazolopyridazinyl or
isothiazolopyridazinyl;
and
said Ar' is optionally substituted as set forth above;
k is 0, 1, 2, 3 or 4;
Y' is a covalent bond, carbonyl, sulfonyl or oxycarbonyl;
R" is (C~-C,)cydoalkyl, Ars-(Co-C,)alkylenyl, NR"R'° or (C,-C6)alkyl
optionally
substituted with one to five fluoro; provided that when Y' is a covalent bond
or
oxycarbonyl, then R" is not NR"R'°;
R" and R'° are taken separately and are each independently selected
from hydrogen,
Ars, (C,-C6)atkyl and Ars-(Ca-C,)alkylenyl; or
R" and R'° are taken together with the nitrogen atom to which they are
attached to
form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,
azepinyl,
azabicydo[3.2.2]nonanyl, azabicydo[2.2.1]heptyl, 1,2,3,4-
tetrahydroisoquinolyl, 6,7-
dihydro-SH-dibenzojc,ejazepinyl or 5,6,7,&tetrahydropyrido[4,3-djpyrimtdyl;
said
azetidinyt in the definition of R" and R'° are optionally substituted
with one hydroxy,


CA 02484282 2000-03-16
WO 00/59510 PCTlIB00100Z96
amino, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy~(C,-C,)alkyl, (C,-C,)alkyl
optionally
substituted with up to five ftuoro or (C,-C,)alkoxy optionally substituted
with up to five
ftuoro; said pyrrolidinyi, piperidinyi and azepinyf in the definition of R"
and R'° are
optionally substituted with up to two hydroxy, amino, hydroxy-(C;-C,)alkyl,
(C,-
C,)alkoxy-(C,-C,)alkyi, (C,-C,)aikyl opfionatlY substituted with up to five
fluoro or (C,-
C,~ikoxy optionally substituted with up to Eve fiuoro; said morpholinyl in the
definition
of R" and R'° is optionally substituted with up to two substituents
independently
selected from hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl
optionally
substituted with up to ftve fluoro and (C;-C,)alkoxy optionally substituted
with up to five
ftuoro; said piperazinyl, 9,2,3,4-tetrahydroisoquinolyl and
5,fi,7,&tetrahydro[4,3-
d]pyrimidyl in the definition of R" and R'° are optionally substituted
with up to three
hydroxy, amino, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)altcyt, (C;-
C,)alkyl
optionally substituted with up to five ftuoro or (C; C,)alkoxy optionally
substituted with
up to five ftuoro; and said fi,7-dihydro-SH-~iibenzo[c,e]azepinyl in the
definition of R"
and R'° are optionally substituted with up to four hydroxy, amino,
halo, hydroxy-(C,-
C,)atkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C;)alkyl optionally substituted with
up to fare
ftuoro or (C,-C,~Ikoxy optionally substituted with up to five ftuoro;
Ars is independently defined as set forth for Ar and Ar' above;
Ars is optionally independently substituted as set forth for Ar and Ar' above.
A compound selected from 1 R-(4-(1'-[2-(1 R-hydroxy-ethyl)-pyrimidin-4 y(j-
[4,4~bipiperidinyl-1-yl}-pysimidin-2-yt)-ethanol; faro[3,2-c]pyridin-2-yl-(4-
[2-(1R-
hydroxy-ethyl)-pyrimidin-4-ylj-3R,5S-dimethyl-piperazin-i-yl}-methanone; (4-
chloro-
furo[3,2-c]pyridin-2-yl)-{4-[2-(1 R-hydroxy-ethyl)-pyrimidin~-y~-3R,5S-
dimethyl-
piperazin-1-yl}-methanone; (4-[2-(1R-hydroxy~thyt)-Pyrimidin-4-yi]-3R,5S-
dimethyl-
piperazin-1 yt}-(4-pyrrotidin-1-y!-furo[3,2-c]Pyridin 2 yl)-methar~one; ~4-[2-
(1R-hydroxy_
ethyl)-pytimidin-4-yt)-3R,5S-dimethyl-piperazin-1-yI}-(4-morpholin~-yl-
furo(3,2-
cjpyridin-2-yl)-methanone; (4-i2-(1R-hydroxy~thyl)-pyrimidin-4-yt]-3R,SS-
dimethy!-
piperazin-1-yl}-imidazo[1,2-a]pyridin-2-yI-methanone; furo[3,2-cjpyridin-2-
y1~4-[2-(1R-
hydroxy-ethyl}-pyrimidin-4-ytJ-2R,6S-dimethyl-piperazin-i-yl}-methanone; 4-[2-
(1R
hydroxy-ethyl)-Pyrimidin~-ylj-2R,6S-dimethyt-piperazine-1-carboxylic acid
pyridin-3-yl
ester; 4-[2-(1R-hydroxy-ethylJ-pyrimidin-4-y!]-2R,6S~imethyl-piperaZine-1-
carboxylic
aad 2-methyl-pyridin-3-yl ester 4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-y(J-2R,6S-
dimethyl-piperazine-1- carboxylic aad 5-chtoro-pyridin-3-yl ester, 4-[2-(1R-
hydroxy-


CA 02484282 2000-03-16
pC'I'/IB00~0296
WO 00/59510
-45-
ethyl)-pyrimidin-4-yt]-2R.6S-dimethyl-piperazine-1-carboxylic acid 6-methyl-
pyridin-3-
yl ester;.(Ej-1-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-y(}-2R,6S-dimethyl-
piperazin-1-y1}-
3-thiophen-2-yl-propenone; 1 R-{4-(4-(4,6-dimethyl-pyrtmidin-2-yl)-3R,5S-
dimethyl-
piperazin-1-yt]-pyrimidin-2-yi}-ethanot;1 R-{4-[4-(4-methoxymethyl~-methyl-
Pyrimidin-
2-yl~3R,5S-dimethyl-piperazin-1-ylJ-pyrimidin-2-yl}-ethanol;1 R-{4-[4-(4-
hydroxymethyl-6-methyl-pyrimidin-2-yl~3R,5S-dimethyl-piperazin-1-yl]-
pycrimidin-2-y1}-
ethanol; 1 R-(4-{3R,5S-dimethyt-4-[2-(4-methyl-piper-azin-1-yl~pyrimidin-4-yl]-

piperazin-1-yl}-pYrimidin-2-yl)-ethanol;1R-(4-{4-[2-(4-ethyl-piperazin-1-yl)-
Pyrirtiidin-4-
yl]-3R.5S-dimethyl-piperazin-1-yl}-pyrimidin-2-ylrethanol;1 R-(4-
{3R,5S~imethyl-4-(2-
(4-methyl-imidazol-1-ylj-pyrimidin-4-ytj-piperazin-1-yl}-pyrimidin-2-yl)-
ethanol; 1R-(4-
{3R,5S-dimethyl-4-[2-(2-methyl-imidazol-1-yl)-pyrimidin-4-ylj-piperazin-1-y(}-
pyrimidin-
2-yl~ethanol; 1R-(4-{4-[2-(2,4-dimethyl-imidazol-1-yl~pyrimidin-4-yl]-3R,5S-
dimethyl-
piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-(4-{4-[2-(4-isopropyl-Plperazin-1-
yl)-
pyrimidin~-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl~ethanol; 1R-(4-
{3R,5S-
dimethyl-4-[4-methyl-6-(4-methyl-piperazin-1-yIH1,3,5]triazin-2-Yl)-Piperazin-
1-YI}-
pyrimidin-2-yl~thanot;1R-{4-[4-(4-methoxy-6-methyl-[1,3,5]triazin-2 yl~-3R,5S-
dimethyl-piperazin-7-y~-pyrimidin-2-y1}-ethanol;1R-(4-[4-(4,6-dimethoxy-
[1,3.5]triazin-
2-yl~3R.5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yt}-ethanol;1R-{4-[4-(4-ethoxy-
6-
methyl-[1,3,5]triazin-2-yl~3R,5S-dimethyi-piperazin-1-yt)-pyrimidin-2-yl}-
ethanol; 1R_ .
{4-[4-(4-isopropoxy-8-methyl-[7,3,5]triazin-2-yl)-3R,5S-dimethyf-piperazin-1-
yl]-
pyrimidin-2-yl}-ethanol; 1R-{4-[3R,5S-dimethyl-4-(4-phenyl-[1,3,S~ria~zin-2-
yl}-
piperazin-1-y(]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-hydroxymethy!-6-n~ethoxy-
j1,3.5]triazin-2-ylr3R.5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-
{4-{4-(4-
isopropoxy-6-methoxy-[1,3,5]triazin-2-yIr3R.5S~imethyl-piperazin-1-yIj-
pYrirrlidin-2-
yl}-ethanol; 1R-{4-[4-(4-isopropyl-[1,3,5]triazin-2-yl)-3R,5S~iimethyl-
piperazin-1-yt]-
pyrimidin-2-yl}-ethanol; 1R~4-[4-(4-ethyl-methoxy-[1,3.5)biazin-2 ylj-3R,5S-
dimethyl-piperazin-1-ylj-pyrimidin-2-y(}-ethanol; 1R-{4-[4-(4,6-dimethyl-
pyrimidin-2-yl}-
2R.6S-dimethyl-piperazin-1 ylj- pyrimidin-2-YI)-ethanol;1R-(4-~4-(4-
hydroxymethyl-6-
methyl-pyrimidin-2-yl)-2R,6S-dimethyl-piperazin-1-ylj.pyrimidin-2-yl}-ethanol;
1R-{4-
[2R,6S-dimethyl-4~-(4-[1,2,4]triazo!-1-yf-pyrimidin-2-yl~piperazin-1 y(j-
pyrimidin-2-ylr
ethanol;1 R-(4-[4-(2.6-dimethyl-pyrimidin-4-yly-2R,6S-dimethyl-piperazin-1 y~-
pyrimidin-2-yt}-ethanol; 1 R-(4-{4-[2-(1 R-hydroxy~thyl~Pyrimidin-4-yl]-2R.fiS-
dimethyl-
piperazin-1-Y(}-pYrimidin-2-yl~ethanol;1R-{4-[4-(2-hydroxymethyl-6-methyl-
pyrimidin-


CA 02484282 2000-03-16
pC'flIB00100296
WO 00!59510
-46-
4-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-y1}-ethanol; 1 R-(4-{4-(2-(1
S=hydroxy-
ethyI~PYnmidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-PYrimidin-2=yf~ethanot: 1
S-(4-{4-
[2-(1 R-hydroxy-ethyl~Pyrimidin-4-YI)-2R,6S-dimethyl-piperazin-1-yl}-Pyrimidin-
2-yl~
ethanol; 1-{4-[4-(2-acetyl-pyrimidin~-yl)-2R,6S-dimethyl-piperazin-1-YI]-
pyrimidin-2-
yl}-ethanone; 1 RS-(4-{4-[2-(1 RS-hydroxy-ethyl)-pyrimidin-4-ylj-2R,6S-
dimethyl-
piperazin-1-yl}-pyrimidin-2-yl~-ethanol; (4-(4-(2-(1R-hydroxy-ethyl)-pyrimidin-
4-y1]-
3R,5S-dimethyf-piperazin-1-yl)-pyrimidin-2-yl~-ethanone; 1R-{4-[2R,6S-dimethyl-
4-(2-
morpholin-4-yl-pyrimidin-4-yl)-piperazin-1-yQ-pyrimidin-2-yl)-ethanol; 1 R-(4-
{2R,6S-
dimethyl-4-(2-{4-methyl-piperazin-1 yl}=pyrimidin-4-yl]-piperazin-1-yl}-
pyimidin-2-yl~
ethanol; 1 R~4-[2R,6S-dimethy!-4-(2-[1,2,4]triazol-1-yl-pyrimidin-4-yl)-
Piperazirrl-yl]-
pyrimidin-2-yi)ethanol;1R-(4-{4-(2-(1R-hydroxy-ethyl)-pyrimidin-4-ylj-2R,fiR-
dimethyl-
piperazin-1-yl}-pyrimidin-2-yl~ethanol;1 R-(4-{4-[2-(4-ethyl-piperazin-1
yl~pyrimidin-4-
yQ-2R.6S~imethyl-piperazin-1-yl}-pyrimidin-2 yl~ethanol; 1R-(4-{2R,6S-dimethyl-
4-[2-
(4-methyl-imidazol-1-ylrpyrimidin-4-ytj-piperazin-1 yl}-pyrimidin-2-yl}-
ethanol; 18-(4-
{4-[2-(2,4-dimethyl-imidazol-1-yl~Pyrimidin-4-yt]-2R.6S-dimethyl-piperazin-1-
yl}-
pyrimidin-2-y1)-ethanol; 1R-{4-[2R,6S-dimethyl-4-(4-morpholin-4-yl-
(1,3,5]triazin-2-yl~
piperazin-1-y~-pyrimidin-2-Y1}-ethanol; 1R-(4-(4-(4-rr~thoxy-6-methyl-
[1.3,5]triazin-2-
yl)-2R,6S-dimethy(-piperazin-1-yfj-Pyrimidin-2-YI}-ethanol; 1 R-[4-(4-(4.6-
dimethoxy_
[1.3.51thazin-2-yl~2R,6S~imethy>-piperazin-1-ylj-pyrimidin-2-yl}-ethanol;1 8-
{4-
[2R,6S-dimethyl-4-(4-phenyl-(1,3,5]triazin-2-yl)-piperazin-1'-ylj-pyrimidin-2-
yl}-ethanol;
1 R-{4-[4-(4-hydroxymethyl-6-methyl-pyrimidin-2-yIr3S-methyl-piperazin-1-yl]-
pyrimidin-2-yl}-ethanol; 1R-{4-[4-(2-hydroxymethyl-pyrimidin-4-yl~3S-methyl-
PiPe~n-1-Y9-PYnmidin-2-yl}-ethanol; 1R-{4-[4-(2-hydroxymethyl-6-methyl-
PYrimidin-
4-yl~3S-methyl-piperazin-1-yI]-py-rimidin-2-yl}~thanol;1 R-[4-(3S-methyl-4-
oxazolo[5,4-b]pyridin-2-Yl-PiPerazin-1-YIrPYrimidin-2-y(j-ethanol;1R-(4-(3S-
methyl-4-
oxazolo[4,5-b]pyridin-2-yl-piperazin-1-yl~pyrimidin-2-ylJ-ethanol;1R-j4-(3S-
methyl-4-
quinoxalin-2-yt-piperazin-1 yl}.pyrimidin-2-yl]~thanot; (4-{4-[2-(1R-hydroxy-
ethyl
pyimidin-4-yt]-2R,5S-dimethyi-piperazin-1-yl}-pyrimidin-2-y1)-ethanol; 1 R-{4-
(4-(4,6-
dimethyl-(1.3.5]triazin-2-yly-3R.5S-dimethyl-piperazin-1 yl]-pyrimidin-2-y1}-
ethanol:1 R-
{4-[3R,5S-~imethyl-4-(4-methyl-phenyl-[1,3,5]triazin-2 yi)-piper3zin-1
yfjpyrimidin-2-
yI}-ethanol; 1R-{4-[4-(4-cydcpropyl-[1,3,5]triazin-2-yl~3R,5S-dimethyl-
piperazin-1-ylJ-
pyrimidin-2-yI}-ethanol;1 R-{4-[4-(4-cydopropyl-[1.3,5jtriaan-2-
yl~2R,6S~dimefhyf-
piperazin-1-y(]-pyrimidin-2-y(}-ethanol; 1R-{4-[4-(4,6-dimethyl-[1,3,5]triazin-
~2 yl~


CA 02484282 2000-03-16
WO 00159510 PCT/IB00/00296
-4?-
2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yt}-ethanol; 1R-{4-[4-(4-
hydroxymethyl-6-
phenyl-[1,3.5]triazin-2 ylr2R,6S-dimethyl-piperazin-1-ylj-Pyrimidiri-2-yi}-
ethanol; 1 R-
{4-[4-(4-methoxy-6-methoxymethyi-[1,3,5]triazin-2 yl~2R,8S-dimethyl-piperazin-
1-yl]-
pyrimidin-2-yt]-ethanol; 1R-(4-[2R,fiS-dimethyl-4-(4-methyl-[1,3,5jttiazin-2-
yt)-
piperazin-1-yl]-pyrimidin-2-yl-ethanol;1-{4-[4-(2-acetyl-pyrimidin-4-
yl~2R=,6S'-
dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanone; 1-(-4-{4-[2-(1R-hydroxy.-
ethyp
pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl)~thanone; 1 R-{4-
j4-(4-
methoxymethyt-6-phenyl-[1,3,Sj-triazin-2-yl)-2R,6 S-dimethyi-piperazin-1-yl]-
pyrimidin-
2-yi}-ethanol; and 1 S-(4-{4-[2-(1 R-hydroxy-ethyl)-pyrimidin-4 ylj-2R,6S-
dim~thyl-
piperazin-1-yf}-pyrimidin-2-yl)~thanol.
A compound of the formula I"
R'
R3
~N
N R'
IA
wherein:
R' is C-(OR°°)R'R5, where R°° is independently
(C,-C,)alkyl, ber~zyl, (C,-
C6)alkylcarbonyl or phenyicarbonyl, where said benzyi and said phenyl are
optionally
substituted with up to three (C,-C,)alkyl, (C,-C,)alkoxy, halo or vitro;
R' and RS are each independently hydrogen, methyl, ethyl or hydroxy-(C,-
C,~Ikyl;
RZ is hydrogen, (C,-C,)alkyl or (C,-C,)alkoxy;
R' is a radical of the fom~ula

CA 02484282 2000-03-16
WO 00159510 PCT/IB00/0029G
~ _R' ~ . : Rm ~ ,
TN N I RZs
I
z)aG G, ( z)r 3G~ N
R24
3a N ; N .
R
' R~ ~ , R3~ N ,
R29 N se
~R
~~'~~'N
Rn
R~ _ I


CA 02484282 2000-03-16
WO 00/59510
-49-
pCTIIB00/00296
R3s
R33 33 ~ ~ R37
R \
A_N ~N 0
\ B N /N O
R~ ~ R~
R3s R3s
R3a I . Rsn I ,
R3.
R3s R3' R4Z' Rsz
HO R~z'
N~R~u R4, R~u R4, R"a
E
N N
R3e R3s R~ I R~ (
' ~sa ' R~~ Y~
a. , Y
R \NiYwRa3 Ras ~ s~ N
~N~R
~s
R \ ~Y (CHz)m (CHI)n
N
R3m I ' R3n ~ .
R,s/N\ R~
Y'
N i \ R43
Ru\N~Y WRaa
(CHz)k
or
N
Rap I N
R3a I _


CA 02484282 2000-03-16
WO 00/59510 PCT/IB00/00296
-50-
wherein said radical of formula R'' is substituted by R6,~ R' and R°;
said radical of formula R'° is substituted by R'°, R'9 and
R~°;
G, G' and GZ are taken separately and are each hydrogen and R° is
hydrogen; (C,-
C,)alkyl, (C,-C,)alkoxycarbonyl, (C,-C,)alkoxy-(C,-C,~Ikyl, hydroxy-(C,-
C,)alkyl or
phenyl optionally independently substituted with up to three hydroxy, hafq,
hydroxy-
(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl or (C,-C,)alkoxy,
wherein said
(C,-C,)alkyl in the definition of R° and said (C,-C,)alkoxy in the
definition of R°are
optiona0y and independently substituted with up to five fluoro; R' and
R° are each
independently hydrogen or (C,-C,)alkyl; or
G and G' are taken together and are (C,-C,)alkylene and R6, R', R° and
G~ are
hydrogen; or
G' and Gz are taken together and are (C,-C,)alkylene and R°, R',
R° and G are
hydrogen;
qis0orl;
X is a covalent bond, -(C=NR'°~, oxycarbonyl, vinylenylcarbonyl,
oxy(C,-
C,)alkylenylcarbonyl, (C,-C,)alkylenylcarbonyi, (C,-C,)alkenylcarbonyl,
thio(C,-
C,)alkylenylcarbonyl, vinylenylsulfonyl, sulfinyl-(C,-C,)alkylenylcarbonyl,
sulfonyl-(C,-
C,)alkylenylcarbonyl or carbonyl(C°-C,)alkylenylcarbonyl; wherein said
oxy(C,-
C,)alkylenyfcarbonyl, (C,-C,)alkylenylcarbonyl, (C,-C,)alkenylcarbonyf and
thio(C,-
C,)alkyfenylcarbonyl in the definition of X are each optionally and
independently
substituted with up to two (C,-C,)alkyl, benzyl or Ar; said vinylenylsulfonyi
and said
vinyienyicacbonyl in the definition of X are optionally substituted
independently on one
or two vinylenyi carbons with (C,-C,)alkyl, benzyl or Ar; and said
carbonyl(C°-
C,)alkylenylcarbonyi in the definition of X is optionally substituted
indepedently with up
to three (C,-C,)alkyl, benzyl or Ar;
R'° is hydn~gen or (C,-C,)alkyl;
R° is (C.°-C,)cydoalkyl, Ar'-(C°-C,)alkylenyl or (C,-
C°)alkyl optionally substituted with
up to five fiuoro; provided that when q = 0 and X is a covalent bond,
oxycarbonyl or
(C,-C,)alkylenylcarbonyl, then R° is not (C,-C°)alkyl;
Ar and Ar' are independently a fully saturated, partially saturated or fully
unsaturated
five- to eight-membered ring optiona8y having up to four heteroatoms selected
independently from oxygen, sulfur and nitrogen, or a bicydic ring consisting
of two


CA 02484282 2000-03-16
WO 00159510 PCTIIB00/00296
-51-
fused independently partially saturated, fully saturated or fully unsaturated
'five- to
seven-membered rings, taken independently, optionally, having up to four
heteroatoms
selected independently from nitrogen, sulfur and oxygen, or a tricydic ring
consisting
of three fused independently partially saturated, fully saturated or fully
unsaturated five
to seven membered rings, taken independently, optionally having up to four
heteroatoms selected independently from nitrogen, sulfur and oxygen, said
partially
saturated, fully saturated ring or fully unsaturated monocydic ring, bicydic
ring or
tricydic ring optionally having one or two oxo groups substituted on carbon or
one or
two oxo groups substituted on sulfur,
Ar and Ar' are optionally independently substituted on carbon or nitrogen, on
one ring
if the moiety is monocydic, on one or both rings if the moiety is bicydic, or
on one, two
or three rings if the moiety is tricydic, with up to a total of four
substituents
independently selected from R", R'~, R'3 and R"; wherein R", R'z, R'3 and R"
are
each taken separately and are each independently halo, formyt, (C,-
C6)alkoxycarbonyl, (C,-Cs)alkylenyloxycarbonyl, (C,-C,)alkoxy-(C,-C,)alkyt,
C(OH)R'5R'6, naphthyl, phenyl, imidazolyl. PY~YI, t~yl, morpholinyi, (Ca-
C,)alkylsulfamoyl, N-(Co-C,)alkytcarbarr~yl, N,N-di-(C,-C,~Ikylcarbamoyl, N-
phenylcarbamoyl, N-(C,-C,~Ikyl-N-phenylcarbamoyt, N,N-diphenyi carbamoyl, (C,-
C,~Ikylcarbonyiamido, (C9-C,)cydoalkytcarbonylamido, phenylcarbonytamido,
piperidinyl, pyrrolidinyl, piperazinyl, cyano, benzimidazolyl, amino, anilino,
pyrimidyl,
oxazolyl, isoxazolyl, tetrazolyl, thienyl, thiazolyt, benzothiazolyl,
pyrroty(, pyrazolyt,
tetrahydroquinoiyl, tetrahydroisoquinoiyl, benzoxa~oiyl, pyridazinyl,
pyridyloxy,
pyridylsutfanyl, furanyl, t3-(C,-C,)alkyl-3,t3-diaza{3.2.1)bicydooctyl,
3,5~lioxo-1,2,4-
triazinyl, phenoxy, thiophenoxy, (C,-C,)atkylsulfanyl, (C,-C,)alkylsutfonyt,
(C~-
C,)cydoalkyl, (C,-C,)alkyl optionally substituted with up to five fluoro or
(C,-C,~tkoxy
optionally substituted with up to five fluoro; said naphthyl, phenyl, pyridyl,
piperidinyl,
benzimidazolyl; pyrimidyl, thienyt, benzothia~olyl. PY~Iy<.
tetrahydroquinolyl,
tetrahydroisoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfanyl,
furanyl,
thiophenoxy, anilino and phenoxy in the definifion of R", R'Z, R" and R" are
optionally substituted with up to three substituents independently selected
from
hydroxy, halo, hydroxy-(C,-C,~lkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,~,~Ikyl
optionally
substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted
with up to five
fluoro; said imidazolyl, oxazolyl, isoxazolyl, thiazolyl and pyrazolyl in the
defiri~tion of


CA 02484282 2000-03-16
wo oas9sio rcr~aooioo2~
-S2-
R". R'~, R" and R" are optionally substituted with up to two subsfttuents
independently selected from hydroxy, halo, hydroxy-(C,-C,)atkyl, (C,-C,)atkoxy-
(C,-
C,)alkyi, (C,-C,)aikyl optionally substituted with up to fnre fluoro and (C,-
C,)alkoxy
optionally substituted with up to five fluoro; said morpholinyl in the
definition of R",
S R'2, R" and R" is optionally substituted with up to two substi~ents
independently
selected from (C,-C,)alkyi; said pyrrolidinyl in the definition of R", Ru,
R','~and'R" is
optionalty substituted with up to two substituents independently selected from
hydroxy,
hydroxy-(C,-C,)alkyl, (C,-C,)aikoxy-(C,-C,)alkyi, (C,-C,)alkyi optionally
substituted
with up to five fluoro and (C,-C,)aikoxy optionally substituted with up to
five fluoro; said
piperazinyi in the definition of R", R'=, R" and R" is optionally substituted
with up to
three substituents independently selected from (C,-C,~Ikoxy-(C,-C,~Ikyl;
hydroxy-
(C,-C,)alkyl, phenyl, pyridyt, (Co-C,~lkylsulfamoyt, (C,-C,~ikyl optionaliy~
substituted
with up to fwe fluoro and (C,-C,)alkoxy optionally substituted with up to five
fluoro: said
triazolyt in the def nition of R", R", R" and R" is optionally substituted
with hydroxy,
halo, hydroxy-(C,-C')atkyt, (C,-C,~Ikoxy-(C,-C,)alkyi, (C,-C,)aiky! optionally
substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted
with up to five
fluoro; said tetrazotyl in the definition of R", R'z, R" and R" is optiona!!y
substituted
with hydroxy-(C2-C3~iky1 or (C,-C,)aHcyl optionally substituted with up to
five fluoro;
and said phenyl and pyridyl which are optionally substituted on piperazine in
the
definition of R", R'~, R" and R" are optionally substituted with up to three
hydroxy,
halo, hydroxy-(C,~C,)a)kyl. (C,-C')alkoxy-(C,-C,)alkyl. (C,-C,)alkyl
optionally
substituted with up to five fluoro and (C,-C,)alkoxy op6onaliy substituted
with up to five
fluoro; or
R" and R's are taken together on adjacent carbon atoms and are
2S -CH=OC(CHs)ZOCHZ- or -0-(CH~p-O-, and R" and R" are taken separately and
are
each independently hydrogen or (C,-C'~Ikyt;
pisl,2ot3;
R's and R'6 are taken separately and are each independently hydrogen, (C,-
C,~Ikyl
optionally substituted with up to five fluoro; or R's and R'6 are taken
separately and R'°
is hydrogen arid R'6 is (C,-Cs)cycloalkyl, hydroxy-(C,-C,)alkyi, phenyl,
pyridyi,
pyrimidyl. thienyt, furanyt, thiazolyl, oxazolyl, imidazolyl, benzothiazolyl
or
benzoxazolyl; or R's and R'6 are taken together and are (C,-Cs~lkylene;


CA 02484282 2000-03-16
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-53-
G', G' and G5 are taken separately and are each hydrogen; r is v0: R'°
is hydrogen,
(C,-C,)alkyl, (C,-C,)alkoxycarbonyl, (C,-C,)alkoxy-(C,=C,~Ikyl, hydroxy-(C,-
C,~lkyl or
phenyl optionally independently substituted with up to three hydroxy, halo,
hydroxy-
(C,-C,)atkyl, (C,-C,)alkoxy-(C,-C,)aikyl, (C,-.C,)alkyl or (C,-C,)alkoxy,
wherein said
(C,-C,)alkyl in the definition of R6 and said (C,-C,)alkoxy in the definition
of RB are
optionally and independently substituted .with up to five fluoro; and
R'° and R~° are
each independently (C,-C,)altcyt; or
G', G' and G5 are taken separately and are each hydrogen; r is 1; R'°
is hydrogen,
(C,-C,)atkyl, (C,-C,)alkoxycarbonyl, (C,-C,)alkoxy-(C,-C,)alkyl, hydroxy-(C,-
C,)alkyl or
phenyl optionally independently substituted with up to three hydroxy, halo,
hydroxy-
(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyt. (C,-C,~Ikyl or (C,-C,)alkoxy,
wherein said
(C,-C,)aikyl in'the definition of R6 and said (C,-C,)alkoxy in the definition
of Rbare
optionally and independenfly substituted with up to five_fiuoro; and R" and
R~° are
each independently hydrogen or (C,-C,)a(kyl; or
G' and G' are taken together and are (C,-C,)alkylene; r is 0 or 1; arui
R'°, R", R~° and
GS are hydrogen; or
G' and G5 are taken together and are (C,-C,)alkylene; r is 0 or 1; and
R'°, R'°, Rm and
G' are hydrogen;
R" is SOxNR~'R~, CONRZ'R~, (C,-C6)alkoxycarbonyl,. (C,-C6)atkylcarbonyl, Arz-
carbonyl, (C;-C6)atkylsulfonyl, (C,-C6)a!lcylsulfinyl, Arz-sulfonyl, Ars-
sufinyl and (C,-
C6)alkyl:
R2' and R~ are taken separately and are each independently selected from
hydrogen,
(C,-C°)alkyl, (C3-C,)cydoalkyt and Arz-(Co-C,)alkylenyl; or
R~' and R~ are taken together with the nitrogen atom to which they are
attached to
form azetidinyl, pyrrolidinyl, piperidinyt, piperazinyl, morphoUnyl, azepinyl,
azabicyGo[3.2.2jnonanyl, azabicydo[2.2.1 jheptyl, fi,7-dihydro-SH-
dibenzo[c,ejazepinyl,1,2,3,4-tetrahydro-isoquinolyt or 5,6,7,8-
tetrahydropyrido[4,3-
d]pyrimidyl; said azetidinyl in the definition of RZ' and R~ is optionally
substduted
independently with one substituent selected from hydroxy, amino, hydroxy-(C,-
C,)alkyl, (C,-C,)aikoxy-(C,-C,~Ikyl, (C,-G,)atkyl optionally substituted with
up to free
fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said
pyrrolidinyl,
piperidinyl,~azepinyl in the definition of R=' and R~ are optionalhr
substituted
independently with up to two substituents independently selected 'from
hydroxy,


CA 02484282 2000-03-16
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amino, hydroxy-(C,-C,)aikyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,~ikyl
optionally
substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted
with up to five
fluoro; said morpholinyl in the definition of Rz' and R~ is optionally
substituted with up
to two substituents independently selected from fiydroxy-(C,-C,~Ikyl, (C,-
C,)alkoxy-
6 (C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro and
(C,-C,)alkoxy
optionally substituted with up to five fluoro; said piperazinyl in the
definition of,R~' and
R~ is optionally substituted independently with up to three substituents
independently
selected from phenyl, pyridyl, pyrimidyl, (C,-C,)alkoxyca~bonyf and (C,-
C,)alkyl
optionally substituted with up to five fluoro; said 7,2,3,4-tetrahydro-
isoquinolyl and said
5,6,7,8-tetrahydropyrido[4,3-dJpyrtmidy! in the definition of R2' and R~ are
optionally
substituted independently with up to three substituents independently selected
from
hydroxy, amino, halo, hydroxy-(C,-C,~lkyt, .(C,-C,~tkoxy-(C,-C,)alkyt, (C,-
C,~Ikyl
optionally substituted with up to flue fluoro and (C,-C,~lkoxy optionally
substituted
with up to five fluoro; and said 6,7-dihydro-SH-dibenzo[c,e)azepinyl in the
definition of
Rz' and R~ is optionally substituted with up to four substituents
independently
selected from hydroxy, amino, halo, hydroxy-(C,-C,~ltcyt, (C,-
C;)afkoxy~C,=C,)atiryl,
(C,-C,)alkyl optionally substituted with up to fnre fluoro and (C,-C,~Ikoxy
optionally
substituted with up to fnre fluoro; said pyrimidyl; pyridyl and phenyl which
are
optionally substituted on said piperazine in the definition of R2' and R~ is
optionally
substituted: with up to three substituents selected from hydroxy, amino,
hydroxy-(C,-
C,)atkyt, (C,-C,)alkoxy-~C,-C,~Ikyt, (C,-C,)alkyl optionally substituted with
up to five
fluoro and (C,-C,)alkoxy optionally substituted with up to flue fluoro;
Ar2 is independently defined as set forth for Ar and Ar' above;
said Are is optionally independently substituted as set forth for Ar and Ar'
above;
R~ is CONR~'R~ or S02R~'R~, wherein R~ is hydrogen (C,-C,~tkyt or Ar'-(C,p-
C,~Ikyienyi and R~ is Ar'-(Co-C,)atkylenyl; provided that when Ar' is phenyl,
naphthyl
or biphenyl, then R~' cannot be CONR~R~ where R~ is hydrogen or Ar' and
R~° is
R~' is hydrogen, (C,-C,)alkyl, (C,-C,)alkoxycarbonyl, (C,-C,)alkoxy-(C,-
C,~IkYI;
hydroxy-(C,-C,)alkyl or phenyl optionally independenby substituted with up to
three
hydroxy, halo, hydroxy-(C,-C,~alkyl, (C,-C,)alkoxy-(C,-C,)alkyi. (C,"C,~Ikyl
or (C,-
C,~Ikoxy, wherein said (C,-C,)alkyl in the defenition of R° and said
(C,-C,)alkoxy in
the definition of R° are optionally and independently substituted with
up to flue fluoro;


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-5b-
Ar' is independently defined as set forth for Ar and Ar' above; '
said Ar' is optionally independently substituted as set forth for Ar and Ar'
above;
RZ' is hydrogen or (C,-C,)alkyl;
R~° and R~ are each independently hydrogen,, hydroxy,, halo, hydroxy-
(C,-C,~Ikyl,
(C,-C,}alkoxy-(C,-C,)alkyl, (C,-C,~Iky! optionally substituted with up to five
fluoro, (C,-
C,~lkoxy optionally substituted with up to five fluoro, phenyl, pyridyl,
pyrimidyl, thienyl,
furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, S02NR'°R",
CONR'°R" or NR'°R";
said thienyl, pyrimidyt, furanyl, thiazolyi and oxazolyl in the definition of
R~° and R~ are
op~ona8y substituted by up to two hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-
C,)alkoxy-
i 0 (C,-C,)alkyl, (C,~C,)alkyl optionally substituted with up to five fluoro
or (C,-C,~lkoxy
optionally substituted with up to five fluoro; said phenyl, pyridyl, phenoxy
and
thiophenoxy in the definition of R" and R~ are optionally substituted by up to
three
hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,~lkoxy (C,-C,)alkyt, (C,-C,~Ikyl
optionally
substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted
with up to five
fluoro;
R'° and R" are each independently hydrogen, (C,-C,)alkyl, (C,-
C,)cydoalky! or
phenyl, said phenyl is optionally substituted with up to three hydroxy, halo,
hydroxy-
(C,-C,}alkyl, (C,-C,)alkoxy-(C,-C,~Ikyl, (C,-C,~Ikyl opfronally substituted
with up to
five fluoro or (C,-C,~lkoxy optionally substituted with up to five fluoco; or
R'° and R" are taken together with the nitrogen to which they are
attached to form
indolinyt, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; said
pyrrolidinyl and
piperidinyt in the definition of R'° and R" are optionally substituted
with up to two
hydroxy, amino, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-{C,-C,)alkyl, {C,-C,)alkyl
optionally substituted with up to five fluoro or (C,-C,}alkoxy optionally
substituted with
up to five fluoro; said indotinyl and piperazinyl in the definition of
R'° and R" are
optionally substituted with up to three hydroxy, amino, hydroxy-(C,-C,~Ikyl,
(C,-
C,)alkoxy-(C,-C,~alkyl, (C,-C,}atkoxycarbonyl, (C,-C,jalkyl optionally
subst~rted with
up to five fluoro of (C,-C,)alkoxy optionally substituted with up to five
fluoro; said
morphotinyl in the deftnition of R'° and R" is optionally substituted
with up to two
substituents independently selected from hydroxy-(C,-C,)alkyl, {C,-C,~lkoxy-
{C,-
C,~ikyl. (C,-C,~Ikyl optionally substituted with up to five fluoro and (C,-
C,)alkoxy
optionally substituted with up to five fluoro;
A is N optionally substituted with hydrogen or (C,-C,~Ikyl and B is carbonyl;
or


CA 02484282 2000-03-16
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-5ti-
A is carbonyl and 8 is N optionally substituted with hydrogen or,(C,-C,)alkyl;
R'~ is hydrogen or (C,-C,)alkyk
R" is phenyl, PYddYI. pYri~dYl, thiazolyl, oxazofyl. benzyi, quinoiyl,
isoquinoiyl,
phthalizinyl, quinoxanlyl, benzothiazoyl, benzoxazolyl, benzofuranyi or
benzothienyl;
said phenyl, pyridyl, pyrimidyl, thiazolyl, oxazolyl, benzyl, quinolyl,
isoquinolyl,
phthatizinyi, quinoxanlyl, benzothiazoyl, berizoxazolyl, benzofuranyi and
4enzothienyl
in the definition of R" are optionally substituted with up to three phenyl,
phenoxy,
NR~'R'~, halo; hydroxy, hydroxy-(C,-C.)alkyl, (C,-C.)alkoxy-(C,-C.~Ikyl, (C,-
C.~Ikyl
optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally
substituted with
up to fnre fluoro;
R~' and R'~ are each independently hydrogen, (C,-C, alkyl), phenyl or
phenylsutfonyt;
said phenyl and phenylsulfonyl in the definition of R" and R'~ are optionally
substituted with up to three halo, hydroxy, (C,-C,~Ikyl optionally substituted
with up to
five fluoro or (C,-C,)aikoxy optionally substituted with up to five fluoro;
D is CO, CHOH or CHI;
E is O, NH or S;
R'~ and R" are taken separately and are each independently hydrogen, halo,
cyano,
hydroxy, amino. (C,-C6)alkylamino, di-(C,-Cs~lkylamino, pyrrolidino,
pipeddino,
morpholino, (C,-C,~tkoxy-(C,-C,)atkyl, hYdroxY-(C,-C.~lkyl, Ar''. (C,-C.)alkyl
optionally substituted with up to five fluoro or (C,-C,~Ikoxy optionally
substituted with
up to five fluoro;
R'°, R'~ and R'° are each independently hydrogen or (C,-C,}-
alley!;
Ar is phenyl, furanyl, thienyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl;
said Ar~ being
optionally substituted with up to three hydroxy, (C,-C,~Ikoxy-(C,-C,~Ikyle
halo,
hydroxy-(C,-C,~lkyl, (C,-C,~Ikyl optionally substituted with up to 5ve fluoro
or (C,-
C,~Ikoxy optionally substituted with up to five fluoro; or
R'~ and R" are taken together on adjacent carbon atoms and are -O-(CHI,-O-;
tisl,2or3;
Y is (CZ-Cs~lkylene:
R", R'S and R'° are each independently hydrogen or (C,-C,)alkyl;
m and n are each independently 1, 2 or 3, provided that the sum of m and n is
2, 3 or
4;
k is 0,' 1, 2, 3 or 4;


CA 02484282 2000-03-16
WO OOI59510 PCT/IB00/00Z96
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Y' is a covalent bond, carbonyl, suffonyl or oxycarbonyt;
R" is (C,-C,)cydoatkyi, Ar5-(Co-C,jalkylenyt, NR"R'° or (C,-C6)alkyl
optionally ' '
substituted with one to five fluoro; provided that when Y' is a covalent bond
or
oxycarbonyl, then R" is not NR"R'°;
R" and R'° are taken separately and are each independently selected
from hydrogen,
Ars, (C,-Ce)alkyl and Ars (C4-C,)alkylenyt; or
R" and R'° are taken together with the nitrogen atom to which they are
attached to
form azetidinyl, pyrroiidinyl, pipecidinyl, .piperazinyl, mo~holinyl,
azepinyl,
azabicyclo[3.2.2]nonanyl, azabicydo[2.2.t]heptyl,1,2.3,4-
tetrahydroisoquinoiyt, 6,7-
111 dihydro-5H-dibenzo[c,e]azepinyl or 5,6,7,8-tetrahydropyrido[4,3-
d]pyrimidyi;said
azetidinyt in the deftnition of R" and R'° are optionally substituted
with one hydroxy,
amino, hydroxy-(C,-C,)alkyl, (C,-C,)aikoxy-(C,-C,)alkyl, (C,-C,)alkyl
optio~aliy
substituted with up to five fluoro or (C,-C,)aikoxjr optionally substituted
with up to five
fluoro; said pyrroiidinyl, piperidiny! and azeptnyl in the definition of R"
and R'° are
optionally substituted with up to two hydroxy, amino, hydroxy-(C,-C,)alkyl,
(C,-
C,)alkoxy-(C,-C,)aikyl, (C,-C,)alkyl optionally substituted with up to fire
fluoro or (C,-
C,)alkoxy optionally substituted with up to five fluoro; said morpholinyt in
the definition
of R" and R'° is optionally substituted with up to two substituents
independently
selected from hydroxy-(C,-C,)alkyl, (C,-C,)atkoxy-(C,-C,)alkyl, (C,-C,)alkyl
optionally
substituted with up to five fluoro and (C,-C,~alkoxy optionally substituted
with up to five
fluoro; said piperazinyl, 1,2,3,4-tetrdhydroisoquinoiyl artd 5,8,7,8-
tetrahydro[4,3-
d]pyrimidyl in the definition of R" and R'° are optionally substituted
with up to three
hydroxy, amino, Nato, hydroxy-(C,-C,)atkyl, (C,-C4)alkoxy-(C,-C,)alkyl, (C,-
C,)alkyl
optionally substituted with up to five fluoro or (C,-C,)atkoxy optionally
substituted with
up to five fluoro; and said 6,7-dihydro-5H-dibenzo[c:e]azepinyl in the
definition of R"
and R'° are optionally substituted with up to four hydroxy, amino,
halo, hydroxy-(C,-
C,~Ikyl, (C,-C,)alkoxy-(C,-C,)aikyt. (C,-C,)alkyi optionally substituted with
up to five
fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro;
Ar5 is independently defined as set forth for Ar and Ar' above;
3t? Ar5 is optionally independently substituted as set forth for Ar and Ar'
above;
R'~ and R'~ are independently hydrogen, (C,-C,jcydoaikyl, Ars-(Co-C3~ikyleny,
Ata-
(C=-C,~Ikenyl, Arb-carbonyl or (C,-C~alkyf optionally substituted with up to
five fluoro;
Ar6 is independently de5ned as set forth for Ar and Ar' above;


CA 02484282 2000-03-16
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-58-
Ar° is optionally independently substituted as set forth for Ar and Ar'
above; and
R" and R"' are each independently hydrogen or (C,=tr,~lkyl.
A compound of formula 1" selected from 1 R-(4-{4-[2-(1 R-butyryloxy-ethyl}-
pyrimidin-4-yt]-2R,6S-dimethyl-piperazinyl-yl}-pyrimidin-2-yl)-ethyl butyrate;
7 R-(4-{4-
[2-(1 S-butyryloxy-ethyl~Pyrimidin-4-yt}-2R.6S-dimethyt-piperazin-1-YI}-
Pyrimidin-2-yi)-
ethyl butyrate:1 S-(4-{4-[2-(1 R-butyiyloxy-ethyl)-pyrimidin-~4-ytj-2R,6S-
dimethyl-
piperazin-1-yl}-pyrimidin-2-yl)-ethyl butyrate; (E)-1 R-{4-[4-(2-methyl-32-
phenyl-
aayloyl~piperazin-1-YIJ-Pyrimidin-2-yl}-ethyl acetate; (R~1-[4-(4-quinoxafin-2-
yi-
piperazin-1-ylrpyrimidin-2-yl]-ethyl acetate;1 R-(4-{4-j2-(1RS-hydroxy-ethyt~
pydmidin-~4-y(]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethyl
butyrate;1 RS-(4-
{4-[2-(1 R-hydroxy-ethyl)-Pyrimidin-.4-yl)-3R,5S=dimethyl-piperazin-1-YI)-
pyrimidin-2-ylj-
ethyl butyrate; iR-[4-(3S-methyl-4-oxazolo[5,4-b)pyridin-2-yl-piperdzin-i-
yl~pyrimidin-
2-yQ-ethyl butyrate; 1R-{4-[3R,5S-dimethyi-4-(4-methyl-6-phenyl-[1,3,5)tria~n-
2 yi)-
piperazin-1-Yil-PY~midin-2-Yl}-ethyl butyrate: 1R-(4-[4-(4-cYdoProPYi-
[~.3,5)hiazin-2-
yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethyl butyrate; 1R-
{4..[4.(4-
cydopropyf-[1,3,5jtriazin-2-yl)-2R.6S-dimethyt-piperazin-1-yl]-pyrimidin-2-yl}-
ethyl
butyrate; iR-{4-[4-(4,6-ciimethyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-
piperazin-1-yt)-
PYhmidin-2-YI}-ethyl butyrate;1R-{4-[4-(4-hydroxymethyl-6-phenyl-
[1,3,5)triazin-2-yl~
2R.6S-dimethyt-piperazin-1-yi]-pYrimidin-2-y!}-ethyl butyrate: 1R-(4-[4-(4-
methoxy-6-
methoxymethyl-[1,3,5)triazin-2-yl~-R,6S-dimethyt-piperazin-1 yiJ-pyrimidin-2-
yl}-ethyl
butyrate; and 1R-{4-[2R,6S-dimethyl~-(4-methyl-[1,3,5)triazin-2-yl~-piperazin-
1-ylJ-
PY~midin-2-yi)-ethyl butyrate.
This invention is atso directed to a mutual prodnrg of the fomwta te,
R'
R~
~N
N R'
IB
wherein:
R' is C-(OR°')R'R5, wherre R°' is independently an acy! radical
of a cartioxyiic add
aldose reductase inhibitor,
R' and R5 are each independently hydrogen, methyl, ethyl or hydroxy-(C,-
C,)alkyl;
RZ is hydrogen, (C,-C,~Ikyl or.(C,~,)alkoxy;

CA 02484282 2000-03-16
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WO 00/59510
-59-
radical of the formula
R fs a , , ,
X,~R9 , , , , Rt7 R23
I
~N , ' ) G3N 4 a N
G C Z ~ GAG R2
~G N N ,
R~ ~ R3b l ~ R~ I
..
. . R2B v
Rzs N Rae
/ N RZS
R2~ ~ R
R~ N ~ ~ R3f ~ ,


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WO 00/59510
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PGT/IBOOIOOZ96
Rae , ,
Rs~
R33 R33 y
/ ~N D
A~N ~ \
B , N /N O
Rs2 ~ , Rs~ . R3a ~Rss . ,
Rs9 N R3" ' R3' N
R4za R42
R"
R36 HO R4z ,
R4ta R4t R4ts
N 1 R4o R4'
E , , R3i N
R3s R3k
R
N
R3i
,..,43 R4~ Y1
Y, ~/tt L
N
R ~N,Y~R43 R~~N~Ra4
,s , ~Ct"~~yCm ~CH~~"
R ~NiY .
3m ~ R3n
R R4a /N \ R~
N~Yt~ Ra3
R'4\N~YwRa3
~C~~k
Of
R3v ~ Rye


CA 02484282 2000-03-16
WO 00/59510 1PCT/IB00/00396
-61-
wherein said radical of formula R" is substituted by f~,1Z' and R°;
said radical of formula R'° is substituted by R'°, R'9 and
R~°;
G, G' and G2 are taken separately and are each hydrogen and R6 is hydrogen,
(C,-
C,)alkyl, (C,-C,)alkoxycarbonyl, (C,-C,)alkoxy-(C,-C,)alkyi, hydroxy-(C,-
C,)alkyl or
phenyl optionally independently substituted with up to three hydroxy, halo,
hydroxy-
(C,-C,)alkyl, (C,-C;)alkoxy-(C,-C,)alkyl, (C,-C,~Ikyl or (C,-C,~tkoxy, wherein
said
(C,-C,)alkyl in the definition of R6 and~said (C,-C,)alkoxy in the definition
of R6 are
optionally and.independentfy substituted with up to five fluoro; R' and
R° are each
t 0 independently hydrogen or (C,-C,~Ikyl; or
G and G' are taken together and are (C,-C,)alkytene and R6, R', R° and
GZ are
hydrogen; or
G' and Gz are taken together and are (C,-C3)alkylene and R6, R', R' and G are
hydrogen;
1~ qis0orl;
X is a covalent bond, -(C=NR'°)-, oxycarbonyl, vinylenylcarbonyl,
oxy(C,-
C,)alkylenylcarbonyl, (C,-C,)alkylenyicarbonyl, (C,-C,~Ikenylcart~onyl,
thio(C,-
C,)aikylenytcarbonyl, vinylenytsulfonyl, sulfinyl-(G,-C,~lkylenylcarbonyl,
sulfonyf-(C,-
C,)alkylenylcarbonyl or carbonyl(C°-C,)alkylenylcarbonyl; wherein said
oxy(C,-
20 C,)alkylenylcarbonyl, (C,-C,)alkyfenyicarbonyl, (C,-C,)atkenylcart~onyl and
thio(C,-
C,)aikyienyicarbonyl in the definition of X are each optionally and
independently
substituted with up to two (C,-C,)alkyl, benzyl or Ar said vinytenylsulfonyl
and said
vinylenylcarbonyl in the definition of X are optionally substituted
independently on one
or two vinyienyl carbons with (C,-C,)alkyl, benzyf or Ar; and said
carbonyl(C°-
25 C,)alkytenylcarbonyl in the deflri~tion of X is optionally substituted
indepedently with up
to three (C,-C,)alkyl, benzyl or Ar,
R'° is hydrogen or (C,-C,~tkyl;
R' is (C,-C,)cydoalkyl, Ar'-(C°-C~)alkylenyl or (C,-C6~Ikyl optionally
substituted with
up to five fluoro; provided that when q = 0 and X is a covalent bond,
oxycarbonyl or
30 (C,-C,~Ikylenylcarbonyl, then R' is not (C,-Ca~lkyl;
Ar and Ar' are independently a fully saturated, partially saturated or fully
unsaturated
five- to eight-membered ring optionally having up to four heteroatoms selected
independently from oxygen, sulfur and nitrogen, or a bicydic ring consisting
of two


CA 02484282 2000-03-16
WO 00159510 PCT/IB00/00~96
-62-
fused independently partially saturated, fully saturated or fully unsaturated
t'ave- to ,
seven-membered rings, taken independently, opttonalty having up to four
heteroatoms 1
selected independently from riatrogen, sulfur and oxygen, or a tricydic ring
consisting
of three fused independently partially saturated, ftally saturated or fully
unsaturated fare
to seven membered rings, taken independently, optionally having up to tour
heteroatoms selected independently, from nitrogen, sulfur and oxygen, said
partially
saturated, fully saturated ring or fully unsaturated monocydic ring, bicydic
ring or
tricydic ring optionally having one or two oxo groups substituted on carbon or
one or
two oxo groups substituted on sulfur .
Ar and Ar' are optionally independently substituted on carbon or nitrogen,1on
one ring
if the moiety is monocydic, on one or both rings if the moiety is bicydic, or
on one, two
or three rings if the moiety is tricydic, with up to a total of four
substituents
independently selected from R", R'2, R" and R"; wherein R", R'Z, R" and R" are
each taken separately and are each independently halo, formyl, (C,-
C6~Ikoxycarbonyl, (C,-C6)alkylenyloxycarbonyl, (C,-C')alkoxy-(C,-C,)alkyl,
C(OH)R'SR'6, naphthyl, phenyl, tmidazolyl, pycidyl, triazolyl, morpholinyl,
(Co-
C')alkylsulfamoyl, N-(Co-C,)alkylcarbamoyl, N,N-di-(C,-C,)alkylcarbamoyl, N-
phenytcarbamoyl, N-(C,-C,)alkyl-N-phenylcarbamoyl, N,N-Biphenyl cari~amoyl,
(G,-
C')alkylcarbonylamido, (C,-C,,)cydoatkylcarbonylamido, phenylcarbonylamido,
piperidinyl, pyrrolidinyl, piperazinyl, cyano, benzimidazolyf, amino, anitino,
pyrimidyl,
oxazolyl, isoxazolyt, tetrazolyl, thienyl, thiazolyl, berazothiazolyl,
pyrrolyl, pyrazolyl,
tetrahydroquinolyl, tetrahydroisoquinolyf, benzoxazolyl, pyridazinyl,
pyridytoxy,
pyridylsutfanyl, furanyl, 8-(C,-C')atky(-3,8-diaza[3.2.1)bicydooctyl,
3,S~iioxo-1,2,4-
triazinyl, phenoxy, thiophenoxy, (C,-C,)alkylsulfanyl, (C,-C,)altrylsulfonyl,
(Cs-
C,)cydoalkyl, (C,-C,~Ikyl optionally substituted with up to flue fluoro or (C,-
C'~Ikoxy
optionally substituted with up to five fluoro; said naphthyl, phenyl, pyaidyl,
piperidinyl,
benzimidazolYl, pyrimidyl, thienyl, benzothiazolyl. PY~IYI.
tetrahydroquinotyl,
tetrahydroisoquinolyl, benzoxazoiyl, pyridazinyl, pyridyloxy, pyridylsutfanyf,
furanyl,
thiophenoxy, anilino and phenoxy in the definition of R", R'2, R" and R" are
optionally substituted with up to three substituents independently selected
fiom
hydroxy, halo, hydroxy-(C,-C')atkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C4)alkyl
optionally
substituted with up to fare fluoro and (C,-C')alkoxy optionally substituted
with up to five
fluoro; said imidazolyl, oxazolyl, isoxazolyl, thiazoiyi and pyrazolyl in .the
definition of


CA 02484282 2000-03-16
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R", R'=, R" and R" are optionally substituted with up to two substituents
independently selected from hydroxy, halo, hydroxy-(C,fC,)alkyl, (C,-C,)alkoxy-
(C,-
C,)alkyl, (C,-C,)alkyl optionally substituted with up to flue fluoro and (C,-
C,)alkoxy
optionally substituted with up to five fluoro; said morpholinyl in the
definition of R",
R'z, R" and R" is optionally substituted with up to two substituents
independently
selected from (C,-C,)alkyl; said pyrrolidinyl in the definition of R", R'2,
R'a and R" is
optionally substituted with up to two substituents independently selected from
hydroxy,
hydroxy-(C,-C3)alkyl, (C,-C,)alkoxy-(C,-C,)afkyl, (C,-C,)alkyl optionally
substituted
with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to
five filuoro; said
piperazinyl in the definition of R", R'2, R" and R" is optionally substituted
with up to
three substituents independently selected from (C,-C,~lkoxy-(C,-C,~lkyf;
hydroxy-
(C,-C3)alkyl, phenyl, pyridyl, (Co-C,~Ikylsuffamoyl, (C,-C,)alkyl
optionally~substituted
with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to
ftve ftuoro: said
triazolyl in the deftnition of R", R'Z, R" and R" is optionally substituted
with hydroxy,
halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,~Ikyl, (C,-C,~Ikyl optionally
substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted
with up to five
fluoro; said tetrazofyl in the definition of R", R'2, R" and R" is optionally
substituted
with hydroxy-(C2-C3~Ikyi or (C,-C,~Ikyl optionally substituted with up to five
fluoro;
and said phenyl and pyridyl which are optionally substituted on piperazine in
the
definition of R", R'2, R" and R" are optionally substituted with up to three
hydroxy,
halo, hydroxy-(C,-C,)atkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)atkyl
optionally
substituted with up to fwe fluoro and (C,-C,)alkoxy optionally substituted
with up to five
fluoro; or
R" and R'~ are taken together on adjacent carbon atoms and are
-CH~OC(CH,)20CH~- or -O-(CHZ)p-O-, and R" and R" are taken separately and are
each independently hydrogen or (C,-C,)alkyl;
pisl,2or3;
R'S and R'6 are taken separately and are each independently hydrogen, (C,-
C,~Ikyl
optionally substituted with up to five fluoro; or R's and R'a are taken
separately and R's
is hydrogen and R'° is (C,-C6)cycloalkyl, hydroxy-(C,-C~)alkyl, phenyl,
pyridyl,
PYn~dY<. thienyl, furanyl. thiazolyl, oxazolyl, imidazolyl, benzothiazolyl or
benzoxazolyl; or R's and R'6 are taken together and are (C~-C6~lkylene;


CA 02484282 2000-03-16
wo oois9sio pc~r~sooroo2~
G', G, and GS are taken separately and are each hydrogen; r is 0: R'°
is hydrogen,
(C,-C,)alkyl, (C,-C,)alkoxycarbonyl, (C,-C4~lkoxy-(C,-C4~Ikyl, hydroxy-(C,-
C,)alky! or
phenyl optionally independently substituted with up tv three hydroxy, halo,
hydroxy-
(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,~Ikyl or (C,-C,~tkoxy, wherein
said
(C,-C,~tky! in the definition of R6 and said (C,-C,)atkoxy in the definition
of R°are
optionally and independently substituted with up to five ttuoro; and
R'° and, R~° are
each independently (C,-C,)alkyl; or
G', G' and Gs are taken separately and are each hydrogen; r is 1; R'°
is hydrogen,
(C,-C,)alkyl, (C,-C,)alkoxycarbonyl, (C,-C,)alkoxy-(C,-C,)alkyl, hydroxy-(C,-
C,)atkyl or
phenyl optionally independently substituted with up to three hydroxy, halo,
hydroxy-
(C,-C,)alkyl, (C,-G,)alkoxy-(C,-C,)alkyi, (C,-C,)alkyl or (C,-C,)atkoxy,
wherein said
(C,-C,)alkyl in the definition of R° and said (C,-C,)alkoxy in the
definition Qf R° are
optionally and independently substituted with up to five fluoro; and
R'° and R'° are
each independently hydrogen or (C,-C,)alkyl; or
G' and G' are taken together and are (C,-C,)alkylene; r is 0 or 1; and
R'°, R", R~° and
G5 are hydrogen; or
G' and G5 are taken together and are (C,-C3)alkylene; r is 0 or 1; and
R'°, R'°, R~° and
G' are hydrogen; ,
R" is S02NRZ'R~, CONR2'R~, (C,-CB)atkoxycartionyl, (C,-C6)alkyicarbonyl, At=-
carbonyl, (C,-C°)alkylsulfonyl, (C,-C°~Ikylsul~nyl, ArZ-
sulfonyl, Are-sufinyl and (C,-
C°)atkyl,
R2' and R~ are taken separately and are each independently selected from
hydrogen,
(C,-Cs)alkyl, (C,-G,k,Ydoalkyl and Arz-(Co-C,~Ikylenyl: or
RZ' and R~ are taken together with the nitrogen atom to which they are
attached to
form aze6dinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl,
azabicycto[322]nonanyl, azabicydoj22.1]hepiyl, 6,7-dihydro-SH-
dibenzojc,e]azepinyl,1,2,3,4-tetrahydro-isoquinolyl or 5.6,7,8-
tetrahydropyrido[4,3-
d]pyrimidyl; said azetidinyl in the definition of RZ' and R~ is optionally
substituted
independently with one substituent selected from hydroxy, amino, hydroxy-(C,-
C,)afkyl, (C,-C,)atkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with
up to five
fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said
pyrrolidinyl,
piperidinyf, azepinyl in the definition of R~' and R'~ are optionally
subst~rted
independently with up to two substituents independently selected from
trydroxy,


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amino, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl. (C,-C,~aikyl
optionally
substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted
with up to five
fluoro; said morpholinyl in the definition of RZ' and R~ is optionally
substituted with up
to two substituents independent#y selected from hydroxy-(C,-C,)alkyl, (C,-
C,)alkoxy-
(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro and
(C,-C,)alkoxy
optionally substituted with up to five fluoro; said piperazinyl in the
definition of.R=' and
R~ is optionally.substituted independently with up to three substituents
independently
selected from phenyl, pyridyl, pyrimidyl, (C,-C,)alkoxycarbonyl and (C,-
C,~Ikyl
optionally substituted with up to five fluoro; said 1,2.3.4-tetrahydro-
isoquinolyl and said
5,6,7,8-tetrahydropyrido[4,3-djpyrfmidyl in the definition of R~' and R~ are
optionally
substituted independently with up to three substituents independently selected
from
hydroxy, amino, halo; hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-
C,)alkyl
optionally substituted with up to five fluoro and ~(C,-C,)alkoxy optionally
substituted
with up to five fluoro; and said 6,7-dihydro-SH~ibenzo(c,eJazepinyl in the
defnition of
RZ' and R~ is optionally substituted with up to four substituents
independently
selected from hydroxy, amino, halo, hydroxy-(C,-C,)alkyt, (C,-C,)alkoxy-(C,-
C,)alkyl,
(C,-C,)alkyl optionally substituted with up to five fluoro and (C,-C,)alkoxy
optionally
substituted with up to five fluoro; said pyrimidyl, pytidyl and phenyl which
are
optionally substituted on said piperazine in the definition of R~' and R~ is
optionally
substituted with up to three substituents selected from hydroxy, amino,
hydroxy-(C,-
C,~Ikyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with
up to five
fluoro and (C,-C,)alkoxy optionally substituted with up to flue fluoro;
Ar2 is independently defined as set forth for Ar and Ar' above;
said Are is optionally independently substituted as set forth for Ar and Ar'
above;
R~' is CONR'~R~ or SO=R~R~, wherein R~ is hydrogen (C,-C,)alkyl or Ar'-(Co-
C,)alkylenyt and R~° is Ar'-(C°-C,)alkylenyl; provided that when
Ar-' is phenyl, naphthyl
or biphenyl, then Ra cannot be CONR~R~ where Rte' is hydrogen or Ar' and
R~° is
Ar';
R~' is hydrogen, (C,-C,)alkyl, (C,-C,)alkoxycarbonyl. (C,rC,)alkoxy-(C,-
C,)alkyl,
hydroxy-(C,-C,)alkyl or phenyl optionally independently substituted with up to
three
hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C.)alkyl
or (C,-
C.)alkoxy. wherein said (C,-C,)alkyl in the definition of R° and said
(C,-C,~Ikoxy in
the definition of R6 are optionally and independently substituted with up to
five fluoro;


CA 02484282 2000-03-16
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PCT/IB00/00296
Ar' is independently defined as set forth for Ar and Ar' above;
said A~ is optionally independently substituted as set forth for Ar and Ar'
above;
R~' is hydrogen or (C,-C,)alkyl;
R~° and R~ are each independently hydrogen, hydroxy, halo, hydroxy-(C,-
C,)alkyl, .
(C,-C,)alkoxy-{C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to
five fluoro, (C,-
C,)alkoxy optionally substituted with up to five fluoro, phenyl, pyridyl,
pyrimidyl, thienyl,
furanyl, thiazofyl, oxazolyl, phenoxy, thiophenoxy, SOzNR'°R",
CONR'°R" or NR'°R";
said thienyl, pyrimidyl, furanyl, thiazolyl and oxazofyl in the definition of
R~° and R~ are
optionally substituted by up to two hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-
C,)alkoxy-
(C,-C,)alkyl, (C;-C,)alkyl optionally substituted with up to five fluoro or
(C,-C,)alkoxy
optionally substituted with up to five fluoro; said.phenyl, pyridyl, phenoxy
and
thiophenoxy in the definition of R~° and R~ are optionally substituted
by up to three
hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)a~koxy-(C,-C,)alkyf, (C,-C,)alkyl
optionally
substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted
with up to five
fluoro;
R'° and R" are each independently hydrogen, (C,-C,)alkyl, (C'-
C,kydoalkyl or
phenyl, said phenyl is optionally substituted with up to three hydroxy, halo,
hydroxy-
(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted
with up to
five fluoro or (C,-C,~Ikoxy optionally substituted with up to flue fluoro; or
R'° and R" are taken together with the nitrogen to which they are
attached to form
indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; said
pyrrolidinyl and
piperidinyl in the definition of R'° and R" are optionally substituted
with up to two
hydroxy, amino, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-
C,)allcyl
optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally
substituted with
up to five fluoro; said indolinyl and piperazinyl in the definition of
R'° and R" are
optionally substituted with up to three hydroxy, amino, hydroxy-(C,-C,~Ikyl,
(C,-
C,)alkoxy-(C,-C,~Ikyl, (C,-C,)alkoxycarbonyl, (C,-C,)alkyl optionally
substituted with
up to flue fluoro or (C,-C,)alkoxy optionally substituted with up to five
fluoro; said
morpholinyl in the definition of R'° and R" is optionally substituted
with up to two
substituents independently selected from hydroxy-(C,-C,)alkyl, (C,-C,~Ikoxy-
{C,-
C,)alkyl, (C,-C,~lkyl optionally substituted with up to five fluoro and tC,-
C,)alkoxy
optionally substituted with up to five fluoro;
A is N optionally substituted with hydrogen or (C,-C,)alkyl and B is carbonyl;
or


CA 02484282 2000-03-16
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A is carbonyl and B is N optionally substituted with hydrogen or (C,-C,)alkyl;
R'~ is hydrogen or (C,-C,)alkyl;
R" is phenyl. PY~dYI. PY~midyl, thiazolyl. oxazolyl, benzyl, quinolyl.
isoquinolyl,
phthaiizinyl, quinoxanlyl, benzothiazoyl, benzoxazoiyi, benzofuranyl or
benzothienyl;
said phenyl, pyridyl, pyrimidyl, thiazoiyl, oxazolyl, benzyl; quinolyl.
isoquinolyl,
phthalizinyl, quinoxanlyl, benzothiazoyl, benzoxazolyl, benzofuranyl and
benzothienyl
in the definition of R" are optionally substituted with up to three phenyl,
ptienoxy,
NR"R", halo, hydroxy, hydroxy-~C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-
C,)alkyl
optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally
substituted with
up to 5ve fluoro;
R" and R's are each~independently hydrogen, (G,-C, alkyl), phenyl or
phenyfsulfonyl;
said phenyl and phenytsulfonyl in the definition of R" and R's are optionally
substituted with up to three halo, hydroxy, (C,-C,)alkyl optionally
substituted with up to
five fluoro or (C,-C,)alkoxy optionally substituted with up to flue fluoro;
D is CO, CHOH or CH2;
EisO,NHorS;
R'~ and R" are taken separately and are each independently hydrogen, halo,
cyano,
hydroxy, amino, (C,-C6)alkylamino, di-(C,-Cs)alkylamino, pyn'olidino,
piperidino,
morphoiino, (C,-C,~Ikoxy-(C; C,)alkyl, hydroxy-(C,-C,)alkyl, A~', (C,-C,~Ikyl
optionally substituted with up to five tluoro or (C,-C,)alkoxy optionally
substituted with
up to five fluoro;
R'°, R~ and R'° are each independently hydrogen or (C,-
C,~alkyl;
Ar is phenyl, furanyl, thienyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl;
said Ar" being
optionally substituted with up to three hydroxy, (C,-C,)alkoxy-(C,-C,)alkyl,
halo,
hydroxy-(C,-C,)alkyi, 7(C,-C,)alkyl optionally substituted with up to five
fluoro or (C,-
C,~Ikoxy optionally substituted with up to five fluoro; or
R'~ and R" are taken together on adjacent carbon atoms and are -O-(CH~~-O-;
tisl,2or3;
Y is (Cz-Cs~lkylene;
R", R's and R's are each independently hydrogen or (C,-C,~Ikyl;
m and n are each independently i, 2 or 3, provided that the sum of m and n is
2, 3 or
kis0,1,2,3or4;


CA 02484282 2000-03-16
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Y' is a covalent bond, carbonyl, sulfonyl or oxycarbonyl;
R" is (C3-C,)cydoalkyl, Ars-(Co-C,)alkylenyl, NR"R'° or (C,-C6)alkyl
optionally
substituted with one to five fluoro; provided that when Y' is a covalent bond
or
oxycarbonyi, then R" is not NR"R'°; , ~ ,
R" and R'° are taken separately and are each independently selected
from hydrogen,
Ars, (C,-C6)alkyl and Ars-(Co-C,)alkylenyl; or ,
R" and R'° are taken together with the nitrogen atom to which they are
attached to
form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,
azepinyl,
azabicydo[3.2.2]nonanyl, azabicydo[2.2.1)heptyl, 1,2.3,4-
tetrahydroisoquinolyl, 6,7-
dihydro-5H-dibenzo[c.e]azepinyl or 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidy(;
said
azetidinyl in the definition of R" and R'° are optionally substituted
with one hydroxy,
amino, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-
C,)alkyl.optionally
substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted
with up to five
fluoro; said pyrroiidinyl, piperidinyl and azepinyl in the definition of R"
and R'° are
optionally substituted with up to two h~roxy, amino, hydroxy-(C, C,)alkyl, (C,-

C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five
fluoro or (C,-
C,)alkoxy optionally substituted with up to five fluoro; said morpholinyl in
the definition
of R" and R'° is optionally substituted with up to tWo substituents
independently
selected from hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl
optionally
substituted with up to five fluoro and (C; C,)alkoxy optionally substituted
with up to five
fluoro; said piperazinyl, 1,2,3,4-tetrahydroisoquinolyl and 5,6,7;8-
tetrahydro[4,3-
djpyrimidyl in the definition of R" and R'° are op6onalty substituted
with up to three
hydroxy, amino, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy~(C,-C,)alkyl, (C,-
C,)atkyl
optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally
substituted with
up to five fluoro; and said 6,7-dihydro-5H-dibenzo[c,e]azepinyl in the
defiti~ti~ of R"
and R'° are optionally substituted with up to four hydroxy, amino,
halo, hydroxy-(C,-
C.~I~. (C,-C.~Ikoxy-(C,-C.)alkyl. (C,-C:~Ikyl optionally substituted with up
to fnre
fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro;
Are is independently defined as set forth for Ar and Ar' above;
Ars is optionally independently substituted as set forth for Ar and Ar' above;
R'Z and R'~ are independently hydrogen, (C,-C,kydoalkyl; Are-(Co-C3)alkylenyl,
A~°
(Cz-C,)alkenyl, A~-carbonyl or (C,-Cs)alkyl optionally substituted with up to
five fiuoro;
Ar° is independently defined as set forth for Ar and Ar' above;


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Ars is optionally indepenc)ently substituted as set forth for Ar and Ar'
above; and
R" and ~R"' are each independently hydrogen or (C,-C;~alkyl. '
A preferred group of compounds within the compound of formula 1° are
those
compounds wherein R°' is the acyl radical of ponaUesiat, tolrestai,
zenarastat,
zopolrestat, epalrestat, ZD5522 or sorbinil.
Espeaally preferred mutual ~prodrvgs of this invention are selected from (Er
[4-oxo-3-(5-triouoromethyl-benzothiazol-2-ylmethyl~-3,4-dihydro-phthafazin-1-
yl]-
acetic acid 1 R-[4-(4-quinoxalin-2-yl-piperazin-1-yl}-pyrimidin-2-yl]-ethyl
ester and
(E~-[4-Oxo-3-(5-trifluoromethyl-benzothiazol-2-ylmethyl}-3,4-dihydro-
phthalatin-'I-
yl]-acetic aad 1 R-{4-[4-(3-thiophen-2-yl-acryloylrpiperazin-1-yl]-pyrimidin-2-
yl}-ethyl
ester.
This invention is also directed to intem~ediate compounds of the fotmula Z
Me
Z
This invention is still further directed to intermediate compounds, designated
Group AA, of the formula T1,
,oo
Me
ZZ
wherein R'°° is (C,-Ca~lkyl, benzyl or phenyl wherein said
benzyl and phettyt are
optionally substituted with up to three halo or (C,-C,~Ikyl.
A preferred group of compounds within Group AA, designated Group AB, are
those compounds wherein R'°° is (C,-C,~Ikyl.
More preferred compounds within the Group AB are those cod
wherein R'°° is n-butyl or ethyl.


CA 02484282 2000-03-16
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This invention is still further directed to a compound of the formula Z~1,
Rio, , , ,
N
Me N Me
~OCOR'°°
~- YYN
Me
Zu
wherein:
R'°° is (C,-Ca)alkyl, benzyl or phenyl wherein said benzyl and
phenyl are optionally
substituted with up to three halo or (C,-C,~tkyl: and
R'°' is hydrogen or a suitable amine protecting group.
A preferred group of compounds of formula ZZZ, designated Group AC, are
those compounds wherein R'°° is (C,-C,)alkyl and R'°' is
benzyl or tert-
butyloxycarbonyi. '
A preferred group of compounds within the Group AC are those compounds
wherein R'°° is n-butyl or ethyl and R'°' is benzyl.
Another preferred group of compounds within the Group AC are those
compuunds wherein R'°° is n-butyl or ethyl and R'°' is
tert-butyloxycarbonyl.
This invention is also directed to a process for preparing a compound of the
formula Z,
OH
~N
~OH
~' YYN
Me
Z
comprising:


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_71_
a) reacting R-(+~-2-hycfroxy-propionamide with trieth~rioxonium '
tetrafluoroborate in a reaction inert solvent for 10 minutes; to 24 hours at 0
°C to
ambient temperature to form the corresponding imidate;
b) reacting said corresponding imidate with anhydrous anunonia in a
reaction inert solvent for 2 hours to 24 hours at 0 °C to ambient
temperature to form
R-(+~2-hydroxy-propionamidine hydrochloride; and
c) reacting said R-(+)-2-hydroxy-propionanridine hydrochloride with ethyl
3-hydroxy-acrylate sodium salt and a suitable base in a n:action inert solvent
to form
said compound of formula Z .
This invention is also directed to a pham~aceutical composifwn, designated
Composition AA, comprising a compound of fomwla !, a prodrug thereof or a
pharmaceutically acceptable salt of said prodrug or said c~mmpourd, and~a
glycogen
phosphorylase inhibitor (GPI), a prodrug of said GPI or a pharmaceutically
acceptable
salt of said GPI or said prodrug.
This invention is also directed to a Itit cx?r~tising:
a. a -compound of formula !, a prodnrg thereof or a
pham~aceutically acceptable salt of said prodrug or said compound in a first
unit
dosage forth;
b. a glycogen phosphorylase inhibitor. (GPI), a prodrug thereof or
a phamiaceuticaAy acceptable salt of said prodrug or said GPI in a second unit
dosage form; and
c. a container.
This invention is also directed to a method of treating or preventing diabetic
complications in a mammal comprising administering to said mammal a
pham~aoeutical composition of Composition AA.
This invention is also directed to a method of treating hyperglycemia in a
mammal oorraprising administering to said mammal a phamvaoeuticat composition
of
Composition AA.
This invention is also directed to a method of treating ischemia in a mammal
suffering from ischemia comprising administering to said mammal a
pham~aceutical
position of Composition AA.


CA 02484282 2000-03-16
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This invention is also directed to a method of treating diabetes in a mammal
,,
comprising adminstering to said mammal a phamiaoeutical composition of
Composition AA.
This invention is also directed to a method of treating diabetic complications
in
a mammal comprising adminstering to said mammal a compound of formula i, a
prodrug thereof or a pham~aceutically axeptable salt of said compound or said
prodrug and a glycogen phosphorylase inhibitor (GPI), a prodnrg of said GPI or
a
pharmaceutically acceptable salt of said GPI or said prodnrg.
This invention is also directed to a method of treating hyperglycemia in a
mammal comprising administering to said mammal a compound of fomurla I, a
prodrug thereof or a pharmaceutically acceptable salt of said compound or said
prodrug and a glycogen phosphorytase inhibitor (GP!), a prodnrg of said GPI or
a
pharmaceutically acceptable salt of said GPI or said prodcug.
This invention is also directed to a method of treating ischemia in a mammal
comprising administering to said mammal a compound of formula 1, a prodrug f
or a pharmaceutically acceptable salt of said compound or sad prodrug and a
glycogen phosphorylase inhibitor (GPI), a prodrug of said GPI or a
pharrnaoeuti~lyr
acceptable salt of said GPI or said prodrug.
This invention is also directed to a method of treating diabetes ut a
rtramrnal
comprising administering to said mammal a compound of fom~ula 1, a prodrug
thereof
or a pharmaceutically acceptable salt of said compound or said prodrug and a
glycogen phosphorylase inhibitor (GPI), a prodrug of said GP1 or a
pham~aceutically
acceptable salt of said GPI or said prodrug.
The subject invention also inGudes isotopically-labeled compounds, which are
identical to those rented in Formula I, but for the fad that one or more at~ns
are
replaced by an atom having an atomic mass or mass number different from the
atomic mass or mass number usually found in nature. Examples of isotopes that
can
be incorporated into compounds of the invention indude isotopes of hydrogen,
carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as
=fi,'H,
"C, "C,'SN,'°C. ,W,'~P,'~P~'~S,'°I= and'~CI, respectively.
Compounds of the
present invention, prodrugs thereof, and phamiaoeutically acceptable salts of
said
compounds or of said prodrugs which contain the aforementioned isotopes andlor
other isotopes of other atoms are within the scope of this invention. Certain


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isotopicalfy-labeted compounds of the present invention; for example those
into which
radoactive isotopes such as'H and "C are incorporated, are useful in drug
and/or
substrate tissue distribution assays. Tritiated, i.e.,'H, and carbon-14, i.e.,
"C,
isotopes are particularly preferred for their ease of preparation and
detectability.
Further, substitution w'tth heavier isotopes such as deuterium, i.e., 2H, can
afford
certain therapeutic advantages re$ulting from greater metabolic stabifity~,
for example
increased in vivo half-life or reduced dosage requirements and, hence, may be
preferred in some arcumstances. Isotopically labeled compounds of Formula I of
this
invention and prodrugs thereof can generally be prepared by carrying out.the
procedures disclosed in the Schemes and lot: in the Examples and Preparations
below, by substituting a readily available isotopicalfy labeled reagent for a
non-
isotopically labeled reagent.
The term "reduction" is intended to include partial prevention or prevention
which, although greater than that which would result from taking no compound
or from
taking a placebo, is less than 100% in addition to substantially total
prevention.
The term "damage resulting from ischemia" as employed herein refers to
conditions directly associated with reduced blood flow to tissue, for example
due to a
dot or obstruction of blood vessels which supply blood to the subject tissue
and which
result, inter alia, in lowered oxygen transport to such tissue, impaired
tissue
perfom~ance, tissue dysfunction andlor necrosis. Alternatively, where blood
flow or
organ perfusion may be quantitatively adequate, the oxygen cartying capaaty of
the
blood or organ perfusion medium may be reduced, e.g., in hypoxic environment,
such
that oxygen supply to the tissue is knnrenrd, and impaired tissue perfom~ance,
tissue
dysfunction, and/or tissue necrosis ensues.
The term "treating", "treat" or "treatment" as used herein includes
preventafrve
(e.g., prophylactic) and palliative treatment.
By "pharmaceutically acceptable" it is meant the carrier, diluent, exapients,
andlor salt must be compatible with the other ingredients of the formulation,
and not
deleterious to the reapient thereof.
The expression "prodnrg" refers to compounds that are drug precursors which
foIIoHring administration, release the drug in vivo via some chemical or
physiological
process (e:g., a prodrug on being brought to the physiological pH or through
enzyme
action is converted to the desired drug form).


CA 02484282 2000-03-16
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PCTIIB00100296
This invention is further directed to compounds.which are mutual proiirugs of
,
aldose reductase inhibitors and sorbitol dehydrogenase inhibitors. By mutual
prodnrg
is meant a compound which contains two active components, in this case, an
aldose
reductase inhibitor and a sorbitol dehydrogenase, inhibitor, which, following
administration, is deaved, releasing each individual active component. Such
mutual
prodrugs of an aldose reductase inhibitor and a sorbitol dehydrogenase
inhibitor are
formed under standard esterification conditions weft known to those skilled in
the art.
By alkyiene is meant saturated hydrocarbon (straight drain or branched)
wherein a hydrogen atom is removed from each of the temunal carbons. Exemplary
of
such groups (as'suming the designated length encompasses the particular
example)
are methytene, ethylene, propylene, butylene, pentylene, hexylene, hepiylene.
By halo is meant diloro, bromo, iodo, or fiuoro.
By alkyl is meant straight chain saturated hydrocarbon or branched saturated
hydrocarbon. Exemplary of such alkyl groups (assuming the designated length
encompasses the particular example) are methyl, ethyl, propyl, isopropyl,
butyl, seo
butyl, tertiary butyl, pentyl, isopentyl, neopenlyl, tertiary pentys, 1-
methylbutyl, 2
methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl.
By alkoxy is meant straight chain saturated alkyl or branched saturated alkyl
bonded through an oxygen. Exemplary of such alkoxy groups (assuming the
designated length encompasses the particular example) are methoxy, ethoxy,
propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy,
neopentoxy, tertiary pentoxy, hexoxy, isohexoxy, heptoxy and octoxy .
It is to be understood that if a carbocydic or heterocydic moiety may be
bonded or otherwise attached to a designated substrate through differing ring
atoms
without denoting a spedfic point of attachment, then all possible points are
intended,
whether through a carbon atom or, for example, a trivatent nitrogen atom. For
example, the term "pyridyl" means 2-, 3-, or 4-pyridyl. the term 'thienyl"
means 2-, or
3-thienyl, and so forth.
The expression °pharmaoeutically-acceptable salt" refers to nontoxic
anionic
salts containing anions such as (but not limited to) chloride, bromide,
iodide, sulfate,
bisulfate, phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate,
dtrate,
gluconate: methanesutfonate and 4-toluene-sulfonate. Where rt~ore than one
basic
moiety exists the expression indudes multiple salts (e.g., di-salt). The
expnsssion also


CA 02484282 2000-03-16
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refers to nontoxic cationic salts such as (but not limited to) sodium,
potassium.
calcium, magnesium, ammonium or protonated benzathine (N,N'-
dibenzylethyfenediamine), choiine, ethanolamine, diethanolamine,
ethylenediamine,
meglamine (N-methyl-glucamine), benethamine (N,-benzylphenethyiamine),
piperazine or tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol).
As used herein, the expressions "reaction inert solvent" and "inert solvent"
refers to a solvent or mixture of solvents which does not interact with
starting
materials, reagents, intermediates or products in a manner which adversely
affects
the yield of the desired product.
The chemist of ordinary skill will recognize that certain compounds of formula
I
of this invention wilt contain one or more atoms which may be in a particular
stereochemical or geometric configuration, giving rise to stereoisomers and
configurational isomers. All such isomers and mixtures thereof are included in
this
invention. Compounds of formula t may be chiral. In such cases, the isomer
wherein
R' has the R configuration is preferred. Hydrates of the compounds of formula
I of this
invention are also included.
The chemist of ordinary skill in the art will also recognize that certain
compounds of formula 1 of this invention can exist in tautomeric form, i.e.,
that an
equilibrium exists between two isomers which are in rapid equilibrium with
each other.
A common example of tautomerism is keto-snot tautomerism, i.e.,
H
O O
N~
F~camples of compounds which can exist as tautomers include hydroxypyridines,
hydroxypym~idines and hydroxyquinolines. Other examples will be recognized by
those skilled in the art. Ali such tautomers and mixtures thereof are included
in this
invention.
DMF means N,N-dimethylfom~amide. DMSO means dimethyl sulfoxide. THE
means tetrahydrofuran.
Whenever the structure of a cyclic radical is shown with a bond drawn from
outside the ring to inside the ring, it will be understood by those of
ordinary skill in the


CA 02484282 2000-03-16
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art to mean that the bond may be attached to any atom on the sing with an
available
site for bonding. If the cyclic radical is a bicydic or tricydic radical, then
the bond may
be attached to any atom on any of the rings with an available site for
bonding. For
example, ,
~N '
6 N
represents any or all of the following radicals:
\ v \ W \ W
I
~N . I ~N / / N
N N ~ N
I\ ~ w
N~N and I / / N
N
Other features and advantages will be apparent from the spedfication and
claims which describe the invention.
DETAILED DESCRIPTION OF THE INVENT10N
In general the compounds of formula I of this invention can be made by
processes which include processes known in the chemical arts, partiartarly in
light of
the description contained herein. Certain processes for the manufacture of the
compounds of formula t of this invention are provided as further features of
the
invention and are illustrated by the following reaction schemes. Other
processes are
described in the experimental section.
Scheme 1
Lv R'
R2 Rx
( ~N, ~- R'-H I ~N
~R~
1-y N R
1-1


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-n-
Compounds of formula 1-3 (i.e., formula I) are prepared as set forth in
Scheme 1, particularly as described below.
Compounds of formula 1-3 are prepared by the displacement reaction of a
pyrimidine of the formula 1-1 where R' and R2 are defined herein. Lv is a
leaving
group preferably selected from fluoro, chloro, bromo, iodo, thiomethyf,
methylsulfone.
or OSOz,J wherein J is (C,-C6}-lower alkyl, trifluoromethyl, pentafluoroethyl,
phenyl
optionally substituted with up to three (C,-C,)alkyl, vitro or halo. The
leaving group Lv
is displaced by~an amine of the formula 1-2 where R' is defined above. The
reaction
is conducted in the presence of a non,aqueous base, preferably an organic
amine or
an inorganic base. ?refer-ed organic amines include triethylamine, pyridine,
dimethylaminopyridine and N,N'-diisopropylethylamine (Hunig's base). Preferred
inorganic bases include alkaline metal carbonates and bicarbonates such as
sodium
or potassium carbonate and sodium or potassium bicarbonate. An espeaally
preferred inorganic base is potassium carbonate. An espeaally preferred
organic
amine is triethylamine. Alternatively, an excess of the reacting amine 1-2 can
be used
as the base for this reaction. The reaction can be conducted in the absence of
solvent or in a reaction inert solvent. Where used herein, "reaction inert
solvent" refers
to a solvent which does not interact with starting materials, reagents,
intermediates or
products in a manner which adversely affects the yield of the desired product
Preferred reaction inert solvents include aqueous media, pyridine, (C,-
C,~ioohol, (C~-
CB)glycol, halocarbon, aliphatirJaromatic hydrocarbon, ethereal solvent, polar
aprotic
solvent, ketonic solvent, or combinations thereof. The reaction time ranges
from 15
minutes to 3 days arid the reaction temperature ranges from 0 °C to 180
°C.
Conveniently, the reaction may be conducted at the retlux temperature of the
solvent
being used. The reaction is preferably conducted at ambient pressure. The term
ambient pressure, where used herein, refers to the pressure of the room in
which the
reaction is being conducted. The term ambient temperature, where used herein,
refers to the temperature of the room in which the reaction is being oonduded.
When R' .contains a hydroxy group, the hydroxyl group may or may not be
protected. When the hydroxyl group is protected, the protecting group may be
any
suitable h~idroxyl protecting group. The conditions used to remove such
optional
hydroxyl protecting groups contained in R' in compounds of formula 1-3 are as


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follows. When the protecting group is an ester, removal of such ester
protecting
groups is conducted under basic conditions using inorganic hydroxides or
carbonates,
preferably lithium hydroxide, sodium hydroxide, potassium hydroxide or
potassium
carbonate. The reaction is carried out in.a reactibn inert solvent, preferably
an
alcoholic solvent. Especially preferred is methanol or methanol in combination
with co-
solvents such as water, tetrahydrofuran, or dioxane. The reaction time ranges
from
minutes to 24 hours and the reaction temperature ranges from 0 °C to
100 °C or to
the reflux temperature of the solvents) of use. Alternatively, ester cleavage
may be
accomplished under acidic conditions. It is preferred to utilize aqueous
hydrochloric
10 acid, genefally 2 N to concentrated, with or without a co-solvent. When a
co-solvent is
used, dioxane or methanol are preferred. The reaction time ranges from 4 hours
to 3
days and the reaction temperature ranges from 0 °C to 60 °C.
When the protecting group is an alkyl ether, removal of such alkyl ether
protecting groups is conducted using well known dealkylative conditions. For
15 example, the alkyl ether may be cleaved by reaction with boron tribromide
or
diethylboron bromide in a reaction inert solvent, preferably a halocarbon
solvent. It will
be recognized by those skilled in the art that a buffer such as triethyiamine
may
faalitate the reaction. The reaction times range from 15 minutes to 24 hours
and the
reaction temperature ranges from 0 °C to 60 °C. tn addition, a
benzyl ether protecting
group can be removed via standard or transfer hydrogenolysis using a palladium
catalyst such as palladium on carbon. The hydrogenolysis reaction is conducted
under a hydrogen atmosphere at ambient pressure to 50 psi in a reaction inert
solvent, preferably methanol. The hydrogen source may be hydrogen gas,
ammonium
formate or trialkylammonium fortnate or cydohexene. The reaction temperature
ranges from room temperature to the reflux temperature of the solvent
employed. The
reaction time ranges from 15 minutes to 24 hours.
When a silyl ether protecting group is employed, removal of such silyl ether
protecting groups is conducted under addic conditions, preferably with aqueous
hydrochloric aad such as 1 N to 6 N hydrochloric acid. The de-protection may
be
carried out in the presence of a co-solvent such as methanol or
tetrahydrofuran. The
reaction time ranges from 2 hours to 48 hours and the reaction temperature
ranges
from 0 °C'to 100 °C. Alternatively, the silyl ether protecting
group maybe removed
via fluoride-mediated deprotection. fn this case, deprotection is conducted
using


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tetrabutylammonium fluoride or one of a variety of hydrofluoric acid sources
in a ,
reaction inert solvent. It is preferred to use ethereal sohrents such as
diethyl ether, .
dioxane or tetrahydrofuran, with tetrahydrofuran being especially preferred.
The
reaction time ranges from 2 hours to 48 hours and~the reaction temperatures
range
from 0°C to the reflux temperature of the solvent being used. Other
methods
for removal of the aforementioned protecting groups are well known to those
skilled in
the art or can be found in Greene, T. W.; Wuts, P. G. M., Protective Groups in
Organic
Synthesis, 2"° ed.; John Wiley and Sons Inc.: New York, 1991. Other
suitable hydroxyl
protecting groups and methods for their removal may be found also be found
therein.
The method of ~ Scheme I is preferred when RS is R"'~ ~'~'~ °~ °
"'° °. Thus, compounds of
formula 1-2 are reacted with compounds of formula 1-1. Compounds of fortnuia 1-
2
where R' is R3'' ~'"'~ 0. ° °' ° are commercially
available or can be prepared, by methods
well known to those skilled in the art.

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Scheme 2
O N R~°
R
~ac~d \
Rz; ~- ,
r
R NHz "w"~ ~R -.
N
2-2 , ,
2-3
r.
Lv R
__
Rzs ~ Rx
N
~Rz'
N
H
2-6
2~T
Compounds of formula 2-7 are prepared as set forth in Scheme 2, particularly
as descxibed below.


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Where R~' is H, ethyl i-benzyf-3-oxo-4-piperidine-carboxytate hydrochloride,
the compound of formula 2-1, which is available from Aldrich, is condensed
with
compounds of formula 2-2 to give compounds of formula 2-3. The compounds of
formula 2-1 where R~' is not H can be prepared according to methods well known
to
those skilled in the art The reaction is conducted in the presence of excess
base
including non-aqueous bases, organic amines and inorganic bases. Preferred
organic
amines include triethyiamine and pyridine. Preferred non-aqueous bases include
alkaline metal (C,-C,)alkoxides. Preferred inorganic bases include potassium
carbonate. The reaction is conducted in a reaction inert solvent. Preferred
such
solvents include (C,-G,)alcohols, aromatic or aliphatic hydrocarbons, polar
aprotic
solvents, halocarbons, and ethereal solvents. (C,-C,)Atcohots are espeaally
preferred. The reaction time ranges from 2 hours to 3 days. The reaction
temperature
ranges from ambient temperature to the reflex temperature of the solvent being
.
employed. The reaction is preferably run at ambient pressure but may be
conducted
at pressures up to 250 psi.
Compounds of formula 2-4 are prepared from compounds of formula 2-3 by
converting a compound of formula 2-3 into an activated compound of formula 2-4
where Lv' is selected from fluoro, chtoro, bromo, iodo,
trifluvromethanesulfonate, (C,-
CB)alkylsulfonate, or phenylsutfonate, wherein said phenyl is optionally
substituted
with up to three (C,-C,)allcyl, halo or vitro. This reaction is accomplished
by reading
compounds of formula 2-3 with a chlorinating agent such as phosphorus
oxychloride
andlor phosphonrs pentachloride to provide compounds of formula 2-4 where Lv'
is
chtoro. This reaction is conducted at ambient pressure in the absence of
solvent or in
a reaction inert solvent, preferably a hatocarbon solvent at. temperatures
ranging from
ambient temperature to 180 °C. Treatment of the chforo compound thus
fom~ed with
the requisite mineral add provides a compound of formula 2~t where Lv' is
bromo or
iodo. A sutfonate of formula 2-4 is prepared by reaction of a compound of
fomwla 2-3
with a sulfonic add chloride or anhydride in the presence of an organic amine
base,
preferably triethyiamine or pyridine. in certain cases recognized by those
skilled in the
art, it may be necessary to add a catalyst to the reaction, fn those cases, a
preferted
catatyst is 4-dimethyiaminopyridine. This reaction is conducted at ambient
pressure in
a reaction inert solvent, preferably pyridine, a halocarbon such as
chloroform,
dichloromethane or carbon tetrachloride, an aromatic or aliphatic hydrocarbon,
an


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WO 00/59510
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ethereal solvent, or combinations thereof. The reaction temperature ranges
from -20°
C to 100 °C and the reaction time ranges from 15 minutes to 1 day.
Compounds of formula 2-5 wherein R~ is defined above are prepared from
compounds of formula 2-4 by a reduction reaction or by displacement of Lv'
with a
nudeophile. The reduction is conducted with a reduang agent, preferably
ammonium
formate or hydrogen gas, in a reaction inert solvent. The reduction is
conducted in the
presence of a palladium catalyst at ambient pressure or under a hydrogen
pressure of
up to 50 psi. Preferred solvents include. (C,-C,}alcohols such as methanol and
ethanol, and ether solvents such as diethyl ether, dioxane and
tetrahydrofuran. The
nucleophilic displacement reaction may be conducted by adding the nudeophile
directly or by pre-forming the nudeophile separately or in situ from a
nudeophile
precursor. Preferred nucleophiies include organoaluminum, organoboron,
organocopper, organotin, organozinc or Grignard reagent; R~-H; or, where R~'
contains a hydroxyl or thiol group, the anion of Rte. The term "organo" in the
terms
organoaluminum, organoboron, organocopper, organotin and organozinc refers to
an
organic radical selected from Rte. It will be recognized by those s>u'lled in
the art that
transition-metal catalysts may be required to effect reaction in certain
displacement
reactions. When required, such transition metal catalysts may include
palladium(0),
palladium(//), nickel(0), and nidcel(II) complexes. Palladium(//)
bis(diphenylphosphinobutane) dichloride is a preferred such catalyst.
Additionally, an
aqueous or non-aqueous base may be required in the displacement reaction.
Preferred such bases include sodium carbonate, sodium hydride, triethyiamine
and
sodium tert-butoxide. The reaction is conducted at ambient pressure in a
reaction
inert solvent such as -a halocarbon, an aromatic or aliphatic hydrocarbon, an
ether or a
polar aprotic solvent or a combination thereof. In certain cases, a (C,-
C,)alcohol is
used as a solvent or co-solvent. The reaction temperature ranges from 20
°C to the
reflux temperature of the solvent employed. The reaction time ranges from 1
hour to 3
days.
Compounds of formula 2-6 are prepared by removal of the benzyl protecting
group from compounds of formuta 2-3 or 2-5. This transformation is
accomplished
using the freebase, or preferably the pre-formed hydrochloride or similar
salt, under
standard ortransfer hydrogenolysis conditions. The catalysts which may be used
in
the hydrogenofysis reaction include, but are not limited to, palladium on
carbon,


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palladium hydroxide on carbon and platinum(IV) oxide.. The reaction is
conducted in a
reaction inert solvent, preferably methanol or ethanol and the reaction
temperature
ranges from room temperature to the reflux temperature of the solvent being
employed. The hydrogen source is hydrogen gas, ammonium fom~ate,
trialkyiammonium fomiate, or cyGohexene. The reaction time ranges from 15
minutes
to 3 days. Generally the reaction i~ conducted at ambient pressure but
pressures of
up to 50 psi of hydrogen may be employed. Altemativeiy, if appropriate, the
benzyl
protecting group is removed in two steps via chloroformate-induced acylative
dealkylation. This involves reaction with a chtorofom~ate derivative to form a
carbamate followed by Geavage of the carbamate. While this reaction is
preferably
conducted with 1-chloroethyl chloroformate and sodium iodide catalysis, it
will be
recognized by those skilled in the art that catalysis may not be required 9n
certain
cases. The reaction is conducted at ambient~temperature in a reat~tion inert
solvent
such as a halocarbon, an aromatic or aliphatic hydrocarbon, a ketone, an ether
or a
potar aprotic solvent. The reaction temperature ranges from -78 °C to
the reflux
temperature of the solvent being employed and the reaction time ranges from 15
minutes to 1 day. Cleavage of the carbamate formed by reaction with 1-
chloroethyl
chloroformate is accomplished upon exposure to methanol or ethanol at ambient
pressure to give compounds of formula 2-6 as a hydrochloride salt. The
reaction
proceeds at temperatures from room temperature to the ~reflux temperaturE of
the
solvent being employed and the reaction time ranges from 15 minutes to 1 day.
Deprotection conditions for other carbamates can be found in Greene, T. W.;
Wuts, P.
G. M. Protective Groups in Organic Synthesis, 2"° ed.; John Wiley and
Sons Inc.: New
York, 1991, pp 315-348.
Compounds of formula 2-7 are prepared from the displacement reaction of
amine 2-G as described in Scheme 1, where the amine 2-6 is equivalent to R'-
NH.
Alternatively, compounds of fomwia 2 7 where R~ is as defined above are
prepared from compounds of formula 2-3 wherein R~° is OH according to
the
sequence outlined in Scheme 2a below, wherein the conditions are as set forth
as
described for Scheme 2.

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WO 00/59510
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Scheme 2a
O N R~°
NH
llacid ~ N
~~ Rze~NH2 ~, ~ R~ ~
N~
2-2 ,
z-i. 2-3 /
--.~ .
2a-1
Rze Rie
R'
2a~ 2-7
Compounds of formula 2-2 which are used in Schemes 2 and 2a above are
commeraally available or ace prepared according to methods well known to those
skilled in the art, such as those described in March, J. Advanced Organic
Chemistry,
3'° ed.; John wley and Sons.: New York,1985, p 359, 374.
2a 2

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-8~
Scheme 3
~~ ~a~
R'~ R"
v
R + o ~ j.
Me OH
3-2
r


~ R


R -


)


R~7



' '9


R R


N


H


3-4



O
R~ ~R~s
~- 3 2 3-5
N
hi
3-6
37
Compounds of formula 3-5 are prepared as set forth in Scheme 3 above and
more particularly as described below.
Compounds of formula 3-3 are prepared by condensing a compound of
formula 3-'i with a compound of fomwia 3-2. Where R'° and R'°
are each H, the
carnpound of formula 3-1 is 1-benryl-4-piperidone, which is commercially
available


CA 02484282 2000-03-16
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pCTIIB00/00296
from Aldrich. Compounds of formula 3-2 are either coriamercially available or
can be
prepared according to methods well known to those skilled in the art"
particularly
according to methods set forth in March, J. Advanced'Organic chemistry,
3'° ed.;
John Wiley and Sons Inc.: New York, 1985, pp 499-500. The reaction is
conducted at
ambient pressure in the presence of a secondary amine. generally an excess of
the
secondary amine, preferably pyrrolidine, piperidine, morpholine or
diethytamine, is
used. An especially preferred secondary amine is pyrrofidine. The reac#ion is
conducted in a reaction inert solvent, preferably a (C,-C,)aioohol, an
aromatic or
aliphatic hydrocarbon, a polar aprotic solvent, a halocarbon or an ether.
An.especially
preferred solvent is ethanol. The reaction time ranges from 2 hours to 3 days
and the
reaction temperature ranges from ambient temperature to the reflex temperature
of
the solvent being employed.
Compounds of the formula 3-4 are prepared by removal of the benzyl
protecting group from compounds of formula 3-3. This transforma#ion is
conducted in
a manner analogous to the procedure set forth for the preparation of compounds
of
formula 2-6 above.
Compounds of formula 3-5 are prepared from the displacement reaction of
amine 3-4 as described in Scheme 1, where the amine 3-4 is equivalent to R'-
NH.
Scheme 3a
Ray
R w
---.-- R'°-~-- ,~--R's --
N FZ ~N~ ~R~
R
3a-~ _ , 3-5 3a 2


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pGT/IB00/00296
Compounds of formulas 3a-1 and 3a-2 are prepared as shown in Scheme 3a , ,
from compounds of formula 3-5. Thus, to prepare a compound of 3a-1, a compound
of formula 3-5 is reduced with a common reduang agent, such as, for example,
sodium borohydride, lithium aluminum hydride or diisobutylaluminum hydride.
Other
reducing agents capable of effecting the reduction of a ketone to an alcohol
are well
known to those skilled in the art (e.g., Larodc, R. D. Comprehensive Or~janic.
.
Transformations, VCH Publishers, lnc.: New York, 1989, pp 527-547). Likewise,
compounds of formula 3a-2 are prepared from compounds of formula 3-5 by
reduction with reducing agents capable of redudng a ketone completety to a
methyfene group. A preferred such reducing agent is aluminum
tridiloridelborane-tert-
butylamine complex. Other such reducing agents are well known to those skilled
in
the art (e.g., J. Org. Chem.1989, 54. 4350; Larodc, R. D. Compr~ehensiv~
Organic
Transformations, VCH Publishers, Inc.: New York, 1989, pp 35-37). It will be
recognized by those skilled in the art that the transformation of 3-5 to 3a-1
or 3a-2 can
be conducted at different points in Scheme 3, depending upon the dynamics of
the
particular system.
Alternatively, compounds of formula 3-5 wherein R'° and R" are
hydrogen can
be prepared from 4-piperidone monohydrate monochloride in a manner analogous
to
the procedure described in Scheme 1, where the amine 3-6 is equivalent to R'-
NH to
give compounds of fom~ula 3-7. Compounds of formula 3-7 can be reacted with
compounds of formula 3-2 in a manner analogous to the procedure set forth for
the
synthesis of compounds of formula 3-3 to afford compounds of formula 3-5.


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Scheme 4 '
o ,
co=at
'f' R~NHNHZ , , ' ,
N Rs~
I 4'Z
BoC A-'~
4-1 \ 6 ,
-f- alkyl~Lv~
OzEt N
R~ J
O I
R'2 ~ -~ R~NHNH~ BoC ' ,
N ,
I 4-2
8oc
4-1a ~ '
4-3 where A = NH and B = CO (C,-C,)alkyi-Lv~ 4~3 where A = N-alkyl and B = CO
or or
M3 where A = CO and B = NH 4.3 where A = CO and 8 = N ~ alkyl
R~ '
/
A-N
\ S /R'u
A~N
N
R~
R~ ~ N N
N ./ \Rt H
4~
4-5
Compounds of formula 4-5 are prepared according to Scheme 4 and more
particularly as described below.
Compounds of formula 4-3 are prepared by reacting a compound of formula 4-
2 with a compound of formula 4-1 or 4-1 a. Compounds of formula 4-1 and 4-1 a
are
prepared according to methods well known to those skilled in the art. Where
R'~ is
hydrogen, 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3~thyl
ester is
condensed with a compound of formula 4-2 to afford a compound of formula 4-3.
Said


CA 02484282 2000-03-16
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.89
compounds of formula 4-2 are readily available from well known
commercial"vendors,
known in the literature, or are synthesized under standard conditions well
known to
those skilled in the art. Preferred conditions to prepare compounds of formula
4-3
from a compound of formula 4-1 where A is CO and B is NH or from a compound of
formula 4-1 a where A is NH and B is CO can be found in March, J. Advanced
Organic
Chemistry, 3'~ ed.; John wley and Sons Inc.: New York, 1985, p 1163. The
reaction is
conducted at ambient pressure in a reaction inert solvent. Preferred such
solvents
include aqueous media, a (C,-C,)alcohol, glacial acetic acid, an aromatic or
aliphatic
hydrocarbon, a polar aprotic solvent, a halocarbon and ethers or combinat'rons
thereof. The reaction time ranges from 2 hours to 3 days and the reaction
temperature ranges from ambient temperature to the reflux temperature of the
solvent
being used. An optional second step using aqueous or non-aqueous base may be
employed in certain cases which will be recognized by those skilled in
the,art. This
second step is conducted at ambient pressure in a reaction inert solvent.
Preferred
such solvents include aqueous media, a (C,-C,)ahhol, glaaal acetic acid, an
aromatic or aliphatic hydrocarbon, a polar aprotic solvent, a halocarbon and
ethers oT
combinations thereof. The reaction time ranges from 2 hours to 3 days and the
reaction temperature ranges from ambient temperature to the reflux temperature
of
the solvent being used.
Compounds of formula 4-3 wherein B is CO and A is N-alkyl or wherein B is
N-alkyl and A is CO are prepared by alkytation of compounds of formula 4-3
where B
is CO and A is NH or wherein B is NH and A is CO, respectively. The anion of
those
compounds of formula 4-3 is formed by reaction with an appropriate base.
Preferred
such bases inGude sodium hydride and sodium hexamethyldisilazide, although
other
bases may be used where conditions warrant, as determined by the skilled
person.
The reaction is conducted in a reaction inert solvent, preferably an ether
such as
tetrahydrofuran, diethyl ether, dioxane or diglyme or polar aprotic solvent
such as
dimethylfomlamide. The reaction proceeds at ambient pressure and at
temperatures
ranging from -100 °C to ambient temperature. The reaction times are
from 10
minutes to 2 hours. Addition of (C,-C,)alkyl halides or (C,-C,~Ikylsulfonates
such as
mesylate, tosylate-or nosylate to the anion of 4-3 proceeds at ambient
pressure and at
temperatures ranging from -20 'C to 50 'C. The reaction times range from 10
minutes to 1 day.


CA 02484282 2000-03-16
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Compounds of formula 4-4 are prepared form compounds of formula 4-3 ,
wherein A is N-alkyl and B is CO or A is CO and B is N-alkyl via acid-
catalyzed ,
deprotection of the Boc carbamate under standard conditions, for example,
hydrochloric acid or trifluoroacetic aad in a reaction inert solvent or in the
absence of
solvent. Such conditions are known to those skilled in the art. Exemplary
conditions
are disGosed in Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2"° ed.; John Wiley and Sons lnc.: New York, 1991, pp
327-330.
Compounds of formula 4-5 are. prepared by the displacement reaction of
amine 4-4 as described in Scheme 1; where the amine ~ is equivalent to R'-H.
Scheme 5
H X~Ra
/ /
~N N
z ~z
Re-X-Lv3 .f: ( ~G' ~ ~ Z~G~
S_1 ~G
N N
s-2 Prt i
Prt
H -°
R9-X-Lv' -t-
5-1
5-4
Compounds of formula 5-4 where X is a covalent bond and G, G', GZ, q, R', R2,
R6, R'
and Ra are as defined above are prepared according to Scheme 5 above and
particularly as described below.
Compounds of formula 5-3 are prepared by reaction of a compound of formula
5-1 with a compound of formula 5-2 where Prt is an optional amine protecting
group
selected from benzyl and C02R~°, where R°° is selected
from (C,-C,~lkyl, (C,-C,)allyl,


CA 02484282 2000-03-16
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pCT/IB00/00296
trichloroethyl and benzyl substitutedby up to two (C,-C,)alkoxy. Compounds of
formula 5-1 where Rg is Ar' and Lv' is halo, (C,-C,)alkytsulfide, (C,-
C,)alkylsulfone, . ,
trifluoromethanesulfonate, (C,-C6)alkylsulfonate or phenyisulfonate, where
said phenyl
is optionally substituted with up to three halo, vitro or (C,-C,)alkyl are
commercially
available or are readily prepared according to methods well known to those
skilled in
the art. For example, to prepare compounds of formula 5-1 wherein Lv' is
chloro, a
compound of formula Ar'-OH, or the Ar'-(=O) tautomer thereof, is reacted with
a
chlorinating agent such as phosphorus oxychloride and/or phosphorus
pentachloride.
This chlorinating reaction is conducted at ambient pressure in the absence of
solvent
~ 0 or in a reaction inert solvent, preferably a halocarbon solvent, at
temperatures ranging
from ambient temperature to 180 °C. Treatment of the chloro compound
with the
requisite mineral acid provides compounds of formula 5-1 where Lv' is bromo or
iodo.
Compounds of formula 5-1 wherein Lv' is trifluoromethanesutfonate, (C,- 1
Cs~lkylsulfonate or phenylsulfonate are prepared from a compound of formula
Ar'-
OH, or the Ar'-(=O) tautomer thereof, by reaction with a sulfonic acid
chloride or
anhydride in the presence of a base, preferably an organic amine such as
triethylamine, N,N'-diisopropylethylamine, dimethytaminopyridine or pyridine.
In
certain cases it wiU be recognized by those skilled in the art that a catalyst
will be
required to effect reaction. In those cases, a preferred catalyst is 4-
dimethylaminopyridine. This reaction is conducted at ambient pressure in a
reaction
inert solvent such as pyridine, a halocarbon, an aromatic or aliphatic
hydrocarbon, an
ether, or a combination thereof. The reaction temperature ranges from -20
°C to 100
°C and the reaction time ranges from 15 minutes to 1 day. Compounds of
formula 5-1
where Lv' is thiomethyl are prepared by reacting a compound of formula Ar'-SH,
or
the Ar'-(=S) tauLomer thereof, with methyl iodide or dimethylsuifate in the
presence of
an inorganic base, preferably potassium carbonate. These reactions are
conducted
at ambient pressure in a reaction inert solvent, preferably an ether or a
polar aprotic
solvent. An espeaalfy preferred polar aprotic solvent is dimethylfomiamide at
a
temperature ranging from 0 °C to 100 °C. Compounds of formula 5-
1 where Lv' is
methylsutfone are, prepared from a compound of formula 5-1 where Lv' is
thiomethyl
by oxidation thereof according to procedures well known to those skilled in
the art,
specifically~s set forth in March, J. Advanced Organic Chemistry, 3"°
ed:; John wley
and Sons.: New York, 1985, pp 1089-1090.


CA 02484282 2000-03-16
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A representative set of compounds of formula 5-1 which are commercially
available or which can be prepared according to methods analogous to a
literature
procedure inGude 4-chloropyridine (Aldrich, P.O. Box 355, Milwaukee, Wisconsin
53201, USA), 3-chlon~-6-methyl-pyridazine (Maybridge, c/o Ryan Saentific, 443
Long
Point Road, Suite D, Mount Pleasant, South Carolina 29464, USA), 2-chloro-
pyrazine
(Aldrich), 2,6-dichloro-pyrazine (Aldrich), 3-chloro-2,5-dimethylpyrazine
(Aidrich), 2,4-
dichloro-pyrimidine (Aldrich), 4,6-dict~loro-pyrimidine (Atdrich), 4-chloro-2-
methyl-
pyrimidine CChem. Ber. 1904, 37, 3641 ), 4-c~loro-6-methyl-pyrimidine CChem.
Ber.
1899, 32, 2931 ), 4-chloro-2,6-dimethyl-pyrimidine (J. Am. Chem. Soc. 1946,
68,
1299), 4-chloro-2,6-bis(trifluoromethyl)-pyrimidine (J. Org. Chem.1961,
26,4504), 4-
chloro-2-methylsulfanyl-pyrimidine (Aldrich), 4-~chloro-2-methoxymethyl-
pyrimidine
(US Patent 5 215 990), 1-chloro-isoquinoline (J. Am. Chem. Soc. 1946, 68,
1299), 2-
chloro-quinoline (Aldrich), 4-chloro-quinazoline (J. Am. Chem. Soc. 1909, 39,
509); 2-
chloro-quinoxaline (US Patent 2 537 870), 2-chloro-3-methyl-quinoxafine
(Aldrich),
2,6,7-trichloro-quinoxaline (J. Chem. Soc., Chem. Commun. 1956, 4731 ), 4-
chtoro-
pteridine (J. Chem. Soc., Chem. Commun. 1954. 3832), 7-chloro-pteridine (J.
Chem.
Soc., Chem. Commun. 1954, 3832), and 6-chloro-9H-purine (Aldrich). Other
compounds of formula 5-1 can be prepared using methods well known to those
skilled
in the art or by using methods analogous to those described in the foregoing
references.
Compounds of formula 5-3 are prepared by the displacement reaction of a
compound of formula 5-1 with an amine of the formula 5-2. The reaction is
conducted
in the presence of a non-aqueous base, prefeably an organic amine such as
pyridine,
4~iimethylaminopyridine, triethylamine or N,N'-diisopropyiethyfamine; an
inorganic
base such as potassium or sodium carbonate or bicarbonate; o~ an alkaline
metal
alkoxide such as potassium t-butoxide. Alternatively, an excess of the
reacting amine
5-2 can be used in lieu of the added base. In cases where the leaving group
Lv' is
unactivated, or in speafic cases which will be recognized by those skilled in
the art,
the use of a transition-metal catatyst such as palladium(0), palladium (II),
nidcel(0) or
nidcel(ll), along with phosphine-based ligands, such as 2,2'-
bis(diphenytphosphino)-
1,1'-binaphthyl (BINAP), may be required to effect reaction. More spedfic
details
concerning this reaction are available in the following references: J. Org.
Chem.1997,
62, 1264; J. Org. Chern: 1997, 62, 1568; SymLett 1997, 329. The reacfron can
be


CA 02484282 2000-03-16
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conducted in the absence of solvent or in a reaction inert solvent. Preferabl2
reaction , ,
inert solvents inGude aqueous media, (C,-C,)alcohol, (CZ-C6)glycol, a
halocarbon, an
aliphatic or aromatic hydrocarbon, an ether, a polar aprotic solvent, a
ketone, or
combinations thereof. The reacfion time ranges from 15 minutes to 3 days and
the
reaction temperature ranges from 0 °C to 180 °C or to the reflux
temperature of the
solvent being used. The reactions are preferably conducted at ambient
pressure.
In certain cases which will be recognized by those skilled in the art,
transformations of existing functionality in Ar' of compound 5-3 may be
necessary to
produce compounds of formula 5-4. This pertains in particular to those cases
where;
for example, R9~ in 5-3 contains an aromatic or heteroaromafic halide, (C,
C,)alkylsulfonate or triflate. Said compounds of formula 5-3 wherein Ar'
contains up
to two substituents selected from halide, (C,-C,)alkylsulfonate or trii3ate,
ray be
converted to a compound of formula Ar' where said halide, (C,-
C,)alkylsulfonate or
triflate is transformed into another functional group by a reduction reaction
or by a
displacement reaction of said halide, (C,-C,)alkylsulfonate or triflate with a
nuGeophile. The reduction reaction is conducted with a reduang agent,
preferably
ammonium fomzate or hydrogen gas, in a reaction inert solvent. The reduction
is
conducted in the presence of a palladium catalyst at ambient pressure or under
a
hydrogen pressure of up to 50 psi. Preferred solvents include (C,-C,)atcohots
such as
methanol and ethanol, and ether solvents such as diethyl ether, dioxane and
tetrahydrofuran. The nucleophilic displacement reaction may be conducted by
adding
the nucleophile directly or by pre-forming the nucleophile separately or in
situ from a
nucleophile precursor. Preferred nuGeophiies include organoaluminum,
organoboron,
organocopper, organotin, organozinc or Grignard reagent; R"-oxide or R"-
thioxide; or
anilino where anilino is within the scope of R". It will be recognized by
those slulled in
the art that transition-metal catalysts may be required to effect reaction in
certain
displacement reactions. When required, such transition metal catalysts may
include
palladium(0), paNadium(II), nickel(0), and nidcel(II) complexes. Palladium(//)
bis(diphenylphosphinobutane) dichloride is a preferred such catalyst.
Additionally, an
aqueous or non-aqueous base may be required in the displacement reaction.
Preferred such bases inGude sodium carbonate, sodium hydride, triethylamine
and
sodium test-butoxide. The reaction is conducted at ambient pressure in a
reaction
inert solvent such as a halocarbon, an aromatic or aliphatic hydrocarbon, an
ether or a


CA 02484282 2000-03-16
WO OOI59510 PCTIIB00/00296
polar aprotic solvent or a combination thereof. In certain cases, a (C,-
C,)alcohol is
used as a solvent or co-solvent. The reaction temperature ranges from -20
°C to the
reflux temperature of the solvent employed. The reaction time ranges from 1
hour to 3
days.
Optional protecting groups which riiay be present in compounds of formula S-3
are removed according to methods set forth above, or according to methods well
known to those skilled in the art, particularly as set forth in: Greene, T.
W.; Wuts, P.
G. M. Protective Groups in Organic Synthesis, 2"° ed.; John Wiley and
Sons inc.: New
York, 1991.
Compounds of formula 5~ are prepared from the displacement reaction of
amine 5-3 as described in Scheme 1, where the amine 5-3 is equivalent to R'-
NH. A
representative set of amines of formula 5-3 which are commercially available
or which
can be prepared by a literature procedure include 1-phenyl-piperazine
(Aldrich), 1-,
pyridin-2-yl-piperazine (Aldrich), 3-piperazin-1-yl-benzo[d)isoxazole (J. Med.
Chem.
1986. 29, 359), 3-piperazin-1-yl-benzo[d]isothiazole (J. Med. Chem. 1986, 29,
359), 2-
piperazin-1-yl-quinoxaline (J. Med. Chem.1981, 24, 93), 1-naphthalen-2-yl-
piperazine
(cf. Tetrahedron Lett. 1994; 35, 7331 ), and 1-(3,5-dimethylphenyl)-piperazine
(cf.
Tetrahedron Lett 1994, 35, 7331 ). Other compounds of formula 5-3 can be
prepared
using methods well khown to those skilled in the art or by using methods
analogous to
those described in the foregoing references.
Alternatively, compounds of formula 5~ can be prepared from reaction with
compounds of formula 5-1 with compounds of formula 5-5 using conditions set
forth
above to prepare 5-3. Compounds of formula 5-5 can be prepared in a manner
analogous to the method used to prepare compounds of formula 1-3.
Compounds of formula 5~ wherein X is oxycarbonyl, vinylenylcarbonyl,
oxy(C,-C,)alkylenylcarbonyl, (C,-C,)alkylenylcarbonyl, (C,-C,)alkenylcarbonyl,
thio(C,-
C,)alkenylcarbonyl, vinylenylsulfonyl or carbonyl(Co-C,)alkylenylcarbonyl;
wherein
said oxy(C,-C,)alkylenylcarbonyl, (C,-C,)alkylenylcarbonyl, (C,-
C,~Ikenyicarbonyl,
and thio(C3-C,)alkenytcart~ony! in the definition of X are each optionally and
independently substituted with up to two (C,-C,)alkyl, benzyl, or Ar; said
vinylenylsulfonyt and said vinylenylcarbonyl in the definition of X are each
optionally
and independently substituted with up to three (C,-C,)alkyl, benzyl, or Ar are
also
prepared according to Scheme 5 above and particularly as described below.


CA 02484282 2000-03-16
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Compounds of formula 5-4 where X is as defined in the immediately preceding
paragraph are prepared by reacting a compound of formula 5-5 with a compound
of
formula 5-1 where Rs is described above, X is as defined in the immediately
preceding
paragraph and Lv3 is chtoro. The reaction is conducted under anhydrous
conditions in
the presence of a non-aqueous base, which includes organic amines such as
triethytamine, N,N'-diisopropylethylamine and pyridine and derivatives
thereof, The
reaction is generally conducted in a reaction inert solvent. Preferred
solvents include
haiocarbon, aliphatic or aromatic hydrocarbon, ethers, ethyl acetate, pyridine
and
combinations thereof. The reaction time ranges from 15 minutes to 24 hours and
the
,.
reaction temperature ranges from 0 °C to 80 °C or to the reflux
temperature of the
solvent being used. The reactions are preferably conducted at from 0 'C to
ambient
temperature and at ambient pressure. Removal of optional protecting groups is
carried out as described in Scheme I.
Compounds of formula 5-4 wherein X is vinylenylcarbonyl, oxy(C,-
C,~Ikylenyicarbonyl, (C,-C,~Ikylenylcarbonyl, (C,-C,)alkenylcarbonyl, thio(Cz-
C,)alkenylcarbonyl, or carbonyl(Co-C,~ifcylenyfcarbonyl ; wherein said oxy(C,-
C,)alkylenylcarbonyl, (C,-C,)atkylenylcarbonyl, (C,-C,)atkenylcarbonyl, and
thio(C=-
C,)alkenylcarbonyl in the definition of X are each optionally and
independently
substituted with up to finro (C,-C,)alkyl, benryl, or Ar; and said
vinylenylcarbonyl in the
definition of X are each optionally and independently substituted with up to
three (C,-
C,)alkyl, benzyt, or Ar are also prepared according to Scheme 5 avove and
particularly as described below.
Compounds of formula 5-4 are prepared by reacting a compound of fomnuta 5-
5 with a compound of formula RQ-X-Lv' where R° is described above, X is
as defined
in the immediately preceding paragraph and Lv' is OH. The reaction is
conducted in
the presence of coupling agents, preferably dicydohexylcarbodiimide or 1-(3-
dimethylaminopropyl~3-ethylcarbodiimide hydrochloride as described in J:
Artier.
Chem. Soc.1996, 178, 4952. The reaction is conducted in a reaction inert
solvent
Preferred solvents include halocarbon, aliphatic or aromatic hydrocarbon and
ethers.
Espeaally preferred solvents include dichloromethane and chloroform. Other
coupling
agents that can be used are well known to those skilled in the art and
include, but are
not limited to, various phosphine reagents, ethyl chlorofom~ate, and N-
hydroxysucanimide. These reagents and procedures are described in "Compendium


CA 02484282 2000-03-16
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WO 00/59510
_gg_
of Organic Synthetic Methods" (Ed., I. T. Harrison and_ S. Harrison, John ~ley
&
Sons). Specific references include the following: J. Org. Chem,~1971, 36,
1305; BuIL
Soc. Chim. Fr., 1971, 3034; Bull. Chem. Soc. Japan, 1971, 44, 1373;
Tetrahedron
Lett., 1973, 28, 1595; Tetrahedron Letf., 1971, 26, 2967, and J. Med. Chem.,
1968,
17, 534. Removal of optional protecting groups is carried out as described in
Scheme
Compounds of formula 5~ wherein X is a covalent bond and Rs is (C,-
C,)cycloalkyl or Ar'-(C,-C3)alkylenyl are also prepared according to Scheme 5
above
and particularly as described below.
Compounds of formula 5-4 wherein X is a covalent bond and R9 is (C,-
C,)cydoalkyl or Ar'-{C,-C,)alkylenyl are prepared by reacting a compound of
formula
5-1 wherein X is a covalent bond, R9 is (C3-C,)cydoalkyl or Ar'-(C,-
C,)alkylenyl and
Lv' is halo, methanesulfonate, p-toluenesulfonate or
trifluoromethanesulfonate. The
reaction is conducted under anhydrous conditions in the presence of a non-
aqueous
base, which inGudes organic amines such as triethylamine, N,N'-
diisopropylethylamine and pyridine and derivatives thereof. The reaction is
conducted
in a reaction inert solvent. Preferred solvents for the reaction include
halocatbons,
aliphatic or aromatic hydrocarbons, ethers, ethyl acetate, pyridine and
combinations
thereof. The reaction time ranges from 15 minutes to 24 hours and the reaction
temperature ranges from -20 °C to 80 °C or to the reflux
temperature of the solvent
being used. The reactions are preferably conducted at ambient temperature of
the
solvent being used and at 'ambient pressure. Removal of optional protecting
groups is
conducted as set forth in Scheme I.


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97-
Scheme 6
H HN Rn Rsz ~
/ ~NHz
N
z~G, ~ ( z~G' .acid + Lv6~0
~G ~ ~ G_
N a
I i R" R'z
Prt
5_2 Prt
O O
6-zd
R"
Ru a
N
~N
TzN
( z~ G,
N
I
Prt
&3 6rt
R"
HN
H ~NHz / ~ Rsx
N N .2CId N _
( z)c G, ( z) x , / N
N
N -.a N ( z)a z~
z
R / ~ Rz / N N
N~Rs N"R' Rz / N
5-5
N R'
Compounds of formula 6-5 wherein G, G', G~, q, R', RZ, 'R6, R' and R°
are as
defined above are prepared as set forth in Scheme 6 above and particularly as
described below.
Compounds of formula 6-1 are prepared from an amine of the formula 5-2
where Prt is an optional amine protecting group selected from benzyl and
C02R~°,
where R~° is selected from (C,-C,)atkyl, (C,-C,)allyl, trichloroethyl
and benzyl
substituted with up to two (C,-C,)aikoxy. The preferred procedure for
preparing


CA 02484282 2000-03-16
' pCT/IB00100296
WO 00159510
-98
compounds of formula 6-1 can be found in Tetrahedron Left. 1993, 48, 7767 or
J. Org.
Chem 1997, 62, 1540. '
Compounds of formula 6-3 are prepared by condensation of ~diketones or ~3-
ketoesters of the formula 6-2b, where R" and.R'Z aye independently substituted
as set
forth above, or compounds of the formula 6-2a where Lv' is, for example,
hydroxy,
chloro or dimethylamino with guanidines of the formula 6-1. The reaction is
conducted in the presence of an aqueous or non-aqueous base, preferably
potassium
or sodium hydroxide, potassium or sodium (C,-C,~alkoxide, triethylamine,
pyridine, 4-
dimethylaminopyridine, potassium or sodium carbonate or potassium or sodium
bicarbonate. The reaction is conducted in a reaction inert solvent, preferably
aqueous
media, a (C,-C,)alcohol, a (CZ-C6)dialcohol, an aroma#ic hydrocarbon, a polar
aprotic
solvent, or combinations thereof. The reaction time ranges from 2 hours to 3
days
and the reaction temperature ranges from room temperature to reflux of the
solvent
employed. The reaction is preferably run at ambient pressure, but may be
conducted
at pressures up to 250 psi.
Removal of of optional protecting groups in compounds of formula 6-3 to
afford compounds of formula 6-4 is accomplished as set forth above.
Compounds of formula 6-5 are prepared from the displacement reaction of
amine 6-4 as described in Scheme 1, where the amine 6-4 is equivalent to R'-
NH.
Alternatively, compounds of formula 6-5 are prepared from compounds of
formula 5-5 by formation of a compound of formula 6-6, or by reaction with
compounds of formula 6-2a or 6-2b under the conditions outlined above in
Scheme 6
Removal of optional protecting groups is conducted as described in Scheme 1.
Compounds of fomlula 5-5 are prepared as set forth above.

CA 02484282 2000-03-16
Y WO 00159510 PCTIIB00/00296
_99_
Scheme 7
H
N
N3
.~. HNRx~R~
R~ " 7.3
/ ~N
\
N~R'
7-0 7.~ 1 . .
H
TN R~
x),~°~G4 Rx,NCO
G ~-0
N
or
Rx / N ---.r
O R'
N- _R' ~ x,
Ct NR R
5-5 7-8
7.4
Compounds of formula 7-4 wherein G', G', G5, r, R', R2, R'°, R'9 and
R~° are defined
as set forth above are prepared as set forth in Scheme 7 and particulariy as
described
below.
Compounds of formula 7-1 are prepared by reaction of an amine of the
formula 7-0 with phosgene or a phosgene equivalent such as triphosgene.
Compounds of 7-1 wherein the chloro group is replaced by an imidazolyl group
are
also useful in this reaction. Such compounds are prepared by reaction of an
amine of
formula 7-0 with carbonyl diimidazole. The reaction is conducted under
anhydrous
conditions in the presence of a nonaqueous base. Preferred such bases indude


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-100-
triethylamine and other tertiary 'amines and pyridine and' derivatives
thereof. The
reaction is conducted in a reaction inert solvent at -78 ~°C to 80
°C or at the reflux
temperature of the solvent being used for 15 minutes to 24 hours. Preferred
solvents
for this reaction indude a halocarbon, an aliphatic or aromatic hydrocarbon,
an ether,
ethyl acetate, pyridine and combinations thereof. The reactions are preferably
conducted at from 0 °C to ambient temperature and at ambient pressun:.
Compounds of formula 7-4 are prepared by reaction of carbamoyl chlorides of
the formula 7-1 with amines of the formula 7-3, where R2' and R~ are defined
above.
The reaction can be conducted in the absence of solvent, or in a reaction
inert
i0 solvent. Preferred such solvents indude aqueous media, a (C,-C,)aloohol, a
(C2-
C6)dialcohol, an aromatic or aliphatic hydrocarbon; a halocarbon, an ether, a
polar
aprotic solvent, a ketone, pyridine or combinations thereof. The reaction time
ranges
from 15 minutes to 3 days and the reaction temperature ranges from
0 °C to the reflux temperature of the solvent being used. 'The reaction
is preferably
conducted at ambient pressure. It will be recognized by those skilled in the
art that
addition of a base may be required to effect reaction. In those cases,
preferred bases
indude potassium or sodium hydroxide, triethyiamine and other tertiary amines,
pyridine and its derivatives and inorganic bases such as sodium or potassium
carbonate and sodium or potassium bicarbonate. Removal of optional hydroxyl
protecting groups contained in R' is canied out according to methods set forth
in
Scheme 1.
Attematively, compounds of formula 7-4 are prepared from compounds of
formula 7-0 by reaction with isocyanates of the formula 7-6 or with carbamoyl
chlorides of the formula 7-8. Said isocyanates are commer~cialiy available,
known in
the literature, or synthesized under standard conditions known to those
skilled in the
art, particularly as described in March, J. Advanced Organic Chemistry,
3"° ed.; John
Whey and Sons Inc.: New York, 1985, p 1166. A preferred method of forming such
isocyanates is the Curtius rearrangement of a suitable aryl azide. Said
carbamoyl
chlorides are synthesized using methods analogous to that described for the
preparation of vompounds of formuta 7-1 in Scheme 7. Removal of optional
hydroxyl
protecting groups contained in R' is carried out according to methods set
forth in
Scheme 1.


CA 02484282 2000-03-16
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-101-
Compounds of formula I containing the radicaLR'' are prepared according to
the procedures set forth in Scheme 7 using the corresponding starting
materials and
reagents.
Scheme 8
Rze
I \ ~ HCHO ,, ,.
R
Rr ,- Rze
NHz Rz9 RZs
8-1a ~
Rr
or
Rze N
I \ ~ H
R 8.2
NHz 8~5
8-1b
Rr ~ --
N
Prt Prt
8-3 8-4
Compounds of formula 8-5 are prepared as set forth in Scheme 8 and
particularly as
described below.
Compounds of formula 8-2 are readily prepared from commercially available
phenethyiamines of formula 8-1 a and formaldehyde or an aidehyde of the
formula
R~'-CHO under Pictet-Spengler conditions. The Pictet-Spengler reaction is
reviewed
in Chem. Rev.1995, 95,1797. A similar route route to 1,2,3,4-
tetrahydroiso4uinolines
using the Bischler Napiecalski reaction, as disclosed in March, J. Advanced
Organic
Chemistry, 3'~ ed.; ,fohn Wiiey and Sons.: New York, 1985, 495, followed by
standaM
reduction of the imine formed may also be employed.


CA 02484282 2000-03-16
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Compounds of formula 8-4 are prepared from compounds of formula 8-3 by
aromatic electrophilic substitution using the appropriate~electrophile. A
genera!
reference for this type of reaction can be found in March, J. Advanced Organic
Chemistry, 3'° ed.; John Wiley and Sons.: New York, 1985, 4.47-
511.
Compounds of formula 8-2 are also prepared by removal of the protecting
group from a compound of formula 8-4. Preferably the protecting group is
trifluoroacetamide which may be removed under basic conditions using inorganic
hydroxides or carbonates in a reaction inert solvent. Suitable suds solvents
include
(C,-C,)aicohols and preferably methanol. Optionally, one or more co-solvents,
preferably selected from water, tetrahydrofuran and dioxane may be employed.
The
reaction time ranges from 15 minutes to 24 hours.and the reaction temperature
ranges from 0 °C to 100 °C or to the reflux temperature of the
solvent or solvent
system being used. The reaction is preferabfy'conducted at ambient
temperature.
Other conditions for deprotection of trifluoroacetamides and deprotection
conditions
for other suitable protecting groups can be found in Greene, T. W.; Wuts, P.
G. M.
Profective Groups in Organic Synthesis, 2"° ed.; John Wiley and Sons
Inc.: New York,
1991.
Compounds of formula 8-4 are prepared by, adding a protecting group to
compounds of fon'nuta 8-2. Preferably the protecting group is
trifluoroacetamide or
tert-butoxycarbonyl (BOC). The protecting group is attached by reaction of a
compound of formula &2 with trifluoroacetyl chloride or di-tart-butyl
dicarboriate or an
equivalent thereof in the presence of a base, preferably triethylamine or
pyridine. The
reaction is conducted in a reaction inert solvent. Preferred such solvents
indude
ethers such as tetrahydrofuran, diethyl ether, dioxane or dimethoxyethane; a
halocafion such as dichloromethane, chloroform or carbon tetrachloride; and
aromatic or aliphatic hydrocarbons such as benzene, toluene or hexanes. The
reaction bme ranges from 15 minutes to 3 days and the reaction temperature
ranges
from 0 °C to the reflux temperature of the solvent being used. The
reaction is
preferably conducted at ambient pressure. Other conditions for protection of
amines
with trifluoroacetamides or tart-butoxycarbonyl groups as welt as other
suitable
protecting groups can be found in Greene, T. W.; Wuts, P. G. M. Prr~tecfive
Groups in
Organic Synfhesis, 2"° ed.; John Wiley and Sons Inc.: New York,
1991:-


CA 02484282 2000-03-16
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Manipulation of the substituents R'° and R~ is cartied out to
provide
isoquinolines with altered substitution. Preferably, transition metal-
catalyzed cross- ,
coupling of a compound of formula 8-4 where R~° or R~' is bromide or
triflate is
employed to afford compounds of formula 8-4 wherein R~° or R~' are as
set forth
above. This reaction is conducted according to methods well known to those
skilled in
the art, particularly as set forth in TetrBhedron,1998, 54, 263 far Stille and
Siizuki
Reactions and in Acc. Chem. Res.1998, 31, 805 for Buchwald Amination
Reactions.
Compounds of formula 8-5 are prepared from the dispia<:ement reaction of
amine 8-2 as described in Scheme 1, where the amine 8-2 is equivalent to R'-
NH.
Scheme 9
O
COi~t , ,
HCI
NH
acid
RZe~N
/ Hz
9-1
or
9-3
9-2
Compounds of formula 9-3 are prepared according to the generat procedures
set forth in Scheme 2 starting from ethyl 1-benzyl-4-oxo-3-piperidine
carboxylate
hydrochloride (9-1 ). In certain cases, where R~' is H, N-tertbutoxycarbonyl-3-

(dimethylaminomethylene~4-piperidone (9-2, Chemical Abstracts 121:157661 ) is
used as the starting material.


CA 02484282 2000-03-16
' WO 00159510
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Scheme 10
pCT/IB00100296
"O


a'
N ~ .NHz
O NYflR u~


\ ~ ~ R R
' H
+ ---.w
J


N N


' , 10-3


10-1 10-2


R~
~N
a '
R \ _N Rs~ ay~N ~ N
N~~ N ~N R
Rs2! ,N ~ N ~ ~ N
'N ~ ~ R~ ' ~ ' ~ , 'NI
Cbz H ~N ~ R~
10-4
10-5 10-6
Compounds of formula 10-6 wherein R', RZ, R~ and R'~ are as defined above
are prepared as set forth in Scheme 10 and more particutarty as described
below.
Compounds of formula 10-2 where R9' is (C,-C,)alkyl are prepared by reacting
a compound of fomwla 10-1, where Cbz is benzyloxycarbonyl, with an O-
alkylating
agent. A prefer-ed compound of formula 10-1 is 3-oxo-piperazine-1-carboxylic
aad
benzyi ester. A preferred O-alkyiating agent is triethyloxonium
tetrafluoroborate. The
reaction is conducted at ambient pressure in a reaction inert solvent.
Preferred
solvents include an aromatic or aliphatic hydrocarbons, halocarbons and
ethers.
Dichloromethane is especially preferred. The reaction time ranges from 2 hours
to 3
days and the reaction temperature ranges from -100 °C to ambient
temperature.
Corripounds of formula 10-4 are prepared by condensation of a compound of
formula 10-2 with a compound of formula 10-3. Said compounds of formula 10-3
are
commercially available, are known in the literature, or are readily prepared
via
standard amidation of hydrazine and an activated carboxylic aad, such as a
carboxylic aad chloride. Such reactions are well known by those skilled in the
art
The condensation reaction is preferably run at ambient pressure, although
higher
pressures up to 250 psi may be employed if necessary. The reaction is
conducted in
a reaction inert solvent, preferably selected from (C,-C,)alcohols, aromatic
or aliphatic


CA 02484282 2000-03-16
WO 00159510 PCT/IB00/00196
-105-
hydrocarbons, polar aprotic media, halocarbons and ethers, or
combination~'thereof.
The reaction is conducted at temperatures ranging from ambient temperature to
180
°C. The reaction times are from 2 hours to 3 days.
Compounds of formula 10-5 are prepared form compounds of formula 10-4 via
Lewis acid-catalyzed cleavage or hydrogenolysis of the~Cbz carbamate under
standard conditions which are well known to those skilled in the art,
particularly as set
..
forth in Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis,
2"° ed.;
John Wiley and Sons Inc.: New York, 1991, pp 335-338.
Compounds of formula 10-6 are prepared from the displacement reaction of
an amine of the formula 10-5 as described in Scheme 1, where the amine 10-5 is
equivalent to R'-NH.
Scheme 11
11-1
3-1
R'°
R~s Rs~
R'~ R"
E m
E ~°
NwRso
Rx ~R~
N
H
1.
11-3 ,


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Compounds of formula 11-4, wherein R', R2, R~, R", R'°; R'~ and
R'° are as
defined above are prepared as set forth in Scheme 11, and more particularly as
described below:
Where R'~ and R'9 are hydrogen, 1-henry!-4-piperidone (3-1 ), available from
Aldrich, is condensed with a compound of formula 11-1, which are either
commercially
available or well known to those skilled in the art, to give compounds of
formula 11-2.
Where R'° and R'~ are not hydrogen, compounds of formula 3-1 can be
prepared
according to methods well known to those skilled in the art. The reaction is
conducted
at ambient pressure in the absence of solvent or in a reaction inert solvent:
Preferred
solvents inGude (C,-C,)alcohols, aromatic or aliphatic hydrocarbons, polar
aprotic
solvents, halocarbons and ethers. The reacfion time ranges from 2 hours to 3
days
and the reaction temperature ranges from ambient temperature to the reflux
temperature of the solvent being employed. More specific conditions can be
found in
Indian J. Chem. 197fi, 14B, 984 and J. Chem. Soc., Perkin Trans. 1 1984, 2465.
Compounds of formula 11-3 are prepared by removal of the henry! protecting
group from a compound of formula 11-2 in a manner analogous to the method
employed for the preparation of compounds of 2-6 described above.
Compounds of formula 11-4 are prepared by the displacement reaction of an
amine of the formula 11-3 as described in Scheme 1, where the amine 11-3 is
equivalent to R'-H.


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Scheme 12
fZn
s
~N N
( Ha)r GaG~ , ( z)~sG~
G'
N .(. R~~-Lv' N
RZ / N 12 2 . ~ RZ ,
/ I
N R~ N~R~
12-1
12-3
H Rxs
N'
Rz~
Rrj-Lv< ----~ N
12-2a
Rz
~~N
N_ 'R'
12-1a 12-3a
Compounds of formula 12-3 and 12-3a where R" and R~' are (C,-
C6)alkoxycarbonyl, (C,-C6)alkylcarbonyl, Are-carbonyl, (C,-C6)alkylsulfonyl,
Arz-
sulfonyl, or Acs-sulfinyl are prepared according to Scheme 12 above and
particularly
as set forth below.
Compounds of formula 12-3 and 12-3a where R" and R~' are as defined in
the immediately preceding paragraph are prepared by condensation with a
compound
of fortnuta 12-2 and 12-2a, wherein Lv' is chloro, respectively. Examples of
compounds of formula 12-2 and 12-2a indude (C,-C6)alkoxyCOCI, (C,-
C6)aIkyICOCI,
Arz-COCI, (C,-C6)alkylSOZCI, Ar=-SOZCI, or Arz-SOC1. The reaction is conducted
under
anhydrous conditions in the presence of a non-aqueous base, which indudes
organic
amines such as triethylamine, N,N'-diisopropylethylamine and pyridine and
derivatives
thereof. The reaction is conducted in a reaction inert solvent. Preferred
solvents for
the reaction indude halocarbon, aliphatic or aromatic hydrocarbon, ethers,
ethyl


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-108-
acetate, pyridine and combinations thereof. The reaction time ranges from 115
minutes to 24 hours and the reaction temperature ranges,from 0 °C to 80
°C or to the
reflux temperature of the sotvent being used. The reactions are preferably
conducted
at from 0 °C to ambient temperature and at ambient. pressure. Removal
of optional
protecting groups is carried out as descxibed in Sd~eme i.
1
Compounds of formula 12-3 and 12-3a wherein R" and R~ are (C,
CB)alkylcarbonyl or Ar2-carbonyl are also prepared according to Scheme 1~2
above
and particularly as described below.
Compounds of fortnuta 12-3 and 12-3a wherein R" and R~' are (C,-
C6)alkylcarbonyl or Arz-carbonyl are prepared by a condensation reaction with
a
compound of formula 12-2 or 12-2a, respectively, wherein Lv' is hydroxy in the
presence of coupling agents such as dicydohexytcarbodiimide or 1-(3-
dimethylaminopropyl}-3-ethyicarbodiimide hydrochloride. The reaction is
conducted in
a reaction inert solvent. Preferred solvents include halocarbon,
aliphaticJaromatic
hydrocarbons and ethers. Especially preferred solvents include dichloromethane
and
chloroform. Other coupling agents that can be used are weA knovm to those
skilled in
the art and include, but are not limited to, various phosphine reagents, ethyl
chloroformate, and N-hydroxysucanimide. Removal of optional protecting groups
is
carried out as described in Scheme I.
Compounds of formula 12-3 where R" is (C,-C6)alkyyl are also prepared
according to Scheme 12 and particularly as descxibed below.
Compounds of formula 12-3 where R" is (C,-CB~Ikyl are prepared by reacting
a compound of formula i 2-i with a compound of formula 12-2 where R" is (C,-
C,)alkyl and Lv'' is CI, Br, I, methanesulfonyloxy, p-toluenesulfonyloxy or
trifluoromethanesulfonyloxy. The reaction is conducted under anhydrous
conditions in
the presence of a nonaqueous base, which includes organic amines such as
triethylamine, Hunig's base and pyridine and derivatives thereof. The reaction
is
conducted in a reaction inert solvent. Prefetted solvents for the reaction
include
halocarbons, aliphatic or aromatic hydrocarbons, ethers, ethyl acetate,
pyridine and
combinations thereof. The reaction time ranges from 15 minutes to 24 hours and
the
reaction temperature ranges from ambient temperature to 80 °C or to the
reflux
temperatufe of the solvent being used. The reactions are preferably conducted
at
ambient temperature and pressure.


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-1 ~-
The starting materials and reagents for the above described compounds are
also readily available or can be easily synthesized by those skilled in the
art using
conventional methods of organic synthesis. For example, many of the compounds
used herein are related to, or are derived from, compounds found in nature, in
which
there is a large scientific interest and commerrcial need, and accordingly
many such
compounds are commeraally available or are reported in the literature or are
easily
prepared from other commonly available substances by methods which are
reported
in the literature.
The compounds of the instant invention inhibit the formation of sorbitol
dehydrogenase and as such have utility in the treatment of diabetic
complications
inGuding but not limited to such complications as diabetic nephropathy,
diabetic
neuropathy, diabetic retinopathy, diabetic micxoangiopathy and diabetic
macroangiopathy and diabetic cardiomyopathy. .The utility of the compounds of
the
present invention as medical agents in the treatment of diseases, such as are
detailed
herein in mammals (e.g., humans) for example, diabetic complications such as
diabetic cardiomyopathy, diabetic neuropathy, diabetic nephropathy, diabetic
retinopathy, diabetic microangiopathy and diabetic maaoang'ropathy is
demonstrated
by the activity of the compounds of formula I of this invention in
conventional assays.
Such assays also provide a means whereby the acFrvities of the compounds of
formula I of this invention can be compared with the activities of other known
compounds. The results of these comparisons are useful for determining dosage
levels in mammals, including humans, for the treatment of such diseases.
Measurement of SDH Activity
Male Sprague-Dawley rats (350-400 g) are used for these experiments.
Diabetes is induced in some of the rats by a tail vein in)ec~ion of
streptozocin, 85
rng/kg. Twenty-four hours later, 4 groups of diabetic rats are given a single
dose of
the test compound of fomwla 1 of this invention (0.001 to 100 mglkg) by oral
gavage.
Animals are sacrificed 4~ hours after dosing and blood and sciatic nerves are
harvested. Tissues and cells are extracted with 6°~ perchloric acid.
Sorbitol in erythrocytes and nerves is measured by a modfication of the
method of R. S. Ciements et al. (Saence,1_~6: 100?-8, 1969). Aliquots of
tissue
extracts are added to an assay system which has frnal oonoentrations of
reagents of
0.033 M glyane, pH 9.4, 800 mM t3-nicotine adenine dinuGeotide, and 4 unitslml
of


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sorbitol dehydrogenase. After incubation for 30 minutes at room temperature,
sample
fluorescence is determined on a fluorescence spectrophotometer with excitation
at
366 nm and emission at 452 nm. After subtracting appropriate blanks, the
amount of
sorbitol in each sample is determined from a fmear regression of sorbitol
standards
processed in the same manner as the tissue extracts.
Fructose is determined by a rnodfication of the method descxibed by M.
Ameyama, Methods in Enzvmoloav, ~: 20-25 (1982). Resazurin is substituted for
ferricyanide. Aliquots of tissue extracts are added to the assay system, which
has
final concentrations of reagents of 12 M citric add, pH 4.5,13 mM resazuriri,
3.3
units/ml of fructose dehydrogenase and 0.068% Triton X-100. After inarbation
for 60
minutes at room temperature, sample fluorescence is detertrr>ined on a
fluorescence
spectrophotometer with exatation at 560 nm and emission at 580 nm. After
subtracting appropriate blanks, the amount of fructose in each sample is
determined
from a linear regression of fructose standards processed in the same manner as
the
tissue extracts.
SDH activity is measured by a modfication of the method described by U.
Gerlach, Methodology of Enzymatic Analyses, edited by H. U. Bergmeyer, 3_,112-
117
(1983). Aliquots of sera or urine are added to the assay system, which has
final
concentrations of reagents of 0.1 M potassium phosphate buffer, pH 7.4, 5 mM
NAO,
20 mM sorbi~l, and 0.7 unitslmi of sorbitol dehydrogenase. After inarbation
for 10
minutes at room temperature, the average change in sample absorbanoe is
detemuned at 340 nm. SDH activity was presented as milliOD"°
unitslminute (00"°
= optical density at 340 nm).
Any aldose reductase inhibitor may be used as the second compound
(active agent) of this invention for combination therapies. The term aldose
redudase inhibitor refers to compounds which inhibit the bioconversion of
glucose
to sorbitol catalyzed by the enzyme aldose redudase. Such inhibition is
readily
detemuned by those skilled in the art acoor~ding to standard assays (J.
Maione,
Diabetes, X9:861-864,1980. "Red CeU Sorbitol, an Indicator of Diabetic
Control").
A variety of aldose ~reductase inhibitors arse described and referenced below,
however, other aldose reductase inhbitors wilt be known to those skilled in
the art.
Also, common chemical USAN names or other designation are in parentheses


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where applicable, together with reference to appropriate patent literature
disdosing
the compound. ' '
The activity of an aldose reductase inhibitor in ~a tissue can be determined
by testing the amount of aldose reductase inhibitor that is required to lower
tissue
sorbitol {i.e., by inhibiting the further production of sorbitol consequent to
bloddng
aldose reductase) or lower tissue fructose (by inhibiting the produdfon of
sorbitol
consequent to blocking aldose reductase and consequently the production of
fructose). While not wishing to be bound by any parircular theory or
mechanism, it
is believed that an aldose reductase inhibitor, by inhibiting aldose
reductase,
prevents or reduces ischemic damage as described hereinafter.
Accordingly, examples of aidose reductase inhibitors useful in the
compositions and methods of this invention indude:
1. 3-(4-bromo-2-tluorobenzylr3,4-dihydro~-oxo-l-phthalazineacetic acid
(ponalrestat, US 4,251,528);
2. N[[(5-trifluoromethyl~6-methoxy-1-naphthalenyl]thioxomethyl}-N-
methyiglydne (toirestat, US 4,600,724); .
3. 5-[(Z,E)-~methylcinnamyiidene]-4-oxo-2-thioxo-3-thiazolideneacetic
acid (epalrestat, US 4,464,382, US 4,791,126, US 4,831,045);
4. 3-(4-bromo-2-fluorobenzyl)-7-chioro-3,4-dihydro-2,4-dioxo-l (2H)-
quinazolineacetic acid (zenarestat, US 4,734,419, and 4.883,800);
5. 2R,4R-6.7-dichloro-~-hydroxy-2-methytchroman-4-acetic acid (US
4.883,410);
6. 2R,4R-6,7-dichioro-6-fluoro~-hydroxy-2-methylchroman-4-acetic add
(US 4,883,410);
7. 3,4-dihydro-2,8-diisopropyl-3-oxo-2H-1,4-benzoxazine~-acetic add
(US 4,771,050);
8. 3,4-dihydro-3-oxo-4~-((4,5,7-trifluoro-2-benzothiazoly!)methyt]-2H-~ ,4-
benzothiazine-2-acetic add (SPR-210, U.S. 5,252,572);
9. N-[3,5-dimethyl-4-[(nitromethyl),suffonytjpheny(}-2-methyl-
benzeneacetamide (ZD5522, U.S. 5,270,342 and U.S. 5,430,060);
10. (S-)-6-fluorospirojchroman~,4'-imidazolidine]-2,5'-dione (sorbinil, US
4,130,714);


CA 02484282 2000-03-16
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pCl'/~800/00296
11. d-2-methyl-6-fluoro-spiro(chroman~',4'-iwiidazolidirter2',5'-dione (US
4.540,704):
12. 2-fluoro-spiro(9H-fluorene-9,4'-imidazolidine~2',5'-dione (US
4,438,272);
13. 2,7-di-fluoro-spiro(9H-fluorerie-9,4'-imidazolidine)-2',5'-dione (US
4,436,745, US 4,438,272);
14. 2,7-di-fluoro-5-methoxy-spiro(9H-fluorene-9,4'-imidazolidine)-2',5'-
dione (US 4,436,745, US 4,438,272);
15. 7-fluoro-spiro(5H-indenoljl,2-b]pyridine-5,3'-pyrrolidine~2,5'-dione (US
4,436,745, US 4,438,272);
16. dais-fi'-chloro-2',3'-dihydro-2'-methyl-spiro-(imidazolidine-4,4'-4'H-
pyrano(2,3-b)pyridine)-2,5-dione (US 4,980,357);
17. sp'iro(midazolidine-4,5'(6H)-quinoline]-2,5-dione-3'-chloro-7,'8'-
dihydro-T-methyl-(5'-as) (US 5,066,659);
18. (2S,4S~6-fluoro-2',5'-dioxospiro(chroman-4,4'-imidazolidine)-2-
carboxamide (US 5,4.47,946); and
19. 2-[(4-bromo-2-fluorophenyl)methyl]-6-fluorospiro[soquinoline-4(1 H),3'-
pymoiidine]-1,2',3,5'(2H)-tetrone (ARI-509, US 5,037,831 ).
Other aldose reductase inhibitors inGude compounds having formula ARI,
Y
Z ~ ~ X
N
,
ARI
or a phamiaoeutically acoeptabie salt thereof, wherein
Z in the compound of formula ARI is O or S;
R' in the compound of formula ARI is hydroxy or a group capable of being
removed in vivo to produce a compound of formula ARI wherein R' is OH; and
X and Y in the compound of formula ARI are the same or different and are
selected from hydrogen, trifluoromethyl, fluoro, and chloro.


CA 02484282 2000-03-16
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-t 13-
A preferred subgroup within the above group of aldose reductase intribitors ,
indudes numbered compounds 1, 2, 3, 4, 5, 6, 9, 10, and 17, and the following
compounds of Formula ARI:
20. 3,4-dihydro-3-(5-fluorobenzothiazol-2-ylmethyl}-4-oxophthalazin-1-yl-
acetic add [R'=hydroxy; X=F; Y=HJ;
21. 3-(5,7-difluorobenzothiazol-2-ylmethyl)-3,4-dihydro-4-oxopht~alazin-1-
yiacetic acid [R'=hydroxy; X=Y=Fj;
22. 3-(5-chlorobenzothiazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-
yiacetic acid [R'=hydroxy; X=CI; Y=Hj; ,
23. 3-(5,7-dichlorobenzothiazol-2-ylmethyt)-3,4-dihydro~-oxophthaiazin-1-
ylacetic add [R'=hydroxy; X=Y=CIJ;
24. 3,4-dihydro-4-oxo-3-(5-trifluoromethylbenzoxazol-2-
ylmethyl)phthalazin-1-ylacetic acid [R'=hydroxy; X=CF3; Y=HJ;
25. 3,4-dihydro-3-(5-fiuorobenzoxazol-2-ylmethyl)~-oxophthalazin-1-yl-
acetic add [R'=hydroxy; X=F; Y=HJ;
26. 3-(5,7-difluorobenzoxazol-2-yimethyl~3,4-dihydro-4-oxophthafazin-1-
ylacetic add [R'=hydroxy; X=Y=F~;
27. 3-(5-chlorobenzoxazol-2-ylmethyl~3,4-dihydro~-oxophthalazin-1-
yfacetic acid [R'=hydroxy; X=CI; Y=HJ;
28. 3-(5,7-dichforobenzoxazol-2-ylmethy1~3,4-dihydro-4-oxophthalazin-1-
ylacetic add [R'=hydroxy; X=Y=CIJ; and
29. zopolrestat; 1-phthalazineacetic add, 3,4-dihydro-4-oxo-3-[[5
(trifluoromethyi}-2-benzothiazolyl]methyt]- [R'=hydroxy; X=trifluorornethyl;
Y=HJ.
In compounds 20-23, and 29 Z is S. fn compounds 24-28, Z is O.
Of the above subgroup, compounds 20-29 are more preferred with 29
espedalfy prefer-ed.
M espedally preferred aldose reductase inhibitor is 1-phthalazineacetic
aad, 3,4-dihydro-4~xo-3-(j5-trifluoromethyl}-2-benzothiazolyl]methylj-.
The term "aryl radical of a carboxylic add aldose reductase inhibitor" refers
to any of the above-mentioned aldose reductase inhbitors which contains a
carboxylic add group in which the carboxylic add group is replaced with a
carbonyl
radical.


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The aldose reductase inhibitor compounds of this invention are readily
available or can be easily synthesized by those skilled in the art using
conventional
methods of organic synthesis, particularly in view of the pertinent patent
specification descriptions.
An amount of the aldose reductase inhibitor of this invention that is
effective
for the activities of this invention may be used. Typically, an effective
dosage for the
aldose reductase inhibitors of this invention is in the range of about 0.1
mg/kglday.to
100 mg/kglday in single or divided doses, preferably 0.1 mglkglday to 20
mg/kg/day in
single or divided doses.
Any sodium hydrogen ion exchange (NHE-1 ) inhibitor may be used as the
second compound (active agent) of this invention for combination therapies.
The term
NHE-1 inhibitor refers to compounds which inhibit the sodiumlproton (Na'IH')
exchange transport system and hence are useful as a therapeutic or
prophylactic
agent for diseases caused or aggravated by the acceleration of the
sodiumlproton
(Na'/H') exchange transport system, for example, cardiovascular diseases
[e.g.,
arteriosderosis, hypertension, arrhythmia (e.g. ischemic arrhythmia,
arrhythmia due to
myocardial infarction, myocardial stunning, myocardial dysfunction,
artfiythmia after
PTCA or after thrombolysis, etc.), angina pectoris, cardiac hypertrophy,
myocardial
infarction, heart failure (e.g. congestive heart failure, acute heart failure,
cardiac
hypertrophy, etc.), restenosis after PTCA, PTCI, shock (e.g. hemorrhagic
shock,
endotoxin shock, etc.)], renal diseases (e.g. diabetes mellitus, diabetic
nephropathy,
ischemic acute renal failure, etc.) organ disorders associated with ischemia
or
ischemic reperfusion [e.g. heart musde ischemic reperfusion assodated
disorders,
acute renal failure, or disorders induced by surgical treatment such as
coronary artery
bypass grafting (CABG) surgeries, vascular surgeries, organ transplantation,
non-
cardiac surgeries or percutaneous transluminal coronary angioplasty (PTCA)],
oerebrovasarlar diseases (e.g. ischemic stroke, hemorrhagic stroke, etc.),
cerebra
ischemic disorders (e.g. disorders assodated with cerebral infarction,
disorders
caused after cerebral apoplexy as sequetae, or oerebrat edema. NHE-1
inhibitors can
also be used as: an agent for myocardial protection during coronary artery
bypass
grafting (CABG) surgeries, vascular surgeries, percutaneous transluminal
coronary
angioplasty (PTCA), PTC1, organ transplantation, or non-cardiac surgeries. The
utility
of NHE-7 inhibitors as medical agents in the treatment of diseases, such as
are


CA 02484282 2000-03-16
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detailed herein in mammals (e.g. humans) for example, myocardial protection
during
surgery or mycardial protection in patients presenting with ongoing cardiac or
cerebral
ischemic events or chronic cardioprotedion in patients with diagnosed coronary
heart
disease, or at risk for coronary heart disease, cardiac dysfunction or
myocardial
stunning is demonstrated by the activity of the compounds of formula ! of this
,
invention in conventional predinical cardioprotedyon assays [see the in viuo
assay in
Klein, H. et aL, Circulation 92:912-917 (1995); the isolated heart assay in
Schotz, W.
et al., Cardiovascular Research 29:260-268 (1995); the antiarrhythmic assa~r
in
Yasutake M- et aL, Am. J. Physiol., 36:H2430-H24.40 (1994); the NMR assay in
Kolke
et al., J. Thorac. t:ardiovasc. Surg.112: 765-775 (1996)] and the additional
in viUo
and in vivo assays described below. Such assays also provide a means whereby
the
activities of the compounds of formula I of this invention can be compared
with the
activities of other known compounds. The results of these comparisons are
useful for
detemuning dosage levels in mammals, inducting humans, for the treatment of
such
diseases.
NHE-1 inhibitors are disclosed in U.S. Pat. No. 5,698,581, European Patent
Application Publication No. EP 803 501 A1, International PatentAppCcation
Publication Nos. WO 94/26709 and PCTIJP97/0465~0.
The NHE-1 inhibitors disclosed therein have utility in the
combination of this invention. Said NHE-1 inhibitors can be prepared as
disclosed
therein.
Preferred NHE-1 inhibitors include compounds of the fom~ula NHE,:
Z" ~NHZ
Oi N~ Hz
NHE
a prodrug thereof or a pharmaceutically acceptable salt of said compound or
of said prodrug, wherein
Z in the compound of formula NHE is carbon oonned~ed and is a fnre-
membered, diaza, diunsaturated ring having two contiguous rirtrogens, said
ring optiortalfy mono-, di-, or tri-substituted with up to three subst~rents-
independently selected from R'; Rz and R3 ;


CA 02484282 2000-03-16
wo oo~s9sio Pcr~sooiooz~
-~ 1 s
Or
Z in the compound of formula NHE carbon connected and is a five-
membered, triaza, diunsaturated ring, said ring optionally mono- or di-
substituted with up to two substituents independently selected from R' and R5;
wherein R', RZ, R3, R' and RS in the'compound of formula NHE are
each independently hydrogen, hydroxy-(C,-C,)alkyl, (C,-C,)alkyl, (C,-
C,)alkylthio, (C,-C,)cydoalkyl, (C,-C,)cydoalkyl(C,-C,)alkyl, (C,-C,)alkoxy,
(C,-
C,)alkoxy(C,-C,)alkyl, mono-N- or di-N,N-(C,-C,)alkylcarbamoyl, M or M(C,-
C,)alkyl, any of said previous (C,-C,)alkyl moieties optionally having from
one
to nine fluorines; said (C,-C,)alkyl or (C,-C,)cycloalkyl op6onaliy mono-or di-

substituted independently with hydroxy, (C,-C,)alkoxy, (C,-C,)alkylthio, (C,-
C,)alkylsulfinyl, (C,-C,)alkylsulfonyl, (C,-C,)alkyl, mono-N- or di-N,N-(C,-
C,)alkylcarbamoyl or mono-N- or di-N,N-(C,-C,)alkytaminosulfonyl; and said
(C,-C,)cydoalkyl optionally having from one to seven tiuorines;
wherein M in the compound of formula NHE is a partially saturated,
fully saturated or fully unsaturated five to eight membered ring optionally
having one to three heteroatoms selected independently from oxygen, sulfur
and nitrogen, or, a bicydic ring consisting of two fused partially saturated,
fully
saturated or fully unsaturated three to six membered rings, taken
independently, optionally having one to four heteroatoms selected
independently from nitrogen, sulfur and oxygen;
said M in the compound of formula NHE is optionally substituted, on
one ring if the moiety is monocyclic, or one or both rings if the moiety is
bicydic, on carbon or nitrogen with up to three substituents independently
selected from R°, R' and R°, wherein one of R6, R' and R°
is optionally a
partially saturated, fully saturated, or fully unsaturated three to seven
membered ring optionally having one to three heteroatoms selected
independently from oxygen, sulfur and nitrogen optionally substituted with (C,-

C,~Ikyl and additionally R6, R' and R° are optionally hydroxy, vitro,
halo, {C,-
C,)alkoxy, (C,-C,)alkoxycarbonyl, (C,-C,~Ikyl, fomiyt, (C,-C,~Ikanoyl, (C,-
C,~Ikanoyloxy, (C,-C,)alkanoylamino, (C,-C,)alkoxycarbonylamino,
sulfonamide, (C,-C,)alkyisulfonamido, amino, mono-N- or di-N,N-(C,-
C,)atkylamino, cartiamoyl; mono-N- or di-N,N-{C,-C,~lkylcarbamoyl, cyano,


CA 02484282 2000-03-16
WO 00159510
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thioi. (C,-C,)alkylthio, (C,-C,)alkylsulfinyl, (C,-C,)alkylsulfonyi, mono-N-
or di-
,,
N,N-(C,-C,)alkylaminosulfonyl, (CZ-C,)alkenyl, (CZ-C,)alkynyl or (C~-
C,)cydoalkenyl,
wherein said (C,-C,)alkoxy, (C,-C,)alkyl, (C,-C,~Ikanoyl, (C,-C,~Ikylthio.
mono-N- or di-N;N-(C,-C,)alkylamino or (C,-C,)cydoalkyl R6. R' and R°
substituents
are optionally mono- substituted independently with hydroxy, (C,-
C,)alkoxycarbonyl,
(C,-C,)cydoalkyl, (C,-C,)alkanoyl, (C,-C,)alkanoylamino, (C,-C,)alkanoyloxy,
(C;
C,)aikoxycarbonylamino, sulfonamido, (C,-C,)alkylsulfonamido, amino, mono-N-
or di-
N,N-(C,-C,)alkylamino, carbamoyl, mono-N- or di-N,N-(C,-C,)alkylcarbamoyl,
cyano,
0 thiol, vitro, (C,-C,)alkylthio, (C,-C,)alkylsulfinyl; (C,-C,)alkylsulfonyl
or mono-N- or di-
N,N-(C,-C,)alkylaminosulfonyl or optionally substituted with one to nine
fluorines.
Especially preferred NHE-1 inhibitors indude [1-(8-bromoquinolin-5-
I -5-cydopropyl-1 H-pyrazofe-4-carbon
y ) yt]guanidine; [1-(6-chloroquinotin-5-yl).
5-cydopropyl-1 H pyrazole-4-carbonyl]guanidine; [1-(indazol-7 ylr5-
cyclopropyt-1H pyrazole-4-carbonyljguanidine; [1-(benzimidazol-5-y1~5-
cydopropyt-1H pyrazole-4-carbonyf]guanidine; [1-(1-isoquinolyl~5-
cydopropyl-1 H-pyrazoie-4-carbonyljguanidine; [5-~ydopropyl-1-(4-quinolinyl~
1 H-pyrazole-4-carbonyf]guanidine; [5-cydopropyl-1-(quinolin-S-yl)-1 H-
pyrazole-4-carbonyf]guanidine; [5-cydopropyl-1-(quinolin-8-yl)-1 H-pyrazole~-
carbonyl]guanidine; [1-(indazol-6-y1~5-ethyl-1 H pyrazole~-
carbonyl]guanidine; [1-(indazol-5-yt}-5-ethyl-1H py~azole-4-
carbonyl]guanidine; [1-(benzimidazol-5-yl)-5~thy1-7H pyrazote-4-
carbonyQguanidine; [1-{1-methylbenzimidazol-6-y1~5-ethyl-1H-pyrazole~-
carbony~guanidine; 1-(5-quinolinylr5-n-propyt-1H pyrazole-4-
carbony(jguanidine; [1-(5-quinolinyl}-5-isopropyl-11+pyrazole~-
carbonyl]guanidine; [b-ethyl-1-(6-quinolinyl)-1H-pyrazole-4-
carbony(]guanidine; [1-{2-methylbenzimidazol-5-y1~5-ethyl-1H-Pyrazole~.
carbonyQguanidine; [1-(1,4-benzodioxan-6-yl~5~thyl-1H-pyrazole-4-
carbony!]guanidine; [1-(benzotriazol-5-yl)-5-ethyl-1H-pyazole-4-
carbonyQguanidine; [1-(3-chloroindazol-5-yl~5~thyl-1 H-pyrazole-4-
ca(bonyl]guanidine; [1-(5-quinolinyl~5-butyl-1H-pyrazole-4-
carbonyt]guanidine; [5-propyl-1-(6-quinolinyl~l H pyrazole-4-
carbonyl]guanidine; [S-isopropyl-1-(6-quinoliny(~1 H pyrazole-4-


CA 02484282 2000-03-16
WO 00/59510 PCTIIBOO/OOZ96
-11 &
carbonyl]guanidine: j1-(2-chloro-4-methylsulfonylphenylr5-cydopropy!-1H-'
pyrazole-4-carbonyiJguanidine; [1-(2-chlorophenylj-5-cydopropyl-1H-pyrazole-
4-carbonyl]guanidine; [1-(2-trifluoromethyl-~-fluorophenyl)-5-cydopropyl-1 H-
pyrazote-4-carbonyQguanidine; j1-(2-brornophenyl)-5-cydopropyt-1H
pyrazole-4-carbonyl]guanidine; [1-(2-fluorophenyl)-5-cydopropyl-1H pyrazole-
4-carbonyljguanidine; [1-(2-chioro-5-methoxyphenyl)-5-cydopropy!-1I+ .
pyrazole-4-carbonyljguanidine; [1-(2-chloro-4-methylaminosutfonylphenyl)-5-
cyclopropyl-1H pyrazole-4-carbonylJguanidine; [1-(2,5~i~lorophenyl~5-
cydopropyl-1 H-pyrazole-4-carbonyf]guanidine; [1-(2,3-dichlorophenyl}-5-
cydopropyl-1H pyrazole-4-carbonyfjguanidine; [1-(2-chloro-5-
aminocarbonylphenyl)-5-cydopropyl-1 H-pyrazole-4-carbonyljguanidine; [1-(2-
chloro-5-aminosulfonytphenyl)-5-cydopropyl-i H-pyrazole-4-
carbonylJguanidine; [1-(2-fluoro-6-trifluoromethylphenyl~5-cydopropyl-1H
pyrazole-4-carbonyiJguanidine; [1-(2-chloro-5-methylsulfonylphenyl~5-
cydopropyl-1H pyrazole-4-carbonyljguanidine; [1-(2-chtoro-5-
dimethylaminosulfonylphenyl~5-cydopropyl-1 H-pyr'azole-4-
carbony(jguanidine; [1-(2-trifluoromethyf~-c~ilorophenyl~5-cyclopropyl-11-~
pyrazole-4-carbonytJguanidine; [1-(2-chlorophenyl~5-methyl-1H-pyrazole-4-
carbonyl]guanidine; [5-methyl-1-(2-trifluoromethylphenyl)'1H-pyrazole-4-
carbonytjguanidine; [5-ethyl-1-phenyl-1 H-pyrazole~-carbonyl]guanidine; [5-
cydopropyl-1-(2-trifluoromethylphenyl)-1 H-pyrazole-4-carbonyljguanidine; [5-
cydopropyl-1-phenyl-1 H-pyrazole-4-carbonyQguanidine; [5-cydopropyl-1-(2,6-
dichiorophenyl~1 H-pyfazole-4-carbonyljguanidine or or a pharmaceutically
acceptable salt thereof.
The preferred and especially preferred NHE-1 inhibitors disdosed in the above
two paragraphs can be prepared according to methods set forth in International
Patent Application No. PCTIlB99/002t76 or as set forth below, where the
vartables in
the following schemes and description refer only to the NHE-1 compounds.

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SCHEME1
O O I ~ ' O O ~ \
R' N(H). / . R' I N~H> /
I_a NwOH t_b
RSNHNH2
1-c
R~ R' COzH
N~H)w
NI ~N ~ I O , , ~ \
~N~ ~Ni
Rs Rs R' I NCH) /
I f I~ N~OH I-d
SCHEME ll
O R' is
R\NH + N/'~ OR f ~ \\ N R'
z~ N
I!- f 1a
II-b O OR
It-c
O
Rs
HZN

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WO 00/59510 PCT1IB00/OQ196
-'120
SCHEME Iil
Rs Rs
N H) ~N~H) CICOC02R
R~
R~ ~ N
O v
111-8 NH2
III-b
4
R O ~ O NHZ
Rs N Rs N
OR ~ ~ N~NH
z
N-N N-N
Ili-C 111-d
SCHEME N
R~
S /N,~H) CICOC02R
~ N
Rs' _NH
a
IV-a RS~NH
z
iV-b
Rs~N~N,--R'~ Rs j wN.~R,
N'
N
OR N
O O ~~NHx
tV-c IV-d H.,N

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-t21
SCHEME V
O O
R''~~~OR
V-a
O O
O O ~ .
R' ~ OR
R' ~ ~OR
R' NMe=
R' OEt
V-c
V-b
RzNHNH2 R2NHNH2
V-d V-d
R' COzR
NON R,
R~
V~
' R' COZRH
NI . ~ R,
N n
(z Rs
R
V_f . V-9

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PCTIIBOOI00296
.122
SCHEME VI
Br R2 R'
N~H~ ~ ,f" . RwN ~ R~
R ~ N C,OZEt RO "'~' N._
OEt
Vha Vi-b ,
O
VI-c
R~
RswN ~ R,
N-
N ,
O ~~NHz
VI-d HzN
SCHEME VII
O OH
~,N Ra
R NHNHZ ~- R3 \ N ROti N
Vii-a ~ ~ HCI
R N OH R ~OR
VII-c ~~O
Vil-b
R'


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WO OOI59510 pCT/IB00/00296
-123-
SCHEME VIII , , ,
O O OLi R~NHNH2 VIII-d
Rz LiN(SiMe~)2 Ri ' V(I
(COZR)z OR +
R' R' / Vlll-e
Vllt-a O
Vtll-b
OR R N
iN ~N NHZ
N~ I \O N~ I \O
R2 R' Rz R'
",
VI11-d V111-f
NH2
OR
N -.-'
R'wNi ~ O R'N/ \ NH
s
~O
R= R'
VIII-e RZ R~
VIII-g
According to Scheme I, the Formula I-a compound, wherein R' is as described
above for the compound of formula NHE, is dissolved or suspended in an aqueous
alkali metal hydroxide solution (e.g. 1 N sodium hydroxide) along with sodium
nitrite
and the mixture is added to an aqueous aadic solution (e.g. 10% v/v sulfuric
acrd) at a
pH of about 0 at a temperature of about 0°C to about 5°C for
about 30 min to about 1
hour. The resulting mixture is filtered to yield the Formula i-b oxime.
AitematNeiy, the
Formula 1-a compound is dissolved in 1:1 acetic aadlpropionic acrd and soC~d
sodium
nitrite is added at about 0°C. The reaction mbct<rre is stirred at
about 0°C for about 2
hours, then poured into ice water and the Fomwla !-b oxime is obtained by
filtration.
The Fortnuia I-b compound is reacted with a Formula t-c cornpour~, vifierein
R5 is as described above for the compound of formula NHE in a erotic solvent
such as


CA 02484282 2000-03-16
WO 00159510
-124-
ethanol at a temperature of about 50°C to about 110°C .for about
10 min to about 1
hour to form the Formula I-d hydrazone. , ,
The Formula I-d hydrazone is cydized and hydrolyzed to the Formula I-a
triazole in an alcoholic solvent such as 2-ethoxyethanol under basic
conditions (e.g.,
potassium hydroxide) at a temperature of about 100 °C to about
175°C for about 1I2
hour to about 2 hours followed by addification to yield the Formula I-a
triazole aad.
The Formula I-a aad is coupled with guanidine in the presence of a suitable
coupling agent. A suitable coupling agent is one which transforms a carboxylic
acid
into a reactive speaes which fortes an amide linkage on readion with an amine.
The coupling agent may be a reagent which effects this condensation in a one
pot process when mixed together with the carboxylic aad and guanidine.
Exemptary
coupling reagents are 1-(3~imethylaminopropyl~3-ethylcarbodiimide
hydrochloride-
hydroxybenzotriazole (EDCIHBT),
dicydohexylcarbodiimidelhydroxybenzotriazole(HBT), 2-ethoxy-1-ethoxycarbonyl-
1,2-
dihydroquinoline (EEDQ), and diethylphosphoryfcyanide. The coupling is
perfom~ed
in an inert solvent, preferably an aprobc solvent at a temperature of about -
20°C to
about 50°C for about 1 to about 48 hours, in the presence of excess
guanidine as
base. Exemplary solvents include acetonitrile, dida~oromethane,
dimethylfom~amide
and chloroform or mixtures thereof.
The coupling agent may also be that agent which converts the carboxylic acid
to an activated intermediate which is isolated and/or fom~ed in a first step
and allowed
to react with guanidine in a second step. Examples of such coupling agents and
activated intermediates are thionyl chloride or oxalyl chloride to form the
aad chloride,
cyanuric fluoride to form an aad fluoride or an alkyl chlorofomiate such as
isobutyl or
isopropenyl chloroformate or propanephosphonic anhydride (propanephosphonic
add
anhydride, PPA) (with a tertiary amine base) to form a mixed anhydride of the
carboxylic aad, or carbonyldiimidazote to form an acylimidazole. ff the
coupling agent
is oxaiyl chloride, it is advantageous to employ a small amount of
dimethylforrrrarrode
as cosolvent with another solvent (such as dichforomethane) to catalyze the
formation
of the acid chloride. This activated aad derivative may be coupled by mixing
with
excess guanidine in an appropriate solvent together with an appropriate base.
Appropriate solvent/base combinations are for example, dichloromethane,
dimethylformamide or acetori~trile or mixtures thereof in the presence of
excess


CA 02484282 2000-03-16
WO OOI59510 PCTIIB~O/00296
-125-
guanidine as base. Other appropriate solvent/base combinations inGude water or
a
(C,-Cs~lcohot or a mixture thereof together with a cosplvent such as
dichloromethane, tetrahydrofuran or dioxane and a base such as sodium,
potassium
or lithium hydroxide in sufficient quantity to consume the acid liberated in
the reaction.
Use of these coupling agents and appropriate selection of solvents and
temperatures
are known to those skilled in the art or can be readily determined from the
literature.
These and other exemplary conditions useful for coupling carboxylic aads are
described in Houben-Weyl, Vol XV, part II, E. Wunsch, Ed., G. Theime
Verlag,1974,
Stuttgart: M. Bodansky, Prinapfes of Peptide Synthesis, Springer Verlag,
8eriin 1984;
and The Peptides, Analysis, Synthesis and Biology led: E. Gross and J.
Meienhofer),
vols 1-5 (Academic Press, NY 1979-1983).
According to Scheme II, the Formula II-a primary amine wherein R5 is as
described above for the compound of formula ~NHE is reacted with a Formula II-
b a-
diazo-p-keto-ester wherein R' is as described above for the compound of
formula
NHE, and R is lower alkyl, in the presence of titanium tetrachioride
analogously to the
method described in Eguchi S. ef al. Synthesis 7993, 793 to form the Formula
II-c
triazole carboxylic acrd ester. The Formula II-c ester is converted directly
to the
acylguanidine 11-d by reaction with guanidine in an,alcoholic solvent at a
temperature
of about 60 to about 110°C, preferably refluxing methanol, for a period
of 8 to 20
hours. .
According to Scheme III, the Formula III-a compound wherein R' and Rs are
as described above for the compound of formula NHE is treated with t-awesson's
reagent (i.e., 2,4-bis(4-methoxyphenyl~l,3-dithia-2,4-diphosphetane-2,4-
disulfide) in
an aprotic solvent suds as dimethoxyethane at a temperature of about
20°C to about
120°C for about one to eight hours. The resulting thioamide is treated
with an
alkyla6ng agent such as methyl iodide in a polar, inert sohrent such as
acetone,
conveniently at ambient temperature for about eight hours to about forty-eight
hours.
The resulting compound is reacted with anhydrous hydrazine in an alcohof~c
solvent
at a temperature of about 0°C to about 25°C for about one to
eight hours to provide
the Formula III-b compound (analogously as described in Doyle and Kurzer,
Synthesis 1974, 583).
The Formula III-b compound is treated with a monoalkyloxalyl chloride in an
aprotic solvent at a temperature of about 25°C to about 50°C for
about one to eight


CA 02484282 2000-03-16
WO 00/59510 PCT/IB00/00296
-12s-
hours to provide the Formula III-c carboxylic ester compound wherein R is
lower alkyl.
The Formula III-c ester is directly coupled with guanidine in an alcoholic
solvent at a
temperature of about 60°C to about 110 °C, preferably refluxing
methanol, for a period
of eight to twenty hours, to prepare the Formula ~ ,
ttl-d triazole carbonyl guanidines.
According to Scheme N the Formula IV-a compound wherein R5 is as
described above for the compound of formula NHE is treated with methyl iodide
in an
inert solvent, conveniently at ambient temperature for about four to twenty-
four hours.
The resulflng compound is reacted with anhydrous R'-hydrazine (wherein R' is
as
described above for the compound of formula NHE) in an alcohofrc solvent at a
temperature of about 0°C to about 25°C for about one to eight
hours to provide the
Formula N-b amidrazone compound (analogously as described in Doylg and
ICurzer,
Synthesis 1974, 583).
The Formula N-b compound is treated with a monoafkyloxalyl chloride in an
aprotic solvent at a temperature of about 25°C to about 50°C for
about one to eight
hours to provide the Fortnuia IV-c carboxylic ester compound wherein R is
lower alkyl.
The Fomzufa N-c ester is directly coupled with guanidine in an alcoholic
solvent at a
temperature of about 60°C to about 110°C, preferably refluxing
methanol, for a period
of eight to twenty hours to prepare the Formula N-d triazole carbonyl
guanidines.
Aaoording to Scheme V the Formula V-a compound wherein R' is as
described above for the compound of fonnuta NHE is combined with excess
(CH,O)ZC(R')N(CH3)= (N,N-dimethy! amide dimethyl acetal) wherein R' is as
described above for the compound of formula NHE, optionally in the presence of
an
aad catalyst such as p-toluenesulfonic aad at a temperature of about
90°C to about
110°C for about one to about two hours to prepare the Formula V-c
compound above.
The Formula V-c compound is cyclized with a Fomurla V-d compound,
wherein R2 is as described above for the compound of formula NHE, in an inert
solvent such as ethanol at a temperature of about 20°C to about
30°C for about 5
minutes to about one hour followed by heating to a temperature of about
70°C to
about 110°C for~about two hours to about four hours to fore the Fomurla
V f pyramle.
Aitemabvely, according to Scheme V the Formula V-a found, wherein R'
is as described above for the compound of formula NHE, is combined with a


CA 02484282 2000-03-16
WO 00159510 IPCTIIB00100296
-127-
triethylorthoester (i.e., R'C(OEt), wherein R' is as described above for the
compound
,,
of formula NHE) and acetic anhydride at a temperature of about 120°C,
to about 150
°C for about two to about five hours to prepare the Formula V-b
compound.
The Formula V-b compound is cyctized with a Fomluta V-d compound,
wherein R2 is as described above for the compound of formula NHE, to form the
Formula V-c pyrazole.
The Formula V-c pyrazole is hydrolyzed with a base such as sodium
hydroxide or lithium hydroxide in a solvent such as water andlor methanol
andlor THF
conveniently at ambient temperature or at elevated temperature (e.g., reflux)
for about
one hour to about ftve hours to prepare the Fomtuta V-f acrd.
The Formula V-f acrd is coupled with guanidine in the presence of a suitable
coupling agent as described for the above coupling of the Fomnula I-a acid and
guanidine. In one embodiment, the Formula V-f acrd is activated with thionyl
chtoiide
at a temperature of about 60°C to about 90°C for about fifteen
minutes to about two
hours. The resulting activated acid chloride is combined with guanidine
hydrochloride
and an inorganic base (e.g., sodium hydroxide) in anhydrous tetratrydrof<rran
and
optionally methanol andlor water. The solution is heated, con~nientiy at
reflux, for
about one hour to about eight hours to prepare the Fomnula V-g compound.
Alternatively according to Scheme V the Fonnuta V-a compound can be
directly converted to the Formula V-g compound by several methods. For
example.
the Formula V-a compound can be heated in the presence of excess guanidine, in
a
polar protic solvent for example, methanol or isopropanol at a suitable
temperature
conveniently, at reflux for about one to about seventy two hours. This
transfomsation
may also be performed by repeatedly removing the solvent; for example removing
ethanol or toluene about four times, from a mixhrre of the Formula Y-a
compound and
excess guanidine at a pressure of about one to about 100 mmHg and at a
temperature of about 25°C to about 95°C. This reaction may also
be performed in the
absence of solvent by heating the rrindure of the Fortnuta V-a compound and
excess
guanidine at a temperature of about 100°C to about 180°C,
optionaily at about a
pressure of about 1 to about 100 mmHg for about five minutes to about eight
hours.
According to Scheme VI, the Formula Vha compound, wherein R' is as
described above for the compound of formula NHE, is reacted with the Formula
VI-b
compound, wherein R' and R2 are as described above for the compound of
formula.


CA 02484282 2000-03-16
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NHE, in an aprotic solvent at a temperature of about 0°C to about
25°C for about two
hours to about twenty-four hours in the presence of ah~appropriate amine base,
such
as triethylamine, to form the Formula VI-c compound.
The resulting Formula VI-c compound is hydrolyzed and coupled with
guanidine using one of the methods described in earlier Schemes, such as the
method employing carbonyldiimidazole, to form the Formula VI-d compound.
According to Scheme VII, the Formula VII-a hydrazine, wherein R2 is as
described above for the compound of formula NHE, is reacted with the
appropriate
Formula VII-b compound to form the Formula VII-c pyrazote ester wherein R is
lower
alkyl according to the method of Bajnati, A. and Hubert Habart, M. Bu!!. Soc.
Chim.
France 1988, 540. 'The resulting pyrazole ester is converted to the Formula
V11-d aryl
guanidine using the hydrolysis and coupling methods described above.
According to Scheme Vlll, the Formula VIII-a compound wherein Rz and' R'
are as described above for the compound of formula NHE is transfom~ed to the
Formula Vllt-b Lithium salt where R is lower alkyl according to the method
described in
J. HeL Chem. ?989, 26,1389. the Formula VIII-b lithium salt is combined with
the
Formula VIII-c hydrazine, wherein R' is as described above for the compound of
formula NHE, in an inert solvent such as ethanol, in the presence of a miners(
acrd, at
a temperatun: of about 20°C to about 30°C for about fare minutes
to about one hour
followed by heating to a temperature of about 70°C to about
110°C for two hours to
about four hours to form both the Formula VIII-d and VIII-e pyrazotes. The
Fom~ula
Vlll-d and Vlll-e pyrazoles are converted to the Formula Vltl-f and VIII acyl
guanidines respectively using the hydrolysis and coupling methods descrtbed
above.
Some of the methods useful for the preparation of the compounds described
herein
may require protection of remote functionality (e.g., primary amine, secondary
amine,
carboxyl in Fom~ula I precursors). The need for such protection will vary
depending on
the nature of the remote functionality and the conditions of the preparation
methods.
The need for such protection is readily determined by one skilled in the art
The use of
such protectioNdeprotection methods is also within the skill in the art For a
general
description of protecting groups and their use, see T.W. Greene, Protective
Groups in
Organic Synthesis, John Wiley ~ Sons, New York, 1991.
The compounds of formula I of the present invention, when used in
combination with NHE-1 inhibitors, inhibit the sodiumlproton (Na'!H') exchange


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transport system and hence are useful as a therapeutic or prophylactic agent
for ,
diseases caused or aggravated by the acceleration of,the sodiumlproton
(Na'!ti')
exchange transport system, for example, cardiovascular diseases [e.g.,
arteriosclerosis, hypertension, atfiythmia (e.g. ischemic arrhythmia,
ant~ythmia due to
myocardial infarction, myocardial stunning, myocardial dysfunction, arrhythmia
after
PTCA or after thrombalysis, etc.), angina pectoris, cardiac hypertrophy,.
myocardial
infarction, heart failure (e.g. congestive heart failure, acute heart failure,
cardiac
hypertrophy, etc.), restenosis after PTCA, PTCI, shock (e.g. hemorrhagic
shock,
endotoxin shock, etc.)], renal diseases (e.g. diabetes mellitus, diabetic
nephropathy,
isdlemic acute renal failure, etc.) organ disorders assodated with ischemia or
tschemic reperfusion [e.g. heart muscle tschemic reperfusion assodated
disorders,
acute renal failure, or disorders induced by surgical treatment such as
coronary artery
bypass grafting (CABG) surgeries, vasarlar surgeries, organ transplantation,
non-
cardiac surgeries or perartaneous transluminat coronary angioplasty (PTCA)j,
cerebrovascutar diseases (e.g. isdzemic stroke, hemorfiagtc stroke, etc.),
cerebra
ischemic disorders (e.g..disorders associated with cerebral infarction,
disorders
caused after cerebral apoplexy as sequelae, or cerebral edema.
Preferably, the compounds of fomwia t pf this invention can be used in
combination with NHE-1 inhibitors as agents for myocardial protection before,
during,
or after coronary artery bypass grafting (CABG) surgeries; vascular surgeries,
pen~rtaneous transluminat coronary angioplasty (PTCA), organ transplantation,
or
non-cardiac surgeries.
Preferably, the compounds of formula ! of this invention can be used in
combination with NHE-1 inhibitors as agents for myocardial protection in
patients
presenting with ongoing cardiac (carte coronary syndromes, e.g. rrryocardial
infarction or unstable angina) or cerebral ischemic events (e.g. stroke).
Preferably, the compounds of fomwta 1 of this invention can be used in
combination with NHE-1 inhibitors as agents for chronic rtryocardial
protection in
patients with diagnosed coronary heart disease (e.g. previous myocardial
infarction or
unstable angina) or patients who are at high risk for myocardial infarction
(age greater
than 65 and two or more risk factors for coronary heart disease).
tn addition, a combination of the compounds of fomwla I of this.invention with
NHE-1 inhibitors has a strong inhibitory effect on the proliferation of cells,
for exar~le


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the proliferation of fibrobtast celis'and the proliferation of the smpQth
muscle cells of
the blood vessels. For this reason, the combination of the compounds of
formula I of
this invention with NHE-1 inhibitors of this invention is a valuable
therapeutic agent for
use in diseases in which cell proliferation fepresents a primary or secondary
cause
and may, therefore, be used as antiatherosderotic agents, and as agents
against
diabetic late complications, cancerous diseases, fibrotic diseases such as
pulmonary
fibrosis, hepatic fibrosis or renal fibrosis, glomerular nephrosderosis, organ
hypertrophies or hyperplasias, in particular hyperptasia or hypertrophy of the
prostate,
pulmonary fibrosis, diabetic complications or recurrent strichrre after PTCA;
or
diseases caused by endothelial cell injury.
The utility of the combination of compounds of the present invention with NHE-
1 inhibitors as medical agents in the treatment of diseases, such as are
detailed
herein in mammals (e.g. humans) for example, myocardial protection during
surgery
or mycardiai protedyon in patients presenting with ongoing cardiac or cerebral
isdzemic events or chronic cardioprotection in patients with diagnosed
coronary heart
disease, or at risk for coronary heart disease, cardiac dysfunction or
myocardial
stunning is demonstrated by the activity of said combination in conventional
predinical
cardioprotection assays [see the in vivo assay in Klein, H. et al.,
Circulation 92:912-
917 (1995); the isolated heart assay in Schotz, W. et al., Cardiovascular
Research
29:260-268 (1995); the antiacrhythmic assay in Yasutake M: et al., Am. J.
Physiol.,
36:H2430-H2440 (1994); the NMR assay in Kolke et at., J. Thorac. Cardiovasc.
Sung.
112 ?65-775 (1996)] and the additional in vitro and in vivo assays described
below.
Such assays also provide a means whereby the activities of the compounds of
fomwla 1 of this invention can be compared with the activi(ies of other known
compounds. The results of these comparisons are useful for determining dosage
levels in mammals, including humans, for the treatment of such diseases.
Measurement of Human NHE-1 Inhibitory Activity
Methodologies for measurement of human NHE-1 adtvity and inhibitor
potency are based on those published by Watson et at., Am. J. Physiol.,
24:6229-
6238,1991 ), where NHE-mediated recovery of intracellular pH is measured
following
intracellular aad~cation. Thus, tabroblasts stably expressing human NHE-1
(Counillon; L et at.,,Mol. Pham~acol., 44:1041-1045 (1993) are plated onto
collagen
coated 96 well plates (50,QOOiwell) and grown to cont3uence in growth media
(DMEM


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high glucose, 10°~ fetal bovine serum. 50 uiml penicillin and
streptomyan)' ~ Confluent
plates are incubated for 30 minutes at 37°C with the pH sensitive
fluorescent probe
BCECF (5 ~M; Molecular Probes, Eugene, OR). BCECF loaded cells are incubated
for 30 minutes of 37°C in aad loading media (70 mM choline chloride, 50
mM NHCI,; 5
mM KCI, 1 mM MgCI?,1.8 mM CaCl2, 5 mM glucose,10 mM HEPES, pN 7.5), and
then placed in a Fluorescent imaging Plate Reader (Mofecuiar Devices, CA):;,
BCECF
,,
fluorescence is monitored using exatation and emission wavelengths of 485 nM
and
525 nM, respectively. Intracellular aadihcatfon is initiated via rapid
replacement of
acid loading media with recovery media (120 mM NaCI, 5 mM KCI,1 mM MgCl2, 1.8
mM CaCl2, 5 mM glucose,10 mM HEPES, pH 7.5) ~ test combination, and NHE-
mediated recovery of intracellular pH is monitored as the subsequent time-
dependent
increase BCECF fluorescence. The potency of the combinations of the compounds
of
formula I of this invention with NHE-1 inhibitors is calculated as the
concentration that
reduces recovery of intracellular pH by 50% (ICS). Under these conditions
reference
NHE inhibitors amiforide and HOE-642 had IC~ values for human NHE-1 of 50 ~AII
and 0.5 pM, respectively.
As background infom~ation, it is noted that brief periods of myocardial
ischemia fo(iowed by coronary artery reperfusion protects the heart from
subsequent
severe myocardial ischemia (Muny et al., Circulation 74:1124-1136,1986).
The therapeutic effects of the combination of the compounds of formula 1 of
this invention with NHE-1 inhibitors in preventing heart tissue damage
resulting from
an ischemic insult can be demonstrated in vitro along lines presented in Liu
et al.
(Cardiovasc. Res., 28:1057-7061, 1994), as described specifically herein.
Cardioprotection, as indicated by a reduction in infarcted myocardium, can be
induced
pharrnacologicaNy using adenosine receptor agonists in isolated, retrogradely
perfused rabbit hearts as an in vitro model of ~rdial ischemic preconditioning
(Uu
et al., Cardiovasc. Res., 28:1057-1061,1994). The in vitro test described
below
demonstrates thata test compound or, in this case a test combination (i.e., a
combination of a compound of formula I with an NHE-1 antagonist) can also
pham~acoiogically induce carciioprotection, i.e., reduced myocardial ir>tarct
size, when
administered to a rabbit isolated heart. The effects of the test combination
are
compared to ischemic preconditioning-and the A1/A3 adenosine agonise, APNEA
(N°-
[2-(4-aminophenyl)ethytJadenosine), that has been shown to pharmaootogicatfy


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induce cardioprotection in the rabbit isolated heart (Liu~et aL, Cardiovasc.
Res.,
28:1057-1061, 1994). The exact methodology is described below.
The protocol used for these experiments closely follows that described by Liu
et al., Cardiovasc. Res., 28:1057-1061,1994. Male New Zealand White rabbits (3-
4
kg) are anesthetized with sodium pentobai~bitel (30 mglkg, i.v.). After deep
anesthesia
is achieved (determined by the absence of an ocular blink reflex) the animal
is
intubated and ventilated with 100°~ OZ using a positive pressure
ventilator. A left
thoracotomy is performed, the heart exposed, and a snare (2-0 silk) is placed
loosely
around a prominent branch of the left coronary artery, approximately 213 of
the
distance towards the apex of the heart The heart is removed from the diest and
rapidly (<30 sec) mounted on a Langendorff apparatus. The heart is
retrogradety
perfused in a non-rearculating manner with a modified Krebs solution (NaCI
118.5
mM, KCI 4.7 mM, Mg SO, 1.2 mM, KHzPO, t.2 mM, NaHC03 24.8 mM, CaCh 2.5
mM, and glucose 10 mM), at a constant pressure of 80 mmHg and a temperature of
37°C. Perfusate pH is maintained at 7.4-7.5 by bubbling with 95% 015%
CO~. Heart
temperature is tightly controlled by using heated reservoirs for the
physiological
solution and water jacketing around both the perfusion tubing and the isolated
heart.
Heart rate and left ventricular pressures an: determined via a latex balloon
which is
inserted in the left ventride and connected by stainless steel tubing to a
pressure
transducer. The intraventricular balloon is inflated to provide a systolic
pressure of 80-
100 mmHg, and a diastolic pressure _< 10 mmHg. Total coronary flow is also
continuously monitored using an in-line flow probe and normalized for heart
weight
The heart is allowed to equilibrate for 30 minutes, over which time the heart
must show stable left ventricular pnasures within the parameters outlined
above. If
the heart rate falls below 180 bpm at any time prior to the 30 minutes period
of
regional ischemia, the heart is paced at about 200 bpm for the remainder of
the
experiment. tschemic preconditioning is induced by total cessation of cardiac
perfusion (global ischemia) for 5 minutes, followed by reperfusi~ for 10
minutes. The
regional ischemia is provided by tightening the snare around the coronary
artery
branch. Following the 30 minutes regional ischemia, the snare is released and
the
heart reperfused for an additional 120 minutes.
Pharmacological cardioprotection is induced by infusing the test combination,
i.e., a corrrbinafron of a compound of formula I with an NHE-1 inhibitor, at


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predetermined concentrations, starting 30 minutes poor to the 30 minutes
regional
ischemia, and continuing until the end of the 120 minutes reperfuston period.
Hearts
which receive the test combination do not undergo the period of ischemic
preconditioning. The reference compound, APNF~ (500 nM) is perfused through
hearts (which do not receive the test compound) for a 5 minutes period which
ends 10
minutes before the 30 minutes regional ischemia. ,
At the end of the 120 minutes reperfusion period, the coronary artery snare is
tightened, and a 0.5% suspension of fluorescent zinc cadmium sulfate par6Ges
(1-10
NM) Duke Scientific Corp.(Palo Atto, CA) is perfused through the hearty this
stains alt
of the myocardium, except that area-at-risk for infarct development (area-at-
risk). The
heart is removed from the Langendorff apparatus, blotted dry, wrapped in
aluminum
foil and stored overnight at -20°C. The next day, the heart is sliced
into ,~ mm
transverse sections from the apex to the top of the ventrides_ The slices are
stained
v~i~th 1 % triphenyt tetrazotium chloride (TTC) in phosphate-buffered saline
for 20
minutes at 37°C. Since TTC reacts with living flssue (containing NAD-
dependent
dehydrogenases), this stain differentiates between fnring (red stained)
tissue, and
dead tissue (unstained infarcted tissue). The infarcted area (no stain) and
the area-
at-risk (no fluorescent partides) are catculated for each slice of left
ventride using a
precalibrated image analyzer. To normalize the ischemic injury for differences
in the
area-at-risk between hearts, the data is expressed as the ratio of infarct
area vs. area-
at-risk (%IAlAAR). All data are expressed as mean t SE and compared
statistiraliy
using a Mann-Whitney non-parametric test with a Bonfemoni cornection for
multiple
comparisons. Significance is considered as p < 0.05.
The results from the above in vitro test demonstrate that a combination of a
compound of this invention with an NHE-1 inhibitor induce signficartt
cardioprotection
relative to the control group.
The therapeutic effects of a combination of a compound of formula t of this
invention with an NHE-1 inhibitor in preventing heart tissue damage otherwise
resulting from an ischemic insult can also be demonstrated in vivo along Unes
presented in tau et at. (Circulation, Voi. &4:350-356,1991 ) as described
speaficalty
herein. The in vivo assay tests the cardioprotedion of the test combination,
i.e., a
compound of formula ! together with an NHE-1 inhibitor, relative to the
control group
which receives saline vehide. Cardioprotection, as indicated by a reducfion in


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infarcted myocardium, can be induced pharmacologically using intravenously
administered adenosine receptor agonists in intact; anesthetized rabbits
studied as an
in situ model of myocardial ischemic preconditioning (Liu et af., Circulation
84:350-
356, 1991 ). The in vivo assay tests whether the instant combination of a
compound of
formula I with an NHE-1 inhibitor can phaiinaGOlogicaliy induce
cardioprotection, i.e.,
reduced myocardial infarct size, when parenterally administered to intact,
anesthetized rabbits. The effects of the combination of a compound of formula
I of
this invention with an NHE-11 inhibitor can be compared to ischemic
preconditioning
using the A1 adenosine agonist, N6-1-(phenyl-2R-isopropyl) adenosine (PIA)
that has
been shown to phamiacologicaAy induce cardioprotection in intact anesthetized
rabbits studied in situ (Liu et al., Circulation 84:350-356, 1991 ). The
methodology is
described below.
Surcrerv: New Zealand White male rabbits (3-4 kg) are anesthetized with sodium
.
pentobarbital (30 mg/kg, i.v.). A tracheotomy is performed via a ventral
midline
cervical incision and the rabbits are ventilated with 100% oxygen using a
positive p
pressure ventilator. Catheters are placed in the left jugular vein for dntg
administration and in the left carotid artery for blood pressure measurements.
The
hearts are then exposed through a left thoracotomy and a snare (00 silk)
placed
around a prorinent branch of the left coronary artery. lschemia is induced by
pulling
the snare tight and damping it in place. Releasing the snare allows the
affected area
to repertuse. Myocardial ischemia is evidenced by regional cyanosis;
reperfusion is
evidenced by readive hyperemia.
Protocol: Once arterial pressure and heart rate have been stable for at least
30
minutes the test is started. Ischemic preconditioning is induced by occluding
the
coronary artery for 5 rtvnutes followed by a 10 minutes reperfusion.
Pharmacological
preconditioning is induced by infusing the test combination, i.e., a
combination of a
compound of formula I of this invention with an NHE-1 inhibitor, over, for
example, 5
minutes and allowing 10 minutes before further intervention or by infusing the
adenosine agonist, PiA (0.25 mg/kg). Following ischemic preconditioning,
pham~acologicat preconditioning or no conditioning (unconditioned, vehicle
control)
the artery is occluded for 30 minutes and then reperfused for two hours to
induce
myocardial infarction. The test combination and PIA are dissolved in saline or
other
suitable vehicle and delivered at 1 to 5 mglkg, respectively.


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Stainin (Liu et al., Circulation 84:350-356, 7 991 ): At the end of the 2 hour
~ , ,
reperfusion period, the hearts are quiddy removed, hung on a Langendorff
apparatus, ,
and flushed for 1 minute with normal saline heated to body temperature
(38°C). The
silk suture used as the snare is then tied tighny to reocdude the artery and a
0.5%
suspension of fluorescent zinc cadmium sulphate particles (1-10 um) Duke
Sdentific
Corp. (Palo Alto, CA) is infused with the perfusate to stain all of the
myocardium
except the area at risk (nonfiuorescent ventricle). The hearts are then quiddy
frozen
and stored overnight at -20°c. On the following day, the hearts are cut
into 2 mm
slices and stained with 7 % triphenyl tetrazolium chloride (1'TC). Since TTY
reacts
with living tissue, this stain differentiates between living (red stained)
tissue, and dead
tissue (unstained infarcted tissue). The infarded area (no stain) and the area
at risk
(no fluorescent particles) are calculated for each slice of left ventricle
using a pre-
calibrated image analyzer. To normalize the ischemic injury for differences in
the area
at risk between hearts, the data is expressed as the ratio of infarct area vs.
area at
risk (%IA/AAR). All data are expressed as MeantSEM and compared statistically
using single factor ANOVA or Mann Whitney non parametric test. Signficance is
considered as p<0.05.
The combination of a compound of formula I of this invention with an NHE-1
inhibitor can be tested for their utility in redudng or preventing ischemic
injury in non-
cardiac tissues, for example, the brain, or the liver, utilizing procedures
reported in the
scientific literature. The combination of a compound of formula I of this
invention with
an NHE-1 inhibitor in such tests can be administered by the preferred route
and
vehicle of administration and at the preferred bme of administration either
prior to the
ischemic episode, during the ischemic episode, following the isdiemic episode
(reperfusion period) or during any of the below-mentioned experimental stages.
The benefit of the combination of NHE-1 inhibitors and compounds of fortnuta 1
of this invention to reduce ischemic brain damage can be demonstrated, for
example,
in mammals using the method of Park, et al (Ann. Neurol.1988;24:543-551 ).
According to the procedure of Park, et al., adult male Sprague Dawley rats are
anesthetized initially with 2% halothane, and thereafter by mechanical
venWabon with
a nitrous oxide-oxygen mixture (70%:30%) containing 0.5-1% halothane. A
tracheostotny is then perfom~ed. The stroke volume of the ventilator is
adjusted to
maintain arterial carbon dioxide tension at approximately 35 mm Hg and
adequate


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arterial oxygenation (PaOz>90 mm Hg). Body temperature can, be monitofed by a
rectal thermometer, and the animals can be maintained normothermic, if
necessary,
by external heating. The animals next undergo subtemporal cxanieto expose
the main trunk of the left middle cerebral artery (MCA) under an operating
microscope, and the exposed artery is occluded with microbipolar coagulation
to
generate large ischemic lesions in the cerebral cortex and basal ganglia.
After three
hours of MCA occlusion, the rats are deeply anesthetized with 2% halothane and
a
thoracotomy is pertormed to infuse heparinized saline into the left ventricle.
The
effluent is collected via an indsion of the right atrium. The saline washout
is followed
by approximately 200 m! of a 40% formaldehyde, glaclal acetic add and absolute
methanol solution (FAM;1:1:8, v/vlv), then the animals are decapitated and the
head
is stored in fixative for 24 hours. The brain is then removed, dissected,
embedded in
paraffin wax, and sectioned (approximately 100 sections 0.2mm per brain). The
sections are then stained with hematoxylin~osin or with a combination of
cresyl violet
and Luxol fast blue, and examined by light microscopy to identify and
quantitate the
ischemic damage using a precalibrated image analyzer. The isdzemic volumes and
areas are expressed in absolute units (mm' and mmz) and as a peroentage of the
total
region examined. The effect of the compositions and methods of this invention
to
reduce ischemic brain damage induced by MCA occlusion is noted based on a
reduction in the area or volume of relative or absolute ischemic damage in the
brain
sections from the rats in the treatment group compared to brain sections from
rats in a
ptaoebo-treated control group.
Other methods which could alternatively be utilized to demonstrate the benefit
of the invention to reduce ischemic brain damage include those described by
Nakayama, et al, in Neurology 1988, 38:1667-1673;_ Memezawa, et al. in Stroke
1992,
23:552-559; Folbergrova, et al. in Pros. Natl. Acad. Sd 1995, 925057-5059; and
Goth, et al. in Brain Res.1990, 522:290-307.
The benefit of the compositions and methods of this invention to reduce
ischemic liver damage can be demonstrated, for example, in mammals using the
method of Yokoyama, et al. (Am. J. Physiol.1990~58:G564-G570). According tp
the
procedure of Yokoyama, et al., fasted adult male Sprague Dawley rats are
anesthetized with sodium pentobarbital (40 mglkg i.p.), then the animals are
trad~eotomized and mechanically ventilated with room air. The fryer is
extirpated and


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placed in an environmental chamber maintained at constant temperature (37
~°C), then
perfused through the portal vein at a constant pressure pf 15 cm H=0 with a
mod~ed,
hemoglobin-free Krebs-Henseleit buffer (n mM:118 NaCI, 4.7 KCI, 27 NaHCO', 2.5
CaClz, 1.2 MgSO" 12 KH=PO,, 0.05 EDTA, and 11, mM,glucose, plus 300 U
heparin).
The pH of the perfusate is maintained at 7.4 by gassing the buffer with 95% 02
- 5%
COZ. Each liver is perfused at a flow rate of 20 mUminutes in a single-pass,
manner for
a 30 minutes washout and equilibration period (preischemic period), followed
by a 2
hour period of global ischemia, and then a 2 hour period of reperfusion under
conditions identical to the preisdtemic period. Aliquots (20 ml) of the
perfusate are
collected during the preischemic period, immediately after the occlusive
isd~emic
period, and every 30 minutes of the 2 hour reperfusion period. The perfusate
samples are assayed for the appearance of hepatocellular enzymes, for example,
aspartate amino-transferase (AS't~, alanine amino-transferase (ALTS, and
lactate
dehydrogenase (LDH), which are taken to quantitatively reflect the degree of
ischemic
liver tissue damage during the procedure. AST, ALT, and LDH activities in the
perfusate can be determined by several methods, for example, by the
reflectometry
method using an automatic Kodak Ektachem 500 analyzer reported by Nakano, et
al.
(Hepatology 1995;22:539-545). The effect of the compositions and methods of
this
invention in reducing ischemic liver damage induced by occlusion is noted
based on a
reduction in the release of hepatooelluiar enzymes immediately following the
ocdus'rve
period andlor during the postischemio-reperfusion period in the perfused
livers from
the rats in the treatment group compared to perfused fivers from rats in a
placebo-
treated control group.
Other methods and parameters which could alternatively be utifrzed to
demonstrate the benefit of the compositions and methods of this invention in
redudng
isd~emic liver damage include those described by Nakano, et at. (Hepatology
1995;22:539-545).
Any glycogen phosphorylase inhibitor may be used as the second compound
of this invention, The term glycogen phosphorylase inhibitor refers to any
substance
or agent or any combination of substances andlor agents which reduces,
retards, or
eliminates the enzymatic action of glycogen phosphorytase. The currently known
enzymatic action of glycogen phosphorylase is the degradation of glycogen by
catalysis of the reversible reaction of a glycogen macrortrolearle and
incxganic


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phosphate to glucose-i-phosphate and a glycogen macromolecule which is one
glucosyl residue shorter than the original glycogen macromolecule (forward
direction
of gfycogenolysis). Such actions are readily determined by those. skilled in
the art
according to standard assays (e.g., as described hereinafter). A variety of
these
compounds are inducted in the following published PCT patent applications: PCT
application publication WO 96139384 and W096I39385. However, other glycogen
phosphoryiase inhibitors will be known to those skilled in the art
Compounds of formula l, prodrugs thereof, mutual prodrugs of the compounds
of formula I with aldose reductase inhibitors, pharmaceutically acceptable
salts of any
of the above and pharmaceutical compositions comprising a compound of formula
1, a
prodrug thereof or a pham~aceutically acceptable salt of said compound or said
prodrug and either (a) an aldose reductase inhibitor, a prodrug thereof or a
pham~aceutically acceptable salt of said aldose reductase inhibitor or said
prodrug, (b)
a NHE-1 inhibitor, a prodrug thereof or a pharmaceutically acceptable salt of
said
NHE-1 inhibitor or said prodrug, or a glycogen phosphorytase inhibitor, a
prodrug
thereof or a pham~aoeutically acceptable salt of said glycogen phosphorylase
inh~itor
or said prodnrg are hereinafter referred to, collectively, as "the active
compounds and
oomopositions of this invention."
The active compounds and compositions of this invention may be
administered to a subject in need of treatment by a variety of conventional
routes of
administration; inducting orally, parenterally and topically. In general,
compounds of
the formula I and their pharmaceutically acceptable salts will be administered
orally or
parenterally at dosages between about 0.001 and about 100 mglkg body weight of
the
subject to be treated per day, preferably from about 0.01 to 10 mglkg, in
single or
divided doses. Mutual prodrugs of compounds of the formula Land aldose
reductase
intu'bitors will generally be administered orally or parenterally at dosages
between
about O.OOi and about 100 mglkg body weight of the subject to be treated per
day,
preferably from about 0.01 to about 10 mglkg, in single or divided doses.
Compositions containing both a compound of the fom~ula I and an aldose
reductase
inhibitor will generally be administered orally or parenterally at dosages
between
about 0.001 and about 100 mg of each active component (i.e., the cor~ound of
fomwia I and the aldose reductase inhibitor) per kg body weight of the subject
to be
treated per day, preferably from about 0.01 to about 10 mglkg. Compositions


CA 02484282 2000-03-16
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containing both a compound of formula I and a NHE-1 inhibitor will generally
be
administered orally or parenterally at dosages between about 0:001 and 100 mg
of
said compound of formula I per kg body weight of the subject to be treated per
day
and about 0.001 to 100 mglkg/day of the NHE-1 inhibitor. An especially
preferred
dosage contains between about 0.01 anti 10 mglkglday of said compound of
formula I
and between about 0.01 and 50 mglkglday of said NHE-1 inhibitor. Compositions
containing both a compound of fortiiula I and a gicogen phosphorylase
inhibitor will
generally be administered orally or parenterally at dosages between about
0.001 and
100 mg of said compound of formula I per kg body weight of the subject to be
treated
per day and 0:005 to 50 mg/kglday of said glycogen phosphorytase inhibitor,
preferably 0.01 and 10 mglkglday of said compound of formula and 0.01 to 25
mglkg/day of said glycogen phosphorylase inhibitor and most preferably 0:01
and 10
mglkg/day of said compound of formula and 0.1 to 15 mglkglday of said glycogen
phosphorylase inhibitor. However, some variation in dosage will necessarily
occur
depending on the condition of the subject being treated. The person
responsible for
administration will, in any event, determine the appropriate dose for the
individual
subject.
The active compounds and compositions of this invention may be
administered alone or in combination with pharme~utically acceptable carriers,
in
either single or multiple doses. Suitable pharmaceutical carriers indude inert
solid
diluents or fillers, sterile aqueous solutions and various organic solvents_
The
pharmaceutical compositions formed by combining the active compounds of
formula I
of this invention and the phamnaceutically acceptable carriers are then
readily
administered in a variety of dosage fom~s such as tablets, powders, lozenges,
syrups,
injectable solutions and the like. These pham~aceutical compositions can, if
desired,
contain additional ingredients such as flavorings, binders, exapients and the
like.
Thus, for purposes of oral administration, tablets containing various
exapients such
as sodium citrate, cafaum carbonate and calaum phosphate may be employed along
with various disintegrants such as starch, alginic aad and certain complex
silicates,
together with binding agents such as potyvinylpyrrolidone, sucrose, gelatin
and
acaaa. Additionally, lubricating agents such as magnesium stearate, sodium
lauryl
sulfate and talc are often useful for tabletting purposes. Solid compositions
of a
similar type may also be employed as 511ers in soft and hard filled gelatin
capsules.


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Prefer-ed materials for this indude lactose or milk sugar and high molearlar
weight
polyethylene gtycols. When aqueous suspensions or elixirs are desired for oral
administration, the essential active ingredient therein may be combined with
various
sweetening or flavoring agents, coloring ri~atter or dyes and, if desired,
emulsifying or
suspending agents, together with diluents such as water, ethanol, propylene
glycol,
glycerin and combinations thereof.
For parenteral administration; solutions of the active compounds and
compositions of this invention in sesame or peanut oil, aqueous propylene
glycol, or in
sterile aqueous solutions may be employed. Such aqueous solutions should be
t 0 suitably buffered if necessary and the liquid diiuent first~rendenrd
isotonic with
sufficient saline or glucose. These partiarlar aqueous solutions are espeaally
suitable for intravenous, intramuscxriar, subcutaneous and intraperitoneal
administration. In this connection, the sterile aqueous media employed arse
all readily
available by standard techniques known to those skilled in the art
Administration of the compounds of formula 1 of this inventi~ can be via any
method which delivers a compound of this invention preferentially to the
desired tissue
(e.g., nerve, kidney, retina andlor cardiac tissues). These methods indude
oral
routes, parenteral, intraduodenal routes; etc. Generally, the compounds of the
present
invention are administered in single (e.g., once daily) or multiple doses or
via ant
infusion.
The compositions of this invention comprising a compound of fomu~la I in
combination with an NHE-1 inhibitor are useful, for example, in reduang or
minimizing
damage effected directly to any tissue that may be susceptible to
ischemialreperfusion injury (e.g., heart, brain, lung, kidney, Liver, gut,
skeletal muscle,
retina) as the result of an ischemic event (e.g., myocardial infarction). The
composition is therefore usefully employed prophytadically to prevent, i.e.
(P~Pe~IY ~ ProPhY~~~IIY) m blunt or stem, tissue darrrage (eg., rtyoc~rdial
tissue) in patients who are~at risk for ischemia (e.g., myocardial
ischert~ia).
Generally, a compound of formula I of this invention is adrronistened orally,
or
parenterany (e.g., intravenous, intramuscutar, subcutaneous or
intramedullary).
Topical administration may also be indicated, for example, where the patient
is
suffering from gastrointestinal disorders or whenever the medication is.best
applied to
the surface of a tissue or organ as determined by the attending physician.


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pCTIIB00/00296
The amount and timing of compounds administered wilt, of course,'be
dependent on the subject being treated, on the severity of the affliction, on
the manner
of administration and on the judgement of the prescribing physidan. Thus,
because of
patient to patient variability, the dosages given below are a guideline and
the
physician may titrate doses of the drug to achieve the treatment that the
physidan
considers appropriate for the patient In considering the degree of treatment
desired,
the physician must balance a variety of factors such as age of the patient,
presence of
preexisting disease, as well as presence of other diseases.
Thus, for example, in one mode of administration the compounds of formula I
of this invention may be administered just prior to surgery (e.g., within
twenty-four
hours before surgery for example cardiac surgery) during or subsequent to
surgery
(e.g., within twenty-four hours after surgery) where there is risk of
myocardial
ischemia. The compounds of formula I of this invention may also'be
administered in a
chronic daily mode.
The compounds of the present invention are generally administered in the
form of a pham~aceutical composition comprising at least one of the compounds
of
formula I of this invention together with a pham~aceutically acceptable vehide
or
diluent. Thus, the compounds of formula I of this invention can be
administered
individually or together in any conventional oral, parenteral, rectal flr
transdem~al
dosage forma
For purposes of transdem~al (e.g.,topical) administration, dilute sterile,
aqueous or partially aqueous solutions (usually in about 0.1 % to 5%
concentration),
otherwise similar to the above parenteral solutions, are prepared.
Methods of preparing various phamiaceubcal compositions with a certain
amount of active ingredient are known, or will be apparent in light of this
disdosure, to
those skilled in this art For examples of methods of preparing pharmaceutical
compositions, see Reminaton's Pharmaceutical Sciences, Madc Publishing
Company,
Easton, Pa:, '19th Edition (1995).
Pham~aoeutical compositions according to the invention may contain for
example 0.0001%-95% of the compounds) of this invention. In any event, the
composition or-formulation to be administered wiA contain a quantity of a
compounds)
according to the invention in an amount effective to treat the
diseaselcondition of the
subject being treated.


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The two different compounds of this combination of this invention can be co-
administered simultaneously or sequentially in any order, or as a single
pharmaceutical composition comprising a compound of Formuta I and an aldose
reductase inhibitor as described above or a giyoQgen phosphorylase inhibitor
as
described above or a cardiovascular agent ~"
Since the present invention has an aspect that relates to the treatment of the
diseaselconditions described herein with a combination of active ingredients
which
may be administered separately, the invention also relates to combining
separate
pharrnaceuticai compositions in kit form. The kit comprises two separate
pham~aceutical compositions: a compound of formula I a prodnrg thereof or a
satt of
such compound or prodnrg and a second compound as described above The k'rt
comprises means for containing the separate compositions such as a container,
a
divided bottle 'or a divided foil packet. TypicaNy the kit comprises
dir~ec~tions for the
administration of the separate components. The kit form is particularly
advantageous
when the separate components are preferably administered in different dosage
fom~.s
(e.g., oral and parenteral), are administered at different dosage intervals,
or when
titration of the individual components of the combination is desired by the
prescxibing
physican.
An example of such a kit is a so-called blister pads. Blister packs are well
known in the packaging industry and are being widely used for the packaging of
phamiaoeutical unit dosage fortes (tablets, capsules, and the like). Blister
packs
generally consist of a sheet of relatively stiff material covered with a foil
of a preferably
transparent plastic material. During the packaging process recesses are formed
in
the plastic foil. the recesses have the size ancJ shape of the tablets or
capsules to be
packed. Next, the tablets or capsules are placed in the recesses and the sheet
of
relatively stiff material is sealed against the plastic foil at the face of
the foil which is
opposite from the direction in which the recesses were formed. As a result,
the tablets
or capsules are sealed in the recesses between the plastic foil and the sheet
Preferably the strength of the sheet is such that the tablets or capsules can
be
removed from tide blister pads by manually applying pressure on the recesses
whereby an opening is fom~ed in the sheet at the place of the recess. The
tablet or
capsule can then be removed via said opening.


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It may be desirable to provide a memory aid on the kit, e.g., in the form of
numbers next to the tablets or capsules whereby the numbers correspond with
the
days of the regimen which the tablets or capsules so specfied should be
ingested.
Another example of such a memory aid is a calendar printed on the card, e.g.,
as
follows ~Fin;t Wesk, Monday, Tuesday, ...etc.... Second Week, Monday,
Tuesday,.. "
etc. Other variations of memory aids will be readily apparent. A "daily dose"~
can be a
single tablet or capsule or several pills or capsules to be taken on a given
day. Also, a
daily dose of Formula I compound can consist of one tablet or capsule while a
daily
dose of the second compound can consist of several tablets or capsules and
vice
versa. The memory aid should reflect this.
tn another speafic embodiment of the invention, a dispenser designed to
dispense the daily doses one at a time in the order of their intended use~is
provided.
Preferably, the dispenser is equipped with a memory-aid, so as to further
facititate
compliance with the regimen. An example of such a memory-aid is a mechanical
counter which indicates the number of daily doses that has been dispensed.
Another
example of such a memory-aid is a battery-powered miao-chip memory coupled
with
a liquid crystal readout, or audible reminder signal which, for example, reads
out the
date that the fast daily dose has been taken andlor reminds one when the next
dose is
to be taken.
The compounds of formula I of this invention generally will be administered in
a convenient formulation. The following formulation examples are illustrative
only and
are not intended to limit the scope of the present invention.
In the formulations which follow, "active ingredient" means a compounds) of
this invention.
Formulation 1: Gelatin Capsules
Hard gelatin capsules are prepared using the following:
Ingredient Quantity (mglcapsule)
Alive ingredient 0.25-100
Starch. NF p.65p
Starch fiowable powder 0.50
Silicone fluid 350 centistokes o-5
A tablet formulation is prepared using the ingredients below:


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pCT/IB00/00296
Formutation 2: Tablets . ,
Ingredient ' Quantity (mg/tablet) '
Active ingredient 0.25-100
Cellulose, microcrystalline , . , ' ' - 200-650
Silicon dioxide, fumed 10-650
Stearate acid 5-15
The components are blended and compressed to form tablets.
Alternatively, tablets each containing 0.25-100 mg of active ingredients are
made up as follows:
Formulation 3: Tablets
Ingredient Quantity (mg/tablet)
Active ingredient 0.25-100
Starch 45
Cellulose, micxocrystalline 35
Polyvinylpyrrolidone (as 10% solution in water) 4
Sodium carboxymethyl cellulose 4.5
Magnesium stearate 0.5
Talc 1
The active ingredient, starch, and cellulose are passed through a No. 45 mesh
U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed
with
the resultant powders which are then passed through a No. 14 mesh U.S. sieve.
The
granules so produced are dried at 50° - 60°C and passed through
a No. 18 mesh U.S:
sieve. The sodium carboxymethyl starch, magnesium stearate, and talc,
previously
passed through a No. 60 U.S. sieve, are then added to the granules which,
after
mixing, are compressed on a tablet machine to yield tablets.
Suspensions each containing 0.25-100 mg of active ingredient per 5 ml dose
are made as follows:


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Formulation 4: Suspensions
Ingredient Quantity (mgl5 ml)
Active ingredient 0.25-100 mg
Sodium carboxymethyl cellulose . 50 mg
Syrup 1.25 mg
Benzoic acid solution 0.10 mL
Flavor q.v.
Color
q.v.
Purified Water to 5 mL ,
The active ingredient is passed through a No. 45 mesh U.S. sieve and mixed
with the sodium carboxymethyl cellulose and syrup to form smooth paste. The
benzoic acid solution, flavor, and color are diluted with some of the water
and added,
with stirring. Suffiaent water is then added to produce the required volume.
An aerosol
solution is prepared containing the following ingredients:
Formulation 5: Aerosol
Ingredient Quantity (% by weight)
Active ingredient X0.25
Ethanol 25.75
Propellant 22 (Chlorodifluoromethane) 74.00
The active ingredient is mixed with ethanol and the mixture added to a portion
of the propellant 22, cooled to 30°C, and transfer-ed to a filling
device. The required
amount is then fed to a stainless steel container and diluted with the
remaining
propellant. The valve units are then fitted to the container.
Suppositories are prepared as follows:
Formulation 6: Suppositories
Ingredient Quantity (mglsuppository)
Active ingredient 25p
Saturated fatty aad glycerides 2,000
The active ingredient is passed through a No. 60 mesh U.S. sieve and
suspended in the saturated fatty aad glycerides previously melted using the
minimal


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_1~
necessary heat. The mixture is then poured into a suppo$i~ry mold of nominal
2.g
capacity and allowed to cool.
An intravenous fomwlation is prepared as follows:
Formulation 7: Intravenous Solution
Ingredient . Quantity. .


Alive ingredient. 25 mg-10,000 mg


Isotonic saline 1,000 mL


The solution of the above ingredients is intravenouslyr administered to a
patient.
The active ingredient above may also be a combination of agents.
GENERAL EXPERIMENTAL PROCEDURES
Melting points were determined on a Thomas-Hoover Capillary Melting Point
tus*, and are uncorrected. 'H NMR spectra were obtained, on a Bndcer AM-250*
(Broker Co., Billeriaa, Massachusetts), a Broker AM.300; a Varian XL 300
(Vari~tl
Co., Palo Alto, Cafifomia), or a Varian Unily 400 at about 23 °C at
250, 300, or 400-
MHz for proton. Chemical shifts are reported it parts per million (5) relative
to residual
chlorofornn (726 ppm), dimethylsulfoxide (249 ppm), or methanol (3.30 ppm) as
an
internal refen:noe. The peak shapes and descriptors for the peak shapes are
der>abed
as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, mufflplet; c,
oompie~ br, broad;
app, apparent Law-resolution mass spectra were obtained under thertnospray
(TS)
conditions;on a Fsons-(now Micromass) Trio 1000 Mass Spec~romete~ (Miaornass
-Inc., Beverly, Massachusetts); under chemical-ionization (CI) conditions on a
Hewlett
Padcard 5989A Particle Beam Mass Spectrometer (Hewlett Padcard Co., Palo Al~o,
. California), or under atmospheric pressure chemical ion~tion (APCI) on a
F~sons .
(now Miaomass) Platform II Spectrometeei optical rotations were obtained on a-
Perkin-Elmer 241 MC Polarimete~ (Perkin-Elmer, Norvvalk, Connec~iart),using a
standard path length of 1 clan at about 23 °C at the indicated
concentration in the
~iaated soiveM.
Liquid column chromatography was performed using foroed flow (flash
cluo<natography) of the indicated solvent on either Baker SH~a lief (40 Nm, J:
-T.
Baker, Phillipsburg, New Jersey) or Silica Gel 60~(EM Sclenoes, Gi>abstawa,
New
Jersey) in glass columns or using low nitrogen or air pressure in Flash 40~ or
Flash
*Trade-stark


CA 02484282 2000-03-16
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12"" (Biotage; Charlottesville, Virginia) cartridges. Radial chromatography
was
perfomled using a Chromatrori (Harrison Research, Paio Alto. California). The
temvs
"concentrated" and "evaporated" refer to removal of solvent using a rotary
evaporator
' at water aspirator pressure or at similar pressures generated by a Bi~chi B-
171
Vacobox (Brinkmann Instrumertts, Inc., Westbury, New York) or a Bilchi B~177 -
Vacobox with a bath temperature equal to or less than 50 °C. Reactions
requiring the
use of hydrogen gas at pressures greater than 1 atmosphere were run using a
Parr
hydrogen apparatus (Parr Instrument Co., Moline, Illinois). Unless otherwise
specified, reagents were obtained from commercial sources. The abbreviations
"d",
"h", and "min" stand for "day(s)", "hour(s)", and "minute(s)", respectively.
~ 1
LRl-1-f4-f4-Quinoxalin-2 vl-~iperazin-1-vll-ovrimidin-2-vil-ethanol.
Me~~~~
Step A: L,RI-1-t4-l4-Quinoxalin-2-vl-oiperazin-1 vll-nyrimidin-2ar11-ethyl
acetate. To a
solution of (R}-1-(4-chioro-pyrimidin-2-yl}-ethyl acetate (prepared axording
to the
method of Preparation Five, 7.3 g, 362 mmol) in isopropanol (240 mL) was added
triethylamine (10.1 mL, 72.4 mmol) followed by 2-(1-piper~azinyl~uinoxaline
(10.1 g,
47.1 mmol; J. Med Chem.~ 1981, 24, 93). This mixture was stirred at room
temperature overnight then concentrated. The residue was diluted with
saturated
aqueous sodium bicarbonate and extracted with chloroform (5x): The combined
organic extracts rare dried over sodium sulfate, filtered, evaporated, and
purified by
flash column chromatography (2% methanoUchloroform) to give 12.4 g t9i %) of
the
tills oompamd of Example 1, Step A as a yellow foam. 'H NMR (CDC~,, 250 MHz) b
8.61 (s,1 H), 8.27 (d,1 H), 7.91 (dd,1 H), 7.72 (dd, 1 H). 7.61 (td,1 H), 7.44
~(td,1 H),
6.43 (d,1 H), 5.70 (q,1 H), 3.96-3.84 (c, 8H), 2.18 (s, 3H),1.G1 (d, 3H); MS
(CIINH~
379 (MH').
Step B: fR)-i-f4-(4-Quinoxafin-2-vl-nioerazin-1 vl)wrimidin-~ vll-ethanol. To
a
solution of(Rr1-[4-(4-quinoxalin-2-yl-piperatin-1-yl~pyrimidin-2-ylj-ethyl
aoebte
(prepared according to the method of Example 1, Step A, 14.1 g, 372 mirrol) in
a
*Trade-mark


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3:1:1 mixture of tetrahydrofuranlwater/methanol (375 mL) was added lithiuri~
hydroxide hydrate (4.7 g, 112 mmol). This mixture wa$,stirred at room
temperature
for 1 h 45 min, concentrated, and extracted with chloroform (6x). The combined
organic extracts were dried over sodium sulfate, filtered, evaporated, and
purified by
flash column chromatography (2x; 2% methanoUchloroform) to give 11.3 g (90%)
of
the title compound as a pale yellow solid after tritration with hexanes. mp:
106.5-108
°C;'H NMR (CDCI,, 250 MHz) b 8.62 (s, 1H), 8.26 (d, 1 H), 7.92 (dd, 1
H), 7.72 (dd,
1 H), 7.61 (td, 1 H), 7.44 (td, 1 H), 6.45 (d, 1 H), 4.75 (m, 1 H), 3.95-3.85
(c, 8H), 1.54 (d,
3H); MS (CI/NH3) 337 (MH'); [a]o +15:3 (c 2.3, MeOH).
Example 2
(Rl-1-f4-t4-Oxazolof5.4-clpvridin-2-yl-oiperazin-1-yl~-ovrimidin-2-vll-
ethanol.
N
Me~
Step A: (R~1-f4-(4-Oxazolof5.4-clpvridin-2-vl-oioerazin-1-vl~ovrimidin-2-vfl-
ethyl
but)rrate. To a sotu6on of 2-(1-piperazinyl~xazoto[5,4-c]pyridine (775 mg, 3.8
mmol;
J. Org. Chem. 1995, 60, 5721 ) in isopropanol (38 mL) was added (Ry-1-(4-
chloro-
pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of
Preparation
Seven, 868 mg, 3.8 mmol) followed by triethylamine (1.6 mL, 11.4 mmol). This
mixture was sfin-ed at reflux overnight, cooled to room temperature, and
evaporated.
The residue was diluted with saturated aqueous sodium bicarbonate and
extracted
with chloroform (3x). , The combined organic extracts were dried over sodium
sulfate,
filtered, evaporated, and purified by flash column chromatography (2x; 3%
methanoUchloroform then 6~8% methanoUethyl acetate, where used herein, the
arrow symbol, ~, indicates a gradient) to give 1.2 g (T9%) of the title
compound of
Example 2, Step A as a pale yellow oil which solidfied upon standing. 'H NMR
(CDCI,, 250 MHz) b 8.57 (s,1 H), 8.39 (d, 1 H), 8.28 (d,1 H), 7.30 (d, 1 H);
6.44 (d, 1 H),
5.70 (q, 1 H), 3.85 (s, SH), 2.42 (t, 2H), 1.78 -1.61 (c, 2H), 1.60 (d, 3H),
0.98 (t, 3H);
MS (APCI) 397 (MH').
Step B: IRS-1-f4-(4-Oxazolof5 4-cjovridin-2-vl-Diperazin-1 yll-ovrimidin 2
vfl~thanol.
To a solution of (Rj'1-[4-(4-oxazolo[5,4-c]pyridin-2-yl-piperazin-1-yl}-
pyrimidin-2-yl]-


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ethyl butyrate (prepared according to the method of Example 2, Step A, 1.2'g,
3.0
mmol) in methanol (30 mL) was added potassium carbonate (823 rng, 6.0 mmol).
This mixture was stirred at room temperature for 5 h, diluted with saturated
aqueous
ammonium chloride, concentrated, and extracted with chloroform (3x). The
combined
organic extracts were dried over sodium sulfate, filtered, evaporated, and
purified by
flash column chromatography (6% methanoUchloroform) to give 915 mg,,(94%,) of
the
title compound as a white solid after tritra6on with hexanes. mp: 181-183
°C; 'H NMR
(CDC13, 300 MHz) b 8.54 (d, 1 H), 8.35 (d, 1 H), 8.25 (d, 1 H), 7.27 (dd, 1
H), 6.44 (d,
1 H), 4.71 (q, 1 H), 4.25 (br s, 1 H), 3.86-3.83 (c, 8H), 1.50 (d, 3H); MS
(APCI) 327
(MH'); (a]D +15.3 (c 0.5, MeOH).
Example 3
1 R-l4-f 1'-f2-f 1 R-Hydroxy-ethyll-avrimidin~-vl1-f4 4'lbipiaeridin~rl-1-vl~-
ovrimidir~ 2 v11-
ethanol.
N~N N~N
\ N~ ~ ~N
Me~~~~ Me
OH OH
A mixture of (R)-1-(4-chloro-pyrimidin-2-ylrethanoi (prepared according to the
method
of Preparation Ten, 100 mg, 0.63 mmol), 4,4'-bipiperidine dihydrochloride (76
mg,
0.32 mmol), and triethylamine (0.44 mL, 32 mmol) in isopropanol (3 mL) was
refluxed
overnight and cooled to room temperature. The reaction mixture was diluted
with
saturated aqueous sodium bicarbonate and extracted with chloroform (4x). The
combined organic extracts were dried over sodium sulfate, filtered,
evaporated, and
purified by flash column chromatography (Biotage Flash 40S"', 5%
methanoUchlorofortn) to give 110 mg (85%) of the title compound as a white
solid.
mp: 144-153 °C,'H NMR (CDCI,, 400 MHz) S 8.14 (d, 2H), 6.36 (d, 2H),
4.67 (q, 2H),
4.53.4.28 (c: 4H), 2.84 (t, 4H), 1.82 (d, 4H), 1.49 (d, 6H), 1.43-1.40 (c,
2H),1.30-1.18
(c, 4H); MS (APCI) 413 (MH'); [a]p +22,6 (c 1.0, MeOH).
Examples 4 to 8
Examples 4 to 8 were prepared from the appropriate starting materials in a
manner
analogous to the method of Example 3.


CA 02484282 2000-03-16
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Example 4
1 R-l4-f4-f2-( 1 R-Hvdroxv-ethvll-ovrimidin-4-v(1-2R.5S-dimethvl-oiperazin-1-
vi~-
wrimidin-2-v1)-ethanol.
Me. ,
N~N N~N
\ N ~---/ ~N
Me~~~~ Me Me
OH OH
mp: 153-155 °C,'H NMR (CDCI,, 400 MHz) 8 8.23 (d, 2H), 6.40 (d, 2H),
4.71 (m, 2H),
4.28 (dd, 2H), 3.51-3.45 (c, 4H),1.51 (d, 6H), 1.23 (d, 6H); MS (APCI) 359
(MH'); [ac)p
+18.6 (c 1.2, CHCI3).
OH HO
Me .... Me
-N N-
N ~ / N-linker- N ~ / N
Example N-tinker-N mp (°C) MS (MHO
5 N,N'~thylenediamine 141-143 333
6 [1,4)diazepane 136-138 345
7 4,4'-ethylenebipiperidine
8 methyl-piperidin~-ylmethyl-amine 373
Example 9
IRl-1-f4-(4-Oxazolof5.4-blpyridin-2-yl-~iperazin-1-vll-wrimidin-2-ytl-ethanol.
N
N~n~~ I
\ N ~ O N
Me"..
OH
Step A: 2-l1-Pioerazinvl)oxazolof5 4-bloyridine. A mixture of 2-
(thiomethyl~xazolo[5,4-b)pyridine (92 g, 55.5 mmol; J. Org. Chem. 1995, 60,
5721 )


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and piperazine (23.9 g, 277 mmol), with a small amount of ethyl acetate wHich
was ; ,
used for washing the compound down the sides of the flask, was heated at 90
°C for , ,
1.5 h. The reaction mixture was cooled to room temperature, diluted with -20%
saturated aqueous sodium bicarbonate solution, and eXtracted with chiorofortn
(4x).
The combined organic extracts were washed with saturated aqueous sodium
bicarbonate {1 x), dried over sodium,sutfate, filtered, evaporated, and
purified by flash
column chromatography (3-~5% methanoUchloroform + 1% ammonium hydroxide) to
give 9.1 g (81 °1°) of the title compound of Example 9, Step A
as an off white solid. 'H
NMR (CDCI,, 300 MHz) S 7.92 (dd, 1 H), 7.55 (dd, 1 H), 7.10 (dd, 1 H), 3.74-
3.70 (c,
4H), 3.02-2.97 (c, 4H); MS (APCI) 205 (MH').
Step B: (R~1-f4-l4-OxazoloT5.4-blavridin-2-vl-oioerazin-1-vl)-ovrimidin-2-vll-
ethyl
bu te. To a solution of (R~1-(4-chloro-pyrimidin-2-yl~ethyl butyrate
(pfepar~ed
according to the method of Preparation Seven, 6.8 g, 29.9 mmol) and
triethylamine
(12.5 mL, 89.6 mmol) in isopropanol (100 mL) was added 2-(1-
piperazinyl)oxazolo[5,4-b]pyridine (prepared according to the method of
Example 9,
Step A, 6.1 g, 29.9 mmol). This mixture was stirred at reflux overnight,
cooled to room
temperature, and evaporated. The residue was diluted with saturated aqueous
sodium bicarbonate and extracted with chloroform {3x). The combined organic
extracts were dried over sodium sulfate, filtered, evaporated, and purified by
flash
column chromatography (1.5->2% methanoUchloroform) to give 11.1 g (94%) of the
title compound of Example 9, Step B as a yellow oil which solidfied upon
standing. 'H
NMR~(CDCI,, 250 MHz) b 8.28 (d, 1 H), 7.97 (dd, 1 H), 7.60 (dd, 1 H), 7.25
(dd, 1 H),
6.44 (d, 1 H), 5.70 (q,1 H), 3.85 (app s, 8H), 2.42 (t; 2H), 1.78 -1.61 (c,
2H),1.60 (d,
3H), 0.98 (t, 3H); MS (APCI) 397 (MH').
Step C: (R)-1-I4-f4-Oxazolof5.4-blpvridin-2-vl-pioerazin-1-vl~ovcimidin-2-vll-
ethanol.
To a solution of (Ry-1-[4-(4-oxazolo[5,4-b]pyridin-2-yl-piperazin-1-yl)-
pyrimidin-2 ylj-
ethyl butyrate (prepared according to the method of Example 9, Step B, 11.0 g,
27.6
mmol) in dioxane (11.5 mL) was added concentrated hydrochloric aad (23 mL, 276
mmol). This mixture was stirred at room temperature overnight, neutralized
with 6 N
aqueous sodium_hydroxide, and extracted with chloroform (3x). The combined
organic extracts were dried over sodium sulfate, filtered, evaporated, and
purfied by
flash column chromatography (3.5% methanoUchloroform) to give 8.4 g (93%) of
the
title compound as a white solid. mp: 153-156 °C; 'H NMR (CDCIj, 300
MHz) S 825


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(d, 1 H), 7.95 (dd, 1 H), 7.58 (dd, 1 H), 7.15 (dd, 1 H), 6.45 (d, 1 H), 4.72
(q, 1 H), 4.25 (br
s, 1H), 3.85-3.82 (c; 8H), 7.51 (d, 3H); MS (CIINH,) 327 (MH'); [~ajp +16.1 (c
t.0,
MeOH)
Examoies 10 tol5
Examples 10 to 15 were prepared from the appropriate starting materials in a
manner
analogous to the method of Example 9.
R~
_ _ ~ N~ ,
~N
Example X-Ar' R' nip (C) MS (MH')


10 oxazolo[4,5-c]pytidin-2-yl(R~CH(CH,)OH 178-180 327


11 oxazofo[5,4-c]pyridin-2-yl-C(CH,)ZOH 181-184 341


12 oxazolo[5,4-c]pyridin-2yl(t)-CH(CH3~H 153-758 327-


13 oxazolo[5,4-cjpyridin-2-yl{S)-CH(CH,)OH 175-179 327


14 quinoxalin-2-yl (t)-CH(CH,~H 102-105 337


(5-iodorbenzoxazol-2-yl(R)-CH(CH,)OH 452


Example 16
1 R-f4-(3S-Methvl~-oxazolof5.4-blnvridin-2-vi-oinerazin-1 vl1-ovrimidin-2-vll-
ethanol.
/~'~ N
N //- ~ --~~
\ N ~ O N
Me~~~~ Me
OH
15 Step A: (Sl-2-f4-Benzv!-2-methyl-~ioerazin-1 vll~xazofo~5 4-blQVridine. A
modure of
2-(thiomethyl)oxazolo[5,4-b]pyridine (44 g, 264 mmol; J. Olg. Chem.1995, 60.
5721 )
and (Sy-1-benzyl-3-methyl-piperazine (25 8,132 mmol; J. Org. Chem.1995, 60,
4177)
was sflmed at 130 °C for 3 d, cooled to room temperature, and purfied
by flash
column chromatography (1783% ethyl acetatelhexanes) to give 30 g (74%) of the
tatte compound of Example 16, Step A as a dark yellow oil. 'H NMR (COCK, 400
MHz)
8 7.89 (d, 1 H), 7.53 (d, 1 H), 7.34-7.25 (c, 5H), 7.10 (dd, 1 H), 4.45 (m, 1
H), 4.11 (d,


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1 H), 3.59 (d, 1 H), 3.52-3.45 (c, 2H), 2.90 (d, 1 H), 2.73 (d, 1 H), 2.32
(dd, 1 H), 2.21 (td, .,,
1 H), 1.41 (d, 3H); MS (APCI) 309 (MH').
Step B: fS)-2-f2-Methyl-oioerazin-1-vl)-oxazolo15.4-blp ny_dine. To a solution
of (S)-2-
(4-benzyl-2-methyl-piperazin-1-yl}-oxazolo[5,4-b]pyridine (prepared according
to the
method of Example 16, Step A, 30 g, 97 mmol) in methanol (970 mL) was added
hydrogen chloride (5.85 M in methanol, 20 mL, 116 mmol), ammonium folmate (122
g, 1.95 mol), and 10 % palladium on carbon (60 g, 200 wt%). This mixture was
stirred
at reflux for 50 min, cooled, and filtered through Celite. The filtrate was
concentrated,
diluted with saturated aqueous sodium bicarbonate, and extracted with
chlproform
(1x) followed by 10% isopropanoUchloroform (4x). The combined organic extracts
were dried over sodium sulfate, filtered, and evaporated to give 16 g (76%) of
the title
compound of Example 16, Step B as a green oil. 'H NMR (CDCl,, 400 (MHz) 8 7.89
(m, 1 H), 7.53 (m, 1 H), 7.09 (m, 1 H), 4.42 (m, 1 H), 4.11 (d, 1 H), 3.35
(td, 1 H), 3.09=
3.03 (c, 2H), 2.85 (d, 1 H), 2.82 (td,1 H), 1.38 (d, 3H); MS (APCI) 219 (MH').
Step C: 1 R~4-l3S-Methvl-4-oxazolof5.4-blpvridin-2-vl-oioerazin-1-yl3-
ovrimidin-2-v(1-
ethvlbutvrate. A mixture of (S}-2-(2-methyl-piperazin-1-yl}-oxazolo[5,4-
b]pyridine
(prepared according to the method of Example 16, Step B, 10 g, 45.9 mmol),
(R~1-(4-
chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of
Preparation
Seven, 9.5 g, 41.7 mmol), and triethylamine (17.3 mL, 125 mmol) in isopropanol
(230
mL) was heated at reflux for 30 h, cooled to room temperature, diluted with
saturated
aqueous sodium bicarbonate, and extracted with chloroform (4x). The combined
organic extracts were dried over sodium sulfate, filtered, evaporated, and
purified by
flash column chromatography (1.5% methanoUchlorofortn) to give 16 g (93%) of
the
title compound of Example 16, Step C as a yellow oil. 'H NMR (CDCI,, 400 MHz)
S
8.23 (d, 1 H), 7.93 (dd, 1 H), 7.57 (d, 1 H), 7.13 (dd, 1 H), 6.39 (d, 1 H),
5.67 (q, 1 H), 4.61
(m, 1 H), 4.42 (m, 1 H), 4.28 (m, 1 H), 4.18 (dt, 1 H), 3.51 (td, 1 H), 3.41
(dd, 1 H), 3.17
(td, 1 H), 2.39 (t, 2H), 1.72-1.59 (c, 2H), 1.57 (d, 3H), 1.30 (d, 3H), 0.95
(t, 3H); MS
(APCI) 411 (MH').
Step D: 1 R~4-(3S-Methvl-4-oxazolof5.4-blavridin-2-vl-oioerazin-1 vl~nvrimidin-
2 ~~
ethanol. A mixture of 1 R-[4-(3S-methyl-oxazolo[5,4-b]pyridin-2-yl-piperazin-1-
ylr
pyrimidin-2-y(]-ethyl butyrate (prepared according to the method of Example
16, Step
C,16 g, 39.0 mmol) and potassium carbonate (10.8 g, 78.1 mmol) in methanol
(195
mL) was stirred at room temperature for 4 h, diluted with saturated aqueous
sodium


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bicarbonate, and extracted with chforofonn (1x) followed by 10%
isopropanol/chloroform (3x). The combined organic extracts were dried over
sodium
sulfate, filtered, evaporated, and purfied by flash column chromatography (1-
>2.5%
methanoUchioroform) to give a white foam that was reaystallized from
ether/chloroform to give 8.9 g (67%) of the tide compound as a white solid.
mp:147-
149 °C; 'H NMR (CDCI,, 400 MHz) S 824 (d,1 H), 7.94 (dd,1 H), 7.58 (d,1
H); 7.14
(dd, 1 H), 6.42 (d, 1 H), 4.72 (m, 1 H), 4.64 (m, 1 H), 4.42 (m, 1 H), 4.32
(m, 1 H), 4.25 (d,
1 H), 4.21 (dt, 1 H), 3.54 (td,1 H), 3.46 (dd, 1 H), 3.24 (td,1 H), i .51 (d,
3H),1.33 (d,
3H); MS (APCI) 411 (MH'); [a]o +70.4 (c 1.1, MeOH).
Examples 17 to 25
Examples 17 to 25 were prepared from the appropriate starting materials in a
manner
analogous to the method of Example 16.
Examcle 17
i R-f4-(3S-Methvl-4-auinoxalin-2-vl-nioerazin-1 vl~-nvrimidin-2-vlt-ethanol.
Me~
'H NMR (CDC13, 400 MHz) b 8.56 (d, 1 H), 8.23 (d, 1 H), 7.89 (d, 1 H), 7.69
(d,1 H), 7.59
(t, 1 H), 7.41 (t, 1 H), 6.42 (d, 1 H), 4.78 (m, 1 H), 4.73 (m, 1 H), 4.43
(m,1 H), 4.38-4.23
(c, 2H), 3.64-3.52 (c, 2H), 3.38 (m, 1H),1.52 (d, 3H), 1.30 (d, 3H); MS (APCI)
351
(MH'); [a]o +57.0 (c 1.2, CHCI3).
Example 18
1R-(4-f 4.6-Dimethvl-ovrimidin-2-vl~3S-methyl-vioerazin-1-vll-rnrrimidin-2-vt~-

ethanol.
Me
N-
N~N N
N ~--~ \N
Me~~~~ Me Me
OH


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'H NMR (CDCI,, 400 MHz) b 8.18 (d, 1 H), 6.37 (d, 1 Hj, 6.30 (s, 1 H), 5.04
(m, 1 H), ~ '
4.70 (q, 1 H), 4.60 (dt, 1 H), 4.37 (br s, 1 H), 4.36.12 (c, 2H), 3.40 (dd, 1
H), 3.34 (td,
1 H), 3.16 (td, 1 H), 2.28 (s, 6H), 1.51 (d, 3H), 1.16 (d, 3H); MS (APCI) 329
(MH'); (a]o
+78.8 (c 1.6, MeOH).
Example 19
1 R-t4-f4-(2-Hvdroxymethvl-6-methyl-oyrimidin-d-vl~-3S-methyl-piperazin-'1-vf1-

p~rrimidin-2 yf~-ethanol.
Me
Me~~~~ ,
'H NMR (CDCI,, 400 MHz) b 8.23 (d, 1 H), 6.38 (d, 1 H), 6.23 (s, 1 H), 4.71
(q, 1 H), 4.58
(s, 3H), 4.36-4.18 (c, 4H), 3.86 (br s, 1 H), 3.57 (dd, 1 H), 3.46 (td, 1 H);
3.32 (td, 1 H),
2.38 (s, 3H), 1.51 (d, 3H), 1.22 (d, 3H); MS (APCI) 345 (MH'); (a]~ +72.6 (c
1.1,
MeOH).
Examaie 20
1 R-f4-(3S-Methyl-4-oxazolof4.5-blflvridin-2-yl-pit~erazin-1-~rl~pvrimidin-2-
yf1-ethanol.
N N
N~N N---C
N ~ O /
Me~w Me
OH
mp: 158-161 °C; 'H NMR (CDCI,, 400 MHz) b 8.22-8.15 (c, 2H), 7.40 (dd,1
H), 6.86
(dd, 1 H), 6.40 (d, 1 Hj, 4.65 (m, 1 H), 4.61 (m, 1 H), 4.44-4.20 (c, 3H),
4.18 (dt, 1 H),
3.50 (td, 1 H), 3.41 (dd, 1 H), 3.19 (td, 1 H), 1.45 (d, 3H), 1.26 (d, 3H); MS
(APCt) 341
(MH'); [aJo +582 (c 1.1, MeOH).
Example 21
1 R-f4-(3S-Methyl-4-oxazolo!'4 5-clpvridin-2 girl-c~ioerazin-1 yl)-nyimidin-2-
v(a~thanol.


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N ~N
N~/ --N N-~r~
N O I
Me ~". , , Me ,
OH
rcrnsooroo~
'H NMR (CDCI,, 400 MHz) b 8.68 (d,1 H), 8.32 (d,1 H), 8.24 (d, 1 H), 7.25
(dd,1 H),
6.42 (d, 1 H), 4.71 (m,1 H), 4.60 (m,1 H), 4.42 (m,1 H), 4.32-4.23 (c, 2H),
4.17 (dt,1 H),
3.56 (td, 1 H), 3.47 (dd, 1 H), 3.24 (td, 1,H),1.51 (d, 3H), 1.32 (d, 3H); MS
(APCI) 341
(MH'); [a]o +57.9 (c 1.6, MeOH).
Example 22
1 R-t4-(3S-Methyl~-oxazolof5.4-ciamidin-2-vl-oioerazin-1 vll-ovrimidin-2=vIl-
ethanol.
N
N .rl ~ -~r I
N ~ O. /
Me~~~~ Me
OH
'H NMR (CDC13, 40D MHz) b 8.56 (s,1 H), 8.37 (d, 1 H), 8.25 (d, 1 H), 7.29 (d,
1 H), 6.43
(d,1 H), 4.72 (m, 1 H), 4.65 (m,1 H), 4.45 (m,1 H); 4.29 (m,1 H), 4.26-420 (c,
2H), 3.58
(td, 1 H), 3.48 (dd, 1 H), 3.26 (td, 1 H), 1.51 (d, 3H), 1.34 (d, 3H); MS
(APCI) 341 (MH');
[a)p +61.1 (c 1.0, MeOH).
HO
Me ~~~~Me
N-
Ar'-X-N N~ . N
Example X~4~' C' Jo (°C) MS (MH"y
23 quinoxaiin-2-yl R 351
24 _ - (2-[C(CH~)zOH]}- py~imidin~-yi S 359
benzoxazol-2-yi S 340


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(=xam~le 26
1 R-l4-f4-f2-(1 R-Hvdroxv-ethyl)-pvrimidin-4-vIl-2R.6S-dimethvl-piperazin-1-
vlf-
pyrimidin-2-vl~ethanol.
Me~
OH OH
Method 1: To a~solution of 1R-[4-(2R,6S-dimethyl-piperazin-1-y!)-pyrimidin-2-
yQ-ethyl
butyrate (prepared according to the method of Preparation Four, 72.8 g, 238
mmol)
and triethylamine (50 mL, 357 mmol) in isopropanol (793 mL) was added (R)-1-(4-

chloro-pyrimidin-2-yl~thyl butyrate (prepared according to the method of
Preparation
Seven, 54.3 g, 238 mmol). This mixture was stirred at reflux for 12 h and
concentrated. The residue was dissolved in a 3:1:1 mixture of
tetrahydrofuraNmethanoUwater (1200 mL) and lithium hydroxide hydrate (60 g,
1.43
mot) was added. This mixture was stirred at room temperature for 2.5 h,
concentrated
somewhat, diluted with saturated aqueous sodium bicarbonate, and extracted
with
10% isopropanoUchloroform (6x). The combined organic extracts were dried over
sodium sulfate; filtered, and evaporated. The residue was diluted with 1:1
ethyl
acetatelmethanol (1100 mL) and stirred at room temperature for 1 h. The
precipitate
was collected by filtration and the filtrate was concentrated to about 850 mL.
After 1 h,
more preapitate had formed and this material was collected by filtration. The
filtrate
was concentrated somewhat and ethyl acetate was added. After 1 h more
precipitate
had again formed and this material was collected by filtration. This was
repeated one
more time to give in total 65.9 g (77%) of the title compound as a white
solid. mp:
163-164.5 °C; 'H NMR (CDCI,, 400 MHz) S 824 (d, 1 H), 823 (d, 1 H);
6.46 (d, 1 H),
6.36 (d, 1 H), 4.74-4.70 (c, 2H), 4.704.50 (c, 2H), 4.50-4.30 (c, 2H), 4.30
(d, 1 H), 427
(d, 1 H), 3.31 (dt, 2H), 1.51 (d, 6H), 1.26 (d, 6H); MS (APCI) 359 (MH'); [a]o
+42.3 (c
1.0, MeOH).
Method 2, Step A: 1 R-(4-f4-f2-(1 R-Buivrvloxv~thvl~pvrimidin-4-vtl-2R 6S-
dimethvl-
piperazin-1-vl~-ovrimidin-2-vll-ethyl butyrate. To a solution of (R~2-(1-
btrtyryloxy-
ethylr3H-pyrimidin-4-one (828 g, 3.9 rr~ol) in dichloromethane (50 L) was
added


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triethylamine (576 mL, 4.1 mol) and the resulting solution was copied to 5
°C. A
solution of trifluoromethanesulfonic anhydride (729 mL, 4.3 mol) in
dichloromethane (6
L) was added slowly such that the internal temperature was maintained at <10
°C.
After the addition was complete, the reaction was judged complete by TLC and
quenched by the addition of water (5.3 L). The organic layer was separated,
washed
with water (20 L) and saturated aqueous sodium bicarbonate (20 L), and'dried
over
sodium sulfate. This solution was then slowly added to a solution of 1 R-[4-
(2R,fiS-
dimethyl-piperazin-1-yl)-pyrimidin-2-ylj-ethyl butyrate dibenzoyl-L-tartrate
salt
(prepared according to the method of Preparation Fifteen, 2.49 kg, 3.75 mdl)
and
triethylamine (1.6 L, 11.6 mol) in dimethylacetamide (18 L) such that the
internal
temperature was maintained at <10 °C. The resulting solution was
allowed to stir for
12 h at 10 °C and then diluted with ethyl acetate (40 L) and water (27
L).' The
aqueous layer was removed and the organic layer was washed twice with water
(40
L) and once with brine (20 L), and dried over sodium sulfate. The resulting
solution
was partially concentrated (8 L) and then hexanes (23 L) was added. The
resulting
suspension was allowed to granulate for 12 h and then filtered over cotton.
The solids
were dried under vacuum (40 °C) to provide 1178 gm (63%) of the title
compound of
Example 26, Method 2, Step A as a white solid. The'H NMR and MS data for this
compound are in agreement with that of Example 266.
Method 2, Step B: 1 R~4-t4-f2-l1 R-Hvdroxy-ethyl~pyrimidin~-v(1-2R.6S-dimethvl-

piperazin-1-vll-pvrimidin-2-v()-ethanol. To a solution of 1 R-(4-(4-[2-(1 R-
butyryloxy-
ethylrpyrimidin-4-ylj-2R,6S-dimethyl-piperazin-1-yI)-pyrimidin-2-yl~ethyl
butyrate
(prepared according to the method of Example 26, Method 2, Step A, 1140 g,
2.28
mol) in isopropanol (11.4 L) was added 40% aqueous potassium hydroxide (800
mL)
at room temperature. The resulting solution was allowed to stir for 16 h and
then
diluted with water (5 L) and dichloromethane (4 L). The organic layer was
separated
and the aqueous layer was extracted with dichloromethane (4 L). The combined
organic layers were washed twice with 1 M aqueous sodium hydroxide (10 L) and
twice with water {5 L), partially concentrated {5 L), diluted with ethyl
acetate (4 L), and
again partially concentrated (6 L). Hexanes (10 L) was added and the resulting
slurry
was allowed to stir at reflux for 12 h, cooled to room temperature, and
filtered. The
resulting solid was dried under vacuum to provide 758 g (93%) of the title
compound


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as a white solid. The mp, 'H NMR, MS, and optical rotation data for this
compound
are in agreement with that of Example 26. Method 1.
Examples 27 to 62
Examples 27 to 62 were prepared from the appropriate, starting materials in a
manner
analogous to the method of Example 26.
Example 27
1 R-f4-f4-(4.6-Dimethyl-avrimidin-2-yll-2R.6S-dimethvl-oioerazin-1-yIl-
pvrimidin-2 yll-
ethanol.
Me Me
N- .,
N~N --~~
\ N N
Me~~w Me Me
OH
mp: 150.5-152 °C;'H NMR (CD,OD, 300 MHz) S 8.14 (d, 1H), 6.62 (d, 1H),
6.46 (d,
1 H), 6.40 (s, 1 H), 4.83 (d, 2 H), 4.72-4.52 (c, 3H), 3.30 (dd, 2H), 2.28 (s,
6H), 1.46 (d,
3H), 1.23 (d, 6H); MS (APCi} 343 (MH'); [a]p +12.0 (c 1.3, MeOH).
Example 28
1 R-f4-12R.6S-Dimethv!-4-oxazolof5.4-clayridin-2-yl-pioerazin-1-vl)-ovrimidin-
2-vl~
ethanol.
Me
N
N~N N--<~
N ~ O ~N
Me~~~~ Me
OH
'H NMR (CD,OD, 300 MHz) S 8.53 (d, 1 H), 8.28 (d, 1 H), 8.20 (d, 1 H), 7.34
(dd,1 H),
fi.68 (d, 1 H), 4.90-4.72 (c, 2H), 4.69 (q, 1 H), 4.32 (d, 2H), 3.56 (dd, 2H),
1.47 (d, 3H),
1.33 (d, 6H); MS (APCf) 343 (MH'); [aj~ +8.1 (c 1.3, MeOH).
Example 29
i R-f4-f4-(4-Hvdroxymethyl-6-methyl-ovrimidin-2-yl~-2R.6S-dimethyl-oinerazin-1-
vft-
gyrimidin-2=vtl-ethanol.


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Me Me ,
N~N N~~
N~ ~ , . ~N
Me".. Me'
OH OH
mp: 139-141 °C;'H NMR (CD,OD, 300 MHz) b 8.24 (d, 1H), 6.51 (d, 1H),
6.38 (s
1 H), 4.90 (m, 1 H), 4.84 (d, 2H), 4.77-4.53 (c, 2H), 4.55 (s, 2H), 3.24 (dd,
2H), 2.37 (s,
3H), 1.61 (d, 3H), 1.32 (d, 6H); MS (APCt) 359 (MH'); [a]p +14.8 (c 1.0,
MeOH).
Example 30
1 R-(4-14-(2.6-Dimethyl-ovrimidin-4-yl1-2R.6S-dimethyl-oiperazin-1-yl1-
oyrimidin-2-vll-
ethanol.
Me~
'H NMR (CDCI,, 300 MHz) b 8.22 (d, 1 H), 6.36 {d,1 H), 626 (s, 1 H), 4.71 (m,
1 H),
4.65-4.50 (c, 2H), 4.42-4.28 (c, 3H), 3.24 (dd, 2H), 2.49 (s, 3H), 2.35 (s,
3H), 1.52 (d,
3H), 1.26 (d, 6H); MS (APCI) 343 (MH'); [a]o +11.4 (c 0.8, MeOH).
Example 31
1 R-f4-(2R.6S-Dimethvl~-oxazolof4.5-blovridin-2-vl-oinerazin-1 vl~-pvdmidin-2-
vIl-
ethanol.
Me
N
N~N N
~ N ~ O /
Me~~~~ Me
~ OH
mp: 231-233 °C;_'H NMR (CDCI3, 400 MHz) 8 8.26-8.23 (c, 2H), 7.47 (d, 1
H), 6.94
(dd, 1 H), 6.39 (d, 1 H), 4.75-4.53 (c, 2H), 4.72 (q, 1 H), 4.35 {d, 1 H),
4.28 (m, 1 H), 3.44
(dd, 2H), 1.51 (d, 3H), 1.34 (d, 6H); MS (APCI) 355 (MH'); [a]p +8.0 (c 0.8,
MeOH).


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Exam~ie 32 ,
1 R-(4-f4-(2-Hvd~oxvmethvl-6-methyl-ovrimidin-4-yl~2R.6S-dimethyi-ainerazin-1-
vil-
p~rrimidin-2-vii-ethanol.
-
N ~ ~~N N~~ / N ,
N/ ~ ~N
Me""' Me
OH OH
'H NMR (CD30D, 300 MHz) b 8.16 (d, 1 H), 6.66 (s, 1 H), 6:63 (d, 1 H), 4.85-
4.63 (c,
2H), 4.67 (q, 1 H), 4.58 (d, 2H), 4.50 (s, 2H), 3.26 (dd, 2H), 2.35 (s, 3H),
1.46 (d, 3H),
1.24 (d, 6H); MS (APCI) 359 (MH'); [a]D +11.8 (c 0.9. MeOH).
Example 33
1 R-f4-(2R.6S-Dimethvl-4-oxazolof5.4-blpyridin-2-vl-pi~erazin-1-vl)-pvrimidin-
2-vtl-
ethanol.
Me~
OH
Me
N
N~N N--<~
\ N ~ O N
Me
mp: 204-207 °C; 'H NMR (CDCI,, 400 MHz) b 8.25 (d, 1 H), 7.95 (dd, 1
H), 7.59 (dd,
1 H), 7.15 (dd, 1 H), 6.39 (d, 1 H), 4.80-4.57 (c, 2H), 4.73 (q, 1 H), 4.30
(d, 2H), 3.42 (dd,
2H), 1.51 (d, 3H), 1.35 (d, 6H); MS (APCI) 355 (MH'); [a]o +7.5 (c 0.7, MeOH).
Example 34
2-(4-~4-f2-(1 R-Hvdroxv-ethvll-ovrimidin-4-vf1-3R.5S-dimethvl-piperazin-1-vfl-
cvrimidin-
2-vi~roaan-2-ol.
~N
~N /
Me
Me~~
OH OH Me


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mp: 138-140 °C;'H NMR (CDCI,, 400 MHz) S 8.23 (d, 2H). 6.45 (d; 1H),
6.36 (d,1H), "
4.86 (s, 1 H), 4.70 (m, 1 H), 4.67-4.33 (c, 4H), 4.30 (d, 1 H), 3.31 (dd, 2H),
1.53 (s, 6H),
1.51 (d, 3H), 1.25 (d, 6H); MS (APCI) 373 (MH'); [a]~ +15.5 (c 1.2, MeOH).
Example 35 ,
1 R-I4-f4-f4-Hvdroxvmethvl-6-methyl-oyrimidin-2-yl~2S-methv!-ni~erazin-1-v(1-
pvrimidin-2-vll-ethanol.
Me
.~ N-
N~N N~~
\ N ~ ~N
Me~~~~ Me
OH OH
' H NMR (CDCI,, 400 MHz) b 8.18 (d,1 H), 6.36. (d,1 H), 6.32 (s,1 H), 4.69
(q,1 H), .
4.60-4.53 (c, 3H), 4.52 (s, 2H), 4.38-4.18 (c, 2H), 3.63 (m,1 H), 3.40-3.29
(c, 2H), 324
(m, 1H), 2.32 (s, 3H), 1.49 (d, 3H), 1.20 (d, 3H); MS (APCI) 345 (MH'); [a]o
+66.5 (c
1.0, MeOH).
Example 36
1 R-f4-f4-f4-Hvdroxvmethyl-6-methv!-ovrimidin-2-yl)-2R-methyl-nit~erazin-1 y~-
pvrimidin-2-vl~-ethanol.
Me~~~
'H NMR (CDCI,, 400 MHz) b 8.21 (d, 1 H), 6.37 (d, 1 H), 6.33 (s, 1 H), 4.72
(m,1 H),
4.fi7-4.54 (c, 3H), 4.54 (s, 2H), 4.34 (d, 1 H), 4.20 (d, 1 H), 3.58 (b~ s,1
H), 3.42-3.32 (c,
2H), 3.26 (td, 1 H), 2.34 (s, 3H), 1.51 (d, 3H),121 (d, 3H); MS (APCI) 345
(MH'); [a]o -
35.0 (c 1.1, MeOH).


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Example 37 , ,
1 R-~4-f4-l2-Hydrox~methvfrpvrimidin-4-vl~3S-methyl-oiaerazin-1 v(1-avrimidin-
2-vl~-
ethanol.
N -I ~ .\.~ N
N ~ N ,
Me",. Me
OH OH
mp: 178-181 °C;'H NMR (CDCI$, 400 MHz) & 8.23 (d, 2H), 6.38 (d, 2H),
4.60 (q,1H),
4.60 (s, 2H), 4.56 (m, 1 H), 4.28-4.15 (c, 4H), 3.72 (br s, 1 H), 3.58 (dd, 1
H),~ 3.48 (m,
1 H), 3.33 (td,1 H), 1.51 (d, 3H),1.23 (d, 3H); MS. (APCI) 331 (MH'); [a]Q
+88.9 (c 1.1,
MeOH). ,,
Example 38
1 R-l4-~4-f2-l1 R-Hvdroxv-ethvll-ovrimidin-4 v1l-2S-methyl-oioerazin-1-
yl)..pyrimidin-2-
I thanol.
N I ~ ~N
I
N ~ N
Me~,~. Me~ ~ Me
OH OH
mp:158-160 °C; 'H NMR (CDC1,, 400 MHz) 8 8.24 (d, 2H), 6.39 (d,1 H),
6.38 (d, 1 H),
4.71 (m, 2H), 4.55 (br s, 1 H), 4.32-4.16 (c, 5H), 3.60 (dd, 1 H), 3.48 (td, 1
H), 3.38 (td,
1 H), 1.52 (d, 6H), 1.24 (d, 3H); MS (APCi) 345 (MH'); [a]p +82.5 (c 1.0,
MeOH).
Exam~ie 39
1 R-(4-~4-f2-(1 R-Hvdroxy~thyl~ovrimidin.-4-vt1-2R-methyl-niDerazin-1-vl~-
ovrimidin-2-
thanol.
Me~~.


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mp: 155-157 °C;'H NMR (CDCI3, 400 MHz) 8 8.24 (d, 2H), 6.39 (d, 1H),
6.38 (d, 1H),
4.73 (m, 2H), 4.58 (br s, 1 H), 4.32-4.16 (c, 5H), 3.59 (dd, 1 H), 3.50 (m, 1
H), 3:38 (m,
1 H), 1.52 (d, 6H), 1.25 (d, 3H); MS (APCI) 345 (MH'); [a]~ -30.4 (c 0.9,
MeOH).
Example 40
1 R-(4-t'3-f2-(1 R-Hydroxy~thyl)-oyrimidin-4-yll-3.9-diaza-bicyclof3.3.1)non-9-
yt)-
pyrimidin-2-vi)-ethanol.
N ~ N N~N
N N
Me
Me~
OH OH
mp: 151-158 °C; 'H NMR (CDC13, 400 MHz) 8 8.24 (d, 2H), 6.42 (d, 1 H),
6.41 (d, 1 H),
4.72 (m, 2H), 4.48.18 (c, 2H), 4.29 (dd, 2H), 3.28 (d, 2H), 2.03 (m, 1
H),11.98-1.82. (c,
4 H), 1.58 (m, 1 H), 1.51 (d, 3H), 1.50 (d, 3H); MS (APCI) 371 (MH'); [a]o
+27.6 (c 0.9,
MeOH).
Examote 41
1 R-l4-f4-f2-l1 S-Hvdroxv-ethvl~pvrimidin-4-v(1-2R.6S~Jimethvt-pioerazin-1-yt~
pyrimidin-2-yl)-ethanol.
Me
N~N N~N
N~ ~ \N
Me~~~~~ Me ~~~ Me
OH OH
mp: 222-223.5 °C; 'H NMR (CDCI,, 400 MHz) 8 8.24 (d, 1 H), 8.23 (d, 1
H), 6.46 (d,
1 H), 6.36 (d, 1 H), 4.75-4.51 (c, 4H), 4.50-4.30 (c, 4H), 3.31 (dt, 2H), 1.51
(d, 6H), 1.26
(d, 6H); MS (APCI) 359 (MH'); [a]o -3.4 (c 0.5, CHCI3).


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Example 42 "
1 S-(4-~4-f2-l1 R-Hvdroxv-ethvll-oyrimidin-d-vfl-2R fiS-dimethvl-piperazin-1-
vll-
hyrimidin-2-vll-ethanol.
N~ ~ ~N
N ~ ~N
Me Me Me
OH OH
mp: 224-226 °C; 'H NMR (CDCI,, 400 MHz) b 8.24 (d, 1 H), 8.23 (d, 1 H),
6.46 (d, 1 H),
6.36 (d, 1 H), 4.76-4.51 (c, 4H), 4.50-4.23 (c, 4H), 3.33 (dt, 2H), 1.51 (d,
6H), 1.25 (d,
6H); MS (APCI) 359 (MH'); [aJo +64.2 (c 0.5, CHCl,).
Example 43
1 S-(4-(4-f2-(1 S-Hydroxy-ethyl)-oyrimidin-4-vfl-2R 6S~imethyl-piaerazin-1 vl~-

pvrimidin-2-vl)-ethanol.
Me
N /rN N~N
\ N/ ~ ~ ~N
Me Me w~~ Me
OH OH
mp: 164-165.5 °C; 'H NMR (CDC13, 400 MHz) b 8.24 (d, 1 H), 8.23 (d, 1
H), 6.46 (d,
1 H), 6.36 (d, 1 H), 4.75-4.51 (c, 4H), 4.50-4.23 (c, 4H), 3.47-3.28 (c, 2H),
1.51 (d, 6H),
1.25 (d, 6H); MS (APCI) 359 (MH'); [a]p -43.8 (c 1.0, MeOH).
Example 4.4
1RS-l4-t4-f2-IIRS-Hvdroxv-ethvl~cvrimidin-4-y(1-2R'6S'~imethv! nioerazin 1 vlf-

nyrimidin-2-vll-ethanol.
Me
N~N N-~(\ N
~ N~ Y \N
Me Me Me
OH OH


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mp: 180-186 °C;'H NMR (CDCI9, 400 MHz) s 8.24 (d, 1 H), 8.23 (d, 1 H},
6.46 (d, 1 H),
6.36 (d, 1H), 4.75-4.51 (c, 4H), 4.50-423 (c, 4H), 3.47,-,3.28 (c, 2H), 1.51
(d, 6H), 1.25
(d, 6H); MS (APCI) 359 (MH').
Example 45..
1-(4-~4-f2-(1 R-Hvdroxv-ethyl~pvrimidin-4-y(1-2R.6S-dimethvl-piaerazin-1-vll-
ovrimidin-
211-ethanone.
Me
N~N N~N
\ N~ ~ ~N
Me Me Me
O OH
mp: 123-i27 °C;'H NMR (CDCI,, 400 MHz) 8.8.41 (d, 1H), 8.24 (d, 1H),
6.56 (d, 1H),
6.47 (d, 1 H), 4.75-4.53 (c, 3H), 4.52-4.28 (c, 2H), 4.26 (m, 1 H), 3.36-3.29
(c, 2H), 2.68
(s, 3H), 1.51 (d, 3H), 128 (d, 6H); MS (APCt) 357 (MH'); [ajo+19.4 (c 1.0,
MeOH).
Example 46
1-l4-~4-f2-l1 R-Hvdroxv-ethyl)-ovrimidin-4-vfl-3R 5S-dimethvl-oioerazin-1-vl~-
ayrimidin-
2-vl~ethanone.
Me
N~N N~N
\ N~ ~ ~N
Me~~~~ Me Me
OH O
mp: 150-164 °C; 'H NMR (CDCI,, 400 MHz) 8 8.40 (d, 1 H), 8.24 (d,1 H),
6.66 (d, 1 H),
6.37 (d, 1H), 4.74-4.52 (c, 3H), 4.51-4.31 (c, 2H), 4.29 (m, 1H), 3.36 (dd,
2H), 2.69 (s,
3H), 1.51 (d, 3H), 1.27 (d, 6H); MS (APCI) 357 (MH'); [ajo+21.8 (c 1.1, MeOH).


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Example 47 "
1 R-l4-~4-f2-f1 R-Hvdroxv-ethyl)-pvdmidin-4-vll-2R.6R~dimethvl-piaerazin-1-vll-

pyrimidin-2-vi)-ethanol.
Me
N ~ N N~N
\ N ~ N
Me~.,.. Me Me
OH OH
mp: 168-171 °C; 'H NMR (CDCI,, 400 MHz) 8 8.27 (d, 1 H), 823 (d, 1 H),
6:33 (d, 1 H),
6.30 (d, 1 H), 4.78-4.69 (c, 2H), 4.68-4.28 (c, 5H), 3.83-3.69 (c, 2H), 3.54
(m, 1 H), 1.53
(d, 3H), 1.52 (d, 3H), 1.43-1.22 (c, 6H); MS (APCI) 359 (MH'); [acJD+92.2 (c
0.5,
MeOH).
Example 48
1 R-(4-~4-f2-l1 R-Hvdroxv-ethyl)-oyrimidin-4-yll-2S.6S-dimethyl-pioeraZin-1-
vf~-
vvrimidin-2-vl)-ethanol.
Me
N ~ N N '~N
N ~ N
Me~~w Me Me
OH OH
mp: 168-178 °C;'H NMR (CDC1,, 400 MHz) 8 8.26 (d, 1H), 8.23 (d, 1H),
6.32 (d, 1H),
6.29 (d, 1 H), 4.78-4.68 {c, 2H), 4.65.27 (c, 5H), 3.82-3.71 (c, 2H), 3.55 (m,
1 H), 1.52
(d, 3H), 1.51 {d, 3H); 7 .43-1.20 {c, 6H); MS (APCI) 359 (MH'); [aJo- 32.4 (c
0.7,
MeOH).


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~~~~Me
Ar'--X
Example X-Ar' R R' mp (C) MS (MH'~


49 benzoxazol-2-yl (R)-Me (S}-Me 354


50 ~ benzothiazol-2-yl(R}-Me (S}-Me ~ 370


51 oxazofa[4,5-c]pyridin-2-yl(R)-Me (SrMe 355


52 quinoxafin-2-yl (R?-Me H 351


53 quinoxaiin-2-yl (S~Me H ~ 351


54 quinoxalin-2-yl (RrMe (S~Me 365


55 (4.6-dimethyl)- H H 132-133 315


pyrimidin-2-yl


56 (4,6-dimethyl)- (S}-Me H 329


pyrimidin=2-yl


57 (2,6-dimethyl~ H H 125.5-127314


pyrimidin-4-yl


58 (2-hydroxymethyl~ (S~Me H 146-148 331


pyrimidin-4-yl


59 (2-hydroxymethyl}- (R~Me (S~Me 168-171 345


pyrimidin-4-yl


60 (2-hydroxymethyl~- (S)-Me H 345


methyl)-pyrimidin-4-yl


HO
~~~~Me
N_
Ar'-X-N~N ~ / N
~5
Example X A~' mp (°C) MS (MHO
61 ~ ~ (4-hydroxymethyl-6-methy)- 357
Ipyrimidin-2-yl
62 (R ~[2-(1-hydroxy-ethyl)]- 357
pyrimidin-4-yl


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Fxamole 63
1-f4-f4-!2-Acety-avrimidin-4-vl)-2R'.6S'-dimethyl-oiaerazin-1-vll-nvrimidin-2-
vl1-
ethanone. , , , .
Me
N ~ N N~N
\ N ~ N
Me Me Me
' O O ,.
A mixture of 1 S-(4-{4-[2-(1 R-hydrooy-ethyl)-pyrimidin-4-yfJ-2R,6S-dimethyl-
piperazin-
1-yl}-pyrimidin-2-yl)-ethanol (prepared according to the method of Example 42,
1.05 g,
2.93 mmol) and manganese(t~ oxide (5.15 g; 59.3 mmol) in dichloroethane (28
mL)
was heated at reflux for 7 h, and filtered through Celite (hot). The filtrate
was
concentrated and purified by flash column chromatography (Flash 40M~, 5%
methanoUchlorofonn) to give 0.67 g (64%) of the title compound as a white
solid. mp:
>235 °C (dec); 'H NMR (CDCI,, 400 MHz) 8 8.42 (d, 1 H), 8.41 (d, 1 H),
6.68 (d, 1 H),
6.57 (d, 1 H), 4.81.36 (c, 4H), 3.39 (dd, 2H), 2.69, (s, 3H), 2.68 (s,
3H),1.29 (d, 6H);
MS (APC1) 355 (MH').
Examflle 64
1 R-(4-f4-(4-Hydroxymethyf-6-methyl=pyrimidin-2-y1)-3R.5S-dimethyl-pinerazin-1
y1
pyrimidin-2-vl~-ethanol.
Me
N \ ,~N N-
N/
Me~~~~ Me
OH
Step A: 1 R-f4-!4-ltart-Butoxvcarbonvlamino-tert-butoxvcarbonvlimino-methyl)-
3R 5S-
dimethvl-oiperazin-1 v(1-o3nimidin-2-yl~-ethyl butyrrate. To a mixture of 1 R-
[4-(3R,5S-
dimethyl-pipera~in-1-yl~pyrimidin-2-yQ-ethyl butyrate (prepared according to
the
method of~Preparation Three, 10 g, 32.7 mmol), N,N'-bis(tert
butoxyc~rbonyt~hiourea
(8.6 g, 32.7 mmol; Synth: Commun. 1993, 23, 1443), and triethytamine (9.0 mL,
65.4


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mmol) in dimethylfonnamide (1 i 0 mL) at 0 °C was added mercury(II)
chloride (9.8 g,
36.0 mmol). This mixture was stirred overnight with wat~ming to room
temperature,
diluted with ethyl acetate, and washed with water (3x) and brine (1x). The
organic
phase was dried over sodium sulfate, filtered, and evaporated to give 17.9 g
(100%)
of the title compound of Example 64, Step A as a yellow foam. 'H NMR (CDCI3,
300
MHz) S 9.61 (s,1 H), 8.19 (d,1 H), 6.37 (d,1 H), 5.66 (q,1 H), 4.51-4.14 (c,,
4H), 3.36-
3.23 (c, 2H), 2.37 (t, 2H), 1.75-1.60 (c, 2H), 1.55 (d, 3H),1.49 (s, 9H), 1.46
(s, 9H),
1.28 (d, 3H), 1.26 (d, 3H), 0.94 (t, 3H); MS (APCI) 549 (MH').
Step B: 1 R-14-l4-Carbamimidovl-3R.5S-dimethvl-piaerazin-1-vl~-ovrimidin.2-vi1-
ethyl
butyrate trifluoroacetic acid salt. A mixture of fR-{4-(4-(tent-
butoxycarbonylamino~ert-
butoxycarbonylimino-methyl}-3R,5S-dimethyl-piperazin-1-yI]-pyrimidin-2-YI}-
ethyl
butyrate (prepared according to the method of Example 64, Step A,17.9~ g, 32.7
mmol) in a 3:1 rt>ixture of dichloromethaneltriflUoroacetic add (300 mL) was
stirred at
room temperature overnight and concentrated to provide ~36 g of the tifle
compound
of Example 64, Step B as an oil that was used as is. 'H NMR (CD,OD, 400 MHz) 8
8.24 (d, 1 H), 7.25 (d, 1 H), 5.69 (q, 1 H), 4.19-4.10 (c, 4H), 3.79-3.42 (c,
2H), 2.45 (t,
2H), 1.67-1.45 (c, 2H), 1.63 (d, 3H),1.32-1.25 (c, 6H), 0.95 (t, 3H); MS
(APCI) 349
(MH').
Step C: 1 R-f4-f4-f4-Methoxvmethvl-6-methyl-ovrimidin-2-vl1-3R 5S~imethvl-
pioerazin-1-vl1-pvrimidin-2y11-ethanol. A solution of 1 M sodium isopropoxide
in
isopropanol was prepared by adding sodium metal (3.8 g, 160 mmol) to
isopropanol
(160 mL) and heating at reflux until all the metal was consumed. 1 R-[4-(4-
Carbamimidoyl-3R,5S-dimethyl-piperazin-1-yl)-pyrimidin-2-yij-ethyl butyrate
t~ifluoroa~tic add salt (prepared according to the method of Example 64, Step
B,
32.7 mmol theory) was added to the refluxing sodium isopropoxidefisopropanof
solution followed, after 1 h, by 1-methoxy-pentane-2,4-dione (212 8,163 mmol;
J.
Am. Chem. Soc 1944, 22, 2092). After 12 h, another aliquot of sodium
fsopropoxide
(1 M in isopropanol, 65 mL, 65 mmol) was added. After refluxing overnight, the
reaction mixture was cooled to room temperature and diluted with water (100
mL).
lithium hydroxide hydrate (6.9 g, 163 mmol) was added and this mixture was
stirred
for 3 h, concentrated, and extracted with 10% isopropanoUchloroform (3x). The
combined organic extracts were dried over sodium sulfate, filtered,
evaporated, and
purfied by flash column chromatography (1-X2.5% methanoUchlorofonn) to give
10.5


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g (87%, 2 steps) of the title compound of Example 64: Step C as a yellow
solid. 'H
NMR {CDCI,, 400 MHz) 8 8.18 (d, 1H), 6.54 (s, 1H), 6.43 (d, 1H), 5_00.94 (c,
2H),
4.69 (m, 1 H), 4.37-4.34 (c, 2H), 4.33 (s, 2H), 3.45 (s, 3H), 3.29-3.23 (c,
2H), 2.33 (s,
3H), 1.51 (d, 3H),1.20 (s, 6H); MS (APCI) 373 (MH').
Step D: 1 R-f4-t4-(4..Hvdroxvmethvl-6-methyl-bvrimidin-2y11-3R.SS-dimethvl-
piperazin-1-vll-oyrimidin-2-vll-ethanol. To a solution of 1R-{4-[4-(4-
methoxymethyi-6-
methyl-pyrimidin-2-yl~3R,5S-dimethyl-piperazin-1 ylj-pyrimidin-2 yt)~thanol
(prepared according to the method of Example 64, Step C, 8.0 g, 21.5 mmol) in
dichloromethane (150 mL) at 0 °C was added boron tribromide (1 M in
i 0 dichloromethane, 64.3 mL, 64.3 mmol). This mixture was stirred overnight
with
warming to room temperature and quenched by careful addition of saturated
aqueous
sodium bicart~onate. The layers were separated and the aqueous phase was
extracted with 10% isopropanoUchloroform (3x). The combined organic extracts
were
washed with brine (ix), dried over sodium sulfate, filtered, and evaporated.
The
resulting solid was refluxed in ethyl acetate and filtered (hot). This
procedure was
repeated and the combined filtrates were concentrated to a minimal volume.
After
standing at room temperature overnight, a tan solid was collected by
filtration. The
resulting filtrate was again allowed to stand at room temperature overnight to
yield an
additional crop of the desired product to give all together 6.0 g (78%) of the
frtie
compound as a tan solid. mp: 149-151 °C;'H NMR (CDCI,, 400 MHz) b 8.19
(d, 1H),
6.45 (d, 1 H), 6.32 (s, 1 H), 5.02-4.96 (c, 2H), 4.71 (q, 1 H), 4.53 (s, 2H),
4.50r4.23 (c,
2H), 3.31-3.25 (c, 2H), 2.33 (s, 3H), 1.51 (d, 3H), 1.23 (s, 6H); MS (APCI)
359 (MH');
[ocj~+18.9 (c 1.1, MeOH).
Examples 65 to 74
Examples 65 to 74 were prepared from the appropriate starting materials in a
manner
analogous to the method of Example 64.


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Exarrroie 65
lR?-1-~4-f4-(4-Hvdroxvmethvl-6-methyl-pvrimidin-2-vl)-cioerazin-1-vI1-
pvrimidin-2-vl~-
ethanol.
Me
N-
N
Me~~~
OH
mp: 139-140 °C; 'H NMR (CDCi,, 300 MHz) 8 8:21 (d, 1 H), 6.41 (d, 7 H),
6.37 (s, 1 H),
4.71 (m, 1 H), 4.54 (s, 2H), 4.32 (d, 1 H), 4.02-3.93 (c, 4H), 3.7&3.68 (c,
4H), 3.65 (b~
s, t H), 2.34 (s, 3H), 1.19 (d, 3H); MS (TS) 331 (MH'); [aj~ +21.6 (c 2.0,
M,eOH).
Example 66
1R-(4-f4-14.6-Dimethvl-pvrimidin-2-vil-3R.5S-dimethvl-ninerazin-1-vll-
avtimidin-2 v!1
ethanol.
Me~~~
mp: 141.5-142.5 °C; 'H NMR (CDCI,, 400 MHz) b 8.17 (d, 1 H), 6.43 (d, 1
H), 6.28 (s,
1 H), 5.03.97 (c, 2H), 4.70 (q,1 H), 4,44.18 (c, 2H), 3.32-3.20 (c, 2H), 2.27
(s, 6H),
1.50 (d, 3H), 1.20 (d, 6H); MS (APCI) 343 (MH'); jaJ~ +19.2 (c 1.1, MeOH).
18 Example 67
1 R-14-t4-l4-Methoxvmethvl-6-methyl-amimidin-2-vl~3R.5S-dimethyl-nioerazin-1
vt1-
ovn'~idin-2-v11-ethanol.
Me~~~
OH


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'H NMR (CDCl3, 400 MHz) b 8.18.(d, 1H), 6.55 (s, 1H), 6:43 (d, 1,H), 5.02-4.9~
(c, 2H),
4.69 (m, 1 H), 4.43-4:20 (c, 2H), 4.36 (d,1 H), 4.33 (s, 2H). 3.46 (s, 3H),
3.30-3.21 (c,
2H), 2.34 (s, 3H), 1.51 (d; 3H), 1.20 (d, 6H); MS (APCI) 373 (MH'); (a]o +16.0
(c 0.9,
MeOH). , ~~ ,
Example 68
1 R-~4-f4-l4-Hvdroxvmethvl-6-methyl-avrimidin-2-yl)-3R-meth~rl-oinerazin-1 vll-
.
p~rrimidin-2-vl~-ethanol.
Me~~~
' H NMR (CDCl3, 400 MHz) S 8. ~ 7 (d,1 H), 6.36 (d, 1 H), 6.32 (s, 1 H), 4.98
(m, 1 H),
4.69 (q, 1 H), 4.58 (dt, 1 H), 4.51 (s, 2H), 4.37-4.11 (c, 3H), 3.62 (br s, 1
H), 3.48-3.36
(c, 2H), 3.18 (td, 1 H), 2.31 (s, 3H), 1.49 (d, 3H),1.17 (s, 3H); MS (APC!)
359 (MH');
[a]o -40.6 (c 1.0, MeOH).
Examole~9
1R-f4-f4-(4-Hvdroxvmethyl-6-meth~midin-2-v(1-3S-methyl-oioerazin-1
Dyrimidin-2,rll-ethanol.
Me""
'H NMR (CDC13, 400 MHz) 8 8.17 (d,1 H), 6.36 (d,1 H), 6.33 (s,1 H), 4.99 (m,1
H),
4.69 (q, 1 H), 4.58 (m,1 H), 4.52 (s, 2H), 4.40-4.i 1 (c, 3H), 3.60 (br s, 1
H), 3.45-3.34
(c, 2H), 3.19 (td;1 H), 2.32 (s, 3H),1.49 (d, 3H),1.16 (s, 3H); MS (APCI) 359
(MH');
[a]Q +68.1 (c 0.7; MeOH).


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R'2 ~ ..,. Me
R'
i N~N~N~ ~
6
R" R6
Example R" R'~ R' R mp (C) MS (MH')


70 H OH 3R-Me SS-Me 331


71 Me OH 3R-Me 5S-Me 231-232 ~ 345


72 Ph OH 3R-Me 5S-Me 407


73 Me ethoxymethyl3R-Me 5S-Me 387


74 Me ethoxymethyl2R-Me 6S-Me 106-108 ~ 387


Example 75
fR)-5-f2-(1-Hvdroxv~thvll-ovrimidin~-vtl-1-methyl-2-giuinoxafin-2-vl-1 2 4 5 6
7-
hexah~rdro-nvrazolof4.3-clovddin-3-one.
N
N
Me~~~
OH
Step A: 3-Oxo-2-ouinoxalin-2 vl-1.2.3.4.6,7fiexat~,ydro-pvrazolof4 3-c]pmidine-
5-
carboxylic aad tert-b ester. To a solution of 4-oxo-piperidine-1,3-
dicartioxylic acid
1-tert-butyl ester 3-ethyl ester (500 mg,1.84 mmol; Tebahedron 1994, 50, 515)
in
toluene (i0 mL) was added quinoxalin-2-ylfiydrazine (295 mg, 1.85 mmol;
Hefenxycles 9985, 23, 2603). This mixture was stirred at refiux overnight,
cooled to
room temperature, concentrated, and purified by flash column chromatography
(25-X75% ethyl acetatelhexanes) to give 600 mg (89°~) of the title
compound of
Example 75, Step A as a tight orange solid. 'H NMR (CDCI,, 250 MHz, 5:1
mixture of
tautomers) b 11:94 (br s, 0.83H), 10.16 (s, 0.17H), 9.57 (s, 0.83H), 8.13 (dd,
1 H),
7.91-7.69 (c, 3H), 4.45 (s, 1.66H), 4.33 (s, 0.34H), 3.79-3.72 (c, 2H), 282-
2.72 (c,
2H), 1.52 (s, 9H); MS (APCI) 368 (MH').


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Step B: 1-Methyl-3-oxo-2-auinoxalin-2~t-1.2.3.4.6.7-hexahvdro-nyrazolof4.3- ,
,
clovridine-5-carboxylic acid tert-b~yt I ester. To a solution of 3-oxo-2-
quinoxalin-2-yl-
1,2,3,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl
ester
(prepared according to the method of Example 75; Step.A, 250 mg, 0.68 mmol) in
dimethylfom~amide (2 mL) at 0 °C with stirring under nitrogen was added
sodium
hydride (60% dispersion in mineral oil, 41 mg,1.02 mmol). After 10 min,
ipdomethane
(51 NL, 0.82 mmol) was added. This mixture was allowed to stir at 0 °C
for 2 h,
quenched by addition of saturated aqueous sodium bicarbonate and extracted
with
ethyl acetate (4x). The combined organic extracts were dried over sodium
sulfate,
t0 filtered, evaporated, and purified by flash column chromatography (40%
ethyl
acetatelhexanes) to give 164 mg (63%) of the title compound of Example 75,
Step B
as a yellow foam. 'H NMR (CDCI,, 250 MHz) 8 9.71 (s, 1 H), 8.15 (dd, 1
H),.8.02 (m,
1 H), 7.80-7.70 (c, 2H), 4.29 (s, 2H), 4.74 (t, 2H), 3.79 (s, 3H), 2.72-2.67
(c, 2H),1.50
(s, 9H); MS (APCI) 382 (MH').
Step C: 1-Methvt-2-auinoxalin-2 yl-1.2.4.5.6.7-hexahvdro-ovrazolot4 3-
clovridin-3-
one hydrochloride. To a solution of 1-methyl-3-oxo-2-quinoxalin-2-
yh1,2,3,4,6,7-
hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylic aad tart butyl ester (prepared
according to the method of Example 75, Step B, 27, 9 mg, 0.73 mmol) in
methanol (6
mL) was added hydrogen chloride (5.85 M in methanol, 1.25 mL, 7.3 mmol). This
mixture was heated at 60 °C for 30 min, cooled to room temperature, and
concentrated to give 249 mg (>100%) of the title compound of Example 75, Step
C as
a dark red solid. 'H NMR (CD,OD, 250 MHz) S 9.45 (s, 1 H), 8.13 (dd, 1 H),
8.05 (m,
1 H), T.9i-7.83 (c, 2H), 4.05 (s, 2H), 3.64 (t, 2H), 3.56 (s, 3H), 3.12 (t,
2H); MS (APCI)
282 (MH').
Step O: (Rl-1-f4-l1-Methyl-3-oxo-2-auinoxalin-2-vl-1.2.3.4.6.7-hexa~dro-
oyrazolof4.3-clovridin-5-vl~ovrimidin-2-v(I~thvl butyrate. To a stirred
solution of 1-
methyl-2-quinoxalin-2-yl-1,2,4,5,6,7fiexahydro-pyrazolo[4,3-cjpyridin-3-one
hydrochloride (prepared according to the method of Example 75, Step C,175 mg,
0.55 nunol) and (R~1-(4-chloro-pyrimidin-2-ylj-ethyl butyrate (prepared
aooording to
the method of Preparation Seven,126 mg, 0.55 mmol) in isopropanol (6 mL) was
added triethylamine (230 NL, 1.66 mmol). This mixture was heated to reflux
overnight,
cooled to room temperature, and evaporated. The residue was diluted with
saturated
aqueous sodium bicarbonate and extracted with chloroform (3x). The dined


CA 02484282 2000-03-16
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organic extracts were dried over sodium sulfate, filtered, evaporated, and
purified by
flash column chromatography (1.5% methanoUchloroform) to give 248 mg (95%) of
the title compound of Example 75, Step D as a yellow oil.'H NMR (CDCI3, 250
MHz) b
9.70 (s, 1 H), 8.29 (d,1 H), 8.15 (dd, 1 H), 8.03 (m, '! H), 7.82-7.70 (c,
2H), 6.48 (d, 1 H)
5.72 (q, 1 H), 4.36 (s, 2H), 4.35-4.15 (c, 2H), 3.42 (s, 3H), 2.77-2.82 (c,
2H), 2.43 (t,
2H), 1.79-1.60 (c, 2H),1.61 (d, 3H)', 0.99 (t, 3H); MS (APCI) 474 (MH'). '
Step E: (R1-5-l2-l1-Hydroxv-ethyl)-dvrimidin-4-v11-1-meth~~l-2-auinoxalin-2-vl-

1.2.4.5.6.7-hexahydro-ovrazolpJ4.3-clgyridin-3-one. To a solution of (R)-1-[4-
(1-
methyl-3-oxo-2-quinoxalin-2-yl-1,2,3,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-
yl}-
pyrimidin-2-y~-ethyl butyrate (prepan:d according to the method of Example 75,
Step
D, 248 mg, 0.52 mmot) in a 52 mixture of methanoUtetrahydrofucan (7 mL) was
added
potassium carbonate (218 mg,1.57 mmol). This mixture was stirred at 'room
temperature overnight and evaporated. The residue was diluted with saturated
aqueous sodium bicarbonate and extracted with chloroform (3x). The combined
organic extracts were dried over sodium sulfate, filtered, evaporated, and
purified by
flash column chromatography (1.5-.~3% methanol/chloroform) to give 150 mg
(71%)
of the title compound as a white solid. mp: 217-219 °C (dec);'H NMR
(CDCI,, 250
MHz) b 9.66 (s,1 H), 825 (d,1 H), 8.12 (dd,1 H), 7.99 (m,1 H), 7.68-7.78 (c,
2H), 6.47
(d, 1H), 4.72 (q, 12H), 4.32 (s, 2H), 4.19-4.14 (c, 3H), 3.4.1 (s, 3H), 2.80
(t, 2H), 1.51
(d, 3H); MS (APCt) 404 (MH'); [a]o +13.4 (c 1.5, CHCI3).
Examoies 76 and 77
Examples 76 and 77 were prepared from the approprtate starting n-iaterials in
a
manner analogous to the method of Example 75.
HO
R ~N~B ....Me
N-
A
~N
Example A R" B mp (C) MS (MH')


76 ~ N-Me benzothiazol-2-ylCO 176-778 4pg


77 . CO quinoxalin-2-ylN-Me 201-204 (dec)404




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~xamole 78 '
LRl-6-Chloro-1'-12-l1-hvdroxy-ettwl)-flvrimidin-4-v(1-sairofchroman-2.4'-
pioeridinl-4-
one.
Me~
Step A: 6-Chloro-soiro[chroman-2.4'-pperidin)~-one hvdrochforide. To a
solution of
1'-benzyl-6-chloro-spiro[chroman-2,4'-piperidinJ-4-one (300 mg, 0.88 mmol,
Chem.
Pharm. Bull. 1981, 29, 3494) in acetone (5 mL) at 0 °C was added 1-
chtoroethyl
chloroformate (0.29 mL, 2.64 mmol). This mixture was warmed to room
temperature,
stirred overnight, and concentrated. The residue was purified by flash column
chromatography {10-X20% ethyl acetatelhexanes) to give the intermediate
carbamate
which was refluxed in methanol (3 mL) for 1 h. Evaporation of the reaction
mbchne
provided 149 mg (59%) of the tifle compound of Example 78, Step A as a
colorless
solid. 'H NMR (CD,OD, 250 MHz) S 7.77 (d,1 H), 7.58 (dd,1 H), 7.15 (d,1 H),
3.33
(buried, 4H), 2.90 (s, 2H), 2.46-2.20 (c, 2H), 2.04-1.81 (c, 2H); MS (APCI)
252, 254
(MH').
Step B:1Rl-1'-(2-l1-Butvrvloxv-ethvl~ovrtmidin-4-v11-6-chloro-sDirolchroman-2
4'-
oioeridinl~-one. To a solution of 6-chforo-spiro[chroman-2,4'-piperidin]-4-one
hydrochloride (prepared according to the method of Example 78, Step A, 175 mg,
.
0.61 mmol) in isopropanol (5 mL) was added {R~1-(4-chloro-pyrimidin-2-ytrethyl
butyrate (prepared according to the method of Preparation Seven, 160 mg, 0.70
mmol) followed by triethylamine (029 mL, 2.1 mmot). This mixture was stirred
at
reflex for 1.5 h, concentrated, and purified by flash column chromatography (1
methanoUchlorofonn) to give 270 mg (100%) of the title compound of Example 78,
Step 8 as a yeElow oil. 'H NMR (CDCI,, 400 MHz) S 8.19 (d, 1 H), 7.83 (d, 1
H), T.44
(dd,1 H), 6.97 (d, ~ H), 6.37 (d,1 H), 5.64 (q,1 H), 4.18 (app s, 2H), 3.34
(t, 2H), 272
(s, 2H), 2.37 (t, 2H), 2.10 (d, 2H),1.71-1.60 (c, 4H),1.55 (d, 3H), 0.94 (t,
3H); MS
(APCI) 444, 446 (MH').


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Step C: LR~-6-Chioro-1'-f2-(1-hvdroxv-ethv(~vvrimidin-4-v!1-svirofchroman-2.4'-
',
pper?dinl-4-one. A mixture of (R)-1'-[2-(1-butyryloxy-ethyl)-pyrimidin-4-yi}-6-
chloro-
spiro[chroman-2,4'-piperidin]-4-one (prepared according to the method of
F~cample
78, Step B, 270 mg, 0.61 mmol) and lithium hydroxide hydrate (80 mg, 1.83
mmol) in
a 3:1:1 mixture of tetrahydrofuraNmetharioUwater (5 mL) was stirred at room
temperature for 1.5 h. The organic solvents were evaporated and the residue
was
extracted with chloroform (4x). The combined organic extracts were dried over
sodium sulfate, filtered, evaporated, and purified by flash column
chromatography
(ethyl acetate) to give 41 mg (18%) of the title compound as a reddish foam.
'H NMR
(CDCt,, 300 MHz) 8 8.19 (d, 1 H), 7.82 (d, 1 H), 7.44 (dd, 1 H), 6.96 (d, t
H), 6.40 (d,
1 H), 4.65 (q, 1 H), 4.20 (app s, 2H), 3.42-3.32 (c,,2H), 2.73 (s, 2H), 2.14
(d; 2H),1.67
(td, 2H), 1.48 (d, 3H); MS (APCI) 374, 376 (MH'); [a]p +12.6 (c 0.5, MeQH).
Exam~~les 79 to 85
Examples 79 to 85 were prepared from the appropriate starting materials in a
manner
analogous to the method of Example 78.
HO
~~~~Me
s
N._
Rs~
IN
Example R'~ R" D mp (C) MS (MH')


79 6-Ph H CH2 402


80 6-Ph H CHOH 418


81 6-Ph H CO 416


82 6-0Me H CO 156.5-157.5 370


83 7-Br H CO 418,420


84 5-CI 6-Ct CO 408,410


85 6-OMe 7-OMe CO 400




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Examn~, 86
~Rl-1-f4-l2-Methyl-4-phenyl-5.8-dihvdro-6H-ovridof3.4-dlovrimidin-7-yl)-
oyrimidin-2-
I -eth ol.
N
Me~~~~~
Step A: 7-Benzvl-2-methyl-5.6.7.8-tetrahvdro-3H-ovridof3.4-dloyrimidin-4-one.
A
solution of sodium ethoxide in ethanol was prepared by addition of sodium
metal (5.7
g, 247 mmol) to absolute ethanol (141 mL). After the sodium metal had all
dissolved,
ethyl 1-benzy!-3-oxo-4-piperidine carboxytate hydrochloride (21 g, 70.5 mmol)
was
added followed by acetamidine hydrochloride (13.3 g, 141 mmol). This mixture
was
stirred at reflex for 1 h, cooled to room temperature, and concentrated. The
residue
was dissolved in a minimum amount of water and the pH was adjusted to about 7
with
glaaal acetic aad. The resulting yellow preapitate was filtered, washed with
water
(3x), air-dried for 2 h, then vacuum-dried overnight to provide 17.1 g (95%)
of the tifle
compound of F~cample 86, Step A as a yellow solid. 'H NMR (CDCI,, 250 MHz) 8
7.35-7.25 (c, SH), 3.70 (s, 2H), 3.42 (s, 2H), 2.73-2.64 (c, 2H), 2.64-2.60
(c, 2H), 2.41
(s, 3H); MS (APCI) 256 (MH').
Step B: 7-Benzvl~-chloro-2-methyl-5.8-dihvdro-6H-pvrfdof3.4-dlovrimidine. 7-
Benzyl-2-methyl-5,6,7.8-tetrahydro-3H-pyrido[3,4-djpyrimidin-4-one (prepared
according to the method of Example 86, Step A,17.1 g, 67.0 mmol) was suspended
in
phosphorus oxychloride (66 mL, 335 mmol). This mixture was stirred at reflex
for 1 h,
pooled to room temperature, evaporated, then chased with toluene. The residue
was
carefully diluted with ice/wateNchloroform and the layers were separated. The
aqueous phase was extracted with chloroform (3x) and the combined organic
extracts
were washed with saturated aqueous sodium bicarbonate (1x) and water (1x),
dried
over sodium sulfate, filtered, and evaporated to give the title compound of
Example
86, Step B as a brown oil that was used without purfication in the next step.:
'H NMR


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(CDCI,, 250 MHz) S 7.36-7.23 (c, 5H), 3.73 (s, 2H), 3.63 (s, 2H), 2.63 (app s,
4H),
2.36 (s, 3H); MS (APCI) 274, 276 (MH').
Step C: 7-Benzvl-2-methyl-4-phenyl-5.8-dihydro-6H-oyrid~3.4-dlovrimidine. To a
suspension of 1,4-diphenylphosphinobutane (1.43, g, 3.35 mmol) in toluene (50
mL)
was added bis(benzonitrile)palladium(II) chloride (1.28 g, 3.35 mmol). This
mixture
was stirred for 25 min at room temperature, then was added to a suspension of
7-
benzyl-4-chioro-2-methyl-5,8-dihydro-6H-pyrido[3,4-djpyrimidine (prepared
according
to the method of Example 86, Step B, 67.0 mmol, assumed) and phenylboronic
acid
(10.6 g, 87.1 mmol) in a mixture of absolute ethanol (40 mL), toluene (175,
mL), and 2
N aqueous sodium carbonate (33.5 mL). This mixture was stirred at reflux for
6.5 h,
cooled to room temperature and stirred for --2.5 d, then filtered through a.
pad of
Celite. The filtrate was concentrated and the residue was diluted with water
and
extracted with chloroform (3x). The combined organic extracts were dried over
sodium sulfate, filtered, evaporated, and purified by flash column
chromatography
(4550% ethyl acetate/hexanes) to give 16.5 g (78%, two steps) of the title
compound of Example 86, Step C as a yellow oil. 'H NMR (CDCI,, 250 MHz) 8 7.57-

7.54 (c, 2H), 7.48-7.24 (c, 8H), 3.71 (app s, 4H), 2.85 (t, 2H), 2.71-2.67 (c,
2H), 2.69
(s, 3H); MS (APCI) 316 (MH').
Step D: 2-Methyl-4-ohenvl-5.8-dihvdnr6H-oyridof3.4-dlovrimidine. 7-Benzyl-2-
methyl-4-phenyl-5,8-dihydro-6H-pyrido[3,4-djpyrimidine hydrochloride was
fom~ed in
situ by addition of hydrogen chloride (1.9 M in methanol, 31.1 mL, 51.1 mmol)
to a
solution of 7-benzyl-2-methyl-4-phenyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine
(prepared according to the method of Example 86, Step C, 16.5 g, 522 mmol) in
methanol (75 mL). After sorting 10 min at room temperature; a preapitate
fom~ed,
and another aliquot of methanol (100 mL) was added to obtain a homogeneous
solution. To this mixture was added a siuny of 10% palladium on carbon (3.3 g,
20
wl%) in methanol followed by ammonium fomiate (16.5 g, 261 mmol). This mixture
was stirred at retlux for 5 h, cooled to room temperature, and filtered
through Celite.
The filtrate was evaporated, diluted with saturated aqueous sodium
bicarbonate, and
extracted with chloroform (3x). The combined organic extracts wen: dried over
sodium sulfate, filtered, evaporated, and purified by flash column
chromatography (3%
methanoUchloroform + 1 % ammonium hydroxide) to give 6.7 g (57%) o~ the Frtle
compound of Example 86, Step D as an off~nrhite solid and 2.4 g (19%) of 7-
fomryl-2-


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methyl-4-phenyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine as a yellow gum.
Treatment
of the 7-formyl byproduct with methanalic hydrogen chloride at room
temperature
overnight followed by aqueous workup and column chromatography provided an
additional 1.4 g (12%) of the title compound of Example 86, Step D. 'H NMR
(CDCt,,
250 Mtiz) b 7.55-7.40 (c, 5H), 4.09 (s, 2H), 3.05 (t, 2H); 2.75 (t, 2H), 2.79
(s, 3H); MS
(APCt) 226 (MH').
Step E: fR)-1-1'4-(2-Methyl-4-phenyl-5.8-dihvdro-6H-avrido(3.4-dlpvrimidin-7
vl~
eyrimidin-2-yll-ethyl butt irate. To a solution of 2-methyl-4-phenyl-
5,8~iihydn~..6H-
pyrido[3,4-djpyrimidine (prepared according to the method of Example 86, Step
D, 6.8
g, 30.0 mmol) in isopropanol (125 mL) was added (R~1-(4-chioro-pyrimidin-2-
yl~thyl
butyrate (prepared according to the method of Preparation Seven. 6.8 g, 30
mmoi)
followed by triethylamine (12.5 mL, 89.9 mmol). This mixture was stirred at
reflux for
8 h, cooled to room temperature overnight, and evaporated. The residue was
diluted
with saturated aqueous sodium bicarbonate and extracted with ethyl acetate
(3x).
The combined organic extracts were dried over sodium sulfate, filtered,
evaporated,
and purified by flash column chromatography (2% methanoUethyl acetate) to give
11.0 g (88%) of the title compound of Example 86, Step E, as a yellow oil. 'N
NMR
(CDCI,, 250 MHz) 8 8.28 (d, 1 H), 7.62-7.40 (c, 5H), 6.45 (d,1 H), 5.69 (q,1
H), 4.78 (s,
2H), 3.93 (app s, 2H), 2.95 (t, 2H), 2.77 (s, 3H), 2.40 (t, 2H),1.?7-1.63 (c,
2H), 1.60 (d,
3H), 0.98 (t, 3H); MS (APCI) 418 (MH').
Step !_: ~Rl-1~t4-!2-Methyl-4-r~henvl 5 8-dihvdro-6H-oyridoL3 4-d~ovrimidin-7
yll~
py~imidin-2-vtl-ethanol. To a solution of (R~1-[4-(2-methyl-phenyl-5,8-dihydro-
6H-
pyrido[3,4-d]pyrimidin-7-yl)-pyrimidin-2-yt]-ethyl butyrate (prepared
according to the
method of Example 86, Step E. 11.0 g, 26.4 mmol) in dioxane (13 mL) was added
concentrated hydrochloric aad (22 mL, 264 mmol). This rriodure was stirred at
room
temperature overnight, cooled to 0 °C, neutralized via slow addition of
6 N aqueous
sodium hydroxide, and extracted with ethyl acetate (4x). The combined organic
extracts were dried over sodium sulfate, filtered, evaporated, and purified by
flash
column chromatography (2-~5% methanoUethyl acetate) to give an oil which after
filtration with hexanes provided 8.0 g (88%) of the title compound as a white
solid.
mp:114-116 °C;~'H NMR (CD,OD, 250 MHz) 8 8.26 (d,1H), 7.62 7.47 (c,
5H), 6.52
(d,1H), 4.79 (s, 2H), 4.66 (q, 1 H), 424 (br s, 9 H), 3.90-3.80 (c, 2H), 295
(t, 2H), 270
(s, 3H),1.49 (d, 3H); MS (APCI) 348 (MH'), [ajp +15.6 (c 1.0, MeOH).

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E~camnles 87 to_ 100 '
Examples 87 to 100 were prepared from the appropriate starting' materials in a
manner analogous to the method of Example 86.
Me
Example R~' R~' mp (C) MS (MH'~


87 H Ph 72 74


88 Ph H ~ 334


89 Ph Et ' 362


90 Ph NH2 225-228 (dec) 349


91 Ph Ph 73-?5 410


92 Ph 4-pyridy! 411


93 (4-OMe)Ph Me 62-64 378


94 (4-t7Ph Me 55-58 366


95 (4-Ct)Ph H 368, 370


96 OMe Me 302


97 OPh Me 156-158 364


98 SPh Me 103-105 380


99 N-indolinyfMe 128-131 38g


100 NMez Et 329


Example 101
~4-f2-(1 R-Hvdroxv~thvl~ovrimidin-4-y~f -2R 6S-dimethvl oioerazin-1~r(~-(2-
ohenvl-7 8-
dihydro-SH-ovridot4.3-dipvrimidin~-vl~methanone.


CA 02484282 2000-03-16
wo oors9sio
-~ s3-
M
Step A: 4-0xo-oioeridine-1-carboxvlic.aad tert-butyl ester. A mixture of 4-
piperidone
monohydrate hydrochloride (9.22 g; 60 mmoi) and di-tert-butyl Bicarbonate,
(10.9 g, 50
mmol) in a 1:1 mixture of dichloromethane/saturated aqueous sodium bicarbonate
(100 mL) was stirred at room temperature for 15.5 h. The layers were separated
and
the aqueous layer was extracted with chloroform (3x). The combined organic
extracts
were washed with 1 N aqueous phosphoric acid (3x), dried over sodium sulfate,
filtered, and evaporated to give 10.0 g (100%) of the title compound of
Example 101,
Step A as a white solid. 'H NMR (CDCl3, 400 MHz) 8 3.70 (t, 4H), 2:42 (t,
4H),1.47
(s, 9H).
Step B: 3-Dimethvlaminomethvlene~4-oxo-oioeridine-1-carboxylic add tert-by~l
ester. To a solution of 4-oxo-piperidine-1-carboxylic acid tart-butyl ester
(prepared
acxording to the method of Example 101, Step A, 4.0 g, 20.0 mmo!) in
dimethyfformamide (40 mL) was added tart-butoxybis(dimethylamino)methane (4.35
mL, 22 mmol). This rriucture was stirred at reflex for 15 h, cooled to room
temperature,
diluted with water, and extracted with ethyl acetate (Sx). The combined
organic
extracts were washed with water (3x) and brine (1 x), drted over sodium
sulfate,
filtered, and evaporated to give 3.64 g (72%) of the title compound of Example
101,
Step B as a brown oil that was suffiaentfy pure to carry on to the next step.
'H NMR
(CDCI,, 400 MHz) S 7.47 (s,1 H), 4.53 (s, 2H), 3.58 (t, 2H), 3.09 (s, 6H),
2.43 (t, 2H),
1.46 (s, 9H); MS (APCI) 255 (MH').
Step C: 2-Phenyl-7 8~iihvdro-SH-ovrido(4 3-dlpvrimidine-6-carboxylic acid tart-
buhrl
ester. A rriucture of 3~imethylaminomethylene-4~xo-piperidine-1-carboxylic aad
tert-
butyl ester (preRared according to the method of Example 101, Step B, 509 mg,
2.0
mmol), benzamidine hydrochloride hydrate (470 mg, 3.0 mmol), and sodium
ethoxide
(1 M in ethanol, 6.0 mL, 6.0 mmol) in,absolute ethanol (4 mL) was heated to
reflex for
about 3 d, cooled to room temperature, and concentrated. The residue was
diluted


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with saturated aqueous sodium bicarbonate and extracted with chloroform (3x).
The
combined organic extracts were dried over sodium suffate, filtered,
evaporated, and
purified by flash column chromatography (Biotage Flash 40S"', 1015% ethyl
acetatelhexanes) to give 304 mg (49%) of the title compound of Example 101,
Step C
as a yellow oil. 'H NMR {CDCI3, 400 MHzj S $.52 (s, 1 H), 8.40-8.38 (c, 2H),
7.50-7.44
(c, 3H), 4.62 (s, 2H), 3.78 (t, 2H) 3.02 (t, 2H),1.50 (s, 9H); MS (APCt) 312
(MH').
Step D: 2-Phenv(-7.8-dihvdro-SH-ovridof4.3-d~pvrimidine hydrochloride. To a
sotution
of 2-phenyl-7,8-dihydro-SH-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-
butyl ester
(prepared according to the method of Example 101, Step C, 304 mg, 0.98, mmol)
in
ethyl acetate (2 mL) was added hydrogen chloride (2.5 M in ethyl acetate, 3.9
mL,
9.76 mmol). This mixture was stirred at room temperature far 16 h and
concentrated
to give 256 mg (>100%) of the title compound of Example 101, Step D es a pale
yellow solid. 'H NMR (CD,OD, 400 MHz) 8 8.75 (s, 1 H), 8.42-8.38 (c, 2H), 7.57-
7.45
(c, 3H), 4.48 (s, 2H), 3.68 (t, 2H) 3.35-3.25 (buried, 2H); MS (APCI) 212
(MH').
Step E: 1 R-f4-(4-Chlorocarbonvt-3R.5S-dimethvl_piperazin-1 vt)-ovrimidin-2-
vll-ethv!
butyrate. To a solution of 1 R-[4-(3R,5S-dimethyl-piperazin-1 yl)-pyrimidin-2-
yI]~thyl
butyrate (prepared according to the method of Preparation Three, 1.36 g, 4.44
mmol)
in dichloromethane (22 mL) at 0°C under nitrogen was added pyridine
(0.36 mL, 4.44
nunol) followed by triphosgene (883 mg, 2.97 mmol). This mixture was stirred
with
wamung to room temperature for 1.5 h and quenched with saturated aqueous
sodium
bicarbonate. The layers were separated and the aqueous phase was extracted
with
chloroform (3x). The combined organic extracts were dried over sodium sulfate,
filtered, evaporated, and purified by flash column chromatography (1.-
~2°~
methanoUchloroform) to give 1.59 g (97%) of the title compound of Example 101,
Step
E as a brown oil. 'H NMR (CDCI,, 400 MHz) 8 8.23 (d,1 H), 6.39 (d,1 H), 5.66
(q, 1 H),
4.54-4.47 (c, 2H), 4.35 (m,1 H), 4.25 (m,1 H), 3.20 (dt, 2H), 2.38 (t,
2H),1.72-1.62 (c,
2H),1.5fi (d, 3H),1.31 (d, 3H),1.30 (d, 3H), 0.95 (t, 3H); MS (APCI) 369, 371
(MH').
Step I=: f4-f2-(1 R-Hvdroxv-ethvl~vrimidin~yl~-2R 6S~iimethvl oioer~rn 1 v11~2
phenyl-7.8-dihvdro-SH-ovridof4.3~ilovrimidin-6 vl~methanone. A mixture of 2-
phenyl-
7,8-dihydro-SH=pyrido[4,3-djpyrimidine hydrochloride (prepared according to
the
method of Example 101, Step D,160 mg, 0.65 mmol),1 R-[4-(4-chlorocarbonyl-
3R,5S-dimethyl-p'~perazin-1-ylj-pyrimidin-2-yl~ethyl butyrate (prepared
according to
the method of Example 101, Step E, 200 mg, 0.54 mmol), and triethylamine (0.19
mL,


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1.36 mmol) in tetrahydrofuran (5 mL) was stirred at reflux for 3 h; cooled to
room
temperature overnight, and concentrated. The residue'was diluted with a 4:1
mixture
of methanoUwater (5 mL) and lithium hydroxide hydrate (114 mg, 2.71 mmol) was
added. This mixture was stirred for 2.5 h, .concentrated; and partitioned
between
saturated aqueous sodium bicarbonate and chtorofortn. The layers were
separated
and the aqueous phase was extracted with 20% isopropanoUchioroform (3x). The
combined organic extracts were dried over sodium sulfate, filtered,
evaporated, and
purified by flash column chromatography (2-.>5% methanollchloroform) to give
183
mg (71%) the title compound as a white foam.'H NMR (CDCI9, 400 MHz) 88.56 (s,
1 H), 8.41-8.39 (c, 2H), 8.20 (d,1 H), 7.50-7.46 (c, 3H), 6.38 (d, 1 H), 4.71
(s, 2H), 4.69
(m, 1 H), 4.28 (d, 1 H), 3.89 (t, 2H) 3.83 (d, 2H), 3.60-3.56 (c, 2H), 3.46-
3.39 (c, 2H),
3.09 (t, 2H), 1.50 (d, 3H), 1.18 (d, 6H); MS (APCI) 212 (MH'); [cz]p +6.i
(c"1.8, CHCh).
Exam~fes 102 to 110
Examples 102 to 110 were prepared from the appropriate starting materials in a
manner analogous to the method of Example 101.


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NO
R,e .,... Mg
O z $ N-
~N " N ~ / N
zz
R N
Rz,. R,a ,
Example R~ Rz' R" R'° mp (°C) MS (MH')
i02 quinolin-2-yl H 3R-Me 5S-Me 772-174:5 407
103 quinolin-3-yl H 2R-Me 6S-Me . 4p7
104 quinolin-4-yl H 3R-Me 5S-Me 407
105 quinolin-6-yl H 3R-Me 5S-Me 4p7
106 pyridin-3-yl- pyridin-3-2R-Me 6S-Me . ' 462
methyl y!-methyl


Example NR='R~ R" R" mp (C) MS (MHO


107 2-amino-7,8-dihydro-SH-2R-Me 6S-Me 225=228 413


pyrido[4,3-dJpyrimidin-6-yl


108 2-(1-hydroxy-1-methyl-2R-Me 6S-Me 4~


ethyl}-7.8~ihydro-5H-


pyiid~[4,3-dJpyrimidin-6-yl


109 5,7-dihydro- 2R-Me 6S-Me 458


dibenzo[c.e]azepin-6-yl


110 4-[2-{1 R-hydroxy-ethyl)-3R-Me 5S-Me 499


pyrimidin-4-ylJ-3R,5S-


dimethyl-piperazin-1-yl


Example 111
(E?-1 R-f4-f4-l2-Phenvl-ethenesulfonvl~-oit~erazin-1-vfl-nyrirnidin-2-vl~-
ethanol.
HO
....Me
N-
~ si, ~ N
II ~ ~ /
0


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Step A: (E)-1 R-f4-t4-f2-Phenyl-ethenesulfonvl)-oiperazin-1-vtlwrimidin-2-vlf-
ethyl
acetate. To a solution of (R~1-[4-piperazin-1-ytrpyrimidin-2-yl)-ethyl acetate
(prepared according to the method of Preparation Two, 0.25 g, 1.0 mmol) and
triethylamine (0.10 g, 1.0 mmol) in tetrahydrofuran~ (5 mL) was added (~
styrenesulfonyl chloride (0.21 g, 1.0 mmol)~at ambient temperature and stirred
for 1 h.
The mixture was diluted with water and extracted twice with ethyl acetate. The
extract
was dried over magnesium sulfate, filtered, and the filtrate was concentrated
to an oil,
which was purified by flash chromatography (9:1 dichloromethane:methanol) to
give
the title compound of Example 111, Step A as an oil, 0.15 g (34%). 'H NMR
(CDCI,,
300 MHz) 81.48' (d, 3H), 2.15 (s, 3H), 323 (m, 4H), 3.84 (m, 4H), 5.67 (q,1H),
6.40
(d,1 H), 6.65 (d,1 H), 7.39-7.52 (m, 6H), 821 (d,1 H); MS (TS) 417 (MH'). ;
Step B: (El-1R-f4-f4-(2-Phenv!-ethenesulfonyl~oiaerazin-1-vll-ovtimidin-2-vll-
ethanol,
To a solution (E)-1 R-{4-[4-(2-phenyl-ethenesuifonyl~piperazin-1-yl]-pyrimidin-
2 yI}=
ethyl acetate (prepared according the method of Example 111, Step A, 0.14 g,
0.33
mmol) in methanol (1 mL) was added at ambient temperature 6 N aqueous
potassium
hydroxide (0.25 mL). After stirring for 3 h, the solution was diluted with
ethyl acetate
and washed twice with water. The organic layer was separated, dried over
magnesium sulfate, filtered, and the filtrate was concentrated to give the
title
compound as a white solid, 0.09 g (69%).'H NMR (CDCI', 300 MHz) 81.48 (d, 3H),
3.23 (m, 4H), 3:84 (m, 4H), 4.20 (br s,1 H), 4.71 (q, 1 H), 6.40 (d, 1 H),
6.65 (d, 1 N),
7.39-7.52 (m, 6H), 8.21 (d, 1 H); mp: 68-70 °C; MS (TS) 375 (MH'); [a]p
+20.9 (c 1.0,
MeOH).
Examples 112 and 113
Examples 112 and 11.3 were prepared from the appropriate starting materials in
a
manner analogous to the method of Example 111.


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HO
R~° :.,.Me
N-
R"-N N, ~ / N
19
R
Example .R' R" R" mp (C) '. MS
(MH')


112 (RrMe (S~Me isopropylsulfonyl 7 52-154 343


113 (R~Me (S)-Me 1-methyl-1 H-imidazol-4-157-158 381


yl-sulfonyl
Example 114
1 R-f4-f5-(4-Bromobenzenesulfonvl~2R.5S-diaza-bievclo[2.2.11heat-2-y(1-
ovrimidin-2-
vl~-ethanol.
HO
~~~~Me
O N-
CI ~ ~ SI-N N N
II ~ /
0
Step A: 1~4-(2R.5S-Diaza-biwclof2.2.11hept-2-yl~ovrimidin-2-y(1-ethyl
butyrate. To
a suspension of 2,5-diaza-bicyGo[2.2.1)heptane dihydrobromide (7.57 g, 88.0
mmot;
Synthesis 1990, 10, 925) in dichloromethane (90 mL) was added 1,8-
diazabicyGo[5.4.0]undec-7-ene (13.7 g, 90 mmol) and stirred until homogeneous.
A
solution of (R~1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according
to the
method of Preparation Seven, 10.2 g, 45 mmol) in dichioromethane (10 mL) was
added and stirred at reflux for 14 h. The mixture was filtered and washed with
saturated aqueous sodium bicarbonate. The organic tayer was dried over sodium
sulfate and filtered. The filtrate was concentrated to obtain a aude product
which was
purified b~ flash chromatography (9:1->5:1 dichloromethane:methanoll to give
the title
compound of Example 114, Step A as an oil, 6.75 g (51 %). 'H NMR (CDCI,, 300


CA 02484282 2000-03-16
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MHz) b 0.92 (t, 3H), 1.54 (d, 3H), 1.68-1.78 (m, 5H), 2.68 (t, 2H), 3:38 (m, 1
H), 3.76
(m, 3H), 4.42 (m, 1 H), 5.35 (q, 1 H), 6.16 (d, 1 H), 8:12 (d, 1 H); MS (CI)
291 (MH').
Step B: 1 R-f4-f5-l4-Bromobenzenesulfonvl)-2R.5S-diaza-bicvclof2.2.11hent-2-
y(1-
Qvrimidin-2-vl)-eth~tyrate. To a solution of 1R~,4~2R,5S-diaza-
bicydoj2.2.1]hept-
2-yl~pyrimidin-2-ylj-ethyl butyrate (prepared according to the method of
Example 114,
Step A, 0.58 g, 2.0 mmol) and triethylamine (0.22 g, 2.2 mmol) in chloroform
(10 mL)
was added 4-bromobenzenesulfonyl chloride (0.56 g, 2.2 mmol) and stirred at
ambient temperature for 16 h. The mixture was washed once with water, once
with
brine, dried over magnesium sulfate, filtered, and the filtrate was
concentrated to give
the title compound of Example 114, Step B as a dear oil, 0.92 g (90%). 'H NMR
(CDCl3, 300 MHz) S 0.92 (t, 3H), 1.54 (d, 3H), 7.68-1.78 (m, 5H), 2.68 (t,
2H), 325 (m,
1 H), 3.46 (m, 3H), 4.28 (m, 1 H), 5.25 (q, 1 H), 6.16 (d, 1 H), 7.58 -7.64
(m, 4H), 8.12 (d,
1 H); MS (CI) 510 (MH').
Step C: 1 R-(4-f5-l4-Bromobenzenesulfonvl)-2R.5S-diaza-bicvclof2.2.11hent-2-
v(1-
evrimidin-2-vl)-ethanol. To a solution of 1 R-{4-[5-(4-
bromobenzenesulfonylr2R,5S-
diaza-bicydo[2.2.1]hept-2-yl]-pyrimidin-2-yl}-ethyl butyrate (prepared
according to the
method of Example 114, Step 8, 0.85 g,1.6 mmol) in a 2:1 mixture of
tetrahydrofuran:methanol (10 mL) was added at ambient temperature 6 N aqueous
potassium hydroxide (1 mL). After stirting for 6 h the solution was diluted
with
dichioromethane and washed twice with water. The organic layer was separated,
dried over magnesium sulfate, filtered, and the filtrate was concentrated to a
viscous
oil which was purified by flash chromatography (9:1 dichloromethane:methanol)
to
give the title compound as a white foam, 0.49 g (66%). 'H NMR (CDCI,, 300 MHz)
8
1.54 (d, 3H), 1.68 (m,,2H), 1.78 (m, 1H), 3.25 (m, 1H), 3.46 (m, 3H), 4.28 (m,
1H),
4.78 (q, 1 H), 6.16 (d, 1 H), 7.64 (m, 4H), 8.12 (d, 1 H); mp: 83-88
°C; MS (C!) 440
(MH'); [a]D -49.2 (c 1.0, MeOH).
Examples 115 to 120
Examples 115 to 120 were prepared from the appropriate starting materials in a
manner analogous to the method of Example 114.


CA 02484282 2000-03-16
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HO
w~~Me
N-
R"-N' \ -N , ~ /N'_
Example R" mp (C) MS (MH')


115 4-chlorophenylsulfonyl 83-88 395, 397


116 2-~ienylsulfonyl 84-86 '~ 367


117 2-(5-chlorothienyl)-sulfonyl62-64 401, 403


118 4-carboxamidoylphenyl-sulfonyl148-151 404


H
119 4-(tart-butylphenyl~sulfonyl72-75 417


120 N,N-dimethylsutfamoyl 110-111 328


Example 121
{4-(4-(Pvrrolidine-1-sulfonvl)-piperazin-1-vll-ovrimidin-2-vl1-methanol.
HO
N-
\NIIN~ ~~N
O
Step A: 2-Methoxvmethvl-4-t4-(QVrrofidine-1-suffonv()-oioerazin-1-vf!-
ovrimidine. To a
solution of 2-methoxymethyl-4-piperazin-1-yl-pyrimidine (prepared according to
the
method of Preparation One, 2.08 g, 10 mmol) and triethylamine (1.01 g, 10
mmol) in
tetrahydrofuran (20 mL) was added N-pyrrolidinesulfonyl chloride {1.69 g, 10
mmol) at
0 °C and stirred for 3 h at ambient temperature. The mixture was
diluted with ethyl
acetate and washed twice with water. The organic layer was separated, dried
over
magnesium sulfate, filtered, and the filtrate was concentrated to an oil which
was
purified by flash chromatography (95:5 dichloromethane:methanol) to give the
title
compound of Example 121, Step A as a dear oil, 3.24 g (93%). 'H NMR (CDCl3,
300
MHz) 81.81-1.85 (m, 4H), 3.12-3.18 (m, 8H), 3.59 (s, 3H), 3.81 (m, 4H~ 4.43
(s, 2H),
6.71 (d, 1 H), 8.18 (d, 1 H); MS (TS) 342 (MH').


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Step B: f4-f4-lPvrrolidine-1-sulfonvll-oiDerazin-1-vll-ovrimidin-2-~rt~-
methanol. To a
solution of 2-methoxymethyl~-[4-(pyrrolidine-1-sulfonyL~piperazin-1-yl]-
pyrimidine I 1 , ,
(prepared according to the method of Example 121, Step A, 3.1 g, 9.4 mmol) in
dichlorornethane (47 mL) was added boron tribromide (1 M in dichioromethane,
19
mL, 18.7 mmol) at 0 °C then stirred at ambient temperature for 2 h. The
mixture was
washed twice with saturated aqueous sodium bicarbonate; and the organic layer
was
separated, dried over magnesium sulfate, filtered, and the filtrate was
concentrated to
give an oil which was crystallized from isopropyl ether to give the title
compound as a
white solid, 2.43 g (7790). 'H NMR (CDCI3, 300 MHz) b 1.82 (m, 4H), 3.15 (m,
8H),
3.81 (m, 4H), 4.35 (d, 2H), 4.83 (t,1H), 6.71 (d;1H), 8.18 (d, 1H); mp:128-131
°C;
MS (Cl) 328 (MH').
Examples g22 to 125 "
Examples 122 to 125 were prepared from the appropriate starting materials in a
manner analogous to the method of Example 121.
R'
N
R" ~ ~ ~\N
Example R' R" mp (C) MS (MHO


122 CHZOH 2,5-dimethyipymolidin-1-128-131 356


ytsulfonyl


123 CHZOH piperidin-1-ylsulfonyl141-142 342


124 (R)-CH(Me)OH aza-bicydo[3.21]octan-8-11 i-112 382


ylsulfonyl


125 (R~CH(Me)OH aza-bicydo(32.1]octan-3-113-114 396


one-8-yl-sulfonyl


Examote 126
(E?-1-f4-f2-f 1 R-Hvdroxv-ethvl~-ovrimidin~.-vll-oinerazin-1-vl~-2-methyl-3-
ohernrl-
pro~enone.


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~~~~ Me
.,
pCTIIB00/00296
Step A: ~E>-1 R-(4-~4-(2-Methvl-3-phenyl-acrvlovl~cioera~in-1-vll-avrimidin-2-
vl~-ethyl
acetate. To a solution of (R}-1-(4-piperazin-1-y!-pyrimidin-2-yl~ethyl acetate
(prepared according to the method of Preparation Two, 0.54 g, 2.1 mmol) and a-
methylcinnamic acid (0.34 g, 2.1 mmol) in diG~loromethane (10 mL) was added 1-
hydroxybenzotriazole (0.50 g, 3.6 mmol) followed by 1-(3-dimethylaminopropyl)-
3-
ethylcarbodiimide hydrochloride (0.45 g, 2.4 mmot) at ambient temperature and
stirred
for 48 h. The mixture was washed once with water, once with saturated aqueous
sodium chloride, dried over magnesium sulfate, filtered, and the ftltrate was
concentrated to an oil which was purified by flash chromatography (9:1
dichloromethane:methanot) to give the title compound of Example 126, Step A as
a
Gear viscous oil, 0.53 g (63%). 'H NMR (CDCI,, 300 MHz) S 1.51 (d. 3H), 2.14
(s,
3H), 2.18 (s, 3H), 3.75 (m, 8H), 5.fi8 (q,1 H), 6.41 (d,1 H), 6.59 (s,1 H),
725-7.43 (m,
5H), 8.23 (d, 1 H); MS (CI) 395 (MH'); ja]~ +38.6 (c 1.0, MeOH).
Step B: ~E?-1-f4-T2-(1R-Hydroxv-ethvl~-ovrimidin-4-vll-flioerazin-1-vl~-2-
methyl-3-
phenvl-aropenone. To a sotution of (E}-1 R-{4-[4-(2-methyl-3-phenyl-acryfoyl~
piperazin-1-yl}-pyrimidin-2-yl}-ethyl acetate (prepared according to the
method of
Example 126, Step A, 0.51 g, 1.3mmo1) in methanol (5 mL) was added at ambient
temperature 6 N aqueous potassium hydroxide (1 mL). Afterstining for 1 h the
solution was diluted with ethyl acetate and washed twice with water. The
organic
layer was separated, dried over magnesium sulfate, ftltered, and the ftltrate
was
concentrated to give the title compound as a white solid, 0.25 g (55%). 'H NMR
(CDC1,, 300 MHz) 51.51 (d, 3H), 2.14 (s, 3H), 3.75 (m, 8H), 4.22 (br s, 1 H),
4.71 (q,
1 H), 6.41 (d, 1 H), 6.59 (s, 1 H), 7.25-7.43 (m, 5H), 8.23 (d,1 H); mp: 119-
121 °C; MS
(CI) 353 (MH'); [c~J~ +16.0 (c 1.0, MeOH).
Examples 127 to 129
Examples 127 to 129 were prepared from the appropriate starting materials in a
manner analogous to the method of Example 126.

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,."Me
R'
Example ~ A~' R° R' mp (°C) ~ ~ MS (MH')
127 thien-2-yl H H 104-106 345
128 thien-2-yl (R}-Me . (S~Me 69-73 373
Ho
~~~~Me
An~ ~ N-
Jr--N N N
O
Example A~ mp (°C) MS (MH')
129 . 4-(o-tolylcarbamoyly-phenyl 9&103 446


CA 02484282 2000-03-16
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Example 130
(E~3-Benzofuran-2-vl-1-(4-f2-(1 R-hvdroxv-ethyl)-ovrimidin-4-vf1-2R,6S-
dimethvi-
piperazin-1-vl~-oropenone.
HO
1Ae w~~Me
N-
Me
Step A: (E)-1 R-(4-f4-(3-Benzofuran-2-vl-acrvIovIJ-3R.5S-dimethvl-oioerazin-1-
vll-
p, r~rimidin-2-vf)-ethyl butyrate. To a solution of 1 R-(4-(3R,5S-dimethyl-
piperazin-1-yl~
pyrimidin-2-yfJ-ethyl butyrate (prepared according to the method of
Preparation Three,
0.79 g, 2.6 mmol) and triethylamine (0.26 g, 2.6 mmol) in dichloromethane (90
mL)
was added (E)-3-benzofuran-2-yl-acryloyl chloride (0.54 g, 2.6 mmol) and
stirred at
ambient temperature for 16 h, then at reflux for 2.5 h. The mixture was washed
successively with saturated aqueous sodium bicarbonate and water, and the
organic
layer was dried over sodium sulfate and filtered. The filtrate was
concentrated to
obtain a crude product, which was purified by flash chromatography (9:1
dichloromethane:methanol) to give the title compound of Example 130, Step A as
a
viscous oil, 0.79 g (54%). 'H NMR (CDCI,, 300 MHz) i; 0.95 (t, 3H), 1.40 (d,
6H), 1.56
(d, 3H), 1.67 (q, 2H), 2.38 (t, 2H), 3.25 (d, 2H), 4.33 (m, 2H), 4.75 (m, 2H),
5.66 (q,
1 H), 5.95 (d, 1 H), 6.40 (d, 1 H), 7.14-7.37, (m, 5H), 8.06 (d, 1 H), 8.22
(d, 1 H); MS (Ci)
477 (MH'); [a]o +49.1 (c 1Ø MeOH).
Step B: (El-3-Benzofuran-2-vl-1-(4-f2-(1R-hvdroxy~thvl)-pvrimidin-4-vfl-2R 6S-
dimethvl-piperazin-1-vl)-orooenone. To a solution of (E~-1 R-(4-[4-(3-
benzofuran-2-yt-
acryloyl)-3R,5S-dimethyl-piperazin-1-yt]-pyrimidin-2-yl}-ethyl butyrate
(prepared
according to the method of Example 130, Step A, 0.51 g, 1.1 mmol) in methanol
(5
mL) was added at ambient temperature 6 N aqueous potassium hydroxide (1 mL).
After stirring for 1 h the solution was diluted with ethyl acetate and washed
twice with
water. The organic layer was separated, dried over magnesium sulfate,
filtered, and
the filtrate was concentrated to give the title compound as a white soiid,
0.49 g (75%).
'H NMR (CDC13, 300 MHz) 8 1.40 (d, 6H), 1.56 (d, 3H); 325 (d, 2H), 4.33 (m,
2H),


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4.75 (m, 2H), 4.68 (q, 1 H), 5.95 (d; 1 H), 6.40 (d, 1 H), 7.14-7.37, (m, 5H),
8.06 (d, 1 H), "
8.22 (d, t H); mp: 80-82 °C; MS (CI) 407 (MH'); [a]~ +17.7 (c t.0,
MeOH).
Examflle 131
Cvclohexvl-f4-f2-(1 R-hvdroxv-ethyl)-pvrimidin~l-vtl-2R.6S-dimethvt-oioerazin-
1-vl)-
methanone.
HO
Me ~~~~Me
N-
N. N ~ /N
O
Me
Step A: 1 R-f4-(4-Cvclohexaneca~onvf-3R.5S-dimethvl-aioerazin-1-vl~oyrimidin-2-

vll-ethyl butyrate. To a solution of 1R-j4-(3R,5S-dimethyl-piperazin-1-yl)-
pynmidin-2-
yfJ-ethyl butyrate (prepared according to the method of Preparation Three, 306
mg,
1.0 mmol) and triethylamine (230 mg, 1.2 mmol) in dichloromethane (10 mL) was
added at ambient temperature cydohexanecarbonyl chloride (161 mg,1.1 mmoi).
After 1 h the mixture was washed with water, and the dichloromethane layer was
dried
over magnesium sulfate and filtered. The filtrate was oonoentrated to give the
tine
compound of Example 131, Step A as an oil, 388 mg (94%). 'H NMR (CDCI,, 300
MHz) 8 0.94 (t, 3H), 1.2-1.4 (m, 6H), 1.54 (d, 3H), 1.5-1.83 (m, t2H), 2.44
(m, 3H),
3.2-3.3 (m, 2Hj, 4.4-4.6 (m, 4H), 5.52 (q, 1 H), 6.44 (d; 1 H), 8.22 (d, 1 H);
MS (CI) 417
(MH').
Step B: Cvdohexvl-(4-f2-f 1 R-hvdroxv-ethyll-ovrimidin-4-vt1-2R.6S-dimethvl-
oioerazin-
1-v(1-methanone. Ta a solution of 1 R-j4-(4-cydohexanecarbonyl-3R.5S-dimethyl-
piperazn-1-yl)-pyrimidin-2-yt]-ethyl butyrate (prepared according to the
method of
Example 131, Step A, 375 mg, 9.0 mmol) in methanol (5 mL) was added 6 N
aqueous
potassium hydroxide (0.5 mL) and stirred at ambient temperature for 4 h. The
reaction mixture was concentrated, diluted with water, and extracted into
dichloromethane. The extract was washed twice with water, dried over magnesium
sulfate, and evaporated to an oil. The cxude product was crystallized from
ethyl ether
to give the title compound as a white soiid,106 mg (34%). 'H NMR (CDCI,, 300
MHz)
81.2-1.4 (m, 6H),1.55 (d, 3H),1.6-1.8 (m,10H), 2.46 (m,1 H), 3.2-3.3 (m, 2H),
42-


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4.6 (m, 4H), 4.78 (q, 1H), 6.43 (d, 1H), 8.22 (d, 1H); mp: 174-175 °C;
MS (CI)
347(MH'); [a]p +18:4 (c 1.0, MeOH).
Example 132
Furof3.2-clovridin-2-vl-f4-f2-( 1 R-hvdroxv-ethyl)-pyrimidin-4-yl]-2R.6S-
dimethvt-
eiperazin-1-vl)-methanone.
~~~~Me
Me
Step A: 7-Chloro-furoL.2-clpvridine-2-cart~oxvlic acid. To a solution of,n-
butyllithium
(2.5 M in hexanes, 17 mt_, g, 42.6 mmol) in anhydrous ethyl ether (90 mL) was
added
dropwise a solution of 4-chloro-furo[3,2-c]pyridine (5.81 g, 37.8 mmot; J.
Heterocycl.
Chem. 1975, 12, 705) in ethyl ether (85 mt-) at 78 °C under nitrogen
atmosphere.
This mixture was stirred for 1.5 h at--65 °C, poured onto dry ice (100
cx) and warmed
to ambient temperature and quenched into water. The separated organic layer
was
extracted once with water and the combined aqueous layers were aadified to pH
2
with concentrated hydrochloric aad to give the title compound of Example 132,
Step A
as a white solid, 3.33 g (45%). 'H NMR (CDCI,, 300 MHz) 8 7.69 (s, 1H), 7.85
(d, 1H),
8.42 (d, 1 H); mp: 233-235 °C (dec); MS (CI) 153 (MH' - CO= ).
Step B: 7-Chloro-furo(3 2-clovridine-2-cart~oxvlic aad chloride. 7-Chloro-
faro[3,2-
c]pyridine-2-carboxylic aad (prepared according to the method of Example 132,
Step
A, 8.94 g, 45.2 mmol) was combined with thionyl chloride (30 ml-) and sodium
carbonate (9.59 g, 90.5 mmol) and heated to reflux for 16 h under nitrogen
atmosphere. The cooled mixture was diluted with dichloromethane and filtered.
The
filtrate was evaporated to give the title compound of Example 132, Step B as
an
orange oil, 9.19 g (94%). The aad chloride was used directly without further
purificafjon.
Step C:1 R-(4=f4-(4-Chloro-faro(3.2-clayridine-2-carbonyl)-3R 5S-dimethyl-
o,perazin-
1-vtl-ovrimidin-2-vl~thyl butyrate. To a soluflon of 1 R-[4-(3R,5S-dimethyl-
piperatin-
1-yl~pyrimidin-2-y~-ethyl butyrate (prepared according to the method of
Preparation


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Three, 13.04 g, 42.5 mmot) and triethytamine (8.61 g, 85.1 mmol) in
dichlorbmethane
(90 mL) was added 7-chloro-furo[3,2-c]pyridine-2-carboxylic acid chloride
(prepared
according to the method of Example 132, Step B, 9.1 g; 84.0 mmol) and stirred
at
ambient temperature for 2 h. The mixture was washed-successively with
saturated
aqueous sodium bicarbonate and water, and the organic layer was dried over
sodium
sulfate and filtered. The filtrate was concentrated to obtain a crude product
which was
purified by flash chromatography (9:1 dichloromethane:methanol) to give the
title
compound of Example 132. Step C as. a viscous oil,18.9 g (91 %). 'H NMR
(CDCI,,
300 MHZ) 8 0.95 (t, 3H),1.40 (d, 6H),1.56 (d, 3H),1.67 (m, 2H), 2.38 (t, 2H),
3.25 (d,
2H), 4.33 (m, 2H), 4.75 (m, 2H), 5.66 (q,1 H), 6.40 (d, 1 H), 7.33 (s. 1 H),
7.41 (d, 1 H),
8.23 (d, 1 H), 8.35 (d, 1 H); MS (CI) 487 (MH'); [ot]p +33.3 (c 1.0, MeOH).
Step D: 1 R-l4-f4-(Furof3.2-clovridine-2-carbonyl)-3R.5S-dimethvt-nioerazin-1-
vl1-
pvrimidin-2-vll-ethyl butyrate. To a solution of 1 R-{4-[4-(4-chloro-furo(3,2-
c]pyridine-2-
carbonyl)-3R,5S-dimethyl-piperazin-1-yfj-pyrimidin-2-yl}-ethyl butyrate
(prepared
according to the method of Example 132, Step C, 18.6 g, 38.4 mmol) in ethanol
(1f0
mL) was added sodium carbonate (4.07 g, 38.4 mmol) and 10% palladium on carbon
(6.10 g, 33 wt%). This mixture was hydrogenated at 50 psi hydn~gen for 6 h
using a
Parr apparatus. The catalyst was filtered and the filtrate was evaporated to
an oil
which was purified by flash chromatography (9:1 dichloromethane:methanol) to
gi~re
the title compound of Example 132, Step D as a yellow oil, 14.2 g
(82°~). 'H NMR
(CDCI,, 300 MHz) S 0.95 (t, 3H),1.40 (d. 6H),1.56 (d, 3H),1.67 (q, 2H), 2.38
(t, 2H),
3.25 (d, 2H), 4.33 (m, 2H), 4.75 (m, 2H), 5.68 (q, 1 H), 6.40 (d, 1 H), 7.37
(s, 1 H), 7.48
(d, 1 H), 8.22 (d,1 H), 9.04 (s,1 H); MS (CI) 452 (MH'); [ac]o +36.7 (c 1.0,
MeOH).
Step E: Furoj3.2-clpyridin-2-v!-f4~-(1R-hvdroxv~thvll-ovrtmidin-.4-v(1-2R.6S-
øimethyl-oioerazin-1-vtl~-methanone. 1 R-{4-{4-(Furo[3,2-c]pyridine-2-ca~onyl)-
3R,5S-
dimethyl-piperazin-1-yIj-pyrimidin-2-yl}-ethyl butyrate (prepared aooording to
the
method of Example 132, Step D, 5.48 8,12.1 mmol) was combined with
concentrated
hydrochloric aad (15 mL) and stirred at ambient temperature for 6 h. The
mixture was
poured into cold 6 M aqueous sodium hydroxide and extracted twice with ethyl
acetate. The organic extract was washed once with water, dried over sodium
sulfate
and evaporated to a foam which crystallized from isopropyl ether to give the
tibe
compound as a white solid, 3.33 g (72%). 'H NMR (CDCl,, 300 MHz) S 1.43 (d,
6H).
1.52 (d, 3H), 3.37 (m; 2H), 4.38 (m, 2H), 4.71 (q,1 H), 4.83 (m, 2H), 6.43
(d,1 H), 7.38


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(s, 1 H), 7.47 (m, 1 H), 8.22 (m, 1 H), 8.54 (d, 1 H), 8.58 (d, 1 H), 9.04 (s,
1 H); inp: 142-
,,
143 °C; MS (CI) 382 (MH'); [aJ~ +15.9 (c 1.0, MeOH). , ,
Example 133
f4-f2-f1R-Hvdroxv-ethyll-pvrimidin-4-yll-2R 6S-dimethyl-piDerazin-1-vl}-(4-
ovrrolidin-1-
yl-furof3.2-cipvridin-2-vl)-methanone.
~~~~Me
Me
A solution of 1 R-{4-[4-(4-chloro-furo[3,2-c]pyridine-2-carbonyl~3R,5S-
dirrtethyf-
piperazin-1-yl]-pyrimidin-2-yl}-ethyl butyrate (prepared according to the
method of
Example 132, Step C, 0.046 g, 0.11 mmol) in pyrrolidine (0.037 mL, 0.44 mmol)
was
heated to reflux for 14 h and evaporated to give the title compound as a tan
solid, 0.04
g (80%). 'H NMR (CDCI,, 300 MHz) 81.43 (d, 6H), 1.53 (d, 3H), 2.08 (m, 4H),
3.43
(m; 2H), 3.77 (m, 4H), 4.43 (m, 2H), 4.71 (q, 1 H), 4.92 (m, 2H), 6.43 (d, 1
H), 6.70 (d,
1 H), 7.60 (s, 1 H), 8.08 (d, 1 H), 8.23 (d, 1 H); MS (CI) 451 (MH').

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Examples 134 to 158 I '
Examples 140 and 142 to 158 were prepared from the appropriate starting
materials
in a manner analogous to the method of Example 131. Example 141 was prepared
from the appropriate starting materials in a manner analogous to the method of
Example 133.
HO
R,e. "" Me
9
N-
R"N N ~ / N
6 5
Example R" R' R" mp (C) MS (MH')


134 cyclopropylcarbonyl2R-Me 6S-Me 110-111 305


135 cyclobutylcarbonyl2R-Me 6S-Me 134-135 319


136 cyclopentylcarbonyl2R-Me 6S-Me 199-200 333


137 tert-butylcart~onyl2R-Me 6S-Me 168-169 321





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'Me
O
z~
Ar
R.- ',
Exampl Ars R" R" mp (°C) MS (MH')
a
138 benzofuran-2 yl 2R-Me 6S-Me 124-126 381


139 furo[3,2-cjpyridin-2-ylH H 55-65 354


140 faro[3,2-cjpyridin-2-yl3R-Me 5S-Me , 382


141 morphofin-4 y!-furoj3,2-2R-Me 6S-Me ~ 467


cjpyridin-2-yl


142 faro[2,3-c]pyridine-2-yl2R-Me 6S-Me 129-131 382


143 5-chtorobenzofuran-2 H H 387, 389
yl


144 5-chlorobenzofuran-2-yl3R-Me 5S-Me 114-116 415, 417


145 5.7-dichtorobenzofuran-2-yl2R-Me 6S-Me 136-137 450, 452


146 5,7-dichtorobenzofuran-2-yl3R-Me 5S-Me 152-153 450, 452
~


147 5-nitrobenzofuran-2-yl2R-Me 6S-Me 153-154 426


148 5,7-dimethyibenzofuran-2-yl3R-Me 5S-Me 134-136 409


149 5-methoxybenzofuran-2-yl3R-Me 5S-Me 137-138 411


150 5-methoxybenzofuran-2-yl2R-Me 6S-Me 118-119 411


151 imidazo[1.2-a]pyridin-2H H 149-150 353
yl


152 imidazo[1.2-a]pytidin-23R-Me 5S-Me 171-173 381
yl


153 imidazo[1.2-a]py~idin-2-yl2R Me 6S-Me 147-149 381


154 6-chtoroimidazo[1,2- 2R-Me 6S-Me 76-84 416, 418


b]pytidazin-2-yl


155 6-methylimidazo[1,2- 3R-Me 5S-Me 164-165 395


ajpyridin-2-yl
'


156 benzoxazol-2-yl 2R-Me 6S-Me i26-127 382


157 4-cyanophenyl 2R-Me 6S-Me 90-a00 366


158 6-hydroxy-pyridazin-3-yl2R-Me 6S-Me 359




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Example 159
1-f4-f2-l1 R-Hvdroxv-ethyl)-ovrimidin-4-vll-2R.6S-dimethvl-oioerazin-1-vl~-2-
(6-
methvl-pvridin-3 yloxv)-ethanone.
N \~--
N
Me ~~"
~H Me
Step A: 1 R-f4-(4-Chloroacetvl-3R.5S-dimethvl-~i~erazin-1-yl?-ovrirnidin-2-vll-
ethyl
bu te. To a solution of 1 R-(4-(3R,5S-dimethyf-piperazin-1-yt~pyrimidin-2-yl]-
ethyl
butyrate (prepared according to the method of Preparation Three, 9.69 g, 31.3
mmol)
and fiethylamine (4.74 g, 46.9 mmol) in chloroform (150 mL) was added dropwise
chloroacetyl chloride (3.00 mL, 37.6 mmol) at 0 °C then stirred at
ambient temperature
for 12 h under nitrogen atmosphere. The mixture was washed success'rvefy with
saturated aqueous sodium bicarbonate and water, and the organic layer was
dried
over sodium sulfate, treated with activated carbon, and filtered. The filtrate
was
concentrated to obtain an oil which was purfied by flash chromatography (9:1
dichloromethane:methanol) to give the title compound of Example 159, Step A as
an
oil, 8.98 g (75%). 'H NMR (CDCI,, 300 MHz) 8 0.96 (d, 3H), 1.32 (d, 6H), 1.59
(d,
3H), 1.71 (m, 2H), 2.40 (t, 2H), 3.28 (m, 2H), 4.28 (s, 2H), 4.35 (m, 4H),
5.68.(q, 1 H),
6.41 (d, 1 H), 8.23 (d, 1 H); MS (CI) 383, 385 (MH').
Step B: 1 R-l4-f3R.5S-Dimethvl-4-fl6-methyl-pvridin-3-vloxv~-acetvll-pioerazin-
1-
pvrimidin-2-v1)-ethyl butyrate. To a suspension of sodium hydride (60%
dispersion in
oil, 0.05 g, 1.3 mmol) in tetrahydrofuran (2 mL) was added a solution of 6-
methyl-3-
pyridinol (0.14 g, 1.3 mmol) in tetrahydrofuran (3 mL) at 0 °C under
nitrogen
atmosphere and stirred for 0.5 h warming to ambient temperature. Next, a
solution of
1R-[4-(4-chloroaoetyl-3R,5R~iimethyl-piperazin-1-yl)-pyrimidin-2-yQ-ethyl
butyrate
(prepared according to the method of Example 159, Step A, 0.40 g, 1.1 mmol) in
tetrahydrofuran (2 mL) was added and fefluxed for 1 h. The mixture was diluted
with
dichloromethane.and washed with saturated aqueous sodium bicarbonate; dried
over
sodium sulfate and filtered. The filtrate was evaporated to an oil which was
purified by
flash chromatography (91 dichloromethane:methanol) to give the title compound
of


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Example 159, Step B as an oil, 0.31 g (66%). 'H NMR (CDCI,, 300 MHz) b 0.96
(d,
3H), 1.32 (d, 6H), 1.59 {d, 3H), 1.71 (m, 2H), 2.40 (t. 2H), 2.46 (s, 3H),
3.28 (m, 2H),
3,78 (s, 2H), 4.35 (m, 4H), 5.68 (q, 1 H), 6.41 (d, 1 H), 6.83 (m, 1 H). 7.14
(m, 1 H), 8.08,
(d, 1 H), 8.23 (d, 1 H); MS (CI) 456 (MH').
Step C: 1~4-f2-l1R-Hvdroxy-ethvl~oyrimidin-4-vll-2R.6S-dimethvl-oiDerazin-1-
v(1-2-
(6-methyl-pyridin-3-vloxv~ethanone. 1 R-(4-{3R,5S-Dimethyl-4-[(6-methyl-
pyridin-3-
yioxy)-acetylj-piperazin-1-yl}-pyrimidin-2-yl)-ethyl butyrate (prepared
according to the
method of Example 159, Step B, 0.30. g, 0.65 mmol) was combined with
concentrated
hydrochloric aad (3 mL) and stirred at ambient temperature for 6 h. The
mixture was
neutralized with 6 N aqueous sodium hydroxide to pH 9 and extracted twice with
ethyl
acetate. The organic extract was washed once with water, dried over sodium
sulfate
and filtered. The filtrate was concentrated to an oil which was purified by
flash
chromatography (9:1 dichloromethane:methanol) to give the title compound as a
white
foam, 0.14 g (55%). 'H NMR (CDCI,, 300 MHz) 8 1.38 (d, 6H), 1.55 (d, 3H), 2.46
(s,
3H), 3.28 (m, 2H), 3.76 (s, 2H), 4.35-4.65 (m, 4H), 4.67 (q, 1 H), 6.38 (d, 1
H), 6.83 (m,
1 H), 7.11 (m, 1 H), 8.08, (d, 1 H), 8.21 (d, 1 H); mp: 55-65 °C; MS
(CI) 330 (MH'); [ajD
+16.0 (c 1.0, MeOH).
Example 160
1-(4-(2-(1R-Hydroxy-ethvl~oyrimidin-4-yft-2R 6S-dimethyt-oioerazin-1-vll-2-
(ovrimidin
2-vlsulfanvll-ethanone.
Me
S
N~ ~ N
\ N ~ ~\
~ O N
Me "' ~ tulea
OH
Example 160 was prepared from the appropriate starting materials in a manner
analogous to example 159. 'H NMR (CDCI3, 300 MHz) 81.38 (m, 6H),1.48 (d, 3H),
3.28 (m, 2H), 3.96 (s, 2H), 4.35 (m, 4H), 4.65-4.97 (m, 3H), 6.28 (d, 1 H),
6.93 (m,1 H),
7.11 (m,1 H), 8.21 (d,1 H), 8.45, (m, 2H); mp: 60-70 °C; MS (CI) 389
(MH'); [aJ~ +16.8
(c 1.0, MeOH).


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pCTIIB00f00296
lExamole i 61
4-[2-f 1 R=Hvdroxv-ethyl)-ovrimidin-4-v(1-2R.6S-dimeth~l-pioerazine-1-
carboxylic acid , ,
phenW ester.
~~~~Me
Me
Step A: 4-I2-f 1 R-Butyrvloxy-ethvll~avrimidin-4-vll-2R.6S-dimethyf-oioerazine-
1-
carboxvlic acid ohenvl ester. To a solution of 1 R-[4-(3R,5S-dimethyl-
piperazin-1 yl~
pyrimidin-2-ylj-ethyl butyrate (prepared according to the method of
Preparation Three,
0.30 g, 0.98 mmol) and triethytamine (0.20 g, 1.9 mmof) in dichloromethane (5
m~)
was added phenyl chloroformate (0.76 g, 4.8 mmot) and stirred at ambient
temperature for 2 h under nitrogen atmosphere. The mixture was washed
successively with saturated aqueous sodium bicarbonate and water, and the
organic
layer was dried over sodium sulfate and filtered. The filtrate was
concentrated to
obtain an oil which was purified by flash chromatography (9:1
dichloromethane:methanol) to give the title compound of Example 161, Step A as
an
oil, 0.35 g (84%). 'H NMR (CDCh, 300 MHz) S 0.96 (d, 3H), 1.32 (d, 6H), 1:59
(d,
3H), 1.71 (q, 2H), 2.40 (t, 2H), 3.28 (m, 2H), 4.35 (m, 4H), 5.68 (q, iH),
6.41 (d,1H),
7.12 (d, 2H), 7.22 (m,1 H), 7.35 (m, 2H), 8.23 (d,1 H); MS (CI) 427 (MH');
[a]~ +39.6
(c 1.0, MeOH).
Step 8: 4-f2-(1 R-Hydroxy-ethvl~-oYrimidin-4-vll-2R.6S-dimeth~l-nioerazine-'~
carboxylic aad ohenvl ester: 4-[2-(1 R-Butyryloxy~thyl)-pyrimidin-4-y(}-2R,6S-
dimethyt-piperazine-1-carboxylic add phenyl ester (prepared according to the
method
of Example 161, Step A, 0.31 g, 0.70 mmol) was combined with concentrated
hydrochloric add (5 mL) and stirred at ambient temperature for 6 h. The
macbune was
neutralized with 6 N aqueous sodium hydroxide to pH 9 and extracted twice with
etfiyl
acetate: The organic extract was washed once with water, dried over sodium
sulfate
and filtered. The filtrate was concentrated to an oil which was purified by
flash
chromatography (9:1 dichloromethane:methanol) to give the title compound as a
white
solid, 0.12 g (81 %). 'H NMR (CDC13, 300 MHz) 81.41 (d, 6H),1.51 (d, 3H), 3.34
(m,


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2H), 4.43 (m, 2H), 4.52 (m, 2H), 4.71 (q, 1 H), 6.46 (d, 1 H), 7.12 (m; 2H),
7.23 (m, 1 H),
7.35 (m, 2H), 8.23 (d, 1 H); MS (CI) 357 (MH'); [aJp +16,9 (c 1Ø MeOH).
Example 162
4-f2-l1 R-H~droxv-ethyl)-avrimidin-4-vll-2R.6S-dimethyl-oioerazine-1-
carboxylic acid
g~ridin-3-yl ester.
HO
Me ~~~~Me
/ \ o ~ N_
N- h--N N \ / N
Me
Step A: 4:I2-l1 R-Hvdroxv-ethyl)-QVrimidin-4-vll-2R.6S-dimethvl-fli~erazine-1-
carbonyl
chloride. To a solution of 1 R-[4-(3R,5S-dimethyl-piperazin-1-yl)-pyrimidin-2-
yl]-ethyl
butyrate (prepared according to the method of Preparation Three, 3.61, 11.8
mmol)
and pyridine (0.93 g, 11.8 mmol) in dichioromethane (50 mL) was added
triphosgene
(1.17 g, 3.9 mmol) and stirred at ambient temperature for 16 h under ri~trngen
atmosphere. The mixture was washed successively with saturated aqueous sodium
bicarbonate and water, and the organic layer was dried over sodium sulfate and
filtered. The filtrate was concentrated to obtain an oil which was purified by
flash
chromatography (ethyl acetate) to give the title compound of Example 162, Step
A as
a yellow oil, 2.12 g, (51 %). 'H NMR (CDCI,, 300 MHz) 8 0.90 (t, 3H),1.31 (d,
6H),
1.56 (d, 3H), 1.68 (m, 2H), 2.38 (t, 2H), 3.21 (m, 2H), 3.88-4.40 (m, 4H),
5.66 (q, 1H),
6.43 (d, 1 H), 8.22 (.d, 1 H); MS (CI) 369, 371 (MH').
Step B: f4-I2-(1R-Butvrvloxv-ethyl?-DVrimidin-4-vl1-2R.6S-dimeth~r!-
oiDerazine~-1-
carboxylic add oyridin-3-v! ester. To a suspension of sodium hydride (60%
dispersion
in oil, 0.046 g, 1.15 mmol) in anhydrous tetrahydrofuran (8 mL) was added 3-
hydroxypyridine (0.11 g,1.15 mmol) at 0 °C. After a homogeneous
solution was
obtained, a solution of 4-[2-(1 R-hydroxy-ethyl)-pyrimidin.~-ytj-2R,6S-
dimethyl-
piperazine-1-cariaonyl chloride (prepared according to the method of Example
162,
Step A, 0.36 g, 0.96 mmol) in tetrahydrofuran (3 mL) was added at 0 °C
and this
mixture was warmed to ambient temperature, then heated to reflux far 6 h. The
mixture was quenched in water and extracted twice with ethyl acetate. The
combined
organic layers were dried over sodium sulfate and filtered. The filtrate was


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concentrated to obtain an oil, which was purified by flash chromatography
(ethyl
acetate) to give the title compound of Example 162, Step B as a semi-solid,
0.31 g
(78%). 'H NMR (CDCI,, 300 MHz) 8 0.90 (t, 3H), 1.35 (m, 6H), 1.61 (d, 3H),
1.69 (m,
2H), 2.41 (t, 2H), 3.30 (m, 2H), 4.11-4.38 (m, 4H), 5.69 (q, 1 H), 6.41 (d, 1
H), 7.32 (m;
1 H), 7.52 (m, 1 H), 8.22 (d, 1 H), 8.46 (s, 1 H), 8.48, (d, 1 H); MS (CI) 428
(MH').
Step C: 412-f 1 R-Hvdroxv-ethvl~ovrimidin-4-yt1-2R.6S-dimethv!-nioerazine-1-
carboxylic acid ovridin-3-of ester. {4-[2-(1R-Butyryloxy-ethyl~pyrimidin-4-yl]-
2R,6S-
dimethyi-piperazine}-1-carboxylic acid pycidin-3-yl ester (prepared according
to the
method of Example 162, Step B, 0.31 g, 0.T0 mmol) was combined with
concentrated
hydrochloric acid (5 mL) and stirred at ambient temperature for 6 h. The
mixture was
neutralized with 6 N aqueous sodium hydroxide,to pH 9 and extracted twice with
ethyl
acetate. The extract was washed once with water, dried over sodium sulfate and
filtered. The filtrate was concentrated to an oil which was purified by flash
chromatography (9:1 dichloromethane:methanol) to give. the title compound as a
white
solid, 0.12 g (81 %). 'H NMR (CDCI,, 300 MHz) b 1.41 (d, 6H), 1.51 (d, 3H),
3.33 (m,
2H), 4.25-4..45 (m, 4H), 4.71 (q, 1 H), 6.43 (d, 1 H), 7.33 (m, 1 H), 7.56 (m,
1 H), 8.23 (d,
1H), 8.25 (d, 1H), 8.48 (d, 1H); MS (CI) 358 (MH'); [a]o +18.5 (c 1.0, MeOH).
Example 163
4-(2-f1 R-Hvdroxv-ethvl~ovrimidin-4-vIl-2R-phenyl-pioerazine-1-carboxylic aad
p~rridin-3-vl ester.
HO
~~~~Me
Step A: 1 R-f4-l3R-Phenyl-o oerazin-1-vll-ovrimidin-2-v>t-ethyl butyrate. To a
solution
of (R~2-phenylpiperazine (0.48 g, 3.0 mmol, Indian J. Chem. Sect B 1994, 33.
285)
and triethylamine (1.21 g, 12.0 mmol) in tetrahydrofuran (10 mL) was added (R}-
1-(4-
chloropyrimidin-2-ylrethyl butyrate (prepared according to the method of
Preparation
Seven, 0.68 g, 3.0 mmot) and stirred at ambient temperature for 18 h. The
mixture
was poured into saturated aqueous sodium bicarbonate and extracted with ethyl


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acetate. The combined organic layer was dried over sodium sulfate and
filtered. The
filtrate was concentrated to obtain a crude product which was purified by
flash
chromatography (95:5 dichloromethane:methanol) to give the title compound of
F~cample 163, Step A as a viscous oil, 0.70 g (67%). 'H NMR (CDCI,, 300 MHz) 8
0.95 (t, 3H), 1.56 (d, 3H), 1.67 (m, 2H), 2.40 (t, 2H), 3.55 (m, 2H), 4.0 (m,
2H), 4.32
(m, 2H), 4.70 (m, 1 H), 5.69 (q, 1 H), 6.49 (d, 1 H), 7.40 (m, 5H), 8.21 (d, 1
H); MS (CI)
355 (MH').
Step B: 4-f2-(1 R-Butvrvloxv-ethvl~pvrimidin-4-vfl-2R-phenyl-piperazine-1-
carboxylic
acid pvridin-3-vl ester. To a solution 1R-[4-(3R-phenyl-piperazin-1-yl)-
pyrimidin-2-yi3
ethyl butyrate (prepared according to the method of Example 163, Step A,~~0.22
g, 0.6
mmol) and triethylamine (0.31 g, 3.1 mmol) in toluene (5 mL) was added
dipyridin-3-yl
carbonate (0.67 g, 3.1 mmol) and.heated to reflex for 3 h. The mixture was
poured
into saturated aqueous sodium bicarbonate, the organic layer was separated and
the
aqueous layer was extracted with ethyl acetate. The combined organic layers
were
dried over sodium sulfate and filtered. The filtrate was concentrated to
obtain a crude
product which was purified by flash chromatography (9:1
dichloromethane:methanol)
to give the title compound of Example 163, Step B as a yellow oil, 0.22 g
(73%). MS
(CI) 476 (MH').
Step C: 4-f'2-l1R-Hvdroxv-ethvf~ovrimidin-4-vf1-2R=ohenvl niperazine 1-
carboxylic
add pvridin-3-vl ester. 4-[2-(1 R-Butyryfoxy-ethyl)-pyrimidin-4-yt]-2R-phenyt-
piperazine-1-carboxylic aad pyridin-3-yl ester (prepared according to the
method of
Example 163, Step B, 0.21 g, 0.4.4 mmol) was combined with concentrated
hydrochloric aad (2 mL) and stirred at ambient temperature for 6 h. The
mixture was
neutralized with 6 N aqueous sodium hydroxide to pH 9 and extracted twice with
ethyl
acetate. The combined extracts were washed once with water; dried over sodium
sulfate and filtered. The ftltrate was concentrated to an oil which was
purifted by flash
chromatography (9:1 dichloromethane:methanol) to give the title compound as a
white
solid, 0.13 g (73%). 'H NMR (CDCI,, 300 MHz) 81.55 (d, 3H), 3.55 (m, 2H), 4.0
(m,
2H), 4.32 (m, 2H), 4.71 (m, 1 H), 4.75 (q, 1 H), 6.40 (d, 1 H), 7.18-7.41 (m,
7H), 824 (d,
1 H), 8.35 (br s, 1 H), 8.45 (d, 1 H); MS (Ct) 408 (MH').
Examples 164 to 173
Examples 164 to 173 were prepared from the appropriate starting materials in a
manner analogous to the method of Example 163.

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wo oo~s9sio rc~rnBOOioo2~
-207-
HO
Ar' , Rs . ..., Me
O ~ N-
~N N ~ / N
O
R'
Example , R' R Ar' mp (C) MS (MH')


164 3R-Me 5S-Me phenyl 357


165 3R-Me 5S-Me 2-methyl-pyridin-3-yl65-75 372


166 H H ~ pyridin-3-yl 107-110 330


167 3R-Me 5S-Me 2-d~ioro-pyridin-3-yl60-70 392, 394


168 3R-Me 5S-Me 5-chloro-pyridirr3-yl65-69 392, 394


169 3R-Me 5S-Me isoquinolin-5-yl60-70 407


170 3R-Me 5S-Me 4-chloro-pyridin-3-yl60-70 392, 394


171 3R-Me 5S-Me 6-methyl-pyridin-3-yl60-70 372


172 2RS- H pyridin-3-yl 388


CHZOMe


173 2RS-COzEt H' pyridirr3-yl 4p2


Example 174
(Rl~-Benzvl-1-f2-( 1-hvd roxv~thvtl-ovrtmidin-4-vt1-oioeridin-4-ot.
~~»Me
Step A: (R>-1.-(4-(4-Benzvl-4-hvdroxv-oic~eridin-1 vll-ovrimidin-2-vll-ethv)
acetate. To
a solution of 4-tienzy!-4-hydroxypiperidine (0.95 g, 5.0 mma<) and
triethytamine (0.51
g, 5.0 mmol) in dichioromethane (10 mL) was added (R)-1-(4-methanesulfonyloxy-
pyrimidin-2-yly-ethyl butyrate (prepared according to the method of
Preparation Eight,
1.23 g, 4.0 mmol) and stirred at ambient temperature for 18 h. The mixture was


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washed once with water, once with saturated aqueous sodium chloride and the
organic layer was dried over sodium sulfate and filten:d. The filtrate was
evaporated
to an oil which was purified by flash chromatography (95:5
dichloromethane:methanol) to give the title compound,of Example 174, Step A as
a
viscous oil, 0.99 g (52%). 'H NMR (CDCIS, 300 MHz) s 0.95 (t, 3H),1.53 (d,
3H),
1.65-1.78 (m, 4H), 1.88 (m, 2H), 2.08 (m, 2H), 2.48 (t, 2H), 3.45 (m, ZH),
4.42 (tar s,
1 H), 5.68 (q, 1 H), 6.41 (d, 1 H), 7.30-7.48 (m, 5H), 8.18 (d, 1 H); MS (Cl)
384 (MH').
Step B: (R~4-Benzvl-1-f2-(1-hvdroxv-ethvl~-ovrimidin-4-vIl-oioeridin~-ol. To a
solution of (R~1-[4-(4-benzyl-4-hydroxy-piperidin-1-y(~pyrimidin-2-ytJ-ethyl
butyrate
(prepared accordEng to the method of Example 174, Step A, 0.20 g, 0.52 mmol)
in
methanol (5 mL) was added 1 N aqueous sodium hydroxide (1 mL) and timed for 4
h
at ambient temperature. The mixture was diluted with dichloromethanq and
washed
once with water, once with saturated aqueous sodium chloride and the organic
layer
was dried over sodium sulfate and filtered. The filtrate v~ras evaporated to
give the title
compound as a foam, 0.12 g (68%). 'H NMR (CDCI', 300 MHz) s 1.49 (d, 3H),1.74
(br s, 2H),1.82 (m, 2H), 2.08 (m, 2H), 3.42 (m, 2H), 4.42 (br s, 1 H), 4.7i
(q, i H), 6.43
(d, 1 H), 7.33-7.48 (m, 5H), 8.21 (d, 1 H); MS (Cl) 314 (MH').
Example 175
fR?-4-Phenv!-1-f2-( 1-hvdroxv~thvl~-ovrimidin-4-yp-nineridin-4-ol.
Me
Example 175 was prepared from the appropriate starting materials in a manner
analogous to the method of Example 174. mp: 114 °C; MS (CI) 300 (MH*).
Example 176
(R~1-f4-f4-(3-Chlorobenzvtidene?-niperidin-1- ~rr~midin-2 vll-Methanol.
HO
CI ~ / ....Me
N
N ~ 'N


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Step A: 1-f4-~3-Chlorobenzvlidene)-oioeridine-1-v(1-1~-carboxylic acid tert-
butyl ester.
To a suspension of 4-chlorobenryltriphenylphosphonium chloride (4.23 g, 10.0
mmol)
in tetrahydrofuran (40 mL) was added n-butyllithium in hexanes (2.5 M in
hexanes, 4.4
mL, 11.0 mmol) at 0 °C under nitrogen atmosphere and stirred 0.5 h. A
solution of 4-
oxo-piperidine-1-carboxylic aad tert-butyl ester (prepared according to the
method of
Example 101, Step A, 1.99 g, 10.0 mmol) in tetrahydrofuran {10 mL) was added
at 10-
°C and warmed to ambient temperature. The mixture was evaporated to an
oil
which was purified by flash chromatography (9:1 hexanes:ethyl acetate) to give
the
title compound of Example 176, Step A as an oil, 2.63 g (85%). 'H NMR (CDCI,,
300
10 MHz) 8 1.39 (s, 9H), 2.48 (m, 2H), 2.57 (m, 2H), 3.68-3.82 (m, 4H), 6.36
(s, 1H), 7.08
(m, 1 H), 7.12-7.28 (m, 3 H); MS (CI) 308 (MH').
Step 8: 4-l3-Chloro-benzviidene>-piperidine hydrochloride. To a solution of 1-
[4-(3-
chlorobenzylidene)-piperidine-1-y(j-1-carboxylic aad tert-butyl ester
(prepared
according to the method of Example 176, Step A, 2.5 g, 8.1 mmol) in
dichloromethane
15 (20 mL) was added hydrogen chloride (4 M in dioxane, 4.0 mL, 16.0 mmol) at
ambient
temperature and stirred for 4 h. The mixture was evaporated to dryness,
suspended
in ethyl ether and filtered to give the title compound of Example 176, Step B
as a white
solid. 1.63 g (82%). 'H NMR (CDCh/D20, 300 MHz) b 2.48 (m, 2H), 2.57 (m, 2H),
3.63 (m, 2H), 3.77 (m, 2H), 6.36 (s,1 H), 7.10 (m, 1 H), 7.12-728 (m, 3H);
rr~: u~-~s~ ~c.
Step C: IR?-1-f4-f4-l3-Chloro-benzvlidenel-piperidin-1-vl1-ovrimidin-2-vll-
ethyl
butyrate. To a solution of 4-(3-chlorobenzylidene~piperidine hydrochloride
(prepared
according to the method of Example 176, Step B, 0.46 g, 2.0 mmol) and
triethylamine
(0.61 g, 6.0 mmol) in dichloromethane (10 mL) was added (R}-1-(4-
chloropyrimidin-2-
yl)-ethyl acetate (prepared according to the method of Preparation Five, 0.54
g, 22
mmol) and stirred at ambient temperature for 12 h. The mixture was washed
successively with saturated aqueous sodium bicarbonate and water, and the
organic
layer was dried over sodium sulfate and filtered. The filtrate was
concentrated to
obtain a crude product which was purified by flash chromatography (95:5
dichforomethane:methanol) to give the title compound of Example 176, Step C as
a
viscous oil, 0.64 g (80%). 'H NMR (CDCI,, 300 MHz) 8 0.95 (d, 6H),1.51 (d,
3H),
1.68 (m, 2H) 2.35 (m, 2H), 2.47-2.64 (m, 4H), 3.67-3.75 (m, 4H), 5.68 (q, 1
H), 6.36 (s,
1 H), 6.40 (d, 1 H), 6.98 (m, 1 H), 7.12-7.28 (m, 3H), 8.18 (m,1 H); MS (CI)
400 (MH').


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Step D: lR)-1-~-[4-(3-Chloro~enzYtid~,ne~viperidin-1=3~(-vvrimidin-2-vl~-
ethanol. To a
,"
solution of (R}-1-{4-[4-(3-chforo-benzylidene~piperidin-1 yfJ-pyrimidin-2-yl}-
ethyl
butyrate (prepared according to the method of Example 176, Step C, 0.62 g,
1.55
mmol) in methanol (8 mL) was added 1 N aqueous sodium hydroxide (1 mL) then
stirred for 4 h at ambient temperature. The mixture was diluted with
chlorofom~ and
washed once with water, once with saturated aqueous sodium chloride,and.the
organic layer was dried over sodium sulfate and filtered. The filtrate was
concentrated
to obtain a crude product which was purified by flash chromatography (95:5
dichloromethane:methanol) to give the title compound as a white solid, 0.31 g
(61 %).
'H NMR (COCI,, 300 MHz) b 1.51 (d, 3H), 2.46 (m, 2H), 2.56 (m, 2H), 3.07 (m,
2H),
3.77 (m, 2H), 4.35 (d,1 H), 4.69 (q,1 H), 6.36 (s, 1 H), 6.40 (d,1 H), 7.07
(m, 1 H), 7.12-
7.28 (m, 3H), 8.18 (m, 1H); mp: 45-S5 °C; MS (CI) 330 (MH'); [a]o +16,8
(c 1.0,
MeOH).
Examples 177 to 181
' 15 Examples 177 to 781 were prepared from the appropriate starting materials
in a
manner analogous to the method of Example 176.
HO
~~~~Me
R'z N ..
N ~ ,N
R
Example R'~ it's' mp (C) MS ~M(~


177 4-chlorophenyi H 33p, 332


178 (E}-2-phenyl-ethen-1-ylH


179 benzoyl H 44-59 324


180 phenyl phenyl 108-109 372


181 . phenyl Pyrid-2-yl98-101 373


Example 7 82
jR~,l~4-L4-P~rridin-2-vlmethvl-niflera~in-1-vl~vvrimidin-2-yg-ethanol.


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N
N ~--J N
Me ~,..
OH
Step A: (R>-1-f4-l4-Pvridin-2-vlmethvl-nioerazin-1-vl)wrimidin-2-vll-ethyl
acetate. To
a solution of (Rj-1-[4-piperazin-1 yl~pyrimidin-2-ytj-ethyl acetate (prepared
according
to the method of Preparation Two, 1.55 g, 6.2 mmol) and triethyfamine (0.86
mL, 6.2
mmol) in tetrahydrofuran (20 mL) was added 2-picoylchloride hydrochloride
(1.01 g,
6.2 mmol) at ambient temperature and stirred for 1 h. The mixture was diluted
with
water and extracted twice with ethyl acetate. The combined extracts were dried
over
magnesium sulfate, filtered, and the filtrate was concentrated to an oil which
was
purified by flash chromatography (95:5 dichtoromethane:methanol) to give the
title
compound of Example 182, Step A, 0.98 g (46%). 'H NMR (CDCl3, 300 MHz) 8 1.58
(d, 3H), 2.15 (s, 3H) 2.62 (t, 4H), 3.72 (t, 4H), 3.75 (s, 2H), 5.67 (q, 1 H),
6.35 (d, 1 H),
7.22 (m, 1 H), 7.46 (d, 1 H), 7.73 (m,1 H), 8.21 (d, 1 H), 8.62 (d,1 H); MS
(CI) 342
(MH').
Step B: iR)-1-f4-(4-Pvridin-2ylmethvl-pioerazin-1-vl)-ovrimidin-2-vll-ethanol.
To a
solution of (R)-t-(4-(4-pyrtdin-2-ylmethyl-piperazin-1-yl}-pyrimidin-2-yQ-
ethyl acetate
(prepared acxording to the method of Example 182, Step A, 0.14 g, 0.33 mmot)
in
dioxane (6 mL) was added at ambient temperature 6 N aqueous potassium
hydroxide
(0.5 mL). After stirring for 3 h the solution was diluted with ethyl acetate
and washed
twice with water. The organic Layer was separated, dried over magnesium
sulfate,
filtered, and the filtrate was concentrated to give the title compound as a
white solid,
0.09 g (69%). 'H NMR (CDCI,, 300 MHz) b 1.52 (d, 3H), 2.38-2.59 (m, 4H), 3.72-
3.77
(m, 6H), 4.69 (q, 1 H), 6.37 (d, 1 H), 7.22 (d,1 H), 7.41 (d, 1 H), 7.69 (m, 1
H), 8.21 (d,
1 H) 8:58, (d,1 H); mp: 68-70 °C; MS (CI) 300 (MH'); [a]~ +162 (c 1.0,
MeOH).
Examples 183 to 187
Examples 183 to 187 were prepared from the appropriate starting materials in a
manner analogous to the method of Example 182.


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HO ,
~~~~Me
N_
R°- ~ N
Example R' mp (C) MS (MH7


183 phenylmethyl 299


184 ' isoquinolin-2-yl-methyl' 350


185 benzothien-2-yl-methyl 355


186 benzothiazot-2-yl-methyl356


187 benzofuran 2-yl-methyl v 339


Example 188
1 R-f4-f2R.6S-Dimethvl-.4-l2-f1.2.41triazof-1-vl-ovrimidin-4-yl~oiaerazin-1-
vl1-nvrimidin-
2-vtl-ethanol.
~~Me
Step A: 4-(3R.5S-Dimethvl-oioerazin-1-v1~2-methanesulfonvl-ovrimidine. To a
solution of cis-2,6-dimethylpiperazine (10.7 g, 94.1 mmol) and triethylamine
(9.52 g,
94.1 mmol) in chloroform (300 mL) was added 4-chloro-2-
methanesulfonylpyrimidine
(15.1 g, 78.4 mrnol; Hetemcycles 1985, 23, 611) at ambient temperdbime and
stin~ed
for 1 h. The mixture was partitjoned with saturated aqueous sodium bicarbonate
and
the separated organic layer was washed once with water, once with saturated
aqueous sodium chloride and the organic layer was dried over sodium sulfate
and
filten:d: The filtrate was evaporated to an orange solid which was slurried in
ethyl
ether and filtered to give the title compound of Example 188, Step A as a
white solid.


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15.4 g (73%). 'H NMR (CDCI,, 400 MHz) 81.01 (m, 6H), 2.35-2.78 (m, 4tfi), 2.85
(s,
3H), 3.32 (m, 2H), 6.81 (d, 1 H), 8.2 (d, 1 H); mp: 182-9 ~3 °C; MS
(CI) 301 (MH').
Step B: 4-(3R.5S-Dimethvl-oioerazin-1-vl)-2-f1.2.41triazol-1-vl-o~rimidine. To
a slurry
of sodium hydride (60% dispersion in oil, 0.37 g; 9.4 mmol) in
dimethylfom~amide (5
mL) was added a solution of 1,2,4-triazole (0.67 g, 9.4 mmol) in
dimethylformamide (4
mL) at 0 °C under nitrogen atrr~sphere. After 10 min, a solution of 4-
(3R,5S-
dimethyl-piperazin-1-y1~2-methanesulfonyl-pyrimidine (prepared according to
the
method of Example 188, Step A, 2.54 g, 9.4 mmol) in warm dimethylfom~amide (5
mL)
was added dropwise and stirred at ambient temperature for 2 h then heated to
100 °C
for 0.5 h. Thelmixture was quenched in saturated aqueous sodium bicarbonate
and
extracted twice with ethyl acetate. The combined extracts were washed once
with
water, once with saturated aqueous sodium chloride and the organic layer was
dried
over sodium sulfate and filtered. The filtrate was evaporated to an oil which
was
purified by flash chromatography (9:1 dichloromethane:methanol) to give the
title
compound of Example 188, Step B as an oil, 0.50 g (62%). 'H NMR (CDCI,, 400
MHz) S 1.01 (m, 6H), 2.35-2.88 (m, 5H), 3.32 (m,1H), 6.81 (d,1H), 8.16-823 (m,
2H),
9.25 (d, 1 H); MS (CI) 260 (MN').
Step C: 1R-f4-f2R.6S-Dimethvl-4-l2-(1.2 3]triazol-1-vl-ovrimidin-4-vi)-
oioerazin-1-v(1
p~rrimidin-2-vll-ethyl butvrat~. To a solution of 4-(3R,5S-dimethyl-piperazin-
1~t)-2
(1,2,4)triazol-1-yl-pyrimidine (prepared according to the method of Example
188, Step
B, 0.46 g,1.8 mmol) in acetonitrile (3 mL) was added (R~1-(4-
methanesulfonyloxy-
pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of
Preparation Eight,
0.57 g, 2.0 mmol) and heated to refiux for 6 h under nitrogen atmosphere. The
mixture was quenched in saturated aqueous sodium bicarbonate and extracted
twice
with ethyl acetate. The combined extracts were washed once with water, once
with
saturated aqueous sodium chloride and the organic layer was dried over sodium
sulfate and filtered. The filtrate was evaporated to an oil which was purified
by flash
chromatography (9:1 dichloromethane:methanol) to give the title compound of
Example 188, Step C as an oil, 0.22 g (54%). 'H NMR (CDCI,, 400 MHz) b 0.95
(t,
3H),1.51 (m; 6H), 1.54 (d, 3H), 1.63 (m, 2H), 2.38 (t, 2H), 3.38 (m, ZH), 4.33-
4.64 (m,
4H), 5.68 (q,1 H), 6.28 (d, 1 H), 6.58 (d,1 H), 8.10 (s,1 H), 8.26-8.32 (m,
2H), 9.10 (d,
1 H); MS (Cl) 452 (MH'); [a]p +50.0~(c 1.0, MeOH).


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Step D: 1R-l4-f2R.6S-Dimethvl-4-l2-f1.2.41triazol-1-vl-pyrimidin-4-vl)-
oioerazin-1-vll-
pvrimidin-2-vl)-ethanol. 1 R-{4-[2R,6S-Dimethyt-4-(2-j.1,2.3jtriazoi-1-yl-
pyrimidin-4-yl)-
piperazin-1-y(j-pyrimidin-2-yl}-ethyl butyrate (prepared acxording to the
method of
Example 188, Step C, 0.18 g, 0.40 mmol) was combined with concentrated
hydrochloric acid (2 mL) and stirred at ambient temperature for 4 h. The
mixture was
quenched in saturated aqueous sodium bicarbonate and extracted twio~ with
ethyl
acetate. The combined extracts were washed once with water, once with
saturated
aqueous sodium chloride and the organic layer was dried over sodium sulfate
and
filtered. The filtrate was evaporated to an oil which was purified by flash ~
,
chromatography (9:1 dichloromethane:methanol) to give the title compound as a
white
solid, 0.13 g (87%). 'H NMR (CDCI,, 400 MHz) 81.31 (d, 6H), 1.51 (d, 3H), 3.42
(m,
2H), 4.42-4.73 (m, 5H), 6.41 (d, 1 H), 6.56 (d, 1 H), 8.12 (s, 1 H), 8.24 {d;
1 H), 8.30 (d,
1 H), 9.10 (s, 1 H); MS (CI) 382 (MH'); [ajo +18.6 (c 1.0, MeOH).
Examples 189 to 195
Examples 189 to 195 were prepared from the appropriate starling materials in a
manner analogous to the method of Example 188.
HO
R" R6 .."Me
~N N-
N~ ~ N
s s
R'
Example R" R' R' mp (C) MS (MH')


189 2-hydroxyphenyl 2R-Me 6S-Me 60-70 407


190 imidazol-1-yl 2R-Me 6S-Me 60-70 381


191 [1,2,3]triazol-1-yl 2R-Me 6S-Me 70-80 382


192 , pyrrol-1-yl 2R-Me 6S-Me 70-80 380


193 4-methylimidazol-1-yl2R-Me 6S-Me 70-80 395


194 2-methylimidazol-1 2RMe 6S-Me 70-80~ 395
yl


195 2.4~imethylimidazol-1-yl2R-Me 6S-Me 70-80 409




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Examote 196 ,
1R-f4-f2R 6S-Dimethvl-4-(4-f1 2 4ltriazol-1-vl-pyrimidin-2-yll-oioerazin-1-yll-
pyrimidin-
2-vl?-ethanol. ,
N~N HO
'N Me ~~~~Me
N ~ N-
~~N N ~ / N
N
Me
Step A: 2-Thiomethvl-4-f1.2.41triazol-1-vl-pvrimidine. To a slurry of sodium
hydride
(60% dispersion in oil, 24.2 g, 605 mmol) in dimethylformamide (800 mL) was
added a
solution of 1,2,4-triazole (0.67 g, 9.4 mmol) in dimethylfom~amide (4.0 mL) at
0 °C
under nitrogen atmosphere. After 10 min, a solution of 4-chloro-2-methylthio-
pyrimidine (97.2 g, 605 mmol) in dimethyffom~amide (200 mL) was added dropwtse
at
10 °C and stirred at ambient temperature for 14 h: The ni~xture was
quenched in
water and the solid precipitate was filtered off and'~dried under vacuum to
give the title
compound of t=xample 196, Step A as a white solid, 113.8 (94%). 'H NMR (CDCt,,
400 MHz) b 2.82 (s, 3H), 6.82 (d, 1 H), 8.18 (d, 1 H), 8.19 (s, 1 H), 9.35 (s,
1 H); mp:
125-126 °C; MS (CI) 194 (MH').
Step B: 2-Methanesulfonvl-4-f1.2.41triazol-1-vl-pvrimidine. To a mechanically
stirred
suspension of 3-chloroperoxybenzoic acid (75%, 127 g, 551 mmol) in chloroform
(625
mL) was added a solution of 2-thiomethyl-4-[1,2,4)triazof-1-yl-pyrimidine
(prepared
according to the method of Example 196, Step A, 50.7 g, 262 mmol) in
chloroform
(625 mL) and stirred at ambient temperature for 16 h. The mixture was filtered
and
the filtrate was washed six times with saturated aqueous sodium cartxmate. The
organic layer was dried over sodium sulfate, filtered, and concentrated to
give the title
compound of Example 196, Step B as a white solid, 37.8 g (64%). 'H NMR (CDCI,,
400 MHz) S 3.62 (s, 3H), 6.82 (d, 1 H), 8.19 (s, 1 H), 8.24 (d, 1 H), 9.35
(s,1 H); mp:
135-136 °C; MS (CI) 226 (MH').


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Step C: 2-(3R.5S-Dimethvl-oiperazin-1-vl>-4-t1.2.4],fiazol-1-vl-ovrimidine, v2-

;,
Methanesulfonyi-4-[1,2,4]triazot-7-yhpyrimidine (prepared according to the
procedure
of Example 196, Step B, 32.5 g, 144 mmol) was combined with cis-2,6-
dimethylpiperazine (34.5 g, 302 mmol) and heated neat at 135 °C for i
h, cooled,
dissolved in 2 N aqueous hydrochloric acid and washed once with ethyl acetate.
The
acidic aqueous layer was basified to pH 9 with 6 N aqueous sodium hydFoxide at
0 °C
then extracted four times with ethyl acetate. The combined extracts were
washed
once with water, once with saturated aqueous sodium chloride and the organic
layer
was dried over sodium sulfate and filtered. The filtrate was evaporated to pn
oil which
crystallized from hexanes to give the title compound of Example 196, Step C as
a
white solid, 31.8 g (71 %). 'H NMR (CDCI,, 400 MHz) b 0.99 (d, 6H), 2.38 (m,
4H),
3.30 (s, 2H), 6.82 (d, 1 H), 8.18 (d, 1 H), 8.19 (s, 1 H), 9.35 (s, 1 H); mp:
14~-145 °C; MS
(CI) 260 (MH').
Step D: 1R~4-f2R.6S-Dimethvl-4-(4-f1.2.41triazol-1-vl-p"~imidin-2-vl~pioerazin-
1-vl1-
wrimidin-2-vl1-eth~f but~rrate. To a solution of 2-(3R,5S-dimethyl-piperazin-1
ylr4~-
[7,2,4jtriazol-1-yl-pyrimidine (prepared according to the method of Example
196, Step
C. 8.33 g, 32.1 mmol) in acetonitrile (30 mL) was added (R}-1-(4-
trifluoromethanesutfonyloxy-pyrimidin-2-yl)-ethyl butyrate (prepan:d according
to the
method of Preparation Nine, 5.50 g, 16.1 mmol) and heated to reflux for 3 h
under
nitrogen atmosphere. The tooted mixture was filtered and the solids were
washed
twice with ethyl acetate. The combined extracts were washed once with water,
once
with saturated aqueous sodium chloride and the organic layer was dried over
sodium
sulfate and filtered. The filtrate was evaporated to an oil which was purified
by flash
chromatography (99:1 dichloromethane:methanol) to give the title compound of
Example 196, Step D as an oil, 3.61 g (50%). 'H NMR (COCI,, 400 MHz) b 0.91
(d.
6H), 1.26 (t, 3H), 7.59 (d, 3H), 1.69 (q, 2H), 2.40 (m, 2H), 3.40 (d, 2H),
4.60 (m, 4H),
5.70 (q,1 H), 6.39 (d, 7 H), 6.58 (d, 1 H), 8.12 (s,1 H), 8.25 (d, 1 H), 8.31
(d,1 H), 8.35
(s, 1 H); MS (CI) 452 (MH').
Step E: 1R-f4-T2R.6S-Dimethvl-4-(4-f1 2 4ltriazol-1 yl-ovrimidin-2-vl>-
ninerazin-1-vt1-
gyrimidin-2-vl~-ethanol. 1R-{4-[2R,6S-Dimethyl~-(4-j1,2,4]triazol-1-yl-
pyrimidin-2-yl~
piperazin-1 yQ-pyrimidin-2-yl}-ethyl butyrate (prepared according to the
method of
Example 196, Step D, 3.60 g, 8.0 mmol) was combined with concentrated
hydrochloric aad (10 mL) and stirred at ambient temperature for 4 h. The
mixture was


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quenched in saturated aqueous sodium bicarbonate and extracted twice with
ethyl
acetate. The combined extracts were washed once with water, once with
saturated
aqueous sodium chloride and the organic layer was dried over sodium sulfate
and
filtered. The filtrate was evaporated to an oi! which was purified by flash
chromatography (99:1 dichloromethane:methanol) to give the title compound as a
white solid, 2.35 g (77%). 'H NMR (CDCI,, 400 MHz) 81.31 (d, 6H), 1.51 (d,
3H),
3.34 (m, 2H), 4.42 (m, 2H), 4.68.82 (m, 3H), 6.42 (d, 1 H), 7.11 (d, 1 H),
8,11 (s, 1 H),
8.23 (d, 1 H), 8.49 (d, 1 H), 9.12 (s, 1 H); mp: ~s~-Fez ~c; MS (CI) 382
(MH').
Examples 197 to 200
Examples 197 to 200 were prepared from the appropriate starting materials in a
manner analogous to the method of Example 196.
HO
Rs ..
R"
N-
- ~---N N ~ / N
N s s
R'
Example R" R' R" mp (~C) MS (Mti~



197 imidazol-1-yl 2R-Me 6S-Me 60-70 381


198 morphQlin-4-yl 2R-Me 6S-Me 70-80 400


199 pyrrolidin-1-yl 2R-Me 6S-Me 70-80 384


200 4-methylpiperazin-1-yl3R-Me 5S-Me 168-170 413


~xamale 201
1R-f4-t2R.fiS-0imethvl-4-!2-ovridin-3-y!-ovrimidin~l-vl>~oiperazin-1-vl~-
ovrimidin 2 vll'
ethanol.


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wo oors9s><o rcrr><aoorooZ9s
-21 &
,,
~~~~Me '
Step A: 2-Pvridin-3-vl-pvrimidin~-vl fifluoromethanesulfonate. To a solution
of 2-
pyridin-3-yi-3H-pyrimidin-4-one (150 mg, 0.87 mmol; J. Med. Chem. 1990, 33,
1230)
and triethytamine (Q.13 mL, 0.95 mmol) in dichloromethane (3 mL) was added
dropwise a solution of trifiuoromethanesulfonic anhydride (0.22 mL, 0.91 mmol)
in
dichloromethane (2 mL) at 0 °C under nitrogen atmosphere. The mixture
was allowed
to stir for 30 min at 0 °C then diluted with dichloromethane and washed
qnce with
water and the aqueous layer was extracted twice with dichloromethane. The
organic
extracts were combined, washed sequentially with saturated aqueous sodium
carbonate and saturated aqueous sodium chloride, dried over sodium sulfate and
filtered. The filtrate was evaporated to give the tifle compound of Example
201, Step
A as an orange oil, 0.22 g (95%), that was used without further purifrcation.
Step B: 1 R-f4-f2R.6S-Dimethvl-4-!2-ovridin-3-vt-pvrimid'm-4-vl~oioerazin-1
v11-
eyrimidin-2-yll-ethanol. A solution of 2-pyridin-3-yl-pyrimidin-4-yl
trifiuoromethanesulfonate (prepared according to the mett~d of Example 201,
Step A,
0.15 g, 0.5 mmol) in tetrahydrofuran (3 mL) at 0 °C was added dropwise
to a solution
of 1R-[4-(2R,6S-dimethyl-piperazin-1yl)-pyrmidin-2-ytJ~thyl butyrate (prepared
according to the method of Preparation Four, 0.15 g, 0.45 mmol) in
tetrahydrofuran (2
mL) and stirred for 1 h at ambient temperature. The mixture was quend~ed in
saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate.
The
combined extracts were washed once with water, once with saturated aqueous
sodium chloride and the organic layer was dried over sodium sulfate and
filtered. The
filtrate was evaporated to an oil and dissolved in concentrated hydrochloric
aad (3
mL) and stirred at ambient temperature for 4 h. The mixture was quendied in
saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate.
The
combined Extracts were washed once with water, once with saturated aqueous
sodium chloride and the organic layer was dried over sodium sulfate and
filtered. The


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filtrate was evaporated to give the title compound as a white foam; 0.091 g
(48%). 'H
NMR (CDCI,, 400 MHz) 81.31 (d, 6H), 1.51 (d, 3H), 3;,34 (m, 2H), 4.42-4.70 (m,
4H),
4.71 (q, 1 H), 6.40 (d, 1 H), 6.56 (d,1 H), 7.37 (m, 1 H), 8.22 (d, 1 H), 8.36
(d, 1 t;), 8.62-
8.68 (m, 2H), 9.53 (m, 1H); mp: 61-70 °C; MS (Ct) 392,(MH').
Examcle 202
1 R-(4-f2R.6S-Dimethvl-4-f2-l4-methyl-oiaerazin-1-vil-avrimidin-4-v11-
oioerazin-1-vlf-
pvrimtdin-2-vll-ethanol.
Me
HO
Me ~~~~Me
N
N~ N ~ ~ N
Me
Step A: 1 R-f4-f4-(2-Methanesulfonvl-ovrimidin~-vll-2R 6S-dimethvl-oioerazin-1
v11=
pvrimidin-2-vf!-ethyl butyrate. To a solution of 4-(3R,5S-dimethyl-piperazin-1-
yl}-2-
methanesulfonyl-pyrimidine (prepared according to the method of Example 188,
Step
A, 7.70 g, 14.3 mmol) in aoetonitrile (30 mL) was added 1 R-(4-
trifluoromethanesulfonyloxy-pyrimidin-2-yl~thyl butyrate, (prepan:d according
to the
method of Preparation Nine, 5.50 g, 16.1 mmol) and heated to reflux for 3 h
under
nitrogen atmosphere. The cooled mixture was filtered and the solids were
washed
twice with ethyl acetate. The combined extracts were washed once with water;
once
with saturated aqueous sodium chloride and the organic tayer was dried over
sodium
sulfate and filtered. The filtrate was evaporated to an oil which was purified
by flash
chromatography (98:2 dichloromethane:methanot) to give the tifle compound of
Example 202, Step A as an oil, 4.01 g (62%). 'H NMR (CDCI,, 400 MHz) 8 0.93
(t,
3H},1.21 (d, 6H),1.55 (d, 3H),1.64 (q, 2H), 2.36 (t, 2H), 3.25 (s, 3H), 3.37
(m, 2H),
4.5-4.7 (m, 4H), 5.65 (q, 1 H), 6.33 (d,1 H), 6.68 (d,1 H), 8.22 (d,1 H), 8.28
(d,1 H); MS
(Cl} 463 (MH').
Step B: 1 R-f4-f4-(2-Methanesulfonvl-pvrimidin-4-yl~2R 6S-dimethyl-o~~erazin-1
vtl-
pvrimidin-2-vIt-ethanol. 1 R-(4-[4-(2-Methanesulfonyl-pyrimidin-4-
yIr2R,6S~imethyl-
piperazin-1 y(]-pyrimidin-2-yI}-ethyl butyrate (prepared according to the
method of


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~~~~Z~
Example 202. Step A, 0.42 g, 0.9 mmol) was combined with concentrated ~'
hydrochloric acid (3 mL) and stirred at ambient temperature for 4 h. The
mixture was ''
quenched in saturated aqueous sodium bicarbonate and extracted twice with
ethyl
acetate. The combined extracts were washed once with water, once with
saturated
aqueous sodium chloride and the organic' layer was dried over sodium sulfate
and
filtered. The filtrate was evaporated to an oil which was purified by flash .
chromatography (99:1 dichloromethane:methano!) to give the title compound of
Example 202, Step B as a white foam, 0.25 g (71 %). 'H NMR (CDCI,, 400 MHz) 8
1.26 (d, 6H).1.50 (d, 3H), 325 (s, 3H), 3.41 (m, 2H), 4.5-4.7 (m, 5H), 6.37
(d, 1 H),
6.71 (d, 1 H), 8:24 (d, 1 H), 8.30 (d, 1 H); MS (CI) 393 (MH').
Step C: 1 R-l4-f2R.6S-Dimethvl-4-f2-!4-methyl-oioerazin-1 of ~nvrimidin-4-vl1-
pic~erazin-1-yl?-wrimidin-2-vl>-ethanol. 1 R-{4-(4-(2-Methanesulfonyf-pyimidin-
4-yt}-
2.6-dimethyl-piperazin-1-yQ-pyrimidin-2-yf}-ethanol (prepared according to the
method
of Example 202, Step B, 0.25 g, 6.4 mmol) was combined with N-methylpiperazine
(2.0 mL) and heated at 80 °C for 1 h under nitrogen atmosphere. The
mixture was
quenched in water and extracted twice with ethyl acetate. The combined
extracts
were washed once with water, once with saturated aqueous sodium chloride and
the
organic layer was dried over sodium sulfate and filtered. The filtrate was
evaporated
to an oil which was purified by flash chromatography (96:4
chlorofortn:methanol) to
give the title compound as a white foam, 0.11 g (41%). 'H NMR (CDCI,, 400 MHz)
8
1.31 (d, 6H),1:51 (d, 3H), 2.47 (s, 3H), 2.63 (m, 4H), 323 (m, 2H), 3.94 (m,
4H), 4.33
(m, 2H), 4.57 (m, 2H), 4.71 (q, 1 H), 5.96 (d, 1 H), 6.46 (d, 1 H), 7.98 (d, 1
H), 823 (d,
1H); mp: 60-70 °C; MS (CI) 413 (MH').
Examples 203 to 207
Examples 203 to 207 were prepared from the appropriate starting materials in a
manner analogous to the method of Example 202.


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HO
R6 I ' ..., Me
// N ~ ~ N-
N~N N ~ / N
s ' s .
R'
Example R" R' R° mp (°C) MS (MH')
203 morpholin-4-yl 2R-Me fiS-Me 70-80 400
204 pyrrolidin-1-yl 2R-Me 6S-Me 70-80 ~ 384
205 2,6-dimethylmorpholin-4-yi 2R-Me 6S-Me 42g
206 3,5-dimethylpiperidin-1-y1 2R-Me 6S-Me 426
207 5-methyl-furan-2-yl 2R-Me 6S-Me 123-128 395
Example 208
1 R-f4-f3R.5S-Dimethyl~-l2-(4-methyl-piaerazin-1-vl)-ayrimidin-4-v(i-oiperazin-
1-vi>'-
gvrimidin-2-vl~thanol.
~~~Me
Me
Step A: ~Benzyl-2R.6S-dimet~l-piperazin-1-vl~-2-methanesulfonvl-vvrimidine.
To a solution of as-1-benzyl-3,5-dimethylpiperazine (24.9 g, 122 mrnol, O~g.
Prep.
Proceed. Int 1976, 8,19) in dimethylacetamide (60 mL) was added 4-.chloro-2-
methanesulfonyl pyrimidine (11.8 g, 61.3 mmol) and stirred for 16 h at 120
°C. The
mixture was partitioned between water and ethyl acetate and the aqueous layer
was
extracted three times with ethyl acetate. The combined organic layers were
washed
three times with 1% aqueous copper sulfate, once with saturated aqueous sodium
chloride and the organic layer was dried over sodium sulfate and filtered. The
filtrate
was evaporated to an orange solid which was slurried in isopropyl ether (100
mL) and
filtered to give the title compound of E~cample 208, Step A as an orange
solid, 16.5 g


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(75%). 'H NMR (CDCI,, 300 MHz) b 1.35 (d, 6H), 2.25 (m, 2H); 2.76 (m, 2H),
3.23 (s,
3H), 3.53 (s, 2H), 4.35-4.65 (m, 2H), 6.51 (d, 1 H), 7.26 (m, 2H), 7.34 (m,
3H), 8.24 (d,
1 H); MS (CI) 361 (MH').
Step B: 4-(4-Benzyl-2R.6S-rJimethvl-piaerazin-1-yl~-2~4-methvlpiperazin-1-vl~
evrimidine.4-(4-Benzyl-2R,6S-dimethyipiperazin-1-y1~2-
methanesulfonylpyrimidine
(prepared according to the method, of Example 208, Step A, 11.5 g, 31.9,mrnol)
was
combined with N-methylpiperazine (15 mL, 128 mmol) and heated to 120 °C
for 2 h.
The mixture was diluted with ethyl acetate and washed once with water, once
with
saturated aqueous sodium chloride and the organic layer was dried over sodium
sulfate and filteted. The filtrate was evaporated to give the title compound
of Example
208, Step 8 as an orange solid, 14.7 g (84%). 'H NMR (CDCI,, 300 MHz) 81.30
(d,
6H), 2.21 (m, 2H), 2.33 (s, 3H), 2.46 (m, 4H), 2.72 (d, 2H), 3.53 (s,
2H),~~.78 (m, 4H),
4.31 (m. 2H), 5.79 (d, 1 H), 7.24 (m, 2H), 7.31' (m, 3H), 7.90 (d, 1 H); MS
(Cl) 381
(MH').
Step C: 4-(2R.6S-Dimethvl-oiperazin-1-vl~-2-(4-methvloiaerazin-1-vl~-
ovrimidine. To
a solution of 4-(4-benzyl-2R,6S-dimethyipiperazin-1-yl)-2-(4-methyl-piperazin-
1-ylr
pyrimidine (prepared according to the method of Example 208, Step B. 9.8 g,
25.8
mmol) in methanol (200 mL) and hydrochloric acid (1 N in ethyl ether, 38.7 mL,
38.7
mmol) was added ammonium fom~ate (16.3 g, 25.8 mmol). After stirring at
ambient
temperature for 5 min, 10% palladium on carbon (1.96 g, 20 wt% pre-wetted with
isopropanol) was added and this mixture was heated to reflux for 2 h. The
cooled
reaction was filtered and the filtrate was concentrated to a solid, which was
diluted
with ethyl acetate and washed twice with water, once with saturated aqueous
sodium
chloride and the organic layer was dried over sodium sulfate and filtered. The
filtrate
was evaporated to give the tide compound of Example 208, Step C as a dear oil,
6.01
g (81%). 'H NMR (CDCI,, 300 MHz) b 1.25 (s, 6H), 2.31 (s, 3H), 2.24-2.44 (m,
4H),
2.90 (m, 4H), 3.76 (m, 4H), 4.25 (m, 2H), 5.79 (d,1 H), 7.90 (d, 1 H); MS (C1)
291
(MH').
Step D: 1 R~4-f3R.5S-Dimethvl-4-f2-l4-meth~rl-piperazin-1-vl~-nvrimidin-4-y,11-

pioerazin-1-yll-pvrimidin-2-vl)-ethyl butyrate. To a solution of 4-(2R,6S-
dimethyl-
piperazin-1-yl)-2-(4-methyl-piperazin-1-yl)-pyrimidine (prepared according to
the
method of Example 208, Step C, 9.0 g, 31.1 mmol) and triethylamine (6.5 g,
46.5
mmol) in dimethytforrnamide (90 mL) was added (R}-1-(4-chloro-pyrimidin-2-yl)-
ethyl


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butyrate (prepared according to the method of Preparation Seven; 7.78 g, 34.1
mmol)
and heated to reflux for 3 h under nitrogen atmosphere, The cooled mixture was
filtered and the solids were washed twice with ethyl acetate. The combined
extracts
were washed once with water; once with saturated aqueous sodium chloride and
the
organic layer was dried over sodium sulfate and filtered: The filtrate was
evaporated
to an oil which was purified by flash chromatography (95:5
chlorofortn:methanol) to
give the title compound of Example 208, Step D as an oil, 11.4 g {76%). 'H
NMft
(CDCI,, 300 MHz) s o.95 (t, 3H), 1.18 (d, 6H), 1.54 (d, 3H), 2.23-2.35 (m,
7H), 2.51
(m, 4H), 3.21 (m, 2H), 3.81 (m, 4H), 4.32 (m, 2H), 4.52 (m, 2H), 5.65 (q, 1
H), 5.82 (d,
1 H), 6.38 (d, 1 H), 7.39 (d, 1 H), 8.18 (d, 1 H); MS (CI) 483 (MH').
Step E: 1 R-(4-f3R.5S-Dimethvl-4-12-f4-methyl-ninerazin-1 girl)-ovrimidin-4-
,y11-
piperazin-1-vl~-oyrimidin-2-vll-ethanol. 1 R-(4-{3R,5S-dimethy(~-[2-(4-methyl-
piperazin-1-yl)-Pyimidin-4-yf)-piperazin-1-yl}-pyrimidin-2-yl)-ethyl butyrate
{prepared
according to the method of Example 208, Step D, 11.3 g; 23.5 mmol) was
combined
i 5 with concentrated hydrochloric acid (60 mL) and stirred at ambient
temperature for 4
h. The mixture was quenched in saturated aqueous sodium bicarbonate and
extracted five times with 10~ isopropanoUchlorofortn. The combined extracts
v~re
washed once with saturated aqueous sodium chloride and the organic layer was
dried
over sodium sulfate and filtered. The filtrate was evaporated to an oil and
crystallized
from isopropanol to give the title compound as a white solid, 7.34 g (76%). 'H
NMR
(CDCI,, 300 MHz) 81.21 (d, 6H), 1.51 {d, 3H), 234 (s, 3H), 2.45 (m, 4H), 3.24
(m,
4H), 3.76 (m, 2H), 4.30.53 (m, 4H), 4.68 (q, 1 H), 5.82 (d, 1 H), 6.42 (d,1
H), 7.94 (d,
1 H), 8.21 (d, 1 H); rr~: ~s~-~e2 ~c; MS (CI) 413 (MH').
Examples 209 to 211
Examples 209 to 211 were prepared from the appropriate starting materials in a
manner analogous to the method of Example 208.

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.."Wle .
Example R" R' R mp (Cj ~ ' MS (MH'j


209 2,6-dimethyfmorpholin-4-yf3R-Me 5S-Me 428


210 4-ethyfpiperazin-1-yl3R-Me 5S-Me 144-146 427


211 4-isopropylpiperazin-1-yl3R-Me 5S-Me 137-139 ' 441


Example 212
1 R-f4-f2R.6S-Dimethvl-4-(4-mornho(ino~-yl-f1.3.51triazin-2-yl~aioe zin-1-vt1-
oyrimidin-2-yl~-ethanol.
~~~Me
Me
Step A: 1R~4-f4-(4-Chloro-6-morphoiino-f1.3.51triazin-2-vl~2R.6S-
dimethyloioerazin-
1-vt~-nvrimidin-2-vl1-~thvl butyrate. To a solution of 1R-[4-(2R,6S-dimethyl-
piperazin-
1-yl)-pyrimidin-2-yq-ethyl butyrate (prepared according to the method of
Preparation
Four, 0.31 g, 1.0 mmol) and sodium bicarbonate (0.17 g, 2.0 mmol) in
dimethyffomiamide (3 mL) was added 2,4-dichloro-6-morpholino-[1,3,5jtriazine
(0.24
g,1.0 mmol; Chem. Pharm. Bull.1997, 45, 291 ) and stirred at ambient
temperature
for 2 hours. The mixture was diluted with ethyl acetate and washed twice with
water,
once with saturated aqueous sodium chloride, and the organic layer was dried
over
sodium sulfate and filtered. The filtrate was concentrated to an oil, which
was purified
by flash chromatography (99:1 chlorofortn:methanol) to give the title compound
of
Example 212, Step A as a white solid, 0.19 g (37%). 'H NMR (CDCIs, 300 MHz) b
0.93 (t, 3H), 1.23 (d, 6H), i :53 (d, 3H), ,1.66 (m, 2H), 2.37 (t, 2H), 3.16
(m, 2H), 3.72-


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3.78 (m, 10H), 4.12-4.78 (m, 2H), 5.65 (q, 1 H), 6.34 (d,-1 H). 8.1~, {m, 2H);
MS (CI)
505, 507 (MH').
Step B: 1R-~4=f2R.fiS-Dimethv!-4-(4-morahofino-4-vl-f1.3.51triazin-2-vl)-
o'roerazin-1-
yj]wrimidin-2-vll-ethanol. To a solution of 1 R-{4-[4-(4-chloro-6-morphotino-
[1,3,5]triazin-2-yIr2R,6S-dimethyl-piperazin-1-y~-pyrimidin-2-yl}-ethyl
butyrate
(prepared according to the method of Example 212, Step A, 0.15 g, 0.35 mmo()
in
ethanol (10 mL) was added 10% palladium on carbon (0.75 g, 500 wt %) and
hydrogenated at 45-50 psi using a Parr apparatus for 12 hours. The catalyst
was
fettered off and the filtrate was concentrated to an oil which was added to
concentrated
hydrochloric acid (2 mL) and stirred at ambient temperature for 6 hours. The
mixture
was diluted with chloroform and washed twice with water, once with saturated
aqueous sodium chloride and the organic layer was dried over sodium sulfate
and
filtered. The filtrate was concentrated to give the title compound as a white
solid, 0.47
g (40%). 'H NMR (CDCI3, 300 MHz) b 1.23 (d, 6H), 1.53 (d, 3H), 3.16 (m, 2H),
3.72-
3.78 (m, 10H), 4.12-4.78 (m, 3H), 6.34 (d,1 H), 8.19 (m, 2H); mp: 78-82
°C; MS (C1)
401 (MH'); [a]o +15.1 (c 1Ø MeOH).
Example 213
1 R~4-f4-l4-Methoxv-6-methyl-f 1.3.51triazin-2-yl)-3R.5S-dimethyloioerazin-1~~
pyrimidin-2-vff-ethanol.
HO
Me0 Me ~~~~Me
N-
N ~N N ~ / N
~N
Met Me
Step A: 1 R-(4-f4-(4-Chlpro-6-methyl-f1.3.51tciazin-2-vl~3R.5S-
dimethylninerazin-1-vfi-
pvrimidin-2-vl)-ethyl butyrate. To a solution of 1R-[4-(3R,5S-dimethyl-
piperazin-1 ylr
pyrimidin-2-yl]-ethyl butyrate (prepared according to the method of
Preparation
Three, 1.47 g, 6.43 mmol) and sodium bicarbonate (2.25 g, 26.8 mmol) in
dimethylfomiamide (10 mL) was added 2,4-dishloco-6-methyl-[1,3,5]triazine
(0.88 g,
5.3 mmol; Monatsh. Chem.1970, 101, 724) and stirred at ambient temperature for
2
h. The mixture was diluted with ethyl acetate (150 mL) and washed twice with
water,
once with 10% aqueous CuSO,, once with saturated aqueous sodium chloride, and


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the organic layer was dried over sodium sulfate and filtered. The filtrate was
;
concentrated to give the title compound of Example 213, Step A as a tan
soi'~d, 2.12 g
(91%). 'H NMR (CDCI,, 300 MHz) b 0.93 (t, 3H), 1.23 (m, 6H), 1.54 (d, 2H),
1.fi6 (m,
2H), 2.31 (s, 3H), 2.37 (m, 2H), 2.41 (s, 1H), 3.19 (m, 2H); 4.22-4.55 (m,
2H), 4.91 (m,
2H), 5.65 (q, 1 H), fi.40 (d, 1 H), 820 (d,1 H); MS (CI) 434, 436 (MH').
Step B: 1 R-14-f4-(4-Methoxv-6-methyl-f1.3.5ltrtazin-2-yl)-
3R.5S~iimethvtoiDerazin-1-
vll-ovrimidin-2-vl)-ethanol. A solution of sodium methoxide in methanol was
freshly
prepared by allowing sodium metal (0.4 g, 17.3 mmol) to dissolve in methanol
(40
mL). To this mixture was added 1R-{4-[4-(4-chloro-6-methyl-[1,3,5)triazin-2-
yf}-
3R,5S-dimethyl-piperazin-1-ylj-pyrimidin-2-yl}~thyl butyrate (prepared
according to
the method of Exarnpie 213, Step A, 1.5 g, 3.46 mmol) which was stirred at
ambient
temperature for 76 h. The reaction mixture was evaporated to an oil, diftrted
with
chloroform and washed twice with water, once with saturated aqueous sodium
chloride, and the organic layer was dried over sodium sulfate and filtered.
The filtrate
was concentrated to a dear oil which was crystallized ft~om isopropyl ether to
give the
title compound as a white solid, 0.85 g (72%). 'H NMR (CDCI,, 300 MHz) 81.23
(d,
6H), 1.48 (d, 3H), 2.36 (s, 3H), 3.20-3.26 (m, 2H), 3.90 (s, 3H), 4.18.43 (m,
2H),
4.63 (m, 2H), 4.68 (q, 1 H), 4.85 (d, 1 H), 6.42 (d, 1 H), 8.18 (d, 1 H); mp:
161-162 °C;
MS (CI) 360 (MH'); [ajo +16.8 (c 1.0, MeOH).
Example 214
1 R-f4-f4-14.6-Dimethoxv-f1.3.51triazin-2-vI)-3R.5S-dimethyl-oiDerazin-1-vI1-
9vrimidin-
2-vl)-ethanol.
Me0 ~~Me
r--N
N~~
~N
Me0' Me
Step A: 1 R-f4-f4-f4.6-Dichloro-f 1.3.51triazin-2-v1)-3R.5S-dimethvl-Dioerazin-
1-vIt-
p~rrimidin-2-vll-ethyl butyrate. To a solution of 1R-[4-(3R,5S-Dimethyl-
piperazin-1-yl)-
pyrimidin-2-yf)-ethyl butyrate (prepared according to the method of
Preparation
Three, 3.25 g, 10.5 mmol) and sodium bicarbonate (1.01 8,19.2 mmol)~ in
dimethylfomlamide (8 mL) was added cyanuric chloride (1.76 g, 9.6 mmol) and
stirred


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at ambient temperature for 2 h. The mixture was diluted with ethyl acetate and
washed twice with water, onoe with saturated aqueous~,sodium diloride, and the
organic layer was dried over sodium sulfate and flitered. The filtrate was
concentrated
to give the title compound of F~cample 214, Step A,as a white semi-solid, 1.42
g
(68%). 'H NMR (CDCl3, 300 MHz) 8 0.93 (i, 3H), 1.23 (m, 6H), 1.54 (d, 3H),
1.66 (m,
2H), 2.37 (m, 2H), 3.19 (m, 2H), 4.42-4.55 (m, 2H), 4.91 (m, 2H), 5.65 (q,1
H), 6.40 (d,
1 H), 820 (d, 1 H); MS (Ci) 446, '448 (MH').
Step B: 1R-f4-f4-(4 6-Dimethoxv-f1 3 5ltriazin-2-vll-3R 5S-dimethvl-oinerazin
1 vi1
wrimidin-2-vlf-ethanol. A solution of sodium methoxide in methanol was freshly
prepared by allowing sodium metal (0.18 g, 8.0 mmol) to dissolve in methanol
(16
mL). To this mixture was added 1R-{4-(4-(4,6-dichloro-[1,3,5)triazin-2-yl}-
3R,5S-
dimethyt-piperazin-1-ylj-pyrimidin-2-yl}-ethyl butyrate (prepared according to
the
method of Example 214, Step A, 0.91 g, 2.0 minoi) at 0 °C, then wam~ed
to ambient
temperature for 1 h. The mixture was evaporated to an oil, diluted with
chloroform
and washed once with water, once with saturated aqueous sodium chloride, dried
over sodium sulfate and filtered. The filtrate was concentrated to a dear oil
which
crystallized from isopropyl ether to give the title compound as a white solid,
0.54 g
(72%). 'H NMR (CDCl3, 300 MHz) b 1.23 (d, 6H), 1.50 (d, 3H), 3.20 (m, 2H),
3.95 (s,
6H), 4.32 (m,1 H), 4.67-4.86 (m, 4H), 6.34 (d, 1 H), 8.22 (d,1 H); mp:187-188
°C; MS
(CI) 376 (MH').
Example 215
1R-f2R 6S-Dimethvl-4-(4-phenyl-f1 3 5ltriazin-2vl~oiDerazin-1-vl1-nvrimidin 2
vt>~-
ethanol.
HO
Me ~~~~Me
N-
---N N
N
Me
Step A: 1 R-f4-f4-l4-Chloro-6-phenyl-f1 3 5ltriazin-2-vl~-2R 6S-dimethvl-
oin~erazin-1
~~pyrimidin-2y11~-ethyl butyrate. To a solution of 1 R-(4-(2R,6S-dimethyl-
piperazin-
1yl}-pyrmidin-2yf}~thyl butyrate (Prepared according to the method of
Preparatron


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Four, 2.35 g, 7.67 mmol) and sodium bicarbonate (1.29.8,15.3 mmol) in ~ ,,
dimethylformamide (25 mL) at 0 °C was added 2,4-dichloro-6-
phenyl[1,3,5)trtazine
(1.73 g, 7.67 mmol; Helv. Chim. Ada 9950, 33, 1365) portionwise. The reaction
mixture was allowed to warm to room temperature and stir under nitrogen for 4
h,
poured into water then filtered to give the title compound of F~cample 215,
Step A as a
light tan solid, 1.99 g (51 %). 1 H NMR (CDCI,, 400 MHz) S 0.94 (t, 3H),1.25
(d, 6H),
1.57 (d, 3H), 1.68 (m, 2H), 2.40 (t, 2H), 327 (d, 2H), 4.65 (m, 2H), 4.82 (d,
1H), 5.00
(d,1 H), 5.68 (q,1 H), 6.34 (d,1 H), 7.46 im, 3H), 821 (d,1 H), 8.40 (d, 2H);
MS (CI)
496, 498 (MH'). ,,
Step B: 1 R-f4-f4-(6-Phenyl-f1.3.51trtazin-2-vIJ-2R.6S-dimethyt-cioerazin-1
yl1-
pvrimidin-2-vll-ethyl buivrate. To a solution of 1 R-{4-[4-(4-chloro-6-phenyl-
[1,3,5]triazin-2-yl~2R,6S-dimethyl-piperazin-1-yQ-pyrimidin-2-yI}-ethyl
butyrate
(prepared according to the method of Example 2i 5, Step A, 4.81 g, 9.7 mmol)
in
methanol (50 mL) was added 10% palladium on carbon (940 mg, 20 wt%),
ammonium fom~ate (5.98 g, 97 mmol), and hydrochloric aad (2 M in ethyl ether,
7.1
mL,14.2 mmol) and refluxed for 1.5 h. The mixture was allowed to cool, then
filtered.
The filtrate was concentrated and partitioned between chloroform and saturated
aqueous sodium bicarbonate. The organic layer was separated, dried over sodium
sulfate, filtered, and the filtrate was evaporated to an oil which was
purified by flash
chromatography (99:1 chlorofortn:methanol) to give the tithe compound of
Example
215, Step B as a dear oil, 2.69 g (59%). 1 H NMR (CDCI3, 400 MHz) b 0.95 (t,
3H),
125 (d, 6H), 1.57 (d, 3H),1.68 (m, 2H), 2.40 (t, 2H), 3.2? (d, 2H), 4.65 (m,
2H), 4.82
(d, 1 H), 5.00 (d, 1 H), 5.68 (q, 1 H), fi.34 (d, 1 H), 7.46 (m, 3H), 821 (d,
1 H), 8.40 (d,
2H), 8.66 (s, 1 H); MS (CI) 462 (MH').
Step C: 1 R--f2R 6S-Dimethvl-4-(4-ohenvl-f1 3 5ltriazin-2vlMioerazin-1 v(1-
ovrimidin 2
thanol. Concentrated hydrochloric add (10 mL) was added to 9 R-{4-[4-(6-phenyl-

[1.3.5]triazin-2-Y1~2R.6S~limethyl-piperazin-1 y(j-pyrimidin-2y(j-ethyl
butyrate
(prepared according to the method of Example 215, Step B, 2.69 g, 5.8 mrnol)
and
alla~nred to stir for 5 h at ambient temperature. The reaction mixture was
cooled to 0
°C, diluted with chloroform, and 6 M aqueous sodium hydroxide was added
slowly
until basic (pH 9). The layers were separated and the aqueous layer was
extracted
lwioe with chloroform. The combined organic extracts were washed once with
saturated aqueous sodium chloride, dried over sodium sulfate, filtered; and
the filtrate


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was concentrated to an oil which was purified by flash chromatography (97:3
chloroform:methanol) to give a white foam that crystallized from isopropyl
ether to give
the title compound as a white solid, 1.55 g (68%). 1 H NMR (CDCI,, 400 MHz) a
1.28
(d, 6H), 1.54 (d, 3H), 3.31 (d; 2H), 4.63 (m, 2H), 4'.77 (q, 1 H), 4.85 (d, 1
H), 5.50 (d,
1 H), 6.42 (d, 1 H), 7.50 (m, 3H), 8.25 (d,1 H), 8.41 (d, 2H), 8.68 (s, 1 H);
mp: 133-134
°C; MS (CI) 392 (MH'); [aJo +18.7 (c 1.07, MeOH).
Examples 216 to 235
Examples 216 to 235 were prepared from the appropriate starting materials in a
manner analogous to the method of Example 215.
~~~~Me
R

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ExampleR" R'= R6 R' , mp (C) MS (MHO
~ , ,


216 C7 morpholin-4-yl 2R-Me 6S-Me 138-141435; 437


217 H morpholin-4-yl 3R-Me 5S-Me 152 401


218 OMe morpholin-4-yl 2R-Me, 6S-Me 176-178431


219 Me 4-methyl-piperazin-3R-Me 5S-Me 428


1-yl " . ,


220 Me H 2R-Me 6S-Me 91-94 330


221 OMe OMe ~ 2R-Me 6S-Me 128-129376


222 OEt Me 3R-Me 5S-Me 141-1~2374


223 OiPr Me 3R-Me 5S-Me 87-91 388


224 phenyl H 3R-Me 5S-Me 154-1<55392


225 phenyl OMe 3R-Me 5S-Me , , 4~


226 phenyl OMe ~ 2R-Me6S-Me 135-138'422


227 iPr H 2R-Me 6S-Me 122-124358


228 iPr OMe 3R-Me 5S-Me 75-80 388


229 phenyl H H H 115-117364


230 OMe Me H H 173-175332


231 o-tolyl H 3R-Me 5S-Me 123-125406


232 o-tolyl OMe 3R-Me 5S-Me 143-145436


233 cydopropylH 3R-Me 5S-Me 134-135356


234 cydopropylH 2R-Me 6S-Me 133-134356


235 OMe CH=OMe 3R-Me 5S-Me 104-105390



Example 236


1R-f4-f4-(4-Hvdroxvm ethvl~-methoxv-f1.3.5itriazin-2-yl)-3R
erazin-1-
5S-dimeth
io


vIl-avrimidin-2-vll-ethanol.


~Me
_


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Step A: 1 R-f4-t4-(4-Chloro-6-diazomethvl-I1.3.51triazin-2-vi~3R.5S-dimethvt-
oiaerazin-1-vll-ovrimidin-2-vll-ethyl butyrate. To a solution of 1R-[4-(3R.5S-
dimethyl-
piperazin-1-yl)-pyrimidin-2-y~-ethyl butyrate (prepared according to the
method of
Preparation Three, 3.06 g, 10.0 mmol) and sodium bicarbonate (1.68 g, 20.0
mmol) in
dimethylformamide (10 mL) was added 2,4-dichloro-6-diazomethyl-[1,3,5jtriazine
(1.90 g, 10.0 mmol; J. Am. Chem. Soc. 1957, 79, 94.4) and stirred at ambient
temperature for 2 h. The mixture was diluted with ethyl acetate, washed twice
with
water, once with saturated aqueous sodium chloride, and the organic layer was
dried
over sodium sulfate and filtered. The filtrate was concentrated and purified
by flash
1fl chromatography (ethyl acetate) to give the title impound of Example 236,
Step A as
a foam, 1.84 g (4i °~). 'H NMR {CDCh, 300 MHz) 8 0.94 (t, 3H), 1.23 {m,
6H), 1.55 (d,
3H), 1.66 (m, 2H), 2.38 (m, 2H), 3.19 (m, 2H), 4.22-4.45 (m, 2H), 4.86 (m,
2H), 5.10
(s, 1 H), 5.65 (q, 1 H), 6.40 (d, 1 H), 8.20 (d, 1 Hj; ~mp: 106-108 °C;
MS (CI) 461, 463
(MH').
Step B: 1R-f4-f4-l4-Hvdroxvmethvl-6-methoxv-f1.3.51triazin-2-vllr3R 5S-
dimethvl-
vioerazin-1-vl1-ovrtmidin-2-vl1-ethanol. 1 R-{4-[4-(4-Chtoro-6-diazomethyl-
[1,3,5]triazin-2 yl)-3R,5S-dimethylpiperazin-1 ylJ-Pyrimidin-2-yt}-ethyl
butyrate
(prepared according to the method of Example 23fa, Step A,1.5 g, 3.2 mmoi) was
dissolved in ethyl acetate (20 mL) and 10% aqueous sulfuric acid {5 mL) was
added
slowly at ambient temperature, stirred 5 min then basfied to pH 9 with 6 N
aqueous
sodium hydroxide. The separated ethyl acetate layer was washed once with
brine,
dried over magnesium sulfate, and conoenVated to a semi-solid. To a freshly
prepared solution of sodium methoxide, generated by dissolving sodium metal
(0.92
g, 4.0 mmol) in methanol (6 mL), was added the crude solid (0.89 g, 2.0 mmol).
This
mixture was stirred for 4 h at ambient temperature then evaporated to dryness.
The
residue was purified by flash chromatography (95:5 dichiorornethane:methanoi)
to
give the title compound as a white solid, 0.084 g (13%). 'H NMR (CDCI,, 300
MHz) 8
1.23 (d, 6H),1.49 (d, 3H), 3.14-3.21 (m, 2H), 3.96 (m, 2N), 3.90 (s, 3H), 4.18-
4.38 (m,
2H), 4.69 (q, 1 H), 4.97 (m, 2H), 6.44 (d,1 H), 820 {d, 1 H); mp:170-171
°C; MS (CI)
376 (MH'); [a]o +16.6 (c 1.0, MeOH).
~amDle 237
1 R-t4-(4-(4-Methoxvmethvl-f 1 3 5ltriazin-2-vl1-3R 5S-dimethvl-niaerazin 1 v0-

pyrimidin=2-vll~-ethanol.


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' HO '.
Me w~~~Me '
~ ~ , N-
N ~N N ~ / N
~N ,
MeO~ Me
Step A: 1 R-(4-f4-(4-Chloro-6-methoxvmethvl-f1.3.51triazin-2-vl)-3R.5S-dime
pperazin-1-vll-ovrimidin-2-vl~-ethyl butyrate. 1R-(4-[4-(4-Chloro-6-
diazomethyl-
(1,3,5]triazin-2-yl}-3R,5S-dimethylpiperazin-1-yl]-pyrimidin-2-yl}-ethyl
butyrate
(prepared according to the method of Example 236, Step A, 1.5 g, 3.2 mmol) was
dissolved in methanol (10 mL) and 10% aqueous sulfuric acid (3 mL) was added.
This mixture was stirred at ambient temperature for 1 h then diluted with
ethyl acetate.
The separated ethyl acetate layer was washed once with saturated aqueous
sodium
chloride, dried over magnesium sulfate, and concentrated to an oil which was
purified
by flash chromatography (99:1 dichloromethane:methanol) to give the title
compound
of Example 237, Step A as an oil, 1.02 (60%). 'H NMR (CDCI,, 300 MHz) 8 0.95
(t,
3H), 1.26 (d, 6H), 1.58 (d, 3H), 1.67 (q, 2H), 2.41 (t, 2H), 3.24 (m, 2H),
3.51 (s, 3H),
4.18-4.38 (m, 4H), 4.69 (q, 1 H), 4.92 (m, 2H), 6.47 (d, 1 H), 8.24 (d, 1 H);
MS (CI) 464,
466 (MH').
Step B: 1 R-f4-f4-(4-Methoxvmethyl-f1.3.51triazin-2-vl)-3R,.5S-dimethvl-
oinerazin-1-v(1-
pvrimidin-2-vl''-ethanol. To a solution of 1 R-{4-(4-(4-chloro-6-methoxymethyl-

[1,3,5]triazin-2-yIr3R.5S-dimethpiperazin-1-yi]-pyrimidin-2-yl}-ethyl butyrate
(prepared according to the method of Example 237, Step A, 0.43 g, 0.92 mmol)
in
methanol (8 mL) and hydrochloric acid (2 M in ethyl ether, 0.7 mL, 1.37 mmol)
was
added ammonium formate (0.58 g, 9.2 mmol) and 10% palladium on carbon (0.085
g,
20 wt%) and heated to reflux for 3 h. The solvents were removed and
concentrated
hydrochloric aad (2 mL) was added and stirred at ambient temperature for 16 h,
based to pH 9 with 6 N aqueous sodium hydroxide and diluted with ethyl
acetate.
The separated ethyl acetate layer was washed once with saturated aqueous
sodium
chloride; dried over magnesium sulfate, and concentrated to an oil which was
purified
by flash chromatography (9:1 dichloromethane:methanol) to give the title
compound
as a whitesolid, 0.12 g (36%). 'H NMR (CDCI,, 300 MHz) 81.25 (d, 6H),1.49 (d,


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3H), 3.24 (m, 2H), 3.51 (s, 3H), 4.18-4.38 (m, 4H), 4.72 (q, 1 H), 4.97 (m,
2W), 6.47 (d,
,
1 H), 8.22 (d, 1 H), 8.57 (s, 1 H); MS (CI) 3fi0 (MH'). ,, ,
Exarrroles 238 to 240
Examples 238 to 240 were prepared from the appropriate starting materials in a
manner analogous to the method of Exariiple 237.
~~~~Me
Example R" Ru R' R mp (C) MS (MHO


238 CHZOH H 3R-Me 5S-Me 173=175 346


239 OMe CHZOMe 3R-Me 5S-Me 143-145 390


240 CHZOH phenyl 2R-Me 6S-Me 173-175 422


'


Example 241
1R-(4-f4-(4 6-Dimethvl-f1 3 5ltriazin-2-vtl-2R 6S~iimethvic~ioerazin-1 yl]-
nvrimidin-2-
th nol.
'Me
Step A: 1R-(4-L4-l4-Methyl-6-trichloromethyl-f1 3 5ltriazin-2-vl1-2R 6S-
dimethyl-
eoerazin-1-vf1-pyrimidin-2-vl>~-ethyl butyrate. To a solution of 1R-[4-(2R,6S-
dimethyl-
piperazin-1-yl}-pyrimidin-2-yl]-ethyl butyrate dibenzoyl-L-tartrate salt
(prepared
according to the method of Preparation Fifteen,1.33 g, Z.0 mmol) and sodium
bicarbonate (0.34 g, 4.0 mmol) in dimethylfomiamide (S mL) was added 2-methyl-
4,6-
R


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pCT/IB00100296
bis-trichloromethyt-[1,3,5jtriazine (1.00 g, 3.0 mmol; Butl. Chem. Soc., Jpn.
"1969, 42,
2924) and stirred at ambient temperature for 14 h. The mixture was diluted
with ethyl 1I
acetate and washed twice with water and the organic layer was dried over
magnesium sulfate and concentrated. The crude oil was purified by flash
chromatography (95:5 dichloromethane:methanoi) to give the title compound of
Example 241, Step A as a foam, 0.71 g (69%). 'H NMR (CDC13, 300 MHz) 8 p.95
(t,
3H), 1.22 (m, 6H), 1.56 (d, 3H), 1.66 (m, 2H), 2.37 (m, 2H), 2.55 (s,1 H),
3.27 (m, 2H),
4.48-4.78 (m, 2H), 4.84 (m, 2H), 5.fi7 (q, 1 H), 6.32 (d, 1 H), 8.22 (d,1 H);
MS (CI) 517,
519 (MH').
Step B: 1R-f4-f4-(4:6-Dimethvhf1.3.51triazin-2-vl~-2R.6S-dimeth~~lnioerazin-1-
vI)-
ovrimidin-2-vI>'-ethanol. A suspension of 1 R-{4-[4-(4-methyl-6-
trichloromethyl-
[1,3,5jtriazin-2-yl~2R.6S dimethyl piperazin-1-yfj-pyrimidin-2-yl}-ethyl
butyrate
(prepared according to the method of Example 241, Step A, 0.65 g, 1.2 mmol)
and
10°~ palladium on carbon (0.2 g) in triethylamine (1 mL) and methanol
(20 mL) was
hydrogenated at 40 psi for 0.5 hours using a Parr apparatus. The catalyst was
filtered
and the filtrate was concentrated to a solid which was dissolved in
concentrated
hydrochloric aad (2 mL) and stirred for 6 hours. This mixture was diluted with
water,
basified to pH 9 with 6 N aqueous sodium hydroxide, and extracted into
dichloromethane. The extract was washed twice with water, once with saturated.
aqueous sodium chloride and the organic layer was dried over sodium sulfate
and
filtered. The filtrate was concentrated to a dear oil which crystallized from
isopropyl
ether to give the title compound as a white solid, 0.25 g (58%). 'H NMR
(CDCI,, 300
MHz) 8 1.21 (d, 6H), 1.49 (d, 3H), 2.40 (s, 6H), 3.16 (m, 2H), 4.45-4.68 (m;
2H), 4.71
(q, 1 H), 4.84 (m, 2H), 6.42 (d, 1 H), 8.20 (d, 1 H); mp: 172-173 °C;
MS (CI) 344 (MH');
[a)o +17.2 (c 1.0, MeOH).
Example 242
1R-f4-f4-14.6-Dimethvl-f1.3.51triazin-2 vf~3R.5S~iimethvl-oioerazin-1-
vil~rimidin-2-
thano .


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HO
Me Me , ~~~~Me
~N ~ N-
N'/ ~~N N ,,~ '/N
~N
Me/ Me
pCT/IB00/00296
Step A: 4-Methyl-6-trichloromethvl-f1.3.51triazin-2-vl methanesuffonate. To a
solution of 2-hydroxyl-methyl-6-trichloromethyi-[1,3,5]triazine (1.74 g, 5.0
mmol; J.
Amer. Chem. Soc. 1956, 78, 2447) and triethylamine (0.51 g, 5.5 rnmol) in
dichloromethane was added methanesulfonyl chloride (0.57 g, 5.0 mmol) at 0
°C and
stirred for 1 h then quenched in saturated aqueous sodium bicarbonate. The
separated organic layer was washed once with saturated sodium chloride, dried
over
magnesium sulfate and filtered. The filtrate was evaporated to give the title
compound
of Example 242, Step A as an orange oil, 0.98 g (65%) which was used directly
without any further purification. MS (CI) 291,293 (MH').
Step B: 1R-(4-f3R.5S-Dimethvt-4-f4-methyl-6-trichloromethvl-f1.3.51triazin-2-
vll-
yiperazin-1-vfl-ovrfmidin-2-vl~thvl butyrate. To a solution of 1R-[4-(3R,5S-
dimethyl-
piperazin-1-yl~-pyrimidin-2-y(j-ethyl butyrate (prepared according to the
method of
Preparation Three; 0.62 g, 2.0 mmol) and sodium~bicarbonate (0.34 g, 4.0 mmol)
in
dimethylfomiamide (5 mL) was added 4-methyl-6-trichloromethyl-[1,3,5]triazin-2-
yl
methanesuifonate (prepared according to the method of Example 242, Step A,
1.00 g,
3.0 mmol) and stirred at ambient temperature for 14 h. The mixture was diluted
with
ethyl acetate and washed twice with water and the organic layer was dried over
magnesium sulfate and concentrated. The crude oil was purified by flash
chromatography (ethyl acetate) to give the title compound of Example 242, Step
B as
a dear oil, 0.41 mg (96%). 'H NMR (CDCI,, 300 MHz) b 0.95 (t, 3H), 7.22 (m,
6H),
1.56 (d, 3H), 1.66 (m, 2H), 2.37 (m, 2H), 2.55 (s, 3H), 327 (m, 2H), 4.48-4.78
(m, 2H),
4.84 (m, 2H), 5.67 (q, 1 H), 6.32 (d, 1 H), 8.22 (d, 1 H); MS (CI) 517, 519
(MH').
Step C: 1R-f4-f4-~4.6-Dimethvl-f1.3.51triazin-2-vl1-3R.5S-dimethvl-oinerazin-1-
yfl-
pyrimidin-2-vll-ethanol. A suspension of 1 R-{4-[3R,5S~irr~thyt-4-(4-methyl-6-
trichloromethyl-[1;3,5jtriazin-2-yl)-piperazin-1-y(j-pyrimidin-2-yt}-ethyl
butyrate
(prepared according to the method of Example 242, Step B, 0.65 g, l2.mmol) and
10% palladium on carbon (0.2 g, 30 wt%) in triethylamine (1 mL) and methanol
(20

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mL) was hydrogenated at 40 psi for 0.5 h using a Parr apparatus. The catalyst
was , ,
filtered off and the filtrate was concentrated to a solid which was dissolved
in
concentrated hydrochloric aad (3 mL) and stirred for 6 h. This mixture was
diluted
with water, basified to pH 9 with ~6 N aqueous sodium hydroxide, and extracted
into
dichloromethane. The extract was washed twice with water and once with
saturated
aqueous sodium chloride and the organic Payer was dried over sodium sulfate
and
concentrated to a Gear oil which crystallized from isopropyl ether to give the
title
compound as a white solid, 025 g (23%). 'H NMR (CDCt,, 300 MHz) 8121 (d, 6H),
1.49 (d, 3H), 2.40 (s, 6H), 3.16 (m, 2H), 4.45-4.68 (m, 2H), 4.71 (q, 1 H),
6.4~ (d, 1 H),
8.20 (d, 1 H); MS (CI) 344 (MH'); mp: 157-159 °C; taJ~ +17.2 (c 1.0,
MeOH).
Examples 243 to 246
Examples 243 to 246 were prepared from the approprtate starting materials in a
manner analogous to the method of Example 242.
~~~~Me
Example R". R'= ~ R' R mp (C) MS (Mli~


243 Me phenyl 2R-Me 6S-Me 406


244 Me phenyl 3R-Me 5S-Me 132-134 _ 406


245 Me tetrahydrofuran-2-yl2R-Me 6S-Me 428


246 Me o-tolyl ZR-Me 6S-Me 14&150 436


Example 247
(Rl-2-f2-(1-Hvdro~cv-ethvl~ovrimidin-~-vt1-1.2.3 4-tetrahvdro-isoouinoline-7-
sulfonic
aad dimethvlamide.
R


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Me= \ i0. , ,
o ~S HO ,
.."Me
\ ''v ~ N-
N ~ ~N
Step A: 2-Trifiuoroacetvl-1.2.3.4-tetra~dn~-isoauinoline-7-sulfonic acid
dimethvlamide. A mixture of 2-fifluoroacelyl-1,2,3,4-tetrahydro-isoquinolirte-
7-
sulfonyl chloride (400 mg, 1.22 mmo(, .l. Med Chem.1980, 23, 837),
dimethylamine
hydrochloride (150 mg,1.83 mmol), and triethy(amine (0.50 mL, 3.66 mmol)~in
dioxane (10 mL) was refluxed with stirring for 30 min, cooled to room
temperature,
concentrated, and purified by flash column chromatography (10-X50% ethyl
acetate/hexanes) to give 337 mg (82%) of the title compound of Example~247,
Step A
as a yellow oil. 'H NMR (CDC13, 300 MHz, 9:5 mixture of rotamers) 8 7.67-7.52
(c,
2H), 7.36 (t, 1 H), 4.87 (s,1.3H), 4.81 (s, 0.7H), 3.96-3.86 (c, 2H), 3.08-
3.02 (c, 2H),
2.72 (s, 6H); MS (TS) 337 (MH').
Step B: 1.2.3.4-Tetrahvdnrisoauinoline-7-sulfonic aad dimethvlamide. A mixture
of
2-trif(uoroacetyt-1,2,3,4-tetrahydro-isoquinotine-7-suffonic aad dimethylamide
(prepared acxording to the method of Example 247; Step A, 337mg,1.0 mmol) and
potassium carbonate (207 mg,1'.5 mmol) in a 3:1 mixture of methanollwater (10
mL)
was stirred at room temperature for 1 h and concentrated. The remaining
aqueous
residue was extracted with 10% isopropanoUchloroform (7x) and the combined
organic extras were dried over sodium sulfate, filtered, and evaporated to
give 214
mg (89%) of the title compound of Example 247, Step B as a white solid. 'H NMR
(CD,OD, 300 MHz) b 7.52 (d, 1 H), 7.48 (s,1 H), 7.36 (d, 1 H), 4.90 (s, 2H),
3.11 (t, 2H),
2.91 (t, 2H), 2.65 (s, 6H); MS (CUNH,) 241 (MH').
Step C: fR~1-f4-t7-0imethvlsulfamovl-3.4-dihvdr~o-1 H-isoouinolin-2-vll-
rnrrimidin-2-
yt~-ethyl acetate. To a solution of 1,2,3,4-tetrahydro-isoquinofine-7-sulfonic
aad
dimethylamide (prepared according to the method of Example 247, Step B, 210
mg,
0.88 mmol) in isopropanol (5 mL) was added (R}-1-(4-chloro-pyrimidin-2-yl)-
ethyl
acetate (prepared according to the method of Preparation five,175 mg, 0.88
mmol)
followed by triethylamine (0.24 mL, 1.75 mmol). This mbchrre was stirred at
room
temperature for 1.75 h then heated to retlux for 1.5 h, cooled to room
temperature,


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evaporated, and purified by flash column chromatography (1%
methanoUcHlbrofonn)
to give 327 mg (92%) of the title compound of Example 247, Step C as a white
solid.
'H NMR (CDCI,, 250 MHz) 8 8.28 (d,1 H), 7.68-7.58 (c, 2H), 7.47 (d, 1 H), 6.44
(d, '1 H),
5.72 (q, 1H), 4.86 (s, 2H), 3.92 (t, 2H), 3.05 (t, 2H), 2.73 (s, 6H), 2.19 (s,
3H), 1.62 (d;
3H); MS (TS) 431 (MH').
Step D: (Rl-2-T2-(1-H~droxv~thvll-ovrimidin-4-of1-1.2.3.4-tetrahvdro-
isoauinoline-7-
sulfonic acid dimethylamide. To a solution of (R)~1-j4-(7-dimethylsulfamoyl-
3,4-
dihydro-lH-isoquinolin-2-yl)-pyrimidin-2-yt]-ethyl acetate (prepared according
to the
method of Example 247, Step G, 326 mg, 0:81 mmol) in a 4:1 mixture of
methanolMrater~(8 mL) was added t'~thium hydroxide hydrate (170 mg, 4.0 mmol).
This mixture was stirred at room temperature for 50 min, concentrated, n.-
suspended
in water, and extracted with 10% isopropanoUchlorofortn (3x). The combined
organic
extracts were dried over sodium sulfate, filtered, evaporated, and purified
1by flash
column chromatography (1 % methanoUchloroform) to give a white foam which was
further purified by recrystallization from ether/methanol to give 90 mg (31%)
of the title
compound as a white solid: mp: '120.5-122 °C;'H NMR (CDCI,, 300 MHz) 8
8.24 (d,
1 H), 7.62-7.59 (c, 2H), 7.35 (d,1 H), 6.44 (d, 1 H), 4.83 (s, 2H), 4.73 (q,1
H), 4.34 (br s,
1 H), 3.93-3.85 (c, 2H), 3.03-(t, 2H), 2.71 (s, 6H), 1 X52 (d, 3H); MS (TS)
363 (MHO.
Example 248
1-f4-(6-Thioohen-3-vt-3.4-dihvdro-1 H-isoauinoGn-2-vll-dvrimidin-2-vil-
ethanol.
HO
~~~~Me
S ~ ~ ~ N-
N ~ /N
Step A: 6-Thioohen-3-vt-3,4-dihvdro-1 H-isoauinoline-2-carbox~c acid tert-
butyl
gster. A mixture of bis(benzonitrile)palladium(II) chloride (30 mg, 0.079
mmof) arid
1,4-bis(diphenyiphosphino)butane (33.6 mg, 0.079 mmol) in toluene (3 mL) was
stirred at room temperature for 20 min. To this mixture was added &
trifluoromethanesulfonyloxy-3,4~ihydro-1 H-isoquinoline-2-carboxylic aad tart-
butyl
ester (300 mg, 0.79 mmol, Synth. Common. 1995, 25, 3255), thiophene-3-boronic
aad (131 mg,1.02 mmol), 1 M aqueous sodium carbonate (1.57 mL,1.57 mmol), and
ethanol (2 mL). This dark mixture was heated to reflux with stirring under
nitrogen


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overnight, cooled to room temperature, diluted with saturated aqueous sodium
bicarbonate, and extracted with ethyl acetate (4x). The,combined organic
extracts ;
were dried over sodium sulfate, filtered through Celite, evaporated, and
purified by
flash column chromatography (hexanes-->5% ethyl acetate/hexanes) to give 252
mg
(100%) of the title compound of Example 248, Step A as a pale yellow waxy
solid. 'H
NMR (CDCI,, 250 MHz) b 7.47-7.38 (c, 5H), 7.14 (d, 1 H), 4.60 (s, 2H), 3.~2-
3.64 (c,
2H), 2.95-2.82 (c, 2H), 1.52 (s, 9H); MS (TS) 316 (MH'). ,
Step B: 6-Thioohen-3-vl-3.4-dihvdro-1 H-isoauinofine ~drochloride. A mixture'
of 6-
(thiophen-3-yl-3,4-dihydro-1 H-isoquinoline-2-carboxylic acid tart-butyl
ester; (prepared
7 0 according to the' method of Example 248, Step A, 250 mg, 0.79 mmol) and
hydrochloric aad (4 M in dioxane, 6 mL, 23.8 mmol) was stir-ed at room
temperature
for 1 h and concentrated to give 170 mg (86%) of the title compound of
F~cample 248,
Step B as a yellow solid that was used without purification in the next step.
'H NMR
(CD,OD, 250 MHz) 8 7.66 (m,1H), 7.61-7.53 (c, 2H), 7.51-7.42 (c, 2H), 7.23 (d,
2H),
4.38 (s, 2H), 3.52 (t, 2H), 3.16 (t, 2H); MS (TS) 216 (MH').
Step C: (R~-1-f4-f6-ThioDhen-3-vl-3.4-dihvdro-1 H-isoauinolin-2-vl~pvdmidin-2-
y(~-
ethvl acetate. To a solution.of 6-thiophen-3-yl-3,4-dihydro-lH-isoquinoline
hydrochloride (prepared according to the method of Example 248, Step B, 170
mg,
0.68 mmol) in isopropanol (6 mL) was added (R~1-(4-chloro-pyrimidin-2-yl)-
ethyl
acetate (prepared according to the method of Preparation Five; 136 mg, 0.68
mmol)
followed by triethylamine (0.28 mL, 2.04 mmol). This mixture was stirred at
reflux for
7 h, cooled to room temperature overnight, evaporated, and purified by flash
column
chromatography (0.51 % methanoUchlorofoml) to give 253 mg (98%) of the title
compound of Example 248, Step C as a yellow solid. 'H NMR (CDCI,, 250 MHz) E
8.26 (d, 1 H), 7:52-7.36 (c, 6H), 6.43 (d, 1 H), 5.73 (q, 1 H), 4.76 (s, 2H),
3.96 3.82 (c,
2H), 3.02 (t, 2H), 2.21 (s, 3H), 1.63.(d, 3H); MS (TS) 380 (MH').
Step D: 1~4-f6-'Thioahen-3-vl-3 4-dihydro-1 H-isoauinolin-2-vl1-ovrimidin-2-
yf1-ethanol.
To a solution of (R}-1-(4-(6-thiophen-3-yl-3,4-dihydro-l H-isoquinolin-2-yl)-
pyrimidin-2-
y(j-ethyl acetate (prepared according to the method of Example 248, Step C,
253 mg;
0.67 mmol) in a 3:1,:1 mixture of methanoUtetrahydrofuranlwater (5 mL) was
added
lithium hydroxide hydrate (84 mg, 2.0 mmol). This mixture was stirred at room
temperature for 1 h, concentrated, re-suspended in water, and extracted with .
chloroform (4x). The combined organic extracts were dried over sodium sulfate,

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filtered, evaporated, and purifed by flash column chromatography (2% ~ ,
methanoUchloroform) to give a yellow solid which was further purified by
recrystallization from ether/methanol to give 163 mg (72%) of the title
compound as a
white solid. mp: 125.5-127.5 °C; 'H NM,R (CDCI,, 300 MHz) S 8.22 (d, 1
H), 7.47-7.35
(c, 5H), 7.22 (d, 1 H), 6.42 (d, 1 H), 4.78.72 (c, 2H), 4.46 (br s, 1 H), 3.93-
3.84 (c, 2H),
2.99 (t, 2H), 1.54 (d, 3H); MS (APCI) 338 (MH'). , ,
Examples 249 to 252
Examples 249 to 252 were prepared from the appropriate starting materials in a
manner analogous to the method of Example 248.
' Rza H O
..... Me
N
N ~ ~N
Example . R= " mp (C) MS (MH') _


249 6-thiophen-2-yl i 04-105 338


250 6-pyrimidin-5-yl ~ 334


251 7-pyrimidin-5-yl 135-137 334


252 6-hydroxy 272



Examples 253 to 258


Examples 253 to 258 were prepared from the appropriate
starting materials in a


manner analogous to the method of Example 86.



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:
HO
~ ...., Me
Rza~~ ,.. ~ ~- .
N N ~ ~ ~N



Example Rz' mp (C) MS (MHO


253 H _ 79-82 258


254 Me ~ 272


255 CFA 130-132 326


~


256 NHz 20&210 273


257 Ph 128-131 334


258 pyridin-4-yl
144-148 335


~ Exarrrole 259
(Rl-1-f4-(3-Benzothiazot-2-vt-5 6-dihvrd~o-8H,~1 2 4Ltriazolof4 3-alo~razin-
7~r1~
pvrimidin-2-vll-e~anol.
Me
Step A: 5-Ethoxy 3.6-dihvdro-2H-nvrazine-1-carboxylic acid benzvi ester. To a
i0 solution of 3-oxo-piperazine-1-carboxylic aad benzyl ester (2.0 g, 8.54
mmol,
Maybridge) in dichioromethane (18 mL) at room temperature was added
triethyloxonium tetrafluoroborate (4.1 g, 21.3 mmol). This mixture was allowed
to stir
for about 3 days then quenched by the addition of ice chips followed by
saturated
aqueous sodium bicarbonate until a neutral pH was obtained. The organic layer
was


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separated and the aqueous layer was extracted with chloroform.(3x). The
aimbined
organic extracts were washed with brine (1 x), dried over sodium sulfate, and
concentrated to give 2.11 g (95%~ of the title compound of .Example 259, Step
A as a
slightly yellow oil that was sufficiently pure,~to carryon to the next step.
'H NMR
(CDCI,, 300 MHz) b 7.43-6.97 (c, 5H), 5.17 (s, 2H), 4.i0 (q, 2H), 3.98 (s,
2H), 3.60-
3.40 (c, 4H),1.27 (t, 3H); MS (APCI) 263 (MH').
Step B: 3-__Benzothiazol-2 vl-5.6-dihvdn3-8H-f1.2.41triazolot4.3-alovrazine-7-
carboxylic
acid benzvl ester. A mixture of 5-ethoxy-3,6-dihydro-2H-pytazine-1-
carboxylic~acid
benzyl ester (prepared according to the method of Example 259, Step A, 490 mg,
1.87 mmol) and benzothiazole-2-cart~oxylic aad hydrazide (360 mg, 1.87 mmot;
J.
Org. Chem.1958, 23, 134.4) in n-butanol (2 mL) was stirred at reflux
overnight, cooled
to room temperature, concentrated, arid purified by flash column
chromatography (1
methanoUchloroform) to give 580 mg of the tibe compound of F-xample 259, Step
B
(contaminated with an equimolar amount of benzothiazole-2-carboxylic aad
hydrazide
which was removed in the subsequent step) as a yellow solid.
Step C: 3-Benzothiazol-2-vl-5.6-dihvdn~-8HJ1.2.41triazolof4 3-alovrazine. To a
solution of 3-benzotniazol-2-y!-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine-
7-
carboxylic aad benzy! ester (prepared according tQ the method of Example 259,
Step
B, 580 mg, contaminated with bdnzothiazole-2-carboxylic aad hydrazide) in
dichioromethane (10 mL) at 0 °C was added a solution of boron
tribromide (1 M in
dichloromethane, 4.45 mL, 4.45 mmol). This mixture was warmed to room
temperature overnight, quenched by addition of water, and cflncentrated. The
residual aqueous layer was washed with ether (6x), neutralized with saturated
aqueous sodium bicarbonate, and extracted with 10% isopropanoUchloroform (3x).
The combined organic extracts v~re dried over sodium sulfate, filtered,
evaporated,
and purified by flash column chromatography (1-X10% metharioUchlorofom~) to
give
175 mg (36%, two steps) of the title compound of Example 259, Step C as a
white
solid. 'H NMR (CDCh; 300 MHz) 8 8.05 (d,1 H), 7.96 (d, 1 H), 7.57-7.41 (c,
2H), 4.62
(t, 2H), 4.36 (s, 2H), 3.35 (t, 2H); MS (APCI) 258 (MH').
Step D: (Rl-1-(4-(3-Benzothiazol-2-vl-5 6-dihvdro-8H~1 2 4lhiazolol4 3-aiovra
rr7
~rt~-ovrimidin-2-yfl~thvl butyrate. A mixture of 3-benzothiazol-2-yl-5,6-
dihydro-8H-
[1.2.4]triazolo[4,3-a]Pyrazine (prepared according to the method of Example
259, Step
C, 170 mg, 0.66 mmol), (R)-1-(4-chloro-pyrimidin-2-y1)-ethyl butyrate
(prepared


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according to the method of Preparation Seven, 150 mg, 0.66 mmvl), and
triethylamine
(0.28 mL, 1.98 mmo() in n-butanol (2.2 mL) was heated to reflux overnight,
cooled to
room temperature, evaporated, and purified by flash column chromatography (1 %
methanol/chloroform) to give 224 mg (76%) of the title compound of Example
259,
Step D as a colorless solid. 'H NMR (CDCI,, 300 MHz) s 8.37 (d, 1 H), 8.08 (d,
1 H),
7.97 (d, 1 H), 7.57-7.43 (c, 2H), 6.53:(d, 1 H), 5.71 (q,1 H), 5.09 (s, 2H),
4.82 (t; ~2H),
4.33-4.26 (c, 2H),.2.42 (t, 2H), 1.78-1.64 (c, 2H),1.61 (d, 3H), 0.99 (t,
3H);~MS (APC1)
450 (MH'). .
Step E: (R~-1-t4-f3-Benzothiazo(-2-v(-5.6-dihvdero-8H-I1.2.41trfazolo14.3-
alovr'azin-7-
vll-ovrimidin-2-vl1-ethanol. To a solution of (Ry-1-[4-(3-benzothiazol-2-yl-
5,6-dihydro-
8H-[1,2,4)triazolo[4,3-a]Pyrazin-7-YI)-Pyrimidin-2 ytj-ethyl butyrate
(prepared according
to the method of Example 259, Step 0, 220 mg, 0.49 mmol) in a 3:1:1 mixture of
tetrahydrofuraNmethanoUwater (5 mL) was added lithium hydroxide hydrate (62
mg,
1.47 mmol). This mixture was stined at room temperature for 3 h, concentrated,
and
extracted with chloroform (3x). The combined organic extracts were died over
sodium sulfate, filtered, evaporated, and purified by flash column
chromatography (5%
methanollchioroform) to give 192 mg (100%) of the title compound as a
cotortess
solid. mp: 216.5-218.5 °C;'H NMR (CDCI,; 300 MHz) S 8.37 (d, 1 H), 8.06
(d, 1 H), -
7.97 (d, 1 H), 7.56-7.45 (c, 2H), 6.56 (d, 1 H), 5.11 (s, 2H), 4.83 (t, 2H),
4.77 (m, 1 H),
4.35-4.25 (c, 2H), 4.16 (s, 1 H), 1.54 (d, 3H); MS (APCI) 380 (MH-), [a]p
+14,2 (c 1.0,
CHCt,).
Examples 260 to 263
Examples 260 to 263 were prepared from the appropriate starting materials in a
manner analogous to the method of Example 259.

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HO '
~N .,...Me
j ~~ . N_
~~N N N
\ ~
xampte R"_ mp (C) MS (MHO


260 phenyl 161-164 ~ 323


261 quinoxalin-6-yl 212-215 375


262 benzothiophen-2-yl 224-226 , 379


263 biphen-4-yl 123-i25 399


Example 264
(Rl-1-14-(Soirofbenzothiaaoline-2.4'-oioeridinel?-pyrimidin-2-v11-ethanol. '
HO
.... Me _
S N-
W l N \ ~N
N
H
Step A: Soirofbenzothiazolip-2.4'-oioeridinel hydrochloride. To a solution of
1'-
benzylspiro[benzothiazoline-2,4'-piperidine) (500 mg, 1.69 mmol; Indian J.
Chem.
19T6, X48, 984) in acetone (5 mL) at 0 °C was added 1-chloroethyl
chlorofom~ate
(0.37 mL, 3.38 mmol). This mixture was stirred at 0 °C for 2 h, warmed
.to room
temperature, and concentrated. The residue was purified by flash column
chromatography (1025% ethyl acetatelhexanes) to give the intem~ediate
carbamate
which was refluxed in methanol (2 mL) for 30 min. Evaporation of the reaction
mixture
provided 128 mg (31 %) of the title compound of Example 264, Step A as a white
solid.
'H NMR (CD30D, 400 MHz) 8 6.98 (dd,1 H), 6.88 (t,1 H), 6.68-6.64 (c, 2H), 3.48-
3.34
(c, 2H), 3~5-3.11 (c, 2H), 2.39-220 (c, 4H); MS (APCI) 207 (MH').


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Step B: (R~1-f4-(Soirofbenzofhiazoline-2.4 -niperidinej~nyrimidin-2-vIl-Ethyl
butyrate.
To a solution of spiro[benzothiazolin-2,4'-piperidine] hydrochloride (prepared
'
according to the method of ExaFnple 264, Step A, 147 mg, 0.60 mmol) in
isopropanol
(4 mL) was added (R~1-(4-chloro-pyrimidin-2-yl}-ethyl butyrate (prepared
according
to the method of Preparation Seven, 140 mg, 0.60 mmol) followed by
triethylamine
(0.25 mL, 1.8 mmol). This mixture was stirred at reflux for 2 h, concentrated,
and
purified by flash column chromatography (1%-~2% methanollchforoform) to give
210
mg (88%) the title compound of Example 264, Step B as a yellow oil. 'H NMR
(CDC13,
300 MHz) 8 8.20 (d,1 H), 7.09 (dd,1 H), 6.95 (t, 1 H), 6.78 (t, 1 H), 6.68 (d,
1 H), 6.40 (d,
1 H), 5.68 (q, 1 H), 4.32-4.18 (c, 2H), 4.02 (s, 1 H), 3.38-3.25 (c, 2H), 2.39
(t, 2 h), 2.36-
2.25 (c, 2H), 1.99-1.83 (c, 2H), 1.75-1.64 (c, 2H);'1.57 (d, 3H), 0.9fi (t,
3H); MS (APCI)
399 (MH').
Step C: (Rl-1-f4-(Soirofbenzothiazoline-2.4'-piperidinel~nyrimidin-2-yfl-
ethanol. A
mixture of (R}-1-[4-(spiro[benzothiazoline-2,4'-piperidine]}-pyrimidin-2-yl}-
ethyl
butyrate (prepared according to the method of Example 264, Step B; 204 mg,
0.51
mmol) and lithium hydroxide hydrate (65 mg, 1.53 mmol) in a 2:2:1 rtiucture of
tetrahydrofuraNmethanoUwater (5 mL} was stirred at room temperature for 1 h.
The
organic solvents were evaporated and the residue was extracted with 10%
isopropanol/chlaroform (3x). The combined organic extracts were dried over
sodium
sulfate, filtered, evaporated, and purified by flash column chromatography (2%
methanol/chlorofoml, 2x) to give a red foam which was further recyrstall'~zed
(ethyl
acetate) to give 42 mg (25%) of the title compound as a yellow solid. 'H NMR
(CDCI,,
400 MHz) b 8.18 (d, 1 H}, 7.07 (d, 1 H), 6.93 (td, 1 li), 6.78 (td, 1 H), 6.69
(d, 1 H), 6.42
(d, 1 H), 4.69 (m, 1 H); 4.35-4.16 (c, 3H), 4.02 (s, 1 H), 3.41-3.28 (c, 2H),
2.37-2.24 (c,
2H), 1.99-1.85 (c, 2H), 1.49 (d, 3H); MS (APCI) 329 (MH'); [a]o +17.3 (c 1.0,
MeOH).


CA 02484282 2000-03-16
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Example 265 , ,
4-f2-l1 R-Hvdroxv-ethvl~ovrimidin-4-v(t-3R.5S-dimethyl-piperazine-1-carboxylic
acid
methyl, ester. :~_
HO
."~ Me
N-
~ IN , ,
To a solution of 9 R-[4-(2R,fiS-dimethyl-piperazin-1-yt)-pyrimidin-2-yl]-ethyl
butyrate
(prepared according to the procedure of Preparation Four, 70 mg, 23 Nmol) in
tetrahydrofuran (2 mL) at room temperature under nitrogen was added
triethylamine
(63 NL; 46 Nmol) followed by methyl chiorofom~ate (21 IrL, 27 Nmol): This
mixture was
stirred for 1 h and concentrated. The residue was dissolved in a 3:1:1 mixture
of
methanoUtetrahydrofuran/water (2 mL) and lithium hydroxide hydrate (29 mg, fig
pmol) was added. This mixture was stirred for 1 h, concentrated, re-suspended
in
water, and extracted with 1 d% isopropanoUchlorofonn (4x). The combined
organic
extracts were washed with saturated aqueous sodium bicarbonate (1x), dried
over
sodium sulfate; filtered, and evaporated to give 50 mg (74%, 2 steps) of the
tifae
compound as a colorless oil. 'H NMR (CDCh, 400 MHz) 8 8.2i (d,1 H), 6.33 (d,1
H),
4.70 (m, 1 H), 4.63-3.92 (c, SH), 3.76 (s, 3H), 3.20-3.02 (c, 2H), 1.50 (d,
3H),1.25 (d,
6H); MS (APCI) 295 (MH'); [aJo +19.0 (c 0.9, MeOH).
Example 26~
1 R,~4~4-(2-f 1 R Butvnrloxv~thvll-pvrimidin~ vtl 2R 6S~imethvl-flioerazin 1
~rl,~
nvrimidin-2-vll-ethyl but)rrate.
Me
To a solution of 1 R-[4-(2R,6S-dimethyl-pipen~zin-1 yi)-pyrimidin-2-yIJ-ethyl
butyrate
(prepared according to the procedure of Preparation Four, 200 mg, 0 65 mmol)
in


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isopropanot (2 mL) at room temperature was added triethylamine (0.18 mL, 1.31
mmol) followed by (Rr1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared
according
to the procedure of Preparation seven, 150 mg, 0.65 mmol). This mixture was
heated
to reflex for 18 h, cooled to room temperature, concentrated and purified by
flash
column chromatography (1% methanoUchlorofortn) to give 321 mg (99%) of the
title
compound as a yellow oil. 'H NMR (CDCI3, 400 MHz) 8 8.22 (d, 2H), 6.43 (d,1
H),
6.32 (d, 1 H), 5.68 (q, 2H), 4.72-4.24 (c, 4H), 3.30-3.12 (c, 2H), 2.39 (t,
4H); 1.77-1.63
(c, 4H), 1.57 (d; 6H),1.28-1.17 (c, 6H), fl.96 (t, 6H); MS (APCI) 499 (MH').
yxamole 267
4-(4-f2-(1R-Hvdroxv-ethvll-pvrimidin-4-vl1-2R.6S-dimethYl-oinerazin-1-vl~-6-
methyl
I1.3.5~triazin-2-ol.
Me Me ,,
N
N~N N~ -.- ~N
N ~ N
Meln~,..
Me OH
OH
1R-[4-[4-(4-Chloro-6-methyl-[1,3,5jtriazin-2 yl~3R,5S-dimethylpiperazin-1-yQ-
pyrimidin-2-yl}-ethyl butyrate (prepared according to the method of t=xample
213, Step
A, 0:30 g, 0.70 mmol) was added to concentrated hydrochloric aad (3 mL) and
heated
to reflex for 12 h. The mixture was neutralized to pH 7 with solid sodium
bicarbonate
and extracted into chloroform. The organic extract was dried over sodium
sulfate and
filtered. The filtrate was concentrated to an oil which was purified by flash
chromatography (92:8 chloroform:methanol) to give the title compound as a
white
solid, 0.15 g (64%). 'H NMR (CDCI,, 300 MHz) 81.21 {d, 6H), 1.49 (d, 3H), 236
(s,
3H), 3.21-3.27 (m, 2H), 4.22-4.43 (m, 2H), 4.63 (m, 2H), 4.69 (q,1 H), 6.42
(d,1 H),
8.18 (d,1 H); mp: 247-248 °C; MS (CI) 346 {MH').
Examotes 268 to 275
Examples 268 to 275 were prepared from the appropriate starting materials in a
manner analogous to the method of Example 267.

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HC .
HO ~, Rs ..nMe
!=N x/12 ,N~ '
N~N ~~~ ~~ /N
R" . sR78 ,
Example R" ~ R' R' mp (C) ~ MS (MHO


268 , , H 3R-Me 5S-Me > 250 332
_


269 isopropyl 3R-Me 5S-Me > 250 374 '


270 cydohexyl 3R-Me 5S-Me > 250 414


271 phenyl 3R Me 5S-Me >: 250 408


272 cydopropyl 3R-Me 5S-Me > 250 ~ 372


273 methyl 2R-Me 6S-Me > 250 346


274 cydopropyl 2R-Me 6S-Me > 250 372


275 phenyl 2R-Me 6S-Me > 250 408


Examoie 27~
(El-f4-Oxo-3-!5-trifiuoromethvl-benzothiaZOl-2-vimethvl~-3 4-dihvdro-
ohthafazin-1-
yl1-acetic acid 1R-f4-f4-l3-thioahen-2-vl-acrvlovfl-oioerazin-1-vft-ovrimidin
2 ytl-ethyl
ester.
. O
~N r
~N, J -
ON N
O CH
~N 3
..
O N.~_ F F
To a solution of {4-oxo-3-(5-trifluoromethyl-benzothiazo!-2-yimethyl~3,4-
dihydro-
phthalazin_1-ylJ-acetic add (0.59 8,1.41 mmoi) in dichloromethane (30 mL) and
4-
dimethyiaminopyridine (0.18 g,1.41 mmol) was added 1-(3-dimethytaminopropyl~3-
ethylcarbodiimide hydrochloride (0.54 g, 2.82 mmol) followed by (E}-1-(4-(2-
(1R-


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hydroxy-ethyl)-pyrirnidin-4-ylj-piperazin-1-y1}-3-thiophen-2-yl-propenone
(prepared
according to the method of F~cample 127, 0.49 8,1.41 rr~mo() at ambient
temperature
and stir-ed for 20 h. The mixture'was washed once with saturated aqueous
sodium
bicarbonate, once with saturated aqueous podium chloride, dried over magnesium
sulfate and filtered. The filtrate was concentrated to an oil which was
purified by flash
chromatography (ethyl acetate) to give the title compound as a white foam,
0.65 g
(62%). 'H NMR (CDCI,, 300 MHz) S 1.51 (d, 3H), 3.41-3.77 (m, 8H), 4.28 (m,
2H),
5.18 (q, 1 H), 5:79 (d, 1 H), 6.35 (d, 1 H); 6.68 (d, 1 H), 7.05, (m, 1 H),
7.32 (d, 1 H), 7.68
(m, 1 H), 7.71-7,90 (m, 5H), 8.18 (d, 1 H), 8.27 (d, 1 H), 8.46 (m, 1 H); mp:
105-109 °C;
MS (CI) 746 (MH'); ja]p +49.2 (c 1.0, MeOH).
Example 277
IE~f4-Oxo-3-l5-trifluoromethvl-benzothiazol-2-vlmethvl~-3.4-dihvdro-
ot~i~thalazin-1-
ytl-acetic acid 1R-f4-(4-ouinoxalin-2-vl-pioerazin-1-vl)-DVrimidin-2-vIl-ethyl
ester.
Example 277 was prepared from the appropriate starting materials in a manner
analogous to the method of Example 276. 'H NMR (CDCI,, 300 MHz) 81.53 (d, 3H),
3.38-3.87 (m, 8H), 4.28 (ms 2H), 5.18 (q, 7 H),. 6.35 (d, 1 H); 7.68 (m, 1 H),
7.58-?.94
(m, 8H), 8.18~(d, iH), 8.21-8.37 (m, 2H), 8.46 (m,1H); mp: 108-112 °C;
NIS (Ct) 738
(MH').
2-Methoxvmethvl-4-~inerazin-1-vl-wrimidine.
Step A: 2-Methoxvmethvl-pyrimidin-4-vl-methanesulfonate. To an ice cold
solution of
2-methoxymethyl-3H-pyrimidin-4-one (35.0 g,~250 mmoi; US 5,215,990) and
triethylamine (25.6 g, 250 mmol) in dichloromethane (250 mL) was added
methanesuffonyl chloride (28.6 g, 250 mmol) dropwise. This mixture was allowed
to
warm slowly to room temperature over 1 h then washed successivelysroith
saturated
aqueous sodium bicarbonate and water. The organic layer was dried ~rer


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- -250-
magnesium sulfate, filtered, and evaporated to give the title compound of
Preparation
One, Step A as a tan solid, 49.2 g (90%). 'H NMR (CDC4~, 300 MHz) 8 3.55 (s,
3H),
3.82 (s, 3H), 4.42 (s, 2H), 6.36 (d; 1 H), 8.12 (d,1 H); mp: 39-40 °C;
MS (TS) 219
(MH'). , ~ ,
Step B: 2-Methoxvmethyl~-Diberazin-1-vl-ovrimidine. To a solution of 2-
methoxymethyl-pyrimidin-4-yl-methanesulfonate (prepared acdrding to the method
of
Preparation One, Step A, 43.6 g, 200 mmol) in tetrahydrofuran (400 mL) was
added
piperazine (34.4 g, 400 mmoi). This mixture was heated to reflux for 0.5 h,
cooled to
room temperature, and filtered. The filtrate was concentrated and dried under
reduced pressure to give the title compound as a semi-solid, 36.6 g (85%). 'H
NMR
(CDCI,, 300 MHz) b 2.45 (br s,1 H), 2.88 (m, 4H), 3.45 (s, 3H), 3.72 (m, 4H),
4.46 (s,
2H), 6.38 (d, 1 H), 8.22 (d, 1 H); MS (TS) 209 (MH'). ,
Preparation Two
~Rl-1-(4-Pioerazin-1 vl-pyrimidin-2-vll-ethvi acetate. A mixture of (R)-i-(4-
methanesulfonyloxy-pyrimidin-2-ylrethyl acetate (prepared according to the
method
of Preparation Six, 24.1 g; 92 mmol) and piperazine (16.0 g, 184 mmol) in
tetrahydrofuran (200 mL) was heated at reflex for 1 h. This mixture was doled,
8ltEred, dncentrated, and purified by flash dlurtm chromatography (9:1
dichloromethanelmethanol) to °give 24.4 g (88%) of the title dmpound as
an oil. 'H
NMR (CDCI,, 300 MHz) 81.56 (d, 3H), 2.25 (s, 3H), 2.83 (m, 4H), 3.63 (m, 4H),
5.54
(q, 1 H), 6.38 (d, 1 H), 8.24 (d, 1 H); MS (CI) 251 (MH').
Preparation Three
1R-f4-l3R.SS-Dimethvl-oioerazin-1-vl~-oyrtmidin-2-v0-ethvt butyrate. A mixture
of (R~ .
1-(4-chloro-pyrimidln-2-yl)-ethyl butyrate (prepared acdniing to the method of
Preparation Seven,18.5 g, 80.9 mmol) and as-2,6-dimethytpiperazine (18.6 8,162
mmol) in tetrahydrofuran (400 mL) was stirred at room temperature overnight,
diluted
with ether, and washed with saturated aqueous sodium bicarbonate (1x) and
water
(3x). The dmbined aqueous extracts were bade-extracted with 10°~
isopropanoUchloroform (6x). The cornbined~organic extracts were dried over
sodium
sulfate, filtered; evaporated, and purified by flash dlumn chromatography (1.-
~5°h
methanoUchloroform) to give 20.9 g (84°~) of the title compound as a
waxy yellow
solid. 'H NMR (CDCI,, 400 MHz) S 8.14 (d, 1 H), 6.31 (d, 1 H), 5.65 (q, 1 H),
4.53.16


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(c, 2H), 2.89-2.78 (c, 2H), 2.47-2.33 (c, 2H), 2.38 (t, 2H).1.73-1.60 (c, 2H),
~f.55 (d,
. 3H), 1.11 (d, 6H), 0.94 (t, 3H); MS (APCI) 307 (MH').
Precaration Four
1 R-f4-12R,.6S-Dimethvl-oioerazin-l:ylj~~rtimidin-2-vli-ethyl butyrate.
Step A: 114-(4-Benzvl-2R.6S-dimethv!-oiderazin-1-vl~dvrimidin-2-vli-ethyl
butyrate.
A mixture of (R)-1-(4-trifluoromethanesulfonyloxy-pyrimidin-2-ylrethyl
butyrate
.. ,
(prepared according to the method of Preparatioh Nine, 84.8 g, 248 mmol) and
cis-1-
benzyl-3,5-dimethy1-piperazine (101 g, 496 mmol, Org. Prep. Proceed. Int.1976,
8,
19) in aoetonitrile (310 mL) was stirred at reflex for 15 h, concentrated, and
purified by
flash column chromatography (15% ethyl acetatelhexanes) to give 52 g
(53°~) of the
title compound of Preparation Four, Step A as an, orange oil. 'H NMR (COCI3,
400
MHz) 8 8.15 (d,1 H), 7.39-7.24 (c, 5H), 6.25 (d,1 H), 5.66 (q,1 H), 4.45 (m,1
H), 4.24
(m, i H), 3.52 (s, 2H), 2.73 (d, 2H), 2.37 (t, 2H), 2.22 (d, 2H),1.70-1.60 (c,
2H),1.55
(d, 3H), i.30 (d, 3H), 127 (d, 3H), 0.93 (t, 3H); MS (APCI) 398 (MH').
Step B: 1 R-f4-(4-Benzvl-2R.6S-dimethvl-oioerazin-1-vl~vrimidin-2-v(l.ethvl
but~rr a
and 1S-f4-l4-Benzvl-2R 6S-dimethvl-eioerazin-1-v11-oyrimidin-2- -ethyl bulb. 1-

I4-(4-Benzyl-2R,6S-dimethyl-piperazin-1-yl~pyrimidin-2-Y(J-ethyl butyrate
(Prepared
according to the method of Preparation Four, Step A,131 g, 79% ee) was
purified by
chiral HPLC under the following conditions (column:15 an id x 25 cm Prochrom
column packed with Chiracel AD obtained from Chiral Technologies inc., 730
Springdale Dr., Exton, Pennsylvania,19341; mobile phase: 90:10 n-
heptanefsopropanol; flow rate: about 1 Umin; loading: 4.2 glcycle) to provide
the title
compounds of Preparation Four, Step B (109 g, >98°~ ee) and (12.6 g,
93% ee),
respectively, both as yellow oils. The 'H NMR and MS data for the preceding
impounds were in agreement with that for scalemic material of Preparation
Four,
Step A.
Step C: 1R-f4-L4-Benzvl-2R 6S-dimethyl~ieerazin-1-vl~-nvrimidin-2-vi1-ethv!
bu~rrate
t~rdrochloride. To a solution of i R-I4-(4-benzyl-2R,6S-dimethyl-piperazin-1
yI~ .
pyrimidin-2-ylJ-ethyl butyrate (prepared according to the method of
Preparation Four,
Step 8,109 g,. 275 mmot) in methanol (500 mL) was added hydrogen chloride (5 M
in
methanol, 56 mL, 278 mmol). This mixture was stirred at room temperature for 5
n~ira
and concentrated to give 118 g (990) of the title compound of Preparation
four, Step
C as a slightly yellow foam.


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PCTIIB00/00296
Step D: 1 R-14-(2R 6S-Dimethyl-oiperazin-1-vl)-pvrimidin-2-vll-ethyl butyrate.
To a
solution of 1 R-[4-(4-benzyi-2R,6S-dimethyl-piperazin;l yl)-pyrimidin-2-ylJ-
ethyl
butyrate hydrochloride (prepares! according to the method of Preparation Four,
Step
C, 54.2 g, 125 mmol) in methanol (200 mL) was added ammonium formate (79 g,
1.25 mol) followed by a slurry of 10% palladium on carbon (13.5 g, 25 wt%) in
methanol (200 mL). This mixture was stirred at reflux for 1 h and filtered
through
Celite. The filtrate was concentrated, diluted with saturated aqueous sodium
bicarbonate, and extracted with chloroform (2x). The combined organic extracts
were
dried over sodium sulfate, filtered, and evaporated to give 40.8 g of the
title compound
as a yellow oil.~'H NMR (CDCl3, 400 MHz) 8 8.16 (d, 1H), 6.26 (d, 1H), 5.66
(q, 1H),
4.39 (m, 1 H), 4.22 (m, 1 H), 2.93 (app s, 4H), 2.38 (t, 2H),1.71-1.62 (c,
2H),1.56 (d,
3H), 1.27 (d, 3H), 1.24 (d, 3H), 0.94 (t, 3H); MS (APC!) 307 (MH').
Preparation Five
fR~-1-(4-Chloro-avrimidin-2-vl)~thvf acetate. (R)-2-(1-Acetoxy-ethyl)-3H-
pyrimidin-4-
one (prepared according to the method of Preparation Thirteen, 3.00 8,16.5
mmol)
was added to phosphorus oxychloride (10 mL) at ambient temperature and stin~ed
for
3 h. Excess phosphorus oxychloride was removed under vacuum and the resulting
oil was partitioned between chloroform and saturated aqueous sodium carbonate.
The layers were separated and °the organic layer was washed twice with
water, once
with saturated aqueous sodium chloride and dried over magnesium sulfate and
filtered. The fltrate was evaporated to give the title compound as an orange
oil, 288
g (87%). 'H.NMR (CDCI,, 300 MHz) b.1.56 (d, 3H), 2.18 (s, 3H), 5.68 (q,1 H),
6.32 (d,
1 H), 821 (d, 1 H); MS {CI) 201, 203 (MH'); [ajo +27.6 (c 1.0, MeOH).
Preparation Six
(R~-1-l4-Methanesulfonvloxv-oyrimidin-2y11-et~rl acetate. To an ice cold
solution of
(Rj-2-(1-acetoxy-ethyl)-3H-pyrimidin-4-0ne (prepared according to the method
of
Preparation Thirteen, 258 g, 142 mmol) and triethylamine (1.43 g, 142 mmol) in
dichloromethane (20 mL) was added methanesutfonyl chloride (1.63 g, 14.2 mmol)
dropwise and stir-ed for 1 h. The mixture was washed successively with
saturated
aqueous sodium bicarbonate and water, dried over magnesium sulfate and
filtered.
The filtFate was evaporated to give the title compound as an oil, 3.15 g
(85%). 'H
NMR (CDCI,, 300 MHz) 81.56 (d, 3H), 2.i8 (s, 3H), 3.82 (s, 3H), 5.56 (q, 1H),
6.38 (d,
1 H), 8.24 (d, 1 H); MS (Cl) 261 (MH'); [a]o +53.8 (c 1.1, MeOH).


CA 02484282 2000-03-16
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Preparation Seven
iRl-i-l4-Chloro-ovrimidin-2-vtl-ethyl butyrate. (R~2-(1-Butyryloxy-ethyl~3H-
pyrimidin~-one (prepared accorrJing to the method of Preparation Fourteen,
3.OO g,
16.5 mmol) was added to phosphorus oxychloride (10 mL) at ambient temperature
and stirred for 3 h. Excess phosphonrs oxychtoride was removed under vacuum
and
the resulting oil was partitioned between dicttloromethane and saturated
aqueous
sodium carbonate. The layers were separated and the organic layer was,washed
once with water, once with saturated aqueous sodium chloride and dried over
magnesium sulfate and filtered. The filtrate was evaporated to give the title
compound
as an orange oil, 3.19 g (85%). 'H NMR (CDCI,, 300 MHz) S 0.98 (t, 3H),1.54
(d,
3H), 1.67 (m, 2H), 2.48 (t, 2H), 5.68 (q,1 H), 6.36 {d, 1 H), 8.21 (d,1 H);
[ajo +27.6 (c
1.0, MeOH ).
Preparation Eiaht
(Rl-1-(4-Methanesulfon~x~ pyrimidin-2-vl)~thvl butvr-ate. To an ioe cold
solution of
(Rr2-(1-butyryloxy-ethyl}-3H-pyrimidin-4-one (prepared according to the method
of
Preparation Fourteen, 17.8: g, 97.8 mmol) and triethylamine (9.9 g, 97.8 mmol)
in
dichloromethane (100 mL) was added methanesulfonyl chloride (11.21 g, 97.8
mmol)
dropwise and stirred for 1 h. The mixture was washed successively with
saturated
aqueous sodium bicarbonate arid water, dried over magnesium sulfate and
filtered.
The filtrate was evaporated to give the title compound as an oil, 24.1 g
(94%). 'H
NMR (CDCI,, 300 MHz) b 0.99 (t, 3H), 1.54 (d, 3H), 1.68 (m, 2H), 2.48 (t, 2H),
3.81 (s,
3H), 5.54 (q, 1 H), 6.38 (d, 1 H), 8.24 (d, 1 H); MS (CI) 281 {MH'); [ajo
+28.8 (c 1.0,
MeOH).
Preparation Nine
(Rl-1-(4-Triftuoromethanesulfonvloxv-~yrimidin-2-vll-ethyl butyrate. '
Method 1: To a solution of (R~2-(1-bufyryfoxy-ethyl)-3H-pyrimidin-4-one
(prepared
according to the method of Preparation Fourteen, 52 g, 248 mmol) and
triethylamine
(36.2 mL, 260 mn~l) in dichloromethane (830 mL) at 0 'C with stirring under
nitrogen
atmosphere was added a solution of trifluoromethanesulfonic anhydride (44 mL,
260
mmot) in dichloromethane (70 mL) dropwise via addition funnel over 30 min,
maintaining an internal temperature of 4-8 °C. This mixture was allowed
to stir an
additional 15 min at 4 °C, then quenched with water. After stirring for
10 min, the
layers were separated and the aqueous layer was extracted with dichloromethane


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pCT/IB00/00296
(3x). The combined organic extracts were dried over sodium sulfate, filterad,
and
concentrated to give 47.2 g (-100°~) of the tifie compound as a dark
oil which was
used immediately in the next step. 'H NMR (CDCI3, 400 MHz) b 8.83 (d, 1H),
7.03 (d,
1 H), 5.82 (q,1 H), 2.41-2.32 (c, ZH),1.72-1.60 (c, 2H),1.62 (d, 3H), 0.95 (t,
3H); MS
(APCI) 343 (MH'). '
Method 2: To a solution of (R~2-(1-butyryloxy-ethyl~3H-pyrimidin-4-one
(prepared
according to the method of Preparation Fourteen, 4.20 g, 20.0 mmol) and,
triethyfamine (2.02 g, 20.0 mmol) in dichloromethane (20 mL) was added
trifluoromethanesulfonyl chloride (3.37 g, 20.0 mmol) dropwise, maintaining an
intemaf temperature less than -20 °C, and stir=ed for 0.5 h. The
mixture was washed
successively with saturated aqueous sodium bicarbonate and water, dried over
sodium sulfate and filtered. The filtrate was evaporated to give the title
compound as
a dark oil, 6.42 g (94%), which was used immediately in the next step. 'H NMR
and
MS data were were in agreement with that from Preparation Nine, Method 1.
Preparation Ten
lRl-1-(4-Chloro-pvrimidin-2;yl~thanol. To a solution of (R)-i-(4-chioro-
pyrimidin 2-
yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 250
mg,
1.1 mmol) in dioxane (0.9 rizL) was added concentrated hydrochloric add (0.9
mL).
This mixture was allowed to stir,at room temperature for 5 h, quend~ed with
saturated
aqueous sodium bicarbonate followed by solid,sodium bicarbonate until no more
gas
evolution was evident Dichloromethane was added and the layers were separated.
The aqueous phase was extracted with dichloromethane (3x) and the combined
organic extracts were dried over sodium sulfate, filtered, and evaporated to
give 125
mg (71%) of the title compound as a pale yellow oil. 'H NMR (CDCt,, 400 MHz) 8
8.59 (d, 1 H), 7.25 (d, i H), 4.92 (q,1 H), 3.81 (br s, 1 H),1.5fi (d, 3H); MS
(APCI) 159,
161 (MH').
Prenarat;on Eleven
fR?-(+1-2-l1-Hvdroxv-ethvll-3H-ovrimidin-4-one hprdro-.
Step A: R-(+~-2-Hvdroxv-orooionamidine hvdrochioride. To a 22L, 3-neck round
bottom flask equipped with reflux condenser, mechanical stirrer, themvometer
and
nitrogen inlet was added tetrahydrofuran (7.3 l-), R-(+~2fiydroxy-propionamide
(T31
g, 82 mol) and triethyloxonium tetrafluorQborate (95°x,1.97 kg, 9.8
mol). The
resulting yellow solution was allowed to stir at room temperature for 2 h, at
which time


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an NMR sample indicated consumption of starting material and the presence of
the
desired imidate. The solution was concentrated under vacuum to provide a
yellow oil
which was taken up in methanol..(2 L). This solution was cooled to 15
°C and
anhydrous ammonia was bubbled through the solution for 5 h. The resulting
suspension was allowed to stir for 2 h. concentrated to a thick mixture,
diluted with
ethyl acetate and filtered through Celite. The filtrate was then cooled to ~0
°C,
anhydrous hydrogen chloride was bubbled through the solution for 2 h, warmed
to
room temperature, and filtered to provide 418 g (41 %) of the title compound
of
Preparation Eleven, Step A. mp: 134-i38 °C;'H NMR (DMSO-ds, 300 MHz) S
1.33 (t,
3H), 4.42 (q, 1 H), 625-6.88 (br s, 1 H), 8.72-9.25 (br s, 3H).
Step B: fR~f+~2-(1-Hydroxv-ethvl~-3H-avrimidin-4-one hydrochloride. To a 22 L,
3-
nedc round bottom flask equipped with a reflux condenser, mechanical stirrer,
thermometer and nitrogen inlet was added methanol (8 L), potassium hydroxide
(946
g, 14.7 mot), R-(+}-2-hydroxy-propionamidine (prepared according to the method
of
Preparation Eleven, Step A,1848 g, 14.7 mot) and ethyl 3-hydroxy-acrylate
sodium
salt (prepared according to, the method of Preparation Twelve, Step C, 2030 g,
14.7
mot). The resulting slurty was stirred at room temperature for 3 h. The pH was
adjusted from 125 to 7 by the addition of concentrated hydrochloric acid (1.32
L).
The solids were filtered off and washed with isopropanol. The filtrate was
concentrated to an oil, diluted with isopropanol.(4 L), cooled to 10 °C
and anhydrous
hydrogen chloride was bubbled through the solution for 4 h. The resulting
suspension
was filtered and the solids were dried to provide 2242 g (87%) of the title
compound.
mp: 180-184 °C (dec);'H NMR (DMSO-db, 400 MHz) b 1.46 (d, 3H), 4.84 (q,
1H), 6.52
(d, 1 H), 8.00 (d, 1 H). -
Preparation Twelve
2-(1-Hvdroxv-ethyl)-3H-oyrimidin-4-one.
Step A: 2-Hvdroxv-orooionimidic aad ethyl ester hydrochloride. A solution of
lactonitrile (378 g, 5.32 mot) in ethyl ether (1.46 L).and ethanol (0.34 L)
was saturated
with hydrogen chloride gas at 0-5 °C for 0.5 h and kept at 5 °C
for 60 h. The resulting
preapitate was filtered off and washed twice with ethyl ether to give the
title compound
of Preparation Twelve, Step A as a solid, 815 g (99%). mp: 165-168
°C;'H NMR
(CD,OD. 250 MHz) 8 1.45-1.53 (c, 6H): 4.40-4.61 (c, 3H).


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Step B: 2-Hvdroxv-orooionamidine hvdrochioride. A suspension of 2- ~ ~ , ,
hydroxypropionimidic acid ethyl ester hydrochloride (prepared according to the
..
method of Preparation Twelve, Step A, 751 g, 4.87 mol) in ethanol (3.75 L) at
0 °C
was saturated with ammonia gas, maintajning an ~intemal temperature < 5
°C, for 1 h
then sorted at ambient temperatun: for 18 h. The solid was filten:d off and
dried under
vacuum at 40 °C to give an initial crop of material. The filtrate was
concentrated to
one-half volume and a second crop was collected and dried under vacuum. The
first
and second crops were combined to give the title compound of Preparation
Twelve,
Step B as a yellow solid, 608 g (99%). mp:134-138 °C;'H NMR (DMSO-
dg, 400
MHz) s 1.30 (d, ~3H), 4.38 (q,1 H), 6.23 (br s, 1 H), 7.35 (br s, 1 H), 8.78
(br s, 3H).
Step C: Ethv13-hvdroxv-acrvlate sodium salt. To a suspension of sodium hydride
(60°!° dispersion in oil, 269 8,16.7 mol) in isopropyl ether (12
L) was addBd slowly
ethyl acetate (1280 g, 14.2 moi) at a rate which maintained an internal
temperature of
45 °C. This mixture was stin~ed for and additional 0.5 h, then ethyl
formats (2232 g,
30.1 mol) was added dropwise at 42 °C and stirred at ambient
temperature for i 8 h.
The mixture was filtered and the solids v~re washed twice with ethyl ether and
once
with hexanes and dried to give the title compound of Preparation Twelve, Step
C as a
white solid, 1930 g (99%). 'H NMR (DMSO-a16, 300 MHz) b 1.03 (t, 3H), 3.86 (q,
2H),
4.08 (d, 1 H), 8.03 (d, 1 H).
Step D: 2-l1-Hvdroxv~th~rll-3H-ovrfmidin-4-one. To a solution of ethyl 3-
hydroxy-
acrylate sodium salt (prepared according to the method of Preparation Twelve.
Step
C,1301 g, 9.42 rrml) in water (1.3 L) was added a solution of 2-hydroxy-
propionamidine hydrochloride (prepared according to the method of Preparation
Twelve, Step B, 610 g, 4.9 mol) in water (1.3 L) at ambient temperature and
stirred for
48 h. The soluticn was adjusted to pH 7.0 with acetic aad then continuously
extracted
with chloroform for 48 h. The extract was dried over sodium sulfate and
filtered. The
filtrate was concentrated to a solid, slurried in ethyl ether, filtered, and
dried to give the
title compound as a solid, 232 g (38%). mp:121-124 °C;'H NMR (DMSO-de,
400
MHz) S 1.30 (d, 3H), 4.46 (q, 1 H), 5.62 (br s, 1 H), 6.13 (d, 1 H), 7.80 (d,
1 H).
~ Preparation Thirteen
1R~2-l1-A~etoxv-ethvll-3H-ovrimidin-4-one. Ta a solution of vinyl acetate (4.3
g, 50
mmol) in dioxane (63 mL) was added 2-(1-hydroxy-ethyl~3H-pyrimidin-4.~one


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pCTIIB00/00296
(prepared according to the method of Preparation Twelve, 2.1 g, 15.1 mmol),
and the ,,
mixture was heated to 50 °C. To the resulting solution was added lipase
P30 (0.21 g, ,
wt%) and the heating was continued for 24 h. The reaction mixture was filtered
and the filtrate was evaporated to obtain a thick synrpy,liquid residue. The
residue
5 was purified by flash column chromatography (95:5 dichloromethane:methanol)
to
give the title compound as a colorless liquid, 0.97 g (92% of theory). 'H
NMR.(CDCI,,
300 MHz) 81.61 (d, 3H), 2.20 (s, 3H), 5.65 (q, 1H), 6.35 (d, 1H), 7.97 (d,
1H), 11.94
(s, 1 H); [a]o +39.9 (c 1.0, MeOH).
Preparation Fourteen
10 (R~2-l1-Butvnrloxv-ethyl?-3H-ovrimidin-4-one.
Method 1: To a solution of vinyl butyrate (17.7 g, 310 mmol) in dioxane (650
mL) was
added 2-(1-hydroxy-ethyl~3H-pyrimidin-4-one (prepared according to the method
of
Preparation Twelve, 21.8 g, 155 mmol), and the mixture was heated to 50
°C. To the
resulting solution was added lipase P30 (4.35 g, 20 wt%) and the heating was
continued for 24 h. The reaction mixture was filtered and the filtrate was
evaporated
to obtain a thick syrupy liquid residue which was partitioned between
dichloromethane
and water. The layers were separated and the organic layer was dried over
sodium
sulfate, filtered, and evaporated to give the title compound as a colorless
liquid, 9.35 g
(86% of theory). 'H NMR (CDCI,, 300 MHz) 0.95 (t, 3H), 1.65 (m, 5H), 2.40 (m,
2H),
5.65 (q, 1 H), 6.45 (d, 1 H), 8.00 (d, 1 H); [a]o +29.5 (c 1.0, MeOH).
Method 2: To a chilled (5 °C) solution of (R)-(+~2-(1-hydroxy-ethylr3H-
pyrimidin-4-
one hydrochloride (prepared according to the method of Preparation Eleven, 750
g,
4.3 mol) in dichloromethane (8 L) was added triethylamine (1216 mL, 8.7 mol)
followed by 4-dimethylaminopyridine (25.9 g, 0.21 mol). A solution of butyric
anhydride (730 mL, 4.4 mol) in dichloromethane (730 mL) was then slowly added
over
a period of 5 h, keeping the temperature <3 °C. The mixture was washed
twice with
half saturated brine (4 L) and once with saturated aqueous sodium bicarbonate
(4 L),
dried over sodium sulfate, filtered, and concentrated under vacuum to give 869
g
(96%) of the title compound as an oil. The'H NMR and MS data for this compound
are in agreement with that of Preparation Fourteen, Method 1.
Preparation Fifteen
1 R-T4-(2R.6S-Dimethvl-oiperazin-1-vl~-ovrimidin-2-v(l-ethyl butyrate
dibenzovl-L-
tartrate salt.


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Step A: 1R~4-Benzvl-2R 6S-dimethvl-oioerazin-1-vl)-ovrimidin-2-vl1-ethyl
butyrate
bis dibenzov!-L-tartrate salt. To a solution of (R)-2-(1-~utyrytoxy-ethyl}-3H-
pyrimidin-
4-one (prepared according to the method of Preparation Fourteen, 254 8,1.25
mol)
and triethylamine (176 mL, 1.3 mol) in dichloromethane (23 L) at 5 °C
was slowly
added a solution of trifluoromethanesulfonic anhydride (211 mL, 1.25 mol) in
dichloromethane (355 mL) over a period of 3 h. The reaction was then quenched
by
the addition of cold water (1.4 L) and the layers were separated. The organic
taye~
was washed once with saturated aqueous sodium bicarbonate (1.5 L), once with
saturated aqueous sodium chloride (1 L), and the solvent was removed under
vacuum. The resulting oil was dissolved in dimethylacetamide (890 mL) and
added
slowly to a solution of as-1-benzy!-3,5-dimethyl-piperazine (735 g, 3.6 mol)
in
dimethytacetamide (1.3 L) at 80 °C over a 1 h period. Heating at 80
°C was continued
for 3.5 h, at which time the reaction was judged complete by gas
chromatography:
After cooling to room temperature, water (2.5 L) and isopropyl ether (25 L)
were
added, the layers were separated, and the organic layer was washed once with
water
(2 L). The isopropyl ether layer was then mixed well with a solution of CuSO,
(126 g)
in water (3 L) and filtered through a layer of Celite, washing the filter cake
with
isopropyl ether (1 L). The aqueous layer of the filtrate was drained off, and
the
remaining organic.tayer was washed with water (ZL) and treated with a solution
of
dibenzoyl-L-tartaric acid (619 g, 2.4 mol) in isopropyl ether (5:3 L). The
resulting thick
white slurry was stirred for 16 h and the solids were filtered off, washed
with isopropyl
ether (2 L), and vacuum dried at
50 °C to yield 854 g (71 %) of the title compound of Preparation
Fifteen, Step A as a
white solid.'H NMR (DMSO-ds, 400 MHz) 8 0.89 (t, 3H),1.23 (d, 3N), 1.25 (d,
3H),
1.48 (d, 3H), 1.54 (dd, 2H), 220 (dd, 2H), 2.31 (dt, 2H), 2T7 (d, 2H), 3.57
(s,1 H),
4.45 (m, 1 H), 4.24 (m, 1 H), 5.51 (q, 1 H), 6.60 (d, 1 H), 7.30 (m, 1 H),
7.39 (m, 4N), 7.64
(m, 7H), 7.77 (m, 4 H), 8.05 (c, 7H), 8.17 (d,1H).


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Step B: 1 R-f4-f2R.6S-Dimethyl-pioerazin-1-vl)-ovrimidin-2-vll-ethyl butyrate
.,
dibenzoyl-L-tartrate salt. To a mixture of 1R-[4-(4-benzyl-2R,6S-dimethyl-
piperazin-1-
yl)-pyrimidin-2-yl]-ethyl butyrate bis dibenzoyl-L-tartrate salt (prepared
according to
the method of Preparation Fifteen, Step A, 50 g, 0.045 mol) and 5% palladium
on
carbon (50% wet, 10 g, 20 wt%) in methanol (400 mL) under a nitrogen
atmosphere
was added cydohexene {4.6 mL, 0.045 mol). This mixture was heated to reflux
for 6
h, at which time the reaction was judged complete by TLC. After cooling to 40
°C, the
mixture was filtered through Celite and washed with methanol (100 mL). The
methanol was gradually displaced with isopropanol by atmospheric pressure
distillation until a constant boiling point of 80-82 °C was attained,
and the resulting
white slung was cooled to room temperature and stirred for 4 h. The solids
were
filtered off, washed with isopropanol (100 mL), and vacuum dried at 50
°C to yield
25.7 g (86%) of the title compound as a white solid. 'H NMR (DMSO-ds, 400 MHz)
b
0.90 (t, 3H), 7.15 (d, 3H), 1.21 (d, 3H), 1.47 (d, 3H), 1.55 (q, 2H), 2.3 (m,
2H), 3.04 (m,
2H), 3.2 (m, 2 H), 4.4 (br s, 1 H), 4.6 (br s, 1 H), 5.5 (q, 1 H), 5.74 (s,
2H), 6.6 (d;1 H),
7.5 (t, 4 H), 7.6 (m, 2H), 8.0 (m, 4H), 8.2 (d, 1 H).

Representative Drawing